Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[C:19]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[C:20]=2[N:21]=[CH:22][N:23]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[C:19]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=4)[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)c1ccc(-c2noc3c(Cl)ncnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c(-c4ccc(S(C)(=O)=O)cc4)noc23)CC1
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.49 mmol) was dissolved in anhydrous THF (5 mL) and treated with NaH, 60% oil dispersion (20 mg, 0.49 mmol) at ambient temperature. After stirring for 10 min, 7-chloro-3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidine (0.15 g, 0.49 mmol) was added. The reaction was stirred for 3 h and concentrated under vacuum. The residue was purified by column chromatography using ethyl acetate and hexane (1/1) to afford 4-[3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.14 g, 61%). 1H NMR (400 Mz, DMSO-d6) δ 8.51 (s, 1H), 8.42 (d, J=7.1, 2H), 8.43 (d, J=7.1, 2H), 4.11˜3.83 (m, 4H), 3.52 (m, 1H), 3.26 (s, 3H), 1.41˜1.22 (m, 4H). LCMS 475.3[M+H].
Reaction SMILES: [CH3:1][N:2]([CH3:47])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:33]([CH3:35])[CH3:34])[CH:27]=5)=[CH:25][C:18]=34)=[CH:15][N:14]([CH2:36][CH2:37][N:38](C)[C:39](=O)OC(C)(C)C)[N:13]=2)=[CH:8][CH:7]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:34][N:33]([CH2:32][C:28]1[CH:27]=[C:26]([C:24]2[NH:23][C:19]3=[N:20][CH:21]=[CH:22][C:17]([C:16]4[C:12]([C:9]5[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[N:2]([CH3:47])[CH3:1])=[CH:11][CH:10]=5)=[N:13][N:14]([CH2:36][CH2:37][NH:38][CH3:39])[CH:15]=4)=[C:18]3[CH:25]=2)[CH:31]=[CH:30][CH:29]=1)[CH3:35]
Reactant: CN(C)Cc1cccc(-c2cc3c(-c4cn(CCN(C)C(=O)OC(C)(C)C)nc4-c4ccc(NC(=O)N(C)C)cc4)ccnc3[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 157 %

Procedure:
To 1,1-dimethylethyl {2-[3-(4-{[(dimethylamino)carbonyl]amino}phenyl)-4-(2-{3-[(dimethylamino)methyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]ethyl}methylcarbamate (1.05 g, 1.65 mmol) was added 25% TFA in CH2Cl2 (25 mL). The reaction was stirred at RT for 1 h and evaporated to dryness under vacuum. Trituration with (1:1) Et2O/Pet. Ether, filtration, and drying under vacuum gave the title compound (1.39 g, 95%) as a yellow solid. ESMS [M+H]+: 537.3
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[S:9][C:10]=1[NH:11]C(=O)C)=[O:5])[CH3:2].N1CCCC1>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(C)=O)sc2ccccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNC1
Product: CCOC(=O)c1c(N)sc2ccccc12
Yield: 85.2 %

