Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:18])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.Br[C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[C:23]([O:26][CH3:27])=[N:24][CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([NH:1][C:20]4[CH:25]=[N:24][C:23]([O:26][CH3:27])=[C:22]([CH2:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[CH:21]=4)[N:3]=[CH:4][C:5]=3[CH2:6][C:7](=[O:18])[NH:8][C:9]=2[CH:16]=1
Reactant: COc1ncc(Br)cc1CCCN(C)C
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ncc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1CCCN(C)C
Temperature: 150 °C
Yield: 20 %

Procedure:
A mixture of 2-amino-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.36 g, 1.38 mmol), 3-(5-bromo-2-methoxypyridin-3-yl)-N,N-dimethylpropan-1-amine (0.38 g, 1.38 mmol), xphos (0.047 g, 0.099 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.023 g, 0.026 mmol) in a sealed microwave tube was evacuated and purged with nitrogen three times. To the solids were added tert-butyl alcohol (3.6 mL) and t-BuOK (1M in t-BuOH, 2.63 mL) via syringe. The mixture was stirred well and then subjected to microwave irradiation (150 watts) while heating at 150° C. for 45 min. The reaction mixture was then poured into water (25 mL) with vigorous stirring. The precipitate that formed was filtered, washed with water, and air dried. The residue was purified by column chromatography to give 9-chloro-2-({5-[3-(dimethylamino)propyl]-6-methoxypyridin-3-yl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.125 g, 18%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH:9](O)[CH:8]([CH:11]([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH:9]=[C:8]([CH:11]([CH3:12])[CH3:13])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(C(C)C)C2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc2cc(C(C)C)sc2c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.8 %

Procedure:
To 28.4 g of 6,7-dichloro-2,3-dihydro-3-hydroxy-2-isopropyl-5-methoxybenzo[b]thiophene in 139 ml of glacial acetic acid is added 35 ml of boron trifluoride etherate. The reaction is heated on a steam bath for 10 minutes and allowed to stir at room temperature for 90 min. The reaction is poured into a mixture of 250 ml of 10% sodium hydroxide solution and 150 ml of ice. The mixture is basified with 50% sodium hydroxide solution, diluted with 600 ml of water and extracted with four 300 ml-portions of ether. The combined ether extracts are washed with one 350 ml-portion of water, one 150 ml-portion of saturated sodium chloride solution and dried over magnesium sulfate to give 26.4 g of a clear, brown oil of high purity by thin-layer chromatography. A 10 g-portion of the oil is chromatographed on 500 ml of silica gel with ether:hexane (1:2) to give 9.55 g of 6,7-dichloro-2-isopropyl-5-methoxybenzo[b]thiophene as a clear, colorless oil which solidified to a low melting solid, mp <37°, pure by thin-layer chromatography (silica gel, 1:1, ether-hexane or carbon tetrachloride).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2([CH3:19])[CH2:17][CH2:16][CH2:15][CH:14]2[NH2:18])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN1CCOCC1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[N:49]1[CH:54]=[CH:53][CH:52]=[N:51][C:50]=1[C:55]1[C:56]([C:61](O)=[O:62])=[N:57][CH:58]=[CH:59][CH:60]=1>C(#N)C.C(Cl)Cl>[F:1][C:2]1[C:3]([NH:12][C:13]2([CH3:19])[CH2:17][CH2:16][CH2:15][CH:14]2[NH:18][C:61]([C:56]2[C:55]([C:50]3[N:49]=[CH:54][CH:53]=[CH:52][N:51]=3)=[CH:60][CH:59]=[CH:58][N:57]=2)=[O:62])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=C(O)c1ncccc1-c1ncccn1
Reactant: CC1(Nc2ncc(C(F)(F)F)cc2F)CCCC1N
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC1(Nc2ncc(C(F)(F)F)cc2F)CCCC1NC(=O)c1ncccc1-c1ncccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-1-methylcyclopentane-1,2-diamine (Intermediate 28; 0.225 g, 0.81 mmol) and 4-methylmorpholine (0.134 ml, 1.217 mmol) in acetonitrile (5 ml) was added TOTU (0.399 g, 1.23 mmol) and 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 0.163 g, 0.81 mmol). The reaction was stirred at room temperature for 1 hour and then was diluted with DCM and washed with brine. The organics were dried over magnesium sulfate, concentrated in vacuo and purified by SCX chromatography (2M ammonia in methanol). The resulting residue was purified by column chromatography (silica, 0-10% methanol/DCM) and further purified by reverse phase chromatography (C18 silica, 5-95% water (0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [PH:1]([OH:3])[OH:2].[C:4]1([CH:10]([NH2:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)C>C(O)C>[PH2:1](=[O:2])[OH:3].[C:11]1([CH:10]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH2:17])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OPO
Agent: NC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: O=[PH2]O

