Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:15][C:16](=[O:22])[C:17](=[CH:20][CH:21]=3)[C:18]#[N:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[K+].I[CH3:26]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]([CH3:26])[C:16](=[O:22])[C:17](=[CH:20][CH:21]=3)[C:18]#[N:19])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(-c3ccc(C#N)c(=O)[nH]3)cc2)CC1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(c2ccc(-c3ccc(C#N)c(=O)n3C)cc2)CC1

Procedure:
A mixture of 9.1 g. of 6-[p-(4-methyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile, 2.0 g. of potassium hydroxide, 5.0 ml. of iodomethane and 250 ml. of absolute ethanol is stirred and heated at reflux for 5 hours, then evaporated at reduced pressure. The residue is washed thoroughly with warm water, then dried, to give 6-[p-(4-methyl-1-piperazinyl)phenyl]-1,2-dihydro-1-methyl-2-oxonicotinonitrile as the remaining solid.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:19](C([Sn])=C(CCCC)CCCC)[CH2:20]CC>C1(C)C=CC=CC=1.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>[C:9]([Si:6]([CH3:8])([CH3:7])[O:5][CH2:4][C:3]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:2]=1[CH:19]=[CH2:20])([CH3:12])([CH3:11])[CH3:10]
Reactant: COc1ccc(Br)c(CO[Si](C)(C)C(C)(C)C)c1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(OC)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 33.63 9 (0.10 mol) of (2-bromo-5-methoxy-benzyloxy)-tert-butyl-dimethyl-silane (14), 32.18 9 (0.10 mol) of tributylvinyl tin and 4.7 g (0.004 mol) of tetrakis(triphenylphosphine)palladium(0) were combined in 250 mL of toluene, and the solution was heated to reflux for 6 hours. The reaction was allowed to cool to ambient temperature and was quenched with 5% NH4OH (2×100 mL). The organic layer was washed with water (1×200 mL) and brine (1×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield crude product. The crude product was chromatographed on a silica gel column, first with hexane, then with 20% CHCl3 in hexane, and finally with 40% CHCl3 in hexane to afford 25.0 9 (89%) of tert-butyl-dimethyl-(2-vinyl-5-methoxy-benzyloxy)-silane (15).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[C:22]2[O:21][CH2:20][CH2:19][NH:18][C:17]=2[CH:16]=[C:15]([Cl:23])[CH:14]=1.[OH-].[Na+]>C(OCC)(=O)C>[CH2:5]([O:4][C:2]([N:18]1[C:17]2[CH:16]=[C:15]([Cl:23])[CH:14]=[C:13]([Br:12])[C:22]=2[O:21][CH2:20][CH2:19]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Clc1cc(Br)c2c(c1)NCCO2
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCOc2c(Br)cc(Cl)cc21
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Benzyl chloroformate (1.877 g, 0.011 mol) was added dropwise to a solution of 8-bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine (2.85 g, 0.01 mol) in a 1:1 mixture of ethyl acetate (30 mL) and 10% aqueous sodium hydroxide (30 mL). After 3 hours at ambient temperature, the layers were separated and the organic phase was washed with water (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), dried (K2CO3) and concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with hexane-ethyl acetate; 7:3,V/V) to give 8-bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzyl ester as an oil (3.47 g, 98%). A sample was recrystallized from ethanol-water. MS: MH+ 383. M.P. 95.0-97.7° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCCCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: ClCCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