Procedure:
To a solution of 1b (1.06 g, 4.03 mmol) in toluene (100 mL) was added pyrrolidine (5 mL). The resultant mixture was heated at 100° C. for 8 h, diluted with brine solution (200 mL) and extracted with ethyl ether (300 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 4:1) then afforded the title compound (0.76 g, 85%) as a yellow solid: MS (ES) m/z 222 (M+H)+; 1H NMR (400 MHz, CDCl3) δ8.14 (d, J=8.0 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.28 (m, 1H), 7.04 (m, 1H), 6.51 (brs, 2H), 4.45 (q, J=7.2 Hz, 2H), 1.50 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][NH:5][C:4](Cl)(C)[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH2:18](N(CC)CC)C.O>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:18])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: CCN(CC)CC
Reactant: C1CNCCN1
Reactant: CC1(Cl)N=C(N)C(C#N)=CN1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc(N2CCNCC2)nc(N)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
A solution of 4-amino-2-chloro-2-methylpyrimidine-5-carbonitrile (Maybridge, 100 mg, 0.6 mmol), piperazine (207 mg, 2.4 mmol), and triethylamine (71 mg, 0.7 mmol) in N,N-dimethylacetamide (20 ml) was heated to 108° C. for 6 h. The reaction mixture was stirred at ambient temperature for 18 h before pouring into water (400 ml) and extracting with ethyl acetate (3×30 ml), and then dichloromethane (20 ml). The combined organic extracts were washed with water (3×150 ml), and then dried (MgSO4) and concentrated to give a yellow solid (120 mg). The crude solid was pre-absorbed onto silica gel (250 mg) and then purified by flash chromatography on silica gel (20 g) eluting with ethyl acetate:methanol (90:10 and then 80:20) to give the title compound as a white solid (28 mg).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]([CH3:21])[C:10]([C:12]2[CH:20]=[CH:19][C:15]3=[N:16][O:17][N:18]=[C:14]3[CH:13]=2)=O)[CH2:5][CH2:4]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>C1(C)C=CC=CC=1>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]([CH3:21])[C:10]([C:12]2[CH:20]=[CH:19][C:15]3=[N:16][O:17][N:18]=[C:14]3[CH:13]=2)=[S:23])[CH2:5][CH2:4]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CO[C@H]1CC[C@H](N(C)C(=O)c2ccc3nonc3c2)CC1
Solvent: Cc1ccccc1
Product: CO[C@H]1CC[C@H](N(C)C(=S)c2ccc3nonc3c2)CC1

Procedure:
N-(trans-4-Methoxycyclohexyl)-N-methyl-[2,1,3]-benzoxadiazole-5-carboxamide (0.91 g, 3.2 is mmol) and phosphorus pentasulfide (1.42 g) were refluxed in toluene (40 ml) for 3 h. The mixture was cooled, filtered through a 2 cm layer of silica gel and washed with dichloromethane. Evaporation of the solvent and trituration with diethyl ether gave a yellow solid (0.11 g). Mp=137-138° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 7.89-7.83 (m, 1H); 7.58-7.55 (m, 1H); 7.36-7.30 (m, 1H); 5.50-5.40 and 3.90-3.75 and 3.50-3.00 (m, 2H); 3.44 and 3.38 (s+s, 3H); 3.27 and 3.04 (s+s, 3H); 2.30-0.95 ppm (s, 8H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([NH:36][CH3:37])[N:35]=1)[C:30](O)=[O:31])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([NH:36][CH3:37])[N:35]=1)[C:30]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:31])([CH3:26])([CH3:24])[CH3:25]
Reactant: CNc1cc(C(=O)O)cc(C(C)(C)C)n1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: CNc1cc(C(=O)Nc2ccc(C)c(-n3ccn4nc(-c5cccnc5)cc34)c2)cc(C(C)(C)C)n1
Reaction time: 16 h

Procedure:
60 mg (0.21 mmol) of the compound of Example 6A and 43 mg (0.21 mmol) of the compound of Example 44A were reacted analogously to the procedure of Example 33, except that in this case the reaction time was 16 h. This gave 31 mg (31% of theory) of the title compound.
Reaction SMILES: [Li].[C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C@@H:15]([CH3:18])[CH2:16][CH3:17])C(O)=O)#[N:3].[B:19](OC)([O:22]C)[O:20]C.Cl>C1COCC1>[C:2]([C:4]1[CH:5]=[C:6]([B:19]([OH:22])[OH:20])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C@@H:15]([CH3:18])[CH2:16][CH3:17])#[N:3]
Reactant: COB(OC)OC
Reactant: CC[C@H](C)COc1ccc(C(=O)O)cc1C#N
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CC[C@H](C)COc1ccc(B(O)O)cc1C#N
Temperature: 25 °C

Procedure:
The experimental procedure for the preparation of the lithium salt was as described in the preparation of compound 43. A solution of trimethyl borate (2.70 g, 0.024 mol) in dry THF (10 ml) was added dropwise to the lithium salt solution. The resultant mixture was allowed to warm to room temperature overnight whilst stirring and dilute hydrochloric acid was then added. The THF/water azeotrope was removed in vacuo and the remaining residue was dissolved in diethyl ether and washed with water until acid-free. The ether was dried (MgSO4) and removed in vacuo to leave a fawn solid.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:20]=[O:21])[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8](F)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[NH:29]1)=[O:27])[CH:23]=[CH2:24].CCN(C(C)C)C(C)C>CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:20]=[O:21])[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8]([N:29]2[CH:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32][N:28]2[C:26]([O:25][CH2:22][CH:23]=[CH2:24])=[O:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCOC(=O)N1CCC(C(=O)O)N1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OC1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1CCC(C(=O)O)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.2 %