Procedure:
To a solution of 8 g (121.2 mmol) of phosphonous acid in 30 ml of anhydrous ethanol, cooled to 0° C., are added dropwise 22.21 g (121.2 mmol) of diphenylmethylamine, while taking care to ensure that the temperature does not exceed 25° C. After addition, a white precipitate forms, to which 200 ml of diethyl ether are added. The precipitate is filtered off, rinsed with diethyl ether and then dried. 22.66 g of product are recovered (yield=98.2%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Br)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:24][C:25]1([CH3:33])[CH2:31][C:30](=[O:32])[NH:29][C:27](=[O:28])[CH2:26]1.[Na]>>[CH3:24][C:25]1([CH3:33])[CH2:31][C:30](=[O:32])[N:29]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:29]2[C:30](=[O:32])[CH2:31][C:25]([CH3:33])([CH3:24])[CH2:26][C:27]2=[O:28])([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:27](=[O:28])[CH2:26]1
Reactant: O=C(c1ccccc1)C(OCCBr)(OCCBr)c1ccccc1
Reactant: CC1(C)CC(=O)NC(=O)C1
Agent: [Na]
Product: CC1(C)CC(=O)N(CCOC(OCCN2C(=O)CC(C)(C)CC2=O)(C(=O)c2ccccc2)c2ccccc2)C(=O)C1
Yield: 97.8 %

Procedure:
When 13.26 g of benzil-di-(β-bromoethyl)ketal and 10.63 g of sodium 3,3-dimethylglutarimide were reacted and worked up in the same way as in Example 4, 16.5 g (yield 95.8%) of benzil-di-(3,3-dimethyl glutarimidoethyl)ketal was obtained. Recrystallization from ethanol afforded crystals having a melting point of 130° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)[CH:8]=O)[CH3:2].[CH3:15][O:16][C:17]([CH2:19][C:20]([CH2:22][C:23](OC)=[O:24])=[O:21])=[O:18]>>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]2[C:7]([CH:8]=[C:22]([C:20]([CH2:19][C:17]([O:16][CH3:15])=[O:18])=[O:21])[C:23](=[O:24])[O:12]2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Product: CCN(CC)c1ccc2cc(C(=O)CC(=O)OC)c(=O)oc2c1

Procedure:
A solution of 1.93 g 4-diethylaminosalicylaldehyde, 1.80 g. dimethyl 1,3-acetone dicarboxylate in 10 ml. alcohol containing 10 drops piperidine was heated under reflux on a steam bath for 2 hours. After chilling in the freezer, the product was collected and recrystallized from a mixture of alcohol and acetonitrile. Yield 2.6 g (82%).
Reaction SMILES: COCC([NH:6][C@H:7]([CH3:16])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.Cl>>[CH3:16][C@@H:7]([NH2:6])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COCC(=O)N[C@H](C)CCc1ccccc1
Agent: Cl
Product: C[C@@H](N)CCc1ccccc1
Yield: 100.2 %

Procedure:
This gives 7.4 g (96.25 % ee, 84% of theory) of (R)-N-methoxyacetyl-1-methyl-3-phenyl-propylamine, which is then heated under reflux with 50 ml of 18% strength aqueous hydrochloric acid for 4 hours. Work-up gives 5.0 g (96% ee, 98% of theory) of (R)-1-methyl-3-phenyl-propylamine.
Reaction SMILES: NC1C=C(C)C=CC=1S(N)(=O)=O.C(N=C=S)(C)C.[NH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[S:27]([NH:30][C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=S)(=[O:29])=[O:28].C(Cl)(Cl)=O>>[Cl:26][C:25]1[C:20]2[NH:19][C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=[N:30][S:27](=[O:29])(=[O:28])[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)NC(=S)NS(=O)(=O)c1cccc(Cl)c1N
Agent: CC(C)N=C=S
Agent: Cc1ccc(S(N)(=O)=O)c(N)c1
Agent: O=C(Cl)Cl
Product: CC(C)NC1=NS(=O)(=O)c2cccc(Cl)c2N1

