Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1.[OH-].[Na+].[C:24]([O:28]C)(=[O:27])[CH:25]=[CH2:26].Cl>O1CCOCC1.ClCCl>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][C:12]1[CH:20]=[CH:21][C:9]([O:8][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH2:26][CH2:25][C:24]([OH:28])=[O:27])=[CH:10][CH:11]=1
Reactant: C=CC(=O)OC
Reactant: c1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)CCN1CCCC1COc1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
The product from Example 167 (125 mg, 0.37 mmol) was treated with 20% NaOH (10 mL) and extracted with EtOAc, dried over Na2SO4 and dried down to give the free base. Dichloromethane (3 mL) and methyl acrylate (1 mL, 7 mmol) were added and the mixture was stirred at ambient temperature overnight. The reaction mixture was dried down to give oil. 4.0M HCl in dioxane was added and the mixture was stirred overnight at ambient temperature. The solvent was evaporated to give the title compound (61 mg, 57%); LC/MS; m/z 343 (M+H) 99%
Reaction SMILES: [Cl:1][CH:2]([Cl:18])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([Cl:17])[CH:6]=1)O.S(Cl)([Cl:21])=O>N1C=CC=CC=1>[Cl:1][CH:2]([Cl:18])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([Cl:17])[CH:6]=1)[Cl:21]
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccc(C2CCCCC2)c(Cl)c1)C(Cl)Cl
Solvent: c1ccncc1
Product: Clc1cc(C(Cl)C(Cl)Cl)ccc1C1CCCCC1
Reaction time: 12 h

Procedure:
β,β-Dichloro-α-(3-chloro-4-cyclohexylphenyl)ethanol (67.5 g.; 0.22 moles) is heated with thionyl chloride (110 ml) containing 1 drop of pyridine until solution is obtained. The heating is discontinued and the reaction is allowed to proceed at room temperature for 12 hours. The reaction mixture is heated for an additional hour and the thionyl chloride removed, chased by benzene several times and distilled to give β,β,α,3-tetrachloro-4-cyclohexylphenylethane.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[Cl:31][C:32]1[C:33]([CH:54]=O)=[C:34]2[C:40]([C:41]([OH:43])=[O:42])=[CH:39][N:38]([S:44]([C:47]3[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[C:35]2=[N:36][CH:37]=1>C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[C@H:16]([NH:15][CH2:54][C:33]1[C:32]([Cl:31])=[CH:37][N:36]=[C:35]2[N:38]([S:44]([C:47]3[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[CH:39]=[C:40]([C:41]([OH:43])=[O:42])[C:34]=12)[C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(C=O)c(Cl)cnc32)cc1
Reactant: CC(C)(C)[C@@H](N)C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@@H](C(=O)OCc4ccccc4)C(C)(C)C)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 10 mL round bottom flask was added sodium triacetoxyborohydride (86 mg, 0.407 mmol), (R)-benzyl 2-amino-3,3-dimethylbutanoate (130 mg, 0.407 mmol) and DCM (2 mL). The mixture was stirred at room temperature for 10 min and then cooled to 0° C. 5-Chloro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (130 mg, 0.271 mmol) was added and the reaction mixture was stirred at 0° C. for 20 min to afford the title compound. [M+H] calc'd for C29H30ClN3O6S, 584; found, 584.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:20]([NH:28][C:29]1[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:30]=1[C:31]([O:33]C)=[O:32])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C(=O)C>[C:20]([NH:28][C:29]1[CH:38]=[C:37]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH:36]=[CH:35][C:30]=1[C:31]([OH:33])=[O:32])(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(-c2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)cc1
Temperature: 90 °C
Reaction time: 21 h
Yield: 11.9 %

