Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.FC(F)(F)C([NH:48][C@H:49]1[CH2:53][CH2:52][NH:51][CH2:50]1)=O>CS(C)=O.COC(C)(C)C>[NH2:48][C@H:49]1[CH2:53][CH2:52][N:51]([C:21]2[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)([CH3:34])[CH3:33])=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])[CH:22]=2)[CH2:50]1
Reactant: O=C(N[C@H]1CCNC1)C(F)(F)F
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@H](N)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 52 h
Yield: 60 %

Procedure:
A mixture of 975 mg (1.83 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 1.26 g (9.15 mmol) potassium carbonate and 800 mg (3.66 mmol) (S)-3-(trifluoro-acetamido)pyrrolidine hydrochloride in 10 ml dimethyl sulfoxide was stirred at 130° C. for 52 h. After cooling to room temperature the reaction mixture was diluted with 30 ml tert-butyl methyl ether and washed with 20 ml of water and 10 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was dissolved in 25 ml of a 2 N solution of ammonia in ethanol. The solution was stirred at room temperature for 18 h. The reaction mixture was concentrated and purified by flash chromatography to give 640 mg (60%) of the title compound as a light brown foam.
Reaction SMILES: N(OCC(C)C)=O.N[C:9]1[CH:32]=[C:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:30]=[CH:29][C:10]=1[O:11][C:12]1[C:21]([Cl:22])=[C:20]2[C:15]([CH:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:18][O:19]2)=[CH:14][C:13]=1[Cl:28].O>CN(C=O)C>[C:36]([O:35][C:33]([C:31]1[CH:32]=[CH:9][C:10]([O:11][C:12]2[C:21]([Cl:22])=[C:20]3[C:15]([CH:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:18][O:19]3)=[CH:14][C:13]=2[Cl:28])=[CH:29][CH:30]=1)=[O:34])([CH3:37])([CH3:38])[CH3:39]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1N)c2Cl
Agent: CC(C)CON=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1)c2Cl
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
To a 2 L four neck round bottomed flask equipped with a thermocouple, a condenser, and an addition funnel were added DMF (200 ml) and isobutyl nitrite (30.8 ml, 260 mmol). The mixture was heated to 70° C. To the preheated mixture was added a solution of ethyl 7-(2-amino-4-(tert-butoxycarbonyl)phenoxy)-6,8-dichlorochroman-4-carboxylate (50.2 g, 104 mmol) in DMF (200 ml) over a period of 15 minutes. The reaction was slightly exothermic and gas evolution was observed. The mixture was stirred at 70° C. for 1.5 hours and cooled to ambient temperature. The mixture was transferred to a separatory funnel containing 2 liters of water. The mixture was extracted with EtOAc (500 ml, 2×250 ml). The combined extracts were washed with water (500 ml, 2×250 ml) and brine (250 ml), dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (EtOAc in hexanes gradient) to provide 45.1 g of the title compound as a very viscous oil (93%).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9](Cl)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.[Cl:17][C:18]1[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>CCOCC>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([NH:24][C:21]2[CH:22]=[N:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Reactant: Nc1ccc(Cl)nc1
Solvent: CCOCC
Product: O=C(NC(Nc1ccc(Cl)nc1)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Yield: 65 %

Procedure:
A mixture of 4-bromoaniline 118 (5.0 g, 24.2 mmol) and chloral (4.7 mL, 48.2 mmol) in THF (4 mL) was heated for 30 minutes. Solvent was removed under vacuum. 4-Bromo-N-(2,2,2-trichloro-1-hydroxyethyl)benzamide 121 (1.26 g, 3.62 mmol) in chloroform (15 mL) and PCl5 (0.8 g, 3.65 mmol) was heated at 50° C. for 30 minutes. The product was isolated from a standard aqueous work-up and extraction to produce 4-bromo-N-(1,2,2,2-tetrachloroethyl)benzamide. 4-Bromo-N-(1,2,2,2-tetrachloroethyl)benzamide (1.21 mmol) in ether (50 mL) was reacted with 6-chloropyridin-3-amine (0.32 g, 2.44 mmol) at room temperature for 18 hours. The mixture was subjected to a standard aqueous work-up and extraction. Chromatography on silica gel (7:3 hexanes:CH2Cl2) gave 4-bromo-N-(2,2,2-trichloro-1-(6-chloropyridin-3-ylamino)ethyl)benzamide (Compound-42, 0.36 g, 65%). 1H NMR (300 MHz, d4-methanol): δ=7.99 (dd, J=3.0, 0.6 Hz, 1H), 7.74 (d, J=9.0 Hz, 2H), 7.65 (d, J=9.0 Hz, 2H), 7.36 (dd, J=9.0, 3.3 Hz, 1H), 7.26 (dd, J=8.7, 0.6 Hz, 1H), 6.36 (s, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[O:6][C:5](=[O:7])[NH:4][C@@H:3]1[C:8]([OH:10])=O.[N+]([O-])(O)=O.[N+:15]([O:18][CH2:19][CH2:20][NH2:21])([O-:17])=[O:16]>>[N+:15]([O:18][CH2:19][CH2:20][NH:21][C:8]([C@@H:3]1[C@@H:2]([CH3:1])[O:6][C:5](=[O:7])[NH:4]1)=[O:10])([O-:17])=[O:16]
Reactant: C[C@H]1OC(=O)N[C@@H]1C(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: C[C@H]1OC(=O)N[C@@H]1C(=O)NCCO[N+](=O)[O-]
Yield: 14.2 %