In a 2 L three-necked round bottomed flask was added piperidine (85.15 g, 1.0 mol) acetone (1000 mL), and anhydrous potassium carbonate (276.42 g, 2.0 mol, 2.0 equiv.). The flask was equipped with a mechanical stirrer and a condenser. 4-chloro-1-bromo-butane (188.6 g, 1.1 mol, 1.1 equiv.) was added dropwise under continuous stirring at room temperature over a period of 30 min. The suspension mixture was then stirred at 40° C. The progress of the reaction was monitored by TLC, which confirmed the reaction was completed after 4 hours. The mixture was cooled to room temperature and the insoluble materials were removed by filtration and washed with dichloromethane (2×100 mL). The combined filtrates were concentrated under vacuum until it became dry. The residue was then mixed with dichloromethane (500 mL). Insoluble materials were removed by filtration and washed by dichloromethane (2×100 mL). The combined filtrate and washings were concentrated and purified through a flash silica gel column, which gave the expected product as light yellow oil (98.39 g, 56% yield).
Reaction SMILES: [OH:1][CH:2]([CH2:13][OH:14])[CH2:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>O1CCCC1.CCOCC>[Si:20]([O:14][CH2:13][CH:2]([OH:1])[CH2:3][CH2:4][P:5](=[O:12])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CCOP(=O)(CCC(O)CO)OCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOP(=O)(CCC(O)CO[Si](C)(C)C(C)(C)C)OCC
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of diethyl 3,4-dihydroxybutylphosphonate (8.5 g, 0.038 mol) in dry tetrahydrofuran (200 ml) was added imidazole (5.25 g, 0.077 mol). After stirring at ambient temperature for 2 minutes, t-butyldimethysilyl-chloride (5.8 g, 0.038 mol) was added. After 18 hours, the solution was filtered and the filtrate evaporated to give a colorless oil. The oil was dissolved in ether, and washed with water. The organic phase was dried (magnesium sulphate) and evaporated to give an oil which was purified by chromatography on silica gel (dichloromethane-methanol (98:2) as eluant). The title compound was obtained as an oil (8 g, 62%). IR:υmax (film), 3400, 2940, 2860, 1250, 1170, 960, 840, 780 cm-1. 1H NMR: δH (CDCl3) 0.00 (6H, s, SiMe2), 0.83 (9H, s, SiBut), 1.25 (6H, t, J=7Hz, (OCH2CH3)2), 1.5-2.0 (4H, m, CH2CH2P), 2.7 (1H, bs, D2O exchangeable, OH), 3.35-3.65 (3H, m, OCH2CH), 4.0 (4H, m, (OCH2CH3)2) Found: C, 48.66; H, 9.83%. C14H33O5SiP requires: C, 49.39; H, 9.77%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]2([CH3:19])[CH2:18][CH2:17]2)=[O:14])[CH2:9][CH2:8]1.[F:20][C:21]1[CH:26]=[C:25](O)[CH:24]=[CH:23][C:22]=1[CH2:28][C:29]([O:31][CH3:32])=[O:30].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][C:21]1[CH:26]=[C:25]([CH:24]=[CH:23][C:22]=1[CH2:28][C:29]([O:31][CH3:32])=[O:30])[O:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]2([CH3:19])[CH2:18][CH2:17]2)=[O:14])[CH2:9][CH2:8]1
Reactant: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCO)CC2)CC1
Reactant: COC(=O)Cc1ccc(O)cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OC3(C)CC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-methylcyclopropyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (Intermediate 9, 0.484 g, 1.81 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of methyl (2-fluoro-4-hydroxyphenyl)acetate (0.400 g, 2.17 mmol) in 10 ml anhydrous dichloromethane, triphenylphosphine, polymer-bound (1.42 g, 4.10 mmol), and di-tert-butyl azodicarboxylate (0.834 g, 3.61 mmol). The reaction mixture was stirred at RT for 3 hours. It was filtered by Celite and concentrated. The residue was purified on Biotage column (50 g silica gel) using a gradient eluent of 0-50% ethyl acetate in hexanes (1000 ml) to afford the title compound. LC/MS (m/z) 434.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.[Na].[H-].[Na+].N1C=CN=C1>CN(C=O)C>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2ccnc2)nc1
Temperature: 120 °C

