Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]1[CH:62]=[CH:61][CH:60]=[CH:59][C:43]=1[CH2:44][N:45]1[CH2:49][CH2:48][N:47]([C@@H:50]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:51](O)=[O:52])[C:46]1=[O:58].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:51](=[O:52])[C@@H:50]([N:47]1[CH2:48][CH2:49][N:45]([CH2:44][C:43]2[CH:59]=[CH:60][CH:61]=[CH:62][C:42]=2[O:41][CH3:40])[C:46]1=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COc1ccccc1CN1CCN([C@H](C(=O)O)C(C)(C)C)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2OC)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 75A (0.018 g, 0.056 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.189 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.016 g, 47% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.89 (m, 9 H), 1.26 (m, 1 H), 1.39 (m, 1 H), 1.54 (m, 1 H), 2.41 (m, 1 H), 2.65 (m, 2 H), 2.89 (m, 3 H), 3.20 (m, 1 H), 3.54 (m, 4 H), 3.81 (m, 4 H), 3.93 (m, 1 H), 4.02 (m, 1 H), 4.28 (m, 3 H), 4.44 (d, J=7.35 Hz, 1 H), 6.91 (m, 2 H), 7.04 (m, 6 H), 7.14 (d, J=7.35 Hz, 1 H), 7.28 (m, 4 H), 7.51 (d, J=9.93 Hz, 1 H), 7.90 (m, 5 H), 8.65 (d, J=4.04 Hz, 1 H).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[CH:19]([C:3]([O:7][CH2:8][CH3:9])=[O:10])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)Cc1c(F)cccc1Cl
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cccc1Cl
Yield: 87.7 %

Procedure:
Into a mixture of 7.2 g of sodium hydride (60% in oil), 17.0 g of diethyl carbonate and 150 ml of tetrahydrofuran, 26.0 g of ethyl 2-chloro-6-fluorophenylacetate were added dropwise under heating, and then refluxed under heating for 8 hours. The reaction mixture was cooled, poured into iced dil. hydrochloric acid and extracted with t-butyl methyl ether. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 30.4 g of diethyl (2-chloro-6-fluorophenyl)malonate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[C:8]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12]Br)#[N:9].O>CN(C=O)C>[N:1]1([CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[C:8]#[N:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1Cn1ccnc1
Reaction time: 0.5 h

Procedure:
To a solution of imidazole (1.0 g, 14.6 mmol) in DMF (10 mL) is added sodium hydride (60% wt. in mineral oil, 0.887 g, 22.17 mmol) at room temperature. The mixture is stirred for 30 min, whereupon 2-cyanobenzyl bromide (2.87 g, 14.6 mmol) is added. After an additional 30 min, water is added and the mixture is extracted with ethyl acetate. The aqueous phase is poured into aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic phase is dried over sodium sulfate, filtered and concentrated in vacuo to give a residue which is purified by silica gel chromatography (dichloromethane-methanol, 19:1) to give 2-imidazol-1-ylmethyl-benzonitrile; MS (ESI) m/z 184.3 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([C:18]4[CH:22]=[C:21]([CH3:23])[N:20]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=5)[N:19]=4)[O:16][CH:17]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:14]=[C:15]([C:18]4[CH:22]=[C:21]([CH3:23])[N:20]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=5)[N:19]=4)[O:16][CH:17]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(C5=CCCCC5)cc4)co3)cc2C)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(C5CCCCC5)cc4)co3)cc2C)cc1
Yield: 43.3 %

Procedure:
A solution of 4-(4-cyclohex-1-en-1-ylphenyl)-2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,3-oxazole (Example 80, 30 mg, 0.073 mmol) in ethanol (1.5 ml) was hydrogenated in a continuous-flow reactor (H-cube, Thales Nano, Hungary) at an hydrogen pressure of 1 bar at rt with a flow rate of 1 ml/min using palladium (10% on charcoal) as a stationary phase. After evaporation of the solvent, the crude material was purified by preparative HPLC to afford the title compound as a white solid (13 mg, 43%): 1H NMR (400 MHz, DMSO-d6) 8.57 (s, 1H), 7.72 (d, 2H), 7.29 (d, 2H), 7.17 (d, 2H), 7.07 (d, 2H), 6.67 (s, 1H), 5.36 (s, 2H), 3.51-3.40 (m, 1H), 2.29 (s, 3H), 2.28 (s, 3H), 1.82-1.69 (m, 4H), 1.48-1.22 (m, 6H); ES-MS m/z 412, HPLC RT (Method D) 3.52 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][N:22](C(OC(C)(C)C)=O)[CH:23]=2)=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+]>C(O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:23]=[N:22][NH:21][CH:20]=4)=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(I)cn1
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc(C(=O)CBr)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Ic1ccc2nc(-c3ccc(-c4cn[nH]c4)cc3)cn2c1