Procedure:
(2R)-3-Cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl fluoride (784 mg, 2.6 mmol) was added into the solution of 1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidine carboxylic acid (677 mg, 3.38 mmol) and Hunig's base (1811 μl, 10.40 mmol) in N,N-dimethylformamide (DMF) (11.1 ml). The reaction was stirred for 5 hrs at ambient temperature. The reaction was purified by RP-HPLC to give 2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidinecarboxylic acid (428 mg, 0.889 mmol, 34% yield). MS (ES+) m/z 482.0 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:25]=[CH:26][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccccc2Oc2ccc(N)cc2)cc1
Yield: 77.4 %

Procedure:
In a 3 l round-bottomed flask equipped with a magnetic stirrer bar, reflux condenser and dropping funnel was placed 64.20 g (0.182 mol) of 1,2-bis(4-nitrophenoxy)benzene (SI-319), 700 mL ethanol and 2 g 5% palladium on charcoal. The mixture was brought to boil when 200 mL of hydrazine hydrate was added dropwise during a period of 1.5 hours. The mixture was refluxed for a further 3 hours. The hot mixture was then filtered over a filter agent and left to crystallize. The next day the crystals were separated and the liquid volume reduced to 400 mL, from which an additional crop of crystals was filtered off. The combined crystalline product was recrystallized twice from methanol/water (3:1) to yield 41.2 g of off-white crystals. By reducing the liquid volume a second crop of 5.7 g of crystals was obtained (overall yield 88.17% theoretical). Melting point 135°-136° C. Elemental analysis: Calc: C,. 73.95%, H, 5.51%, 9.59%; Found: C, 74.10%, H, 5.62%, 9.77%.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11](C(=O)C)[N:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:27]([BH3-])#N.[Na+].[C:31]([OH:34])(=O)[CH3:32]>CO>[CH2:2]([CH2:1][NH:8][C:9]1[CH:10]=[C:11]([C:31](=[O:34])[CH3:32])[N:12]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH:13]=1)[C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:27]=1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(NCc2ccccc2)cn1Cc1ccc(F)cc1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1cc(NCCc2ccccc2)cn1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an addition funnel topped by an argon inlet was added 1-[4-benzylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVIII-1-1 (0.472 g, 1.46 mmol), MeOH (20 mL), formalin (1.19 mL of 37% aqueous solution, 14.64 mmol) and sodium cyanoborohydride (0.628 g, 10.00 mmol). The addition funnel was charged with a solution of glacial acetic acid (0.57 mL, 10.0 mmol) in MeOH (20 mL). The acetic acid solution was added dropwise to the reaction mixture over 1.5 h. When the addition was complete, the resulting mixture was stirred at ambient temperature 18 h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (100 mL) and water. The layers were separated and the organic phase was washed with saturated aqueous NaHCO3, aqueous sodium potassium tartrate and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 30% EtOAc in hexanes as eluant to give 1-[4-benzylmethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVIII-2-1 as a crystalline solid. 1H NMR (CDCl3) δ 2.25 (3H, s), 2.36 (3H, s), 4.16 (2H, s), 5.43 (2H, s), 6.33 (1H, d, j=2.2 Hz), 6.53 (1H, d, j=2.2 Hz), 6.93 (2H, m), 7.06 (2H, m), 7.27 to 7.32 (5H, complex multiplet).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][C:5]1([C:10]#[N:11])[CH2:9][CH2:8][CH2:7][CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>CCOCC>[CH3:13][O:12][CH:3]([O:2][CH3:1])[CH2:4][C:5]1([CH2:10][NH2:11])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC(CC1(C#N)CCCC1)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(CC1(CN)CCCC1)OC
Temperature: 25 °C
Yield: 88 %