Procedure:
56 mg of (4-(tert-butyl)phenyl)boronic acid, 55 mg of sodium carbonate and 30 mg of polymer supported bis(acetate)triphenylphosphine palladium(11) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of methyl 2-(benzamido)-4-bromobenzoate, and stirred at 90° C. for 21 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 1.0 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and she solvent was evaporated under reduced pressure. 1.0 mL of 2.0 mol/L aqueous sodium hydroxide and 5.0 mL of ethanol were added to the obtained residue and stirred at room temperature for 1 hour and 30 minutes. 0.5 mol/L hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated and the solvent was evaporated under reduced pressure to obtain 9.3 mg of 2-(benzamido)-4-(4-(tert-butyl)phenyl)benzoic acid as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[N:14]([C:17]3[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH:13]=[N:12]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:36]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[N:14]([C:17]3[S:18][C:19]([C:23]([N:25]([CH3:36])[CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH:13]=[N:12]2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-n2cnn(CCNc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-n2cnn(CCNc3ccc(F)cc3)c2=O)sc1C(=O)N(C)Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A solution of 2-(1-(2-(4-fluorophenylamino)ethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.10 g, 0.40 mmol) in anhydrous tetrahydrofuran (10 mL) was treated with sodium hydride (60% suspension in mineral oil, 0.02 g, 0.47 mmol) at ambient temperature for 30 minutes, followed by the addition of iodomethane (0.015 mL, 0.24 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate to afford the title compound as a white solid in 25% yield (0.03 g): 1H NMR (300 MHz, CDCl3) δ 8.60-8.49 (m, 2H), 8.24 (s, 1H), 7.69-7.59 (m, 1H), 7.35-7.27 (m, 1H), 6.91-6.77 (m, 2H), 6.59-6.49 (m, 2H), 4.69 (s, 2H), 4.15-4.04 (m, 2H), 3.99-3.87 (m, 1H), 3.54-3.44 (m, 2H), 2.98 (s, 3H), 2.39 (s, 3H); MS (ES+) m/z 468.18 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Clc1ccnc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccnc(Cl)n2)C1
Temperature: 90 °C
Yield: 68.5 %

Procedure:
A solution of 2,4-dichloropyrimidine (2.0 g, 13.4 mmol), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (2.7 g, 13.5 mmol) and NN-diisopropylethylamine (2.3 mL, 13.4 mmol) in N,N′-dimethylformamide (15 mL) was stirred and heated overnight at 90° C. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (2.87 g, 68%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].Cl.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][NH2:19])=[CH:22][CH:23]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: NCc1ccc(B(O)O)cc1
Agent: Cl
Product: NCc1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-aminomethyl-phenylboronic acid hydrochloride gives “A77”; method 1: HPLC/MS: 1.07 min, [M+H]=320;
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:21])[CH3:19])[C@H:14]([C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[O:21])[CH3:19])[C@H:14]([C:30]3[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc([C@@H]2CN(C(=O)C3CCN(C(C)=O)CC3)CC[C@H]2N(C)C(=O)c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)N(C)[C@@H]2CCN(C(=O)C3CCN(C(C)=O)CC3)C[C@H]2c2ccc(C(=O)O)cc2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of the compound (0.20 g) obtained in Example 240 in methanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 50° C. for 2 hr. Methanol was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water and concentrated to give the title compound (0.092 g, 47%) as a white powder.
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[CH2:11]([C:19]1[CH2:33][C@@H:32]([O:34][Si](C(C)(C)C)(C)C)[C@H:31](/[CH:42]=[CH:43]/[C@@H:44]([O:52][Si](C(C)(C)C)(C)C)[CH2:45][C@H:46]([CH3:51])[CH2:47][CH2:48][CH2:49][CH3:50])[C:20]=1[S:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH2:11]([C:19]1[CH2:33][C@@H:32]([OH:34])[C@H:31](/[CH:42]=[CH:43]/[C@@H:44]([OH:52])[CH2:45][C@H:46]([CH3:51])[CH2:47][CH2:48][CH2:49][CH3:50])[C:20]=1[S:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(CCc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(CCc2ccccc2)C[C@H]1O
Reaction time: 15 h
Yield: 88.4 %

Procedure:
To a solution of ice-cooled acetonitrile (1 ml) and pyridine (0.1 mL) was added hydrogen fluoride-pyridine (0.1 mL). To this solution was added methyl (11R,12S,13E,15S,17R)-9-phenethyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (52 mg, 0.072 mmol) in pyridine (0.1 mL). The ice bath was removed and the solution was agitated for 15 hours wile returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution by ethyl acetate. The extract was washed with brine, then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then was purified by silica gel column chromotography (40 to 50% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-9-phenethyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (32 mg, 90%).
Reaction SMILES: [OH:1][C:2]1([CH2:19][OH:20])[C:6](=[O:7])[O:5][C@H:4]2[C:8]3[C@@:13]([CH3:16])([CH2:14][CH2:15][C:3]12[OH:18])[CH2:12][CH2:11][CH2:10][C:9]=3[CH3:17].[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22].N1C=CC=CC=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:28][C:27]1[CH:29]=[CH:30][C:24]([S:21]([O:20][CH2:19][C:2]2([OH:1])[C:6](=[O:7])[O:5][C@H:4]3[C:8]4[C@@:13]([CH3:16])([CH2:14][CH2:15][C:3]23[OH:18])[CH2:12][CH2:11][CH2:10][C:9]=4[CH3:17])(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1=C2[C@@H]3OC(=O)C(O)(CO)C3(O)CC[C@@]2(C)CCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1=C2[C@@H]3OC(=O)C(O)(COS(=O)(=O)c4ccc(C)cc4)C3(O)CC[C@@]2(C)CCC1
Reaction time: 72 h