Procedure:
Subsequently, 2-amino-5-iodopyridine (478 mg) and tert-butyl 4-[4-(2-bromoacetyl)phenyl]-1H-1-pyrazolecarboxylate mg) were dissolved in ethanol (20 mL), and sodium hydrogencarbonate (183 mg) was added to the solution, followed by refluxing for 16 hours. The precipitated matter was recovered through filtration and dried, to thereby yield the title compound (535 mg).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl[CH2:18][C:19]1[CH:37]=[CH:36][C:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[CH:21][CH:20]=1.BrCC1C=CC(F)=C(C(F)(F)F)C=1.OCC1C=CC(O)=CC=1.ClCC1(C(F)(F)F)C=CC(OCC2C=CC=CC=2)=CC1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:37][CH:36]=2)=[CH:26][C:27]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: Fc1ccc(COc2ccc(CCl)cc2)cc1C(F)(F)F
Agent: FC(F)(F)C1(CCl)C=CC(OCc2ccccc2)=CC1
Agent: Fc1ccc(CBr)cc1C(F)(F)F
Agent: OCc1ccc(O)cc1
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(F)c(C(F)(F)F)c3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 4-(4-Chloromethyl-phenoxymethyl)-1-fluoro-2-trifluoromethyl-benzene prepared from 1-bromomethyl-4-fluoro-3-trifluoromethyl-benzene and 4-hydroxymethyl-phenol in the manner analagous to Examples 14A and 14B. MS m/z 283 (M−237).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:8](I)[C:7]1=[O:22].[Li+].[Cl-].[CH3:28][Sn](C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:8]([CH3:28])[C:7]1=[O:22]
Reactant: C[Sn](C)(C)C
Reactant: O=c1c(I)c(OCc2ccc(F)cc2)ccn1Cc1cccc(F)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(F)cc2)ccn(Cc2cccc(F)c2)c1=O

Procedure:
To a degassed solution of 1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(1H)-one (0.804 g, .7 mmol) in DMF (10 mL) and LiCl (0.25 g, .9 mmol) was added tetramethyltin (0.49 mL, 3.54 mmol) followed by bistriphenylphosphine-palladium chloride catalyst (0.124 g, 0.177 mmol). The reaction mixture was heated in an oil bath (85°-90° C.) under nitrogen for 3 hours. The solvent was concentrated and the residue was diluted with ethyl acetate and washed with water. The organic extracts were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by flash column chromatography (20% ethyl acetate in hexane). The appropriate fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 7.59 (d, 1H, J=7.6 Hz), 7.46 (m, 2H), 7.34 (m, 1H), 7.10 (m, 4H), 6.46 (d, 1H, J=7.6 Hz), 5.17 (s, 2H), 5.15 (s, 2H), 1.99 (s, 3H); ES-HRMS m/z 342.1314 (M+H calculated for C20H18NO2F2 requires 342.1300).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)SC)#[N:2].[CH3:17][NH2:18]>>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)=[N:18][CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1ccsn1)NC#N
Reactant: CN
Product: CN=C(NC#N)NCCSCc1ccsn1

