Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH2:21])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)C(N)(CO)CO>ClCCCl>[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH:21][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: O=S(=O)(NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was synthesized as part of library using the following procedure in a parallel synthesis fashion using 48 well red and blue minireactors. Typical procedure: To a solution of 22B (14 mg, 0.05 mmol) in DCE (0.5 mL) at RT was added NMM (0.109 mL, 0.1 mmol), followed by addition of benzene sulfonylchloride (17.6 mg, 0.1 mmol) in DCE (0.5 uL). The reaction mixture was shaken at RT for 24 h, and treated with 100 mg of PS-Trisamine (4 mmol/g loading) for 2 h to remove excess sulfonyl chloride. Contents were filtered into a synthesis tube rack (STR) and the solvent was dried in a speed vac. The resulting residue was chromatographed using Prep HPLC (conditions: Xterra MS-C18 (30×50 mm); Eluted with 10% to 100% B, 6 min gradient. (A=100% water−0.1% TFA and B=acetonitrile with 0.1% TFA); Flow rate at 30 mL/min. UV detection at 220 nm) to give compound 50 (13.8 mg, 69%). HPLC: 99% at 1.74 min (retention time) (Conditions: Xterra MS-C18 (2.1×50 mm); Eluted with 0% to 100% B, 2.75 min gradient. (A=100% water−0.1% TFA and B=acetonitrile with 0.1% TFA); Flow rate at 1 mL/min. UV detection at 220 nm). MS (ES): m/z 413 [M+H]+.
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].[NH3:18]>C(O)C.CO>[NH2:18][C:3]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6]
Reactant: COC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Reactant: N
Solvent: CCO
Solvent: CO
Product: N#CC(C#N)=C(N)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
3-Methoxy-3-(4-nitrophenyl)-2-cyanoacrylonitrile (14.4 g, 0.063 mol) was suspended in ethanol (1 L) in a flask equipped with a magnetic stirrer. To the suspension was added 60 mL (ca. 0.20 mol) of a 10% (w/w) solution of ammonia in methanol. The mixture was stirred vigorously for 15 min, at which time HPLC analysis showed the absence of starting material. The now homogeneous mixture was concentrated in vacuo to ca. 80 mL. The solid that had formed was collected with the aid of a small amount of additional ethanol and was pressed well with rubber dam. The cake was washed with of ethanol (2×5 mL) and was left to dry in a hood draft. The dry solid weighed 8.8 g. The filtrate was concentrated and mixed with dichloromethane (10 mL). The resulting solid was collected, washed with dichloromethane (2×2 mL), dried, and combined with the 1st crop to yield 9.9 g (46% for 2 steps). HPLC analysis indicated a purity of 91%. NMR (60 MHz) (DMSO-d6) δ 8.8 (bs, 0.5H); 8.0 (AB, 4H); 3.2 (bs, 1H); 2.8 (bs, 0.5H). The IR spectrum showed nitrile stretches at 2221 and 2207 cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH:35]#[C:36][CH2:37][CH2:38][CH3:39].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:15]([C@H:17]1[CH2:19][C@@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:16])[C:27]1[CH:32]=[CH:31][C:30]([C:35]#[C:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:28]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1cccc(F)n1)c1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: C#CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC#Cc1ccc(N(C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC)C(=O)[C@H]2C[C@@H]2c2cccc(F)n2)cc1
Temperature: 90 °C
Yield: 99.6 %