Procedure:
Compound of example 2 (126.6 mg, 0.449 mmol) was dissolved in dichloromethane (5 mL). Tosyl chloride (427.9 mg, 2.24 mmole), pyridine (355.05 mg, 4.48 mmole) and DMAP (2 mg) were added to this solution and reaction mixture was stirred for 72 hours. Reaction mixture was extracted with dichloromethane (5 mL). Dichloromethane was removed and crude product was purified by column chromatography (silica gel, 5-10% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[CH3:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[S:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=2)[N:18]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:24]([C:22]3[S:23][C:19]([C:17]4[N:18]=[C:14]([CH3:13])[S:15][CH:16]=4)=[CH:20][CH:21]=3)=[O:25])[CH2:3]1)[CH2:9]2
Reactant: Cc1nc(-c2ccc(C(=O)O)s2)cs1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: Cc1nc(-c2ccc(C(=O)NC3C4CC5CC3CN(C5)C4)s2)cs1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-(2-methylthiazol-4-yl)thiophene-2-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 2.74 (s, 3H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.49 (d, J=4.1 Hz, 1H), 7.68 (s, 1H), 7.79 (d, J=4.1 Hz, 1H). MS (DCI/NH3) m/z 360.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:25]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)(=[O:27])=[O:26])[CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Agent: Cl
Solvent: CCOCC
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Yield: 80.5 %

Procedure:
from 5-chloro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4d, 25 mg, 0.1 mmol) and 4-fluorophenylsulfonyl chloride (29.1 mg, 0.15 mmol). The HCl salt ether (32.6 mg, 74%) was prepared from the crude product using 1M HCl in ether. m.p 256-7° C., HRMS-FAB+ for C20H18N2O2SClF.HCl, calculated MH+ (--HCl): 405.08398; found: 405.0797.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:14][CH2:15][C:16](Cl)=[O:17].C(OCC)(=O)C.CCCCCCC>C(OCC)(=O)C>[Cl:14][CH2:15][C:16]([N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1)=[O:17]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(CCl)N1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1.78 g of 7-nitro-1,2,3,4-tetrahydroquinoline (0.01 mol) are dissolved in 15 ml of ethyl acetate. This solution is run into a mixture of 15 ml of ethyl acetate and 0.80 ml of chloroacetyl chloride. A white precipitate forms immediately, and stirring is continued at 30° C. for 2 h (the reaction is monitored by thin layer chromatography (90/10 ethyl acetate/heptane)). After 2 h, since the reaction is incomplete, 0.2 equivalent of chloroacetyl chloride is added and the temperature is raised to 60° C.; the solid formed undergoes dissolution. When the reaction has finished, the medium is cooled and the solvent is evaporated off. 2.46 g of a beige product which corresponds to the expected compound are recovered.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6](=[O:9])[CH2:7][SH:8].Cl[CH2:11][C:12](=[O:14])[CH3:13].O>CO>[CH3:4][O:5][C:6](=[O:9])[CH2:7][S:8][CH2:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)CCl
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CSCC(C)=O