Procedure:
The reaction of N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-S-methylisothiourea (0.27 g.) with excess methylamine according to the procedure described in Example 3(c) and recrystallisation of the product from isopropyl acetate afforded N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-N"-methylguanidine (0.12 g.), m.p. 91°-93°. (Found: C, 42.4; H, 5.1; N, 27.3; S, 25.2. C9H13N5S2 requires: C, 42.3; H, 5.1; N, 27.4; S, 25.1).
Reaction SMILES: [F:1][C:2]1[CH:42]=[CH:41][C:5]([C:6]([NH:8][C@:9]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([O:38][CH:39]=[CH2:40])[CH:32]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:43]([F:46])([F:45])[F:44].[Zn](CC)[CH2:48]C.C(I)I>C1(C)C=CC=CC=1>[CH:39]1([O:38][C:33]2[CH:32]=[C:31]([C@@:9]([NH:8][C:6](=[O:7])[C:5]3[CH:41]=[CH:42][C:2]([F:1])=[C:3]([C:43]([F:46])([F:45])[F:44])[CH:4]=3)([C:17]3[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:20]=[C:19]([F:30])[CH:18]=3)[CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:36]=[CH:35][C:34]=2[F:37])[CH2:48][CH2:40]1
Reactant: CC[Zn]CC
Reactant: C=COc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Solvent: Cc1ccccc1
Solvent: ICI
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(OC2CC2)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of (R)-4-fluoro-N-(1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (66 mg, 0.10 mmol) in 0.5 ml toluene was added Et2Zn (1 N, 0.2 ml, 0.2 mmol), followed by CH2I2 (16 ml, 0.2 mmol). The reaction mixture was stirred at 120° C. for 3 h. The reaction mixture was quenched by addition of 1 N HCl and the aqueous layer was extracted with CH2Cl2. The organic layer was washed with sat. NaHCO3 and concentrated under reduced pressure. The resulting residue was purified by ISCO silica gel column using 0 to 50% to EtOAc in hexane as eluting solvents and Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5 u column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford (R)—N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 305) as white lyophillate (36 mg, 52% yield). LCMS: RT=4.268 min [M+H] 672.3 (4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm. NMR: 400 MHz 1H (CDCl3) ppm 0.45-0.73 (m, 4H), 3.51-3.59 (m, 1H), 3.76 (d, J=13.18 Hz, 1H), 4.22 (d, J=12.74 Hz, 1H), 6.13-6.44 (m, 1H), 6.66-6.76 (m, 3H), 6.97-7.08 (m, 3H), 7.10-7.23 (m, 5H), 7.42-7.50 (m, 1H), 7.95-8.03 (m, 2H).
Reaction SMILES: Cl[C:2](=[O:16])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.CC1C=CC=C(C)N=1.[H][H]>[Pd].O1CCCC1>[O:16]=[CH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(CCC(=O)Cl)CC1
Agent: [Pd]
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(CCC=O)CC1
Yield: 81 %

Procedure:
A mixture of 102 parts of ethyl 4-(3-chloro-3-oxopropyl)-1-piperidinecarboxylate, 45 parts of 2,6-dimethylpyridine and 630 parts of tetrahydrofuran was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 650 parts of dichloromethane. The solution was washed twice with 100 parts of a hydrochloric acid solution 5% and twice with 100 parts of water, dried, filtered and evaporated. The residue was distilled, yielding 71.1 parts (81%) of ethyl 4-(3-oxopropyl)-1-piperidinecarboxylate; bp. 130°-135° C. at 133 Pa (int. 46).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:12]1([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(C(C)C)CC)(C)C.[F:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[F:49])[C:43](Cl)=[O:44]>C(Cl)Cl>[F:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[F:49])[C:43]([NH:1][CH2:2][CH2:3][CH:4]([C:12]1([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:44]
Reactant: CC(C)CC1(C(CCN)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CC1(C(CCNC(=O)c2ccc(F)c(F)c2)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
To a solution of tert-butyl α-(2-aminoethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (549 mg, 1.36 mmol), CH2Cl2 (8.4 mL), and diisopropylethylamine (0.29 ml, 1.6 mmol) at 0° C. is added 3,4-difluorobenzoyl chloride (0.21 mL, 1.6 mmol). The solution is stirred at 0° C. for 1 hour and 16 hours at room temperature. Basic workup (CH2Cl2, NaHCO3, MgSO4) and purification by flash chromatography (1:1 hexane:EtOAc) gives 477 mg (64%) of the title compound as a white solid (mp 147°-148° C.):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C:35]([OH:40])([CH3:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:41].O1CCOCC1>C(Cl)Cl>[ClH:1].[ClH:41].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C:35]([OH:40])([CH3:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3(C)O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)NCC(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3(C)O)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A solution of tert-butyl 2-(4-chlorophenyl)-3-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (46 mg, 0.080 mmol) in DCM (6 mL) was added to a 4.0M HCl solution in dioxane (1.4 mL, 5.63 mmol). The mixture was stirred at room temperature for 16 hours. The solvents were removed in vacuo to give 2-(4-chlorophenyl)-1-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride (49 mg, 100%) as a mixture of diastereomers. Rt: 2.05 and 2.18 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH3:25])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:23]#[N:24])[CH2:5]1.[O:26]=[C:27]1[CH2:32][S:31][C:30]2[CH:33]=[CH:34][C:35]([CH:37]=O)=[N:36][C:29]=2[NH:28]1>CO.C(Cl)Cl>[CH3:25][C:4]1([CH2:3][NH:2][CH2:37][C:35]2[CH:34]=[CH:33][C:30]3[S:31][CH2:32][C:27](=[O:26])[NH:28][C:29]=3[N:36]=2)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:23]#[N:24])[CH2:5]1
Reactant: COc1ccc2ncc(C#N)c(CCN3CCC(C)(CN)C3)c2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(C#N)c(CCN3CCC(C)(CNCc4ccc5c(n4)NC(=O)CS5)C3)c2c1
Reaction time: 24 h
Yield: 25.8 %