Procedure:
A procedure similar to that described in Example 19 was repeated, but using 180 mg of (4S,5R)-5-methyl-2-oxooxazolidine-4-carboxylic acid and 230 mg of N-(2-nitrooxyethyl)amine nitrate, after which the product was recrystallized from methylene chloride, to obtain 41 mg of the title compound as colorless needles, melting at 81.5°-82.5° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:9]([C:11]([N:13]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:14]3[CH2:19][C@@H:18]([C:20]4[NH:24][CH:23]=[N:22][N:21]=4)[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)=[O:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[ClH:48]>>[ClH:48].[ClH:48].[F:1][C:2]1[C:7]2[N:8]([CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:9]([C:11]([N:13]([CH2:32][CH:33]([CH3:34])[CH3:35])[C@H:14]3[CH2:19][C@@H:18]([C:20]4[NH:24][CH:23]=[N:22][N:21]=4)[CH2:17][NH:16][CH2:15]3)=[O:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3nnc[nH]3)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](c3nnc[nH]3)C2)nc2cccc(F)c21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
tert-Butyl (3S,5R)-3-{{{7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (130 mg) was dissolved in 2M hydrogen chloride-ethyl acetate (3 ml), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated to give the object product (91 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][N:12]=[C:13]=[O:14]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:13]([NH:12][CH3:11])=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: C[C@@H](N)c1ccc(Br)cc1
Solvent: ClCCl
Product: CNC(=O)NC(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.5 g, 2.49 mmol) in anhydrous CH2Cl2 was added methyl isocyanate (0.15 mL, 2.49 mmol). The resulting solution was stirred at 25° C. overnight. CH2Cl2 was evaporate and residue partitioned between EtOAC and 1 N HCl. The organic layer was washed with H2O, brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (80% EtOAc in hexanes) to provide the desired product (0.60 g, 94%) as a white solid.
Reaction SMILES: CS([C:5]1(C)[C:8](=[C:9]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C@H:22]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)(=O)=O.[NH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1>ClCCl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C@@H:22]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:39]3[CH2:44][CH2:43][S:42][CH2:41][CH2:40]3)=[CH:32][CH:31]=2)[N:6]2[CH2:7][C:8](=[C:9]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=3)[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:5]2)=[CH:24][CH:25]=1
Reactant: C1CSCCN1
Reactant: CC1(S(C)(=O)=O)C(=C(c2cc(F)cc(F)c2)S(C)(=O)=O)CN1[C@@H](c1ccc(Cl)cc1)c1ccc(CCl)cc1
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CN3CCSCC3)cc2)C1)c1cc(F)cc(F)c1
Yield: 79.4 %

Procedure:
The operation is carried out as described in Example 87, starting with 0.05 g of methylsulfonyl methyl 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm3 of dichloromethane and 0.025 g of thiomorpholine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.038 g of 1-{(R*)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): from 2.60 to 2.75 (mt, 8H), 2.80 (s, 3H), 3.44 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=8.5 and 2.5 Hz, 1H), 6.97 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=[CH:16][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:20]=1.C1C2CCC3C=CC=CC=3SC=2C=C(C(O)=O)C=1>>[OH:18][CH2:17][C:14]1[CH:15]=[CH:16][C:10]2[CH:9]=[CH:8][C:7]3[CH:20]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=3[S:12][C:11]=2[CH:13]=1
Reactant: CSc1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2
Agent: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2
Product: CSc1ccc2c(c1)C=Cc1ccc(CO)cc1S2