Procedure:
54 mmol of the product obtained in Stage A, in 100 ml of ether, are added dropwise to 109 mmol of lithium aluminum hydride suspended in 200 ml of ether stirred at room temperature under a nitrogen atmosphere. When all the nitrile has disappeared, 10 ml of ethyl acetate are added to the mixture, followed by 10 ml of water. The mixture is stirred for 1 hour, filtered and dried over MgSO4 and the solvent is evaporated off. The expected product is obtained in an 88% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21]Cl.O>CN(C=O)C.[I-].[K+]>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccc(OCc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 3′-hydroxyacetophenone (19 g) in DMF (400 mL) was added K2CO3 (38.5 g) and the mixture was stirred for 3 hours at room temperature. 3,4-Dichlorobenzyl chloride (32.7 g) and potassium iodide (1.16 g) were added to the reaction mixture and stirred for 48 hours. After completion of the reaction, the mixture was poured into ice and water mixture and stirred for 15 minutes, solid was filtered and washed with water and hexanes. Solid was dissolved in DCM and precipitated by adding hexanes to get pure 1-[3-(3,4-dichloro-benzyloxy)-phenyl]-ethanone (30 g) 1H NMR (400 MHz, CDCl3) 7.53-7.60 (m, 3H), 7.46 (d, 1H), 7.39 (t, 1H), 7.25-7.30 (m, 1H), 7.14-7.19 (m, 1H), 5.07 (s, 2H), 2.60 (s, 3H).
Reaction SMILES: C([N:8]1[C@@H:13]([CH:14]=[CH:15][CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:19][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH:14]=[CH:15][CH:16]([CH3:18])[CH3:17])[NH:8]1
Reactant: CC(C)C=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C=C[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-(1-isopentenyl)piperidine (1.5 g, 5.56 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-(1-isopentenyl)piperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occured. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 157.5-156.5° C.; 1H NMR (250 MHz) δ9.37 (br. d, 2H), 5.59-5.46 (m, 2H), 4.19 (s, 1H), 3.59 (s, 1H), 2.66-2.59 (m, 1H), 1.8-1.5 (m, 9H), 1.0 (pair of d, 6H); 13C NMR (62.7 MHz) δ143.6 (s), 120.6 (s), 48.3 (s), 47.9 (s), 28.9 (s), 28.6 (s), 27.3 (s), 23.01 (s), 22.6 (s), 17.5 (s), 16.9 (s). FT-IR (neat): 3426, 3188, 3018, 2952, 1625, 1584, 1464, 1359, 1180, 1099, 958, 881. Elemental Analysis for C11H22NCl: C, 64.84%; H, 10.91%; N, 6.87%. Found: C, 64.06%; H, 10.77%; N, 6.78%.
Reaction SMILES: [C:1]([C:5]1[C:6]([S:16][S:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH2:26][CH2:27][OH:28])=[CH:20][C:19]=2[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[O:10][CH2:11][CH2:12][OH:13])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.C(N(C(C)C)CC)(C)C.[CH3:45][O:46][CH2:47]Cl.C[CH2:50][O:51][C:52](C)=O>>[CH3:30][C:29]([C:19]1[CH:20]=[C:21]([O:25][CH2:26][CH2:27][O:28][CH2:45][O:46][CH3:47])[C:22]([CH3:24])=[CH:23][C:18]=1[S:17][S:16][C:6]1[CH:7]=[C:8]([CH3:15])[C:9]([O:10][CH2:11][CH2:12][O:13][CH2:50][O:51][CH3:52])=[CH:14][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:32])[CH3:31]
Reactant: CCOC(C)=O
Reactant: COCCl
Reactant: Cc1cc(SSc2cc(C)c(OCCO)cc2C(C)(C)C)c(C(C)(C)C)cc1OCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCCOc1cc(C(C)(C)C)c(SSc2cc(C)c(OCCOCOC)cc2C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared using 7.0 g (29 mmol) of 2-{5-tert-butyl-4-[2-tert-butyl-4-(2-hydroxy-ethoxy)-5-methyl-phenyldisulfanyl]-2-methyl-phenoxy}ethanol (prepared in Example MMM), 200 mL of CH2Cl2, 15.2 g (118 mmol) of diisopropylethylamine and 9.45 g (118 mmol) of chloromethyl methyl ether. The reagents were mixed at 0° C. and stirred at that temperature for 1 hour. The reaction mixture was warmed to room temperature and stirred for 15 hours, then diluted with EtOAc and quenched with 1N HCl. The organic layer was washed with sodium bicarbonate solution and brine and dried (MgSO4). The solvents were removed, and the residue was subjected to flash silica gel chromatography, eluting with EtOAc:hexane (5:95, then switching to 1:4).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[NH:30]N>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:30]([C:26]4[S:25][CH:29]=[CH:28][N:27]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1nccs1