Procedure:
Starting from 2-amino-4-methylbenzenesulfonamide and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amino-3-chlorobenzenesulfonyl)-N′-isopropylthiourea was prepared; m.p. 124-125° C. Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound; m.p. 204-206° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: BrCCCOCc1ccccc1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(CCCOCc2ccccc2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 100.4 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.49 g) is alkylated using (3-bromo-propoxymethyl)-benzene (1,36 g; 5.95 mmol) and K2CO3 (2.07 g; 15.0 mmol) at RT for 16 h. After aqueous work-up the crude material is de-acetylated in hydrochloric acid (6 N, 60 ml) at reflux. After aqueous work-up 5-amino-1-(3-benzyloxy-propyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (2.1 g) is obtained and used without further purification.
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][C:12]([O:14]C)=[O:13])[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1.[OH-].[K+].Cl>O>[C:12]([CH2:11][C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=[C:2]([SH:1])[N:7]2[N:8]=1)([OH:14])=[O:13]
Reactant: COC(=O)Cc1nc2nc(C)cc(S)n2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(S)n2nc(CC(=O)O)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
The product obtained in Step 5 (1.5 g) was added to a solution of 0.75 g potassium hydroxide in 10 ml of water, the mixture was stirred at room temperature for two hours, and its pH was lowered to 1-2 with 6N hydrochloric acid. The crystals thus formed were collected by filtration, washed with 50 ml of water and dried, giving 1.3 g of the objective compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]([CH:8]([N:13]=CC2C=CC(OC)=CC=2)[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.O1CCOCC1.Cl.O>>[Br:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]([CH:8]([NH2:13])[C:9]([F:10])([F:11])[F:12])=[N:6][CH:7]=1
Reactant: COc1ccc(C=NC(c2cc(C)c(Br)cn2)C(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(N)C(F)(F)F)ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a solution of 1-(5-bromo-4-methylpyridin-2-yl)-2,2,2-trifluoro-N-(4-methoxybenzylidene)ethanamine (77 mg; 0.1989 mmol) in dioxane (1.0 mL; 12 mmol) was added a 1 mol/L solution of hydrochloric acid in water (1.0 mL; 1.0 mmol). The reaction mixture was stirred at room temperature for 2 hours and then heated at 60° C. for 4 hours. The reaction mixture was partitioned between ethyl acetate and water. The layers were separated, and the aqueous layer adjusted to pH 7 with saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice with dichloromethane. The combined dichloromethane extracts were dried over magnesium sulfate, filtered, and concentrated to yield 33.3 mg (62%) of the title compound, which was carried forward without purification. LCMS (ESI): M+H=269.2; 1H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.59 (s, 1H), 4.54 (dd, J=15.9, 7.9 Hz, 1H), 2.55 (d, J=7.8 Hz, 2H), 2.39 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([N+:14]([O-])=[O:15])[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[Al]>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[N:14][OH:15])[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C=C(C)[N+](=O)[O-])cc1
Agent: [Al]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C)=NO)cc1
Yield: 58.5 %

Procedure:
1-(4-Carbomethoxyphenyl)-2-nitroprop-1-ene (31.0 g) in tetrahydrofuran (900 ml) was stirred with aluminium amalgam, made in the usual way from aluminium (13.5 g) and mercuric chloride (6.9 g). The mixture was cooled in ice and stirring was continued until reaction was complete. The slurry was filtered through celite and the filtrate was evaporated to give a cream solid (17.0 g). τ (CDCl3) 8.27 (3H, s), 6.22 (2H, s), 6.13 (3H, s), 2.63 (2H, d, J=8 Hz), 1.95 (2H, d, J=8 Hz).
Reaction SMILES: C([NH:8][C:9]([CH3:22])([CH3:21])[CH2:10][O:11][CH:12]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:13]1([CH3:20])[CH3:19])(OC(C)(C)C)=O.O.[OH-].[K+]>FC(F)(F)C(O)=O>[NH2:8][C:9]([CH3:22])([CH3:21])[CH2:10][O:11][CH:12]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:13]1([CH3:20])[CH3:19]
Reactant: CC(C)(COC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)COC1C(C)(C)CCC1(C)C
Reaction time: 8 h