Procedure:
[(1S,2S)-1-({(4-Bromo-phenyl)-[trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-2-methyl-butyl]-carbamic acid t-butyl ester (0.068 g, 0.127 mmol), 1-pentyne (0.05 mL, 0.509 mmol), PdCl2(PPh3)2 (0.017 g, 0.025 mmol) and 1N TBAF in THF (0.76 mL, 0.762 mmol) were mixed in THF (1 mL) in sealed microwave flask. The reaction mixture was heated at 90° C. at normal setting for 30 minutes. The reaction mixture was quenched with brine. The aqueous phase was extracted by ethyl acetate (3×7 mL). The combined organic layers were washed brine and dried over MgSO4, filtered and concentrated to give yellow oil. The crude product was purified via column chromatography on silica gel with a gradient of 0%-50% of ethyl acetate in hexanes to afford the title product as yellow oil (0.066 g, 99% yield): 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (m, 4H), 6.86 (m, 3H), 6.42 (m, 1H), 4.76 (d, J=9.1 Hz, 1H), 4.11 (m, 1H), 3.48 (m, 1H), 2.95 (td, J=13.1, 3.8 Hz, 1H), 2.42 (m, 1H), 2.16 (td, J=7.0, 3.4 Hz, 2H), 1.67 (m, 1H), 1.40 (m, 4H), 1.22 (m, 11H), 0.84 (m, 3H), 0.63 (m, 6H); LCMS (ESI) m/e 522.4 [(M+H), calcd for C31H41FN3O3 522.7].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9].CCO[C:13]([S-:15])=[S:14].[K+].Cl>CN(C=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[S:14][C:13]([SH:15])=[N:9][C:3]=2[CH:4]=1
Reactant: Nc1cc(F)ccc1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc2sc(S)nc2c1
Temperature: 120 °C
Yield: 67 %

Procedure:
A mixture of 2,5-difluoro-phenylamine (129 mg, 1 mmol) and potassium o-ethyl dithiocarbonate (352 mg, 2.2 mmol) in DMF (5 mL) was heated to 120° C. for 15 min in microwave. The reaction mixture was cooled, diluted with 10 mL of ice water, and acidified with 3 mL of HCl solution (1 mol/L). Then the mixture was extracted with EtOAc (3×50 mL), washed with brine and dried over Na2SO4. The dried organic layers were concentrated to give 5-fluorobenzo[d]thiazole-2-thiol (120 mg, 0.67 mmol, 67%). ESI-MS (M+1): 185 calc. for C7H4FN4S2 184.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:16])[NH2:15])=[N:6]1.[CH:21]12[O:28][CH:25]([CH2:26][CH2:27]1)[CH2:24][N:23]([CH:29]([C:35](OCC)=[O:36])[C:30](OCC)=[O:31])[CH2:22]2>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:30]([OH:31])[C:29]([N:23]3[CH2:24][CH:25]4[O:28][CH:21]([CH2:27][CH2:26]4)[CH2:22]3)=[C:35]([OH:36])[N:16]=2)=[N:6]1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: CCOC(=O)C(C(=O)OCC)N1CC2CCC(C1)O2
Solvent: Cc1ccccc1
Product: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(O)c1N1CC2CCC(C1)O2
Temperature: 140 °C
Reaction time: 8 h

Procedure:
0.50 g (1.11 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide (example I, step 5) are suspended in 40 ml of toluene. Then 1.40 g (5.16 mmol) of diethyl 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)malonate from step 5 are added. The mixture is stirred at 140° C. overnight. The solid is then filtered off with suction, washed with diethyl ether dried in vacuo.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@@H:9]2[O:10][C@@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[NH:29][CH2:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@H:9]([OH:10])[C@@H:8]([N:29]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=2[CH3:21])[CH2:30][C:31]2[NH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: Cc1cccc(NCc2ncc[nH]2)c1C
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2ncc[nH]2)c2cccc(C)c2C)[C@H]1O
Yield: 48.7 %

Procedure:
The title compound (416 mg, 49%) was prepared using (2R,3R,4R)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (500 mg, 1.77 mmol) and 2,3-dimethylphenyl-1H-imidazol-2-ylmethylamine (358 mg, 1.77 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[NH:11][C:10]=2[OH:20])=[N:7][CH:8]=1)=O.[CH2:21]1[CH:25]2[CH2:26][NH:27][CH2:28][CH:24]2[CH2:23][O:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH2:21]1[CH:25]2[CH2:26][N:27]([CH2:1][C:3]3[CH:4]=[CH:5][C:6]([C:9]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=5)[NH:11][C:10]=4[OH:20])=[N:7][CH:8]=3)[CH2:28][CH:24]2[CH2:23][O:22]1
Reactant: C1NCC2COCC12
Reactant: N#Cc1ccc2[nH]c(O)c(-c3ccc(C=O)cn3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]c(O)c(-c3ccc(CN4CC5COCC5C4)cn3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42 %