Procedure:
A solution of the methyl ester obtained in Step 1. above (16.29 g) in DMF is added dropwise to a DMF suspension of sodium imidazole [prepared from NaH (4.19 g) and imidazole 6.49 g)] at RT. The reaction mixture is heated to 120° C. for nineteen hours. The cooled reaction mixture is partitioned between water and chloroform, the organic layer separated, washed with water, dried over Na2SO4, filtered, evaporated, and residual DMF removed under high vacuum yielding the desired product as a tan solid which is recrystalized from methanol (M.P. 183°-184.5° C.) before use in the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][CH:25]=2)=[O:34])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1c[nH]c2ccccc12
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c[nH]c3ccccc23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 1H-Indole-3-carboxylic acid. LC-MS (basic): tR=0.76 min; [M+H]+=476.3.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[O:28]>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:39]=[CH:38][CH:37]=2)=[O:28])=[CH:31][CH:32]=1
Reactant: Nc1cccc(C(=O)Nc2ccc(F)cc2)c1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccc(F)cc3)c2)c2cc(C(C)=O)ccc21

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(4-fluoro-phenyl)-benzamide. Recrystallized from ethyl acetate-hexanes-benzene. Calculated for C26H22FN3O4 : C 67.97; H 4.83; N 9.15; found C 68.34; H 5.31; N 8.80.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][C:9](=[O:11])[CH3:10])=S)=[CH:4][CH:3]=1.Cl.Cl.[NH2:16][CH:17]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:18]([NH:20][C:21]1([C:28]#[N:29])[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=[O:19]>>[C:9]([N:8]=[C:6]([NH:16][CH:17]([CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:18]([NH:20][C:21]1([C:28]#[N:29])[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1)=[O:19])[C:5]1[CH:12]=[CH:13][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)NC(=S)c1ccc(F)cc1
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Agent: Cl
Product: CC(=O)N=C(NC(CC1CCCCC1)C(=O)NC1(C#N)CCN(C)CC1)c1ccc(F)cc1

Procedure:
The title compound was prepared starting from N-(4-fluoro-thiobenzoyl) acetamide and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 72, step b. MS, m/z 456=M+1.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[NH:21]1[CH2:26][CH2:25][C:24]2([C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:21]3[CH2:26][CH2:25][C:24]4([C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27]4)[CH2:23][CH2:22]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nsc(-c2ccc(N3CCC4(C=Cc5ccccc54)CC3)nn2)n1

Procedure:
The object product (22 mg, 25%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (51 mg), spiro[indene-1,4′-piperidine] trifluoroacetate (105 mg) and potassium carbonate (70 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:8][C:7](=[O:9])[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][N:4]=1.C([O:23][CH2:24][CH3:25])(=O)C>CO.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[N:4]([O:23][CH:24]([C:25]2[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:7](=[O:9])[CH:8]=1)=[O:1]
Reactant: CCOC(C)=O
Reactant: COc1ccc(COC2=CN=C(CO)CC2=O)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Product: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(C=O)cc2=O)cc1

Procedure:
In 300 ml of anhydrous methanol is suspended 6 g of 2-hydroxymethyl-5-p-methoxybenzyloxy-4-pyridone, and 15 g of active manganese dioxide is added thereto. The reaction is performed under heating at a refluxing temperature for 30 minutes. At the end of the reaction, the manganese dioxide is removed by filtration, and the filtrate is condensed under reduced pressure. The residue is dissolved in 150 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and condensed under reduced pressure to give the title compound (5.63 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][N:8]=[C:9]=[O:10]>ClCCl>[CH3:7][NH:8][C:9]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:10]
Reactant: C1CNCCN1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCNCC1

Procedure:
To the solution of piperazine (3 g) in dichloromethane (30 ml) was added methyl isocyanate (2.16 ml) in an ice water bath with stirring. After 10 minutes the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated in vacuo. The residue was diluted with acetonitrile (15 ml) and crystals were filtered off. The filtrate was evaporated in vacuo. To the residue was added xylene and the solvent was azeotropically removed in vacuo to give N-methyl-1-piperazinecarboxamide (2.43 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8]/[N:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12].[Br:15]N1C(=O)CCC1=O>O1CCCC1>[Br:15]/[C:10](=[N:9]\[NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])/[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)/C=N/Nc1ccccc1Cl
Solvent: C1CCOC1
Product: COC(=O)/C(Br)=N/Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of the title compound of Step A (16.5 g, 77 mmol) in tetrahydrofuran (150 mL) was added N-bromosuccinimide (13.7 g, 77 mmol) and the mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated and extracted with hexane and the hexane solution was concentrated to give the title compound of Step B (16 g) as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:22])NCOC)=[CH:14][CH:15]=2)[C:10]([CH2:23][CH2:24][N:25]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:9]1[C:43]1[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:51][Li]>CCOCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:22])[CH3:51])=[CH:14][CH:15]=2)[C:10]([CH2:23][CH2:24][N:25]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:9]1[C:43]1[CH:44]=[C:45]([CH3:50])[CH:46]=[C:47]([CH3:49])[CH:48]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [Li]C
Reactant: COCNC(=O)c1ccc2c(c1)c(CCN(CCCCc1ccncc1)C(=O)OC(C)(C)C)c(-c1cc(C)cc(C)c1)n2C(=O)OC(C)(C)C
Solvent: CCOCC
Product: CC(=O)c1ccc2c(c1)c(CCN(CCCCc1ccncc1)C(=O)OC(C)(C)C)c(-c1cc(C)cc(C)c1)n2C(=O)OC(C)(C)C
Reaction time: 0.75 h