Procedure:
To a solution of the HCl salt of 4-{2-[3-(aminomethyl)-3-methyl-1-pyrrolidinyl]ethyl}-6-(methyloxy)-3-quinolinecarbonitrile (50 mg) in MeOH (2 mL) and DCM (2 mL) were added NaHCO (130 mg, 1.6 mmol) followed by 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (30 mg, 0.18 mmol). After 24 h at 25° C., NaBH (10 mg, 0.27 mmol) was added. After 1 h, the reaction was concentrated and the residue was partitioned between DCM-H O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO, concentrated and purified via column chromatography (silica, 4% MeOH in DCM (1% NH OH)) yielding the title compound (20 mg) as a brown oil: LC/MS (ES) m/e 503 (M+H) 1H NMR (CDCl3, 400 MHz) δ 8.85 (s, 1H), 8.22 (d, J=9.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.35 (s, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.12 (s, 3H), 3.83 (s, 2H), 3.51 (m, 3H), 2.9-2.5 (m, 6H), 2.3 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.1 (s, 3H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[NH:10])[NH2:9])[CH:3]=1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(-c2cccnc2)ns1
Temperature: 25 °C
Yield: 4.4 %

Procedure:
To a solution of pyridine-3-carboximidamide hydrochloride (2.00 g, 12.7 mmol) and perchloromethyl mercaptan (1.75 ml, 16.3 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (3.26 g, 81.5 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 110 mg (4.38%) of the desired product as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.C(N(CC)CC)C.[N:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(#N)C>[O:20]=[C:14]1[CH:13]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][C:34]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:35])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)N1CCOCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)N4CCOCC4)ccc3C2=O)C(=O)N1
Reaction time: 4 h
Yield: 20.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and triethylamine (0.30 mL, 2.2 mmol) in acetonitrile (10 mL) was added morpholine-4-carbonyl chloride (012 mL, 1.05 mmol) at room temperature under nitrogen. After 4 h, the reaction mixture was filtered and rinsed with acetonitrile (30 mL) and the filtrate was concentrate on the rota-yap. The residue was stirred with 20 mL of acetonitrile and water mixture (1:1). The resulted suspension was filtered to give morpholine-4-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.08 g, 20% yield): HPLC: Waters Nova-Pak C18 column, 3.9×150 mm, 4 μm; gradient CH3CN/0.1% aq H3PO4, 10 min, 1.0 mL/min, 4.8 min (96%); mp: 208-210° C.; 1H NMR (DMSO-d6) δ 1.92-2.07 (m, 1H, CHH), 2.39 (qd, J=4.4, 13.3 Hz, 1H, CHH), 2.55-2.66 (m, 1H, CHH), 2.84-2.99 (m, 1H, CHH), 3.27-3.32 (m, 4H, CH2+CH2), 3.52-3.59 (m, 4H, CH2+CH2), 4.25-4.49 (m, 4H, CH2+CH2), 5.11 (dd, J=5.0, 13.3 Hz, 1H, CHN), 7.22 (t, J=5.8 Hz, 1H, Ar), 7.40 (d, J=7.9 Hz, 1H, Ar), 7.47 (s, 1H, NH), 7.67 (d, J=7.9 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.51, 31.20, 43.54, 43.86, 47.10, 51.56, 65.92, 121.88, 122.77, 126.89, 130.11, 142.23, 145.28, 157.57, 168.02, 171.01, 172.86; LCMS: MH=387; Anal Calcd for C19H22N4O5+0.6H2O: C, 57.45; H, 5.89; N, 14.10. Found: C, 57.10; H, 6.07; N, 13.97.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH3:14][NH2:15]>C1COCC1>[CH3:14][N:15]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Solvent: C1CCOC1
Product: CN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with THF (350 mL), 101c (10.0 g, 32.2 mmol), 2M methylamine solution in THF (113 mL, 225 mmol) and stirred at room temperature for 72 h. After this time the reaction was concentrated to dryness under reduced pressure, and the resulting solid was stirred with a mixture of ethyl acetate (75 mL) and 10% aqueous potassium carbonate (75 mL). The aqueous layer was separated and extracted with ethyl acetate (2×75 mL). The combined organic extracts were washed with 10% aqueous potassium carbonate (75 mL), followed by brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate concentrated under reduced pressure to afford 101d in 97% yield (5.70 g) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 6.62 (s, 1H), 4.28 (t, 2H, J=5.4 Hz), 3.67 (s, 2H), 2.95 (t, 2H, J=5.4 Hz), 2.52 (s, 3H); MS (ESI+) m/z 183.0 (M+H)