Procedure:
To a mixture of a 5.4 M methanolic solution of sodium methylate (185 mL, 1.00 mol) in 500 mL methanol is added mercapto-acetic acid methyl ester (97.0 g, 912 mmol) at RT. After stirring for 20 minutes at RT chloro acetone (80 mL, 1.0 mmol) is added carefully. After complete addition the reaction mixture is heated at reflux for 20 minutes. The reaction mixture is added to water and extracted with diethyl ether. The organic layer is washed with brine, dried over Na2SO4 and the solvent is evaporated under reduced pressure. The crude reaction product is distilled under reduced pressure (75° C.-90° C., 0.3 mbar) yielding the desired product as colorless liquid. Yield: 61.5 g. (M+H)+=163
Reaction SMILES: I[CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.[C-:12]#[N:13].[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:12]([CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)#[N:13]
Reactant: ICC1Cc2ccccc2N1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC1Cc2ccccc2N1
Temperature: 80 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
To a mixture of 2-hydroxymethylindoline (7.77 g, 52.08 mmol), imidazole (8.86g, 130.2 mmol), triphenylphosphine (34.15 g, 130.2 mmol)in toluene (500 mL) was added iodine (26.44 g, 104.16 mmol) in acetonitrile (100 mL) at 0° C. The mixture was stirred for 10 min and water was added. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated. The residue was triturated with diethyl ether and insoluble solids were removed by filtration. The filtrate was concentrated to give crude 2-iodomethylindoline. The crude 2-iodomethylindoline was dissolved in DMF (130 mL) and KCN (4.07 g, 62.5 mmol) was added. The mixture was heated at 80° C. for 12 h and after addition of KCN (4.07 g), the heating was further continued for 5 h. The mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 3:1 to 2:1 hexane/ethyl acetate to give 3.04 g of 2-cyanomethylindoline (37%): 1H NMR (270 MHz, CDCl3) δ7.03 (m, 2 H), 6.77 (t, 1H, J=7 Hz), 6.54 (t, 1H, J=7 Hz), 4.42 (m, 1H), 4.13 (bs, 1H), 3.07 (m, 1H), 2.81 (dt, 1H, J=16, 4 Hz), 2.22 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16](O)[CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:27].C(=O)([O-])O.[Na+]>C1C=CC=CC=1.CCOCC>[Br:27][CH:16]([CH2:17][CH3:18])[CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: BrP(Br)Br
Reactant: CCC(O)CCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCC(Br)CCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
1-(4-(diphenylmethyl)piperazinyl)pentane-3-ol (940 mg) was dissolved in benzene (10 ml) and ether (10 ml), and then phosphorus tribromide (0.2 ml) was added thereto, followed by stirring the mixture overnight at room temperature. To the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added and the resultant was extracted 3 times with ethyl acetate. Organic layers were combined and washed with brine. The resultant was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 340 mg of 1-(3-bromopentyl)-4-(diphenylmethyl)piperazine. Yield: 31%.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:21][C:15]3[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26]>CS(C)=O>[OH:26][CH2:25][C:24]([NH:23][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:21][C:15]3[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:28])[CH3:27]
Reactant: CC(C)(N)CO
Reactant: Cc1nc2cccc(-c3cc4c(=O)[nH]cnc4[nH]3)c2nc1F
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c(=O)[nH]cnc4[nH]3)c2nc1NC(C)(C)CO
Yield: 10.8 %

Procedure:
Prepared similarly to that described in Example 260 using 6-(3-fluoro-2-methylquinoxalin-5-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (Example 264; 60 mg, 0.203 mmol) and 2-amino-2-methylpropanol (81 μl, 0.847 mmol, Sigma-Aldrich) in DMSO (2 mL) at 50° C. for 20 min. The mixture was purified by rpHPLC (Phenomenex Gemini C18 column (100×50 mm, 10 μm), 90 mL/min, 5-30% ACN in water with 0.1% TFA) to give 6-(3-((1-hydroxy-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (8.0 mg, 0.022 mmol, 13% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 365.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.44 (1H, s), 11.86 (1H, br. s.), 8.00 (1H, dd, J=7.5, 1.3 Hz), 7.90 (1H, d, J=3.7 Hz), 7.70 (1H, d, J=8.0 Hz), 7.41 (1H, t, J=7.8 Hz), 7.28 (1H, d, J=2.2 Hz), 5.94 (1H, s), 5.12 (1H, t, J=5.9 Hz), 3.65 (2H, d, J=5.7 Hz), 2.57 (3H, s), 1.54 (6H, s)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[C:30]([CH3:33])[CH2:31]O)=[CH:25][CH:24]=1>C(#N)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[C:30]([CH3:33])[CH2:31][Br:20])=[CH:25][CH:24]=1
Reactant: CC(=Cc1ccc(Br)cc1)CO
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(=Cc1ccc(Br)cc1)CBr
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To an acetonitrile solution (180 mL) of triphenylphosphine (24.3 g, 92.7 mmol) was added dropwise bromine (4.78 mL, 185 mmol) at 0° C. and the mixture was stirred at the same temperature for 30 minutes. To the solution was added the acetonitrile solution (60 mL) of 3-(4-bromophenyl)-2-methyl-2-propen-1-ol obtained in Reference Example 106 (20.1 g, 88.3 mmol) and the mixture was stirred at 0° C. for 1 hour. The reaction solution was concentrated under reduced pressure, diethyl ether (200 mL) was added to the residue, and the insolubles were filtered off. The solution was washed with a saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure to obtain 25.0 g (yield 98%) of the title compound as an oily matter.