Procedure:
N-Boc-1-(2-amino-2-methylpropoxy)-2,2,5,5-tetramethyl cyclopentane is dissolved in trifluoroacetic acid and stirred overnight. The solution is poured into 0 water and neutralized with 20% aqueous KOH. The mixture is extracted with ethyl acetate, dried over MgSO4, filtered and evaporated to give 1-(2-amino-2-methylpropoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: [Cl:1][C:2]1[C:6]([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[NH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[OH:26]O>C(O)(=O)C>[Cl:1][C:2]1[C:6]([S:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:26])=[O:8])=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[NH:4][C:3]=1[C:22]([F:24])([F:23])[F:25]
Reactant: OO
Reactant: O=S(c1ccccc1)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Cl
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Cl
Temperature: 50 °C
Reaction time: 7 h

Procedure:
A mixture of 3-chloro-5-(p-chlorophenyl)-4-(phenylsulfinyl)-2-(trifluoromethyl)pyrrole (0.335 g, 0.83 mmol) and 30% hydrogen peroxide solution (0.28 mL, 2.49 mmol) in acetic acid is stirred at 50° C. for 7 hours, cooled and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid which is washed with water and dried to give the title product as a colorless solid (mp 158°-161° C.).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:27])[C@@H:6]([N:18]1[C:24](=[O:25])[CH2:23][CH2:22][NH:21][C@H:20]([CH3:26])[CH2:19]1)[CH2:7][CH2:8][N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1.[Cl:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>>[CH3:3][O:4][C:5](=[O:27])[C@@H:6]([N:18]1[C:24](=[O:25])[CH2:23][CH2:22][N:21]([C:36](=[O:37])[NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=2)[C@H:20]([CH3:26])[CH2:19]1)[CH2:7][CH2:8][N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)NCCC1=O
Agent: Cl
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(C(=O)Nc2cccc(Cl)c2)CCC1=O
Yield: 59 %

Procedure:
In analogy to the procedure described in example 58F, (S)-4-((S)-4-hydroxy-6-aza-spiro[2. 5]oct-6-yl)-2-((R)-3-methyl-7-oxo-[1,4]diazepan-1-yl)-butyric acid methyl ester dihydrochloride and 3-chlorophenyl isocyanate gave the title compound in 59% yield as off-white solid. MS: 506.2 (MH+, 1Cl).
Reaction SMILES: ClCCl.CS(C)=O.C(N(C(C)C)CC)(C)C.[OH:17][C@@H:18]([C@@H:29]([NH:34][C:35](=[O:52])[C@@H:36]([NH:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:30][CH2:31][CH2:32][CH3:33])[C:19]([NH:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[OH:28])=[O:20]>CS(C)=O>[O:20]=[C:19]([NH:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])[C:18](=[O:17])[C@@H:29]([NH:34][C:35](=[O:52])[C@@H:36]([NH:41][C:42]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:43])[CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)C(=O)N[C@H]1CCCCC1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 79.7 %

Procedure:
Under argon gas stream, to 4 ml of an anhydrous dimethylsulfoxide-dichloromethane (1:1) solution containing 567 mg (3.6 mmol) of sulfur trioxide pyridine complex salt were successively added dropwise at 0° C. 0.62 ml (3.6 mmol) of diisopropylethylamine, and then, 2 ml of an anhydrous dimethylsulfoxide solution containing 150 mg (0.3 mmol) of (2S)-N-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-4-methyl-2-[N-(phenylmethoxycarbonyl)amino]pentanamide, and the mixture was stirred at the same temperature for 5 hours. After completion of the reaction, 25 ml of ice-water was added to the reaction mixture, and the resulting mixture was extracted with 20 ml of ethyl acetate three times. The organic layers were combined, washed successively with 50 ml of a 10%-aqueous citric acid solution, 50 ml of a saturated aqueous sodium hydrogen carbonate solution, and then 50 ml of a saturated NaCl solution, dried over anhydrous sodium sulfate, and then, concentrated under reduced pressure. The residue was applied to neutral silica gel column chromatography, and eluted by a hexane-ethyl acetate (11:9) eluent to obtain 120 mg of the title compound, and further recrystallized from 5 ml of ethyl acetate-hexane (3:2) to obtain 90 mg (Yield: 60.5%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[OH:11][CH2:12][C:13](=O)[CH3:14]>>[OH:11][CH2:12][CH:13]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:10])=[C:8]([F:9])[C:2]=1[F:1])[CH3:14]
Reactant: CC(=O)CO
Reactant: Nc1ccc(F)c(F)c1F
Product: CC(CO)Nc1ccc(F)c(F)c1F