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3nccs3)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and thiazol-2-yl-hydrazine according to the method described for example 91. MS: M=400.1 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([O:24][Si:25]([C:28]([CH3:31])([CH3:29])[CH3:30])([CH3:27])[CH3:26])[CH2:15][CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:4][CH:3]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)=[O:36])[CH3:33]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(CCCc4ccccc4)O[Si](C)(C)C(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, using 5-(4-bromo-phenyl)-4-[1-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=2)[CH:19]=[N:18]1>O1CCOCC1.CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:26][C:22]4[CH:21]=[C:20]5[C:25](=[CH:24][CH:23]=4)[NH:17][N:18]=[CH:19]5)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: C1COCCO1
Solvent: CCCCO
Product: c1cc(Nc2cc(C3CC3)[nH]n2)nc(Nc2ccc3[nH]ncc3c2)n1
Temperature: 100 °C
Yield: 5.3 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.8 5 mmol, 1 equiv.) and 1H-indazol-5-amine (340 mg, 2.55 mmol, 3 equiv.) in 1,4-dioxane (1 ml) and n-BuOH (0.5 ml) was heated to 100° C. The mixture was allowed to react overnight (about 15 hr). The mixture was filtered under reduced pressure to afford title compound N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1H-indazol-5-yl)pyrimidine-2,4-diamine (Compound 13) (44.5 mg, 15.8%) as solid. LC-MS (m/z)=333.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.44 (s, J=17.7 Hz, 2H), 0.82 (t, J=17.7 Hz, 2H), 1.758 (s, 1H), 6.02 (s, 1H), 6.41 (s, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.56 (d, J=9 Hz, 1H), 7.92 (d, J=6.6 Hz, 1H), 8.04 (d, J=9.6 Hz, 2H), 9.71 (s, 1H), 10.38 (s, 1H), 11.77 (s, 1H), 13.05 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])=[O:4].C1N2CN3CN(C2)C[N:16]1C3.C(OCC)C.[Cl:30]C(Cl)Cl>>[ClH:30].[NH2:16][CH2:2][C:3]([C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])=[O:4]
Reactant: Cc1c(C(=O)CBr)sc2ccccc12
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1c(C(=O)CN)sc2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
1.11 g 2-Bromoacetyl-3-methyl-benzothiophene and 0.56 g hexamethylenetetramine in 20 ml trichloromethane were stirred at room temperature for 16 hours. After addition of 15 ml diethylether the mixture was filtered. The solid residue was stirred at room temperature for 3 hours in a mixture of 15 ml methanol and 1.9 ml concentrated hydrochloric acid. The solvents were distilled off and the residue recrystallized from water to yield 0.90 g (93%) 2-amino-1-(3-methyl-benzo[b]thiophen-2-yl)-ethanone hydrochloride as off-white solid; MS (El): m/e=205 (M+, 40%), 175 (M-CH2NH2, 100%), 147 (M-COCH2NH2, 20%).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CCOCC>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:21]
Reactant: SCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CSCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 49.9 %

Procedure:
To a solution of benzyl mercaptan (1.18 mL, 10.0 mmol) in DMF (20 mL) is added potassium carbonate (1.51 g, 10.9 mmol) and ethyl bromoacetate (1.17 mL, 10.6 mmol), and the mixture is stirred at RT for 25 min. Et2O is added, and the mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is vacuum distilled (130-140° C.) to give 1.05 g of the product 402.