Procedure:
164 mg of 3-(5-Formylpyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile (0.62 mmol) from example 1.3 were dissolved in DMSO at 50° C. To this solution 134 mg (1.18 mmol) of hexahydro-1H-furo[3,4-c]pyrrole were added and the resulting deep-red solution was stirred at this temperature for 90 min. Afterwards 263 mg (1.24 mmol) of sodium triacetoxyborohydride were added and the mixture was stirred for 4 h and then cooled to RT followed by further stirring for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with sat. NaHCO3 solution. The aqueous phase was re-extracted with ethyl acetate and the combined organic phases were washed with brine (5×), dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude was purified by flash chromatography (silica gel, DCM/MeOH) yielding a yellow solid. Amount 95 mg. Yield 42%.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].O[CH2:36][C@H:37]1[NH:41][C:40](=[O:42])[CH2:39][CH2:38]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:22])[N:13]([CH2:36][C@@H:37]3[CH2:38][CH2:39][C:40](=[O:42])[NH:41]3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NC(=O)N2c1ccccc1
Reactant: O=C1CC[C@@H](CO)N1
Product: O=C1CC[C@@H](CN2C(=O)N(c3ccccc3)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)N1

Procedure:
The title compound, MS: m/e=583.1 (M+), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and (S)-5-(hydroxymethyl)-2-pyrrolidinone.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[CH:8][N:7]=1)([CH3:5])[C:3]#[N:4].[NH2:21][C:22]1[C:23]([C:29]2[O:33][C:32]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][N:41]([CH3:49])[C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:36][CH:35]=3)=[N:31][N:30]=2)=[N:24][C:25](Br)=[CH:26][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:21][C:22]1[C:23]([C:29]2[O:33][C:32]([C:34]3[CH:35]=[CH:36][C:37]([CH2:40][N:41]([CH3:49])[C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[CH:38][CH:39]=3)=[N:31][N:30]=2)=[N:24][C:25]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]([C:2]([C:3]#[N:4])([CH3:1])[CH3:5])[CH:11]=2)=[CH:26][N:27]=1
Reactant: CC(C)(C#N)c1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(Br)cnc3N)o2)cc1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(Cc1ccc(-c2nnc(-c3nc(-c4ccnc(C(C)(C)C#N)c4)cnc3N)o2)cc1)C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propane nitrile (103 mg, 0.3784 mmol) in dioxane (1.133 mL) was added of tert-butyl N-[[4-[5-(3-amino-6-bromo-pyrazin-2-yl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (174.6 mg, 0.3784 mmol) and reaction was treated with 2 M aqueous solution of sodium carbonate (567.5 μL of 2 M, 1.135 mmol). The reaction mixture was degassed with 5× vacuum/nitrogen cycles. Then Pd(PPh3)4 (43.85 mg, 0.03795 mmol) was added to the reaction mixture. The reaction mixture was degassed further with 5× vacuum/nitrogen cycles and the reaction mixture was stirred in a microwave at 150° C. for 30 minutes. The reaction was diluted with ethyl acetate and aqueous sodium bicarbonate solution. The organic extracts were separated and washed with brine (×1), dried over MgSO4, filtered and concentrated in vacuo to