Procedure:
2,3,4-trifluoroaniline was reductively alkylated in the presence of hydroxyacetone using a sulfided palladium on carbon catalyst. 30 g of 5% Pd/C catalyst (50% H2O)) was slurried in 200 ml of absolute methanol. The mixture was allowed to settle and 90-95% of the liquid was decanted. This process was repeated three times. 2,3,4-Trifluoroaniline (118 g, 0.8 mole) was charged into a glass autoclave liner containing the catalyst. Hydroxyacetone (80 g, 1.08 mole) was then added and the mixture was purged with nitrogen. Hydrogenation was initiated at 65° C. and continued to a maximum temperature of 107° C. Hydrogen uptake continued for one hour between 430 and 450 psi at which time 75% of the alkylated product (3) was obtained with the remainder being unreacted 2,3,4-trifluoroaniline and hydroxyacetone.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[S:15])[CH:9]2[CH3:16])([O:3][CH2:4][CH3:5])=[O:2].[Cl:17]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:17][C:9]1([CH3:16])[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:7]=2)[NH:11][C:10]1=[S:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ccc2c(c1)C(C)C(=S)N2
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)C(C)(Cl)C(=S)N2

Procedure:
A solution of 5-carboethoxy-3-methylthiooxindole (1.50 g, 7 mmol) and N-chlorosuccinimide (1.25 g, 9.3 mmol) in methylene chloride (150 ml) was stirred at room temperature for 24 hours. The solvent was removed in vacuo, yielding crude 3-chloro-5-carboethoxy-3-methylthiooxindole and the residue was dissolved in tetrahydrofuran and added to a vigorously stirred slurry of red mercuric oxide (1.53 g, 7 mmol) and boron trifluoride etherate (1.00 g, 7 mmol) in 100 ml of 50 percent aqueous tetrahydrofuran. After stirring at room temperature for 1 hour, the red solution was extracted with chloroform. The organic extracts were dried over anhydrous magnesium sulfate, filtered, evaporated, and the residue was chromatographed on silica gel. Elution with chloroform gave 5-carboethoxyisatin (860 mg, 56%) as a yellow solid, mp 205°-207° (recrystallized from ether), ir (KBr) 3265 (NH), 1765 (ester C=O), 1750 (C=O), and 1700 cm-1 (amide C= O); nmr (DMSO-d6) π -1.00 (1H, b, s, NH), 1.80 (d of d, 1H, J4,6 =2 Hz, J6,7 =9 Hz, H6), 1.90 (d, 1H, J4,6 =2H3, H4), 3.20 (d, 1H, J6,7 =9Hz, H7), 5.65 (q, 2H, CO2CH2CH3), and 8.60 (t, 3H, CO2CH2CH3); mass spectrum m/e obs. 219.0534 (calc. 219.0531).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([N:26]([CH3:34])[CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].CO.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.C(O)C.C(Cl)(Cl)Cl.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>[CH3:34][N:26]([CH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:24]1[CH:23]=[N:22][CH:21]=[C:20]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[N:25]=1
Reactant: CN(CC1CCOCC1)c1cncc(Cl)n1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(CC1CCOCC1)c1cncc(-c2cnc3[nH]ccc3c2)n1
Temperature: 80 °C

Procedure:
A stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (100 mg, 0.409 mmol) and 6-chloro-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (69) (90 mg, 0.409 mmol) in toluene (8 mL) and ethanol (2 ml) was degassed and purged under nitrogen for 10 min followed by the addition of Cs2CO3 (260 mg, 0.819 mmol, 2.0 eq) and Pd(PPh3)4 (14 mg, 0.022 mmol, 0.03 eq) and the reaction mixture was degassed and purged again for 15 min. The resulting reaction contents were heated at 80° C. overnight under sealed condition. After completion of the reaction the mixture was diluted with chloroform and filtered through Celite and the organic layer was distilled off to get the crude product. The crude was passed through neutral alumina eluting with 1-2% MeOH/CHCl3 to give off white colored solid N-methyl-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine 143 in 9 mg quantity. 1H NMR (400 MHz, CDCl3) δ: 9.05 (s, 1H), 8.97 (d, J=1.95, 1H), 8.53 (d, J=1.95, 1H), 8.34 (s, 1H), 7.94 (s, 1H), 7.36 (s, 1H), 6.60 (d, J=3.29, 1H), 4.01 (s, 2H), 3.56 (d, 2H), 3.21 (s, 3H), 3.01 (m, 4H), 2.24 (m, 2H), 2.22 (s, 1H); MS m/z 324.1 (M+H)+.