Procedure:
To a solution of 3-{2-[tert-butoxycarbonyl-(4-pyridin-4-yl-butyl)amino]ethyl}-2-(3,5 -dimethylphenyl)-5-(methoxymethylcarbamoyl) indole-1-carboxylic acid tert-butyl ester (0.069 g in 3 mL dry tetrahydrofuran) at -10° C. was added 0.20 mL of a 1.5M solution of methyllithium in ether and the mixture stirred at low temperature. After 45 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acatate. The organic portion was washed with brine, dried over sodium sulfate and the concentrate purified by preparative TLC on silica gel (hexane:ethyl acetate, 2:3) to give the title compound (58 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[CH:4][C:3]=1[OH:15].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]>CC(C)=O>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:15][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH:4]=2)[S:10][CH:11]=1
Reactant: Cc1csc(Nc2ccc(C)c(O)c2)n1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2nc(C)cs2)ccc1C
Yield: 56 %

Procedure:
Following the procedure general for O-alkylation, Method A, a mixture of 2-methyl-5-(4-methylthiazol-2-ylamino)phenol (79 mg, 0.36 mmol) and K2CO3 (54 mg, 0.39 mmol) in acetone (3.6 mL) was treated with 4-bromo-2-methyl-2-butene (0.05 mL, 0.43 mmol). The reaction mixture was heated at reflux for 4 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 56% yield (57 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[S:26]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1ccccc1F)c1ccccn1
Solvent: Cc1ccccc1
Product: Fc1ccccc1NC(=S)c1ccccn1
Yield: 56.8 %

Procedure:
N-(2-fluorophenyl)-2-pyridinecarboxamide (11.81 g, 55 mmol) was reacted with Lawesson's reagent (26.04 g, 64 mmol) in toluene (160 mL) at reflux temperature for 5 hours. The solution was preadsorbed onto silica gel and flash chromatographed (eluted with 2.5% ethyl acetate in petroleum ether) to give N-(2-fluorophenyl)-2-pyridinecarbothioamide as a yellow solid (7.26 g, 39%) m.p. 94°-97° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:19]([CH3:21])([CH3:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:22]([O:24]C)=[O:23])[CH:16]=3)[NH:11]2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[OH-].[Na+]>CO>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:19]([CH3:21])([CH3:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:22]([OH:24])=[O:23])[CH:16]=3)[NH:11]2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(N)=O)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(N)=O)c1

Procedure:
A mixture of methyl 2-(3-carbamoylphenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxy late (84 mg, 0.25 mmol) in methanol (4.5 mL) and 1 M sodium hydroxide aqueous solution (3.2 mL, 3.2 mmol, 13.0 eq.) was heated to reflux for 30 min, LC-MS showed the reaction was complete and only the desired product formed. The solvent was concentrated in vacuo and the residue was dissolved in water and acidified with 1 M hydrochloric acid solution to pH=6. The white precipitated solid was collected by filtration and dried in vacuo to afford 50 mg of 2-(3-carbamoylphenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 62.1%. MS (ESI+APCI) M+1=325.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:38][CH2:37][C:36]5[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=5[Cl:34])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1Cl
Reactant: CS(=O)c1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4ccnc(NCc5ccccc5Cl)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 48 supra) (100 mg, 0.21 mmol) and 2-chlorobenzylamine (120 mg, 0.84 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude (4-{3-[2-(2-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 60 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12](O)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl.C(=O)(O)[O-].[Na+]>[C:1]1([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][CH:11]2[C:12]([Cl:21])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCCN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
To a solution of the N-phenylsulfonyl proline (1.5 g, 5.8 mmol) in anhydrous dichloromethane (20 mL), were added oxalyl chloride (2.0 M in dichloromethane, 5.9 mL, 11.8 mmol) and a catalytic amount of dimethylformamide. The solution was stirred for 1 hour at room temperature. The reaction mixture was then condensed and diluted with a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with dichloromethane (20 ml). The organic layers were dried over magnesium sulfate (MgSO4) and filtered and concentrated under reduced pressure to yield 1-benzenesulfonyl-pyrrolidine-2-carbonyl chloride (220 mg) as a yellow solid used without any further purification.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:5]([NH:13][C@H:14]2[CH2:15][CH2:16][C@H:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH2:19]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1

Procedure:
Ethyl {trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetate (160 mg, 0.44 mmol) and 10% Pd/C (20 mg) in methanol (4 mL) was subjected to balloon pressure of H2 at room temperature for 2 h. The mixture was filtered. The filtrate was concentrated and purified on silica gel column (eluting with 0-10% MeOH in methylene chloride) to give the desired product. LCMS calculated for C17H24N3O2S (M+H)+: m/z=334.2. Found: 334.1.