give a black oil. Taken onto the next step without further purification (199.3 mg, assumed 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=O)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])[CH2:22]2)=[N:18][C:19]=1[NH2:20].O1CCOCC1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[NH:20][C:19]3=[N:18][C:17]([N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:28])[CH2:22]4)=[CH:16][CH:15]=[C:14]3[N:13]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(C1CCCN(c2ccc3nc(COc4ccc(Cl)cc4)[nH]c3n2)C1)N1CCCC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
2-(4-Chlorophenoxy)acetic acid (75 μmol) was added into an 8-mL vial followed by a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone in anhydrous dioxane (600 μL, 127.5 μmol, 0.21M). Triethylamine (90 μL, 648 μmol) and 1-propanephosphonic acid cyclic anhydride (120 μL, 50% in ethyl acetate, 202 μmol) were added. The vial was capped and the reaction mixture was shaken at 140° C. for 16 h. The solvent was removed by Speedvac and the residue was purified via HPLC to afford the title compound. MS API-ES+ (M+H) 440; HPLC retention time 2.473 min (Method D).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:24][CH2:25][C@H:26]([OH:39])[CH2:27][O:28][C:29]1[C:37]2[NH:36][C:35](=[O:38])[NH:34][C:33]=2[CH:32]=[CH:31][CH:30]=1>>[OH:39][C@@H:26]([CH2:25][NH:24][CH:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:12]=[CH:11][C:10]([S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:23])=[CH:6][CH:5]=3)(=[O:9])=[O:8])=[CH:15][CH:14]=2)[CH2:17][CH2:18]1)[CH2:27][O:28][C:29]1[C:37]2[NH:36][C:35](=[O:38])[NH:34][C:33]=2[CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: Cc1ccc(S(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 from 0.13 g (0.4 mmol) of Reference Example 25, 1-[4-(toluene-4-sulfonyl)-phenyl]-piperidin-4-one, and 0.13 g (0.6 mmol) of 4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one, yielding 0.18 g of a white solid; m.p. 130-132° C.; MS (ES) m/z 537.0 (MH+); HRMS (FAB) Calcd. for C28H33N4O5S (MH+): 537.2166, Found: 537.2169.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[O:9])=[CH:6][N:5]=[C:4]([NH:42][CH:39]2[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2c(OC)cc(F)c(F)c2F)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(2,3,4-trifluoro-6-methoxy-phenyl)-methanone (Example 194) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C18H21N5O4SF3 [(M+H)+] 460.1261, observed 460.1267. CDK4 IC50=0.001; CDK1 IC50=0.005; CDK2 IC50=0.002; HCT 116 IC90=0.630 μM.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[C:13](=[O:18])[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:11]3)[N:4]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:44]1[CH2:49][C@@H:48]2[CH2:50][C@H:45]1[CH2:46][NH:47]2)=O)(C)(C)C>CC#N.O>[CH:45]12[CH2:50][CH:48]([NH:47][CH2:46]1)[CH2:49][N:44]2[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[C:13](=[O:18])[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:11]3)[N:4]=1
Reactant: Cc1cc(-c2noc(CCl)n2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2noc(CN3CC4CC3CN4)n2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 72.9 %

Procedure:
To a solution of 5-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one (100 mg, 0.228 mmol) in MeCN (4 mL) was added K2CO3 (95 mg, 0.684 mmol) and (1s,4s)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (90 mg, 0.451 mmol). After 48 hours the mixture was diluted with water, then extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated to a yellow oil. This residue was dissolved in 1:1 TFA/CH2Cl2 (6 mL) for 30 minutes, then the reaction mixture was concentrated and basified with NaHCO3 to pH˜9-10. The product was extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica (2-8% 2M NH3 in MeOH/CH2Cl2) to provide 5-[5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-[1,2,4]oxadiazol-3-yl]-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one as a light yellow solid (83 mg). 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.91 (s, 1H), 7.34 (d, 2H), 7.18 (d, 2H), 4.77 (s, 2H), 4.28 (s, 2H), 4.05 (dd, 2H), 3.57 (d, 2H), 3.20 (d, 1H), 3.13 (dd, 1H), 2.88 (dd, 1H), 2.79 (s, 3H), 2.61 (d, 1H), 1.86 (d, 1H), 1.64 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]=[N:10][OH:11])[CH:3]=1.[CH2:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH2:12][CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)[CH:3]=1
Reactant: Cc1nc(Br)cc(C=NO)n1
Reactant: C=Cc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Cc1nc(Br)cc(C2=NOC(c3ccccc3)C2)n1
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a cold solution of 6-bromo-2-methylpyrimidine-4-carbaldehyde oxime (0.4 g, 1.852 mmol Preparation #17) and styrene (0.257 mL, 2.222 mmol) in DCM (10 mL) was added sodium hypochlorite solution (0.229 mL, 3.70 mmol). The reaction mixture was stirred for about 2 h and diluted with DCM (50 mL), successively washed with water (2×30 mL) and brine (1×30 mL). The organic layer was dried over sodium sulphate and evaporated to dryness under reduced pressure. The resulting mixture was purified by silica gelchromatography eluting with 40% EtOAc in hexane. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford 3-(6-bromo-2-methylpyrimidin-4-yl)-5-phenyl-4,5-dihydroisoxazol 0.25 g (42.4%), 1H NMR (400 MHz, DMSO): δ 8.00 (s, 1H), 7.40 (m, 5H), 5.90 (m, 1H), 3.93 (m, 1H), 3.41 (m, 1H), 2.64 (s, 3H), MS m/z: 320 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:19]=[C:9]2[NH:10][C:11](=[O:18])[C:12]3[C:17]([N:8]2[N:7]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=2)[CH2:5][C:6]2[CH:19]=[C:9]3[NH:10][C:11](=[O:18])[C:12]4[C:17]([N:8]3[N:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:24]=1
Reactant: OB(O)c1cccnc1
Reactant: O=c1[nH]c2cc(Cc3cccc(Br)c3)nn2c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=c1[nH]c2cc(Cc3cccc(-c4cccnc4)c3)nn2c2ccccc12

Procedure:
A mixture of Example 61B (0.05 g, 0.141 mmol), pyridine-3-ylboronic acid (0.018 g, 0.148 mmol) cesium fluoride (0.064 g, 0.423 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.1 g, 0.014 mmol) in DME (2 mL) was heated in a microwave (Personal Chemistry SmithSynthesizer) at 150° C. for 10 minutes. The mixture was filtered evaporated. The residue was purified by HPLC on a C18 column with 0-100% CH3CN/H2O/0.1% TFA to provide the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.10 (s, 2 H) 5.75 (s, 1 H) 7.41-7.51 (m, 3 H) 7.63-7.73 (m, 2 H) 7.76 (s, 1 H) 7.83-7.88 (m, 1 H) 8.04 (d, J=7.67 Hz, 1 H) 8.12 (dd, J=8.13, 1.38 Hz, 1 H) 8.35 (dt, J=7.98, 1.84 Hz, 1 H) 8.68 (dd, J=5.06, 1.38 Hz, 1 H) 9.01 (d, J=2.15 Hz, 1 H) 12.08 (s, 1 H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]1[C:33]([OH:40])=[CH:34][CH:35]=[C:36]([CH:39]=1)[CH:37]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:37][C:36]3[CH:35]=[CH:34][C:33]([OH:40])=[C:32]([O:31][CH2:29][CH3:30])[CH:39]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(C=O)ccc1O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CCOc1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)ccc1O

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-ethoxy-4-hydroxybenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 529; MS (ESI) m/z 527.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][N:15]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[N:16]2)[CH2:10]1)(OC(C)(C)C)=O.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>ClCCl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[N:16]1[N:15]([CH2:14][C@@H:11]2[CH2:12][CH2:13][C@H:9]([NH2:8])[CH2:10]2)[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[CH:21]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Cn2cc3ccccc3n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](Cn2cc3ccccc3n2)C1

Procedure:
Deprotection of N1-BOC-(1S,3R)-3-(2H-indazol-2-ylmethyl)cyclopentan-1-amine (400 mg, 1.27 mmol), the more polar isomer from Step 1, Example 67, using TFA (3 ml) in dry dichloromethane (3 ml) as described in Example 1, Step 2 gave 273 mg of the amine as its TFA salt, which was used as such for the coupling reaction.