Procedure:
Repeat the process of Example 1, substituting an equivalent quantity of 8-methylthiodibenzo[b,f]thiepin-3-carboxylic acid for the 10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid, to obtain the title product.
Reaction SMILES: C([C@@H]1COC(=O)[N:9]1[C:14](=[O:40])[C@H:15]([CH2:30][C:31]1[CH:36]=[C:35]([CH3:37])[C:34]([F:38])=[C:33]([CH3:39])[CH:32]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=1)C1C=CC=CC=1.[C-]#N.[K+].Cl.C1C[O:48]CC1.CO>>[OH:48][NH:9][C:14](=[O:40])[C@H:15]([CH2:30][C:31]1[CH:36]=[C:35]([CH3:37])[C:34]([F:38])=[C:33]([CH3:39])[CH:32]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=1
Reactant: Cc1cc(CCCCCC[C@@H](Cc2cc(C)c(F)c(C)c2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Reactant: C1CCOC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: Cc1cc(CCCCCC[C@@H](Cc2cc(C)c(F)c(C)c2)C(=O)NO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of (R)-4-Benzyl-3-[(S)-2-(4-fluoro-3,5-dimethyl-benzyl)-8-(4-fluoro-3-methyl-phenyl)-octanoyl]-oxazolidin-2-one (0.036 g, 0.0657 mmol) in 2.5 mL of THF/MeOH/50% NH2OH—H2O (2:2:1), was added KCN (0.001 g, 0.007 mmol). After stirring at room temperature for overnight, the reaction mixture was acidified with concentrated HCl to pH=2 and filtered. The product was isolated by RP-HPLC eluting with 20-100% acetonitrile (0.025% TFA)/water (0.025% TFA) to give the title compound as an off-white solid (0.005 g, 18% yield). LC-MS: tR=11.1 min, m/z 404 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 1.21-1.33 (m, 6H), 1.34-1.48 (m, 2H), 1.49-1.66 (m, 2H), 2.18 (s, 6H), 2.21 (s, 3H), 2.23-2.32 (m, 1H), 2.51 (t, J=7.32 Hz, 2H), 2.56-2.62 (m, 1H), 2.67-2.78 (m, 1H), 6.81 (d, J=6.74 Hz, 2H), 6.88 (t, J=9.37 Hz, 1H), 6.91-6.97 (m, 1H), 7.00 (d, J=7.03 Hz, 1H).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.[ClH:30]>[Pd].CO>[ClH:30].[C:24]1([C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]3[CH:15]([CH2:16][NH:8][CH2:9]3)[C:14](=[O:17])[CH2:13][CH2:12]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
150 g of (3aRS, 7aRS)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone, 1500 cm3 of methanol and 450 cm3 of 1N hydrochloric acid are added to 15 g of 10% palladium on carbon; the reaction mixture is hydrogenated, with stirring, at room temperature and under atmospheric pressure. The theoretical volume of hydrogen is absorbed after reacting for 5 hours; the reaction mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa); the residue is crystallized from 200 cm3 of ethanol; the crystals obtained are drained, washed with 50 cm3 of ethanol and dried. 110 g of (3aRS, 7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride are obtained; melting point 270° C., with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C1COCC1.O>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[N:9]([CH2:21][CH3:22])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:32])[CH3:31])=[CH:7][CH:6]=1)#[N:18]
Reactant: CC(=O)Cl
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1c(-c2ccc(NC(C)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Yield: 71.2 %

Procedure:
A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example 1Ga, step B in THF (3 mL) is cooled to 0° C. and treated with triethylamine (0.04 mL, 0.31 mmol) and acetyl chloride (0.02 mL, 0.29 mmol) and stirred, warming to room temperature overnight. The reaction mixture is then diluted with H2O and extracted with ethyl acetate (3×). The organic phase is washed with H2O and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-50%) to afford 57 mg (71%) of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]acetamide as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:32]([NH2:34])=[O:33])[CH:30]=4)[CH:25]=[CH:24]3)[CH2:19][CH2:18]2)=[CH:5][C:6]2[C:12](=O)[CH2:11][CH2:10][CH2:9][O:8][C:7]=2[CH:14]=1.Cl.[O:36]([NH2:38])[CH3:37].C([O-])(=O)C.[Na+].[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O1CCCC1.CO>[CH3:1][O:2][C:3]1[C:4]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:32]([NH2:34])=[O:33])[CH:30]=4)[CH:25]=[CH:24]3)[CH2:19][CH2:18]2)=[CH:5][C:6]2[C:12](=[N:38][O:36][CH3:37])[CH2:11][CH2:10][CH2:9][O:8][C:7]=2[CH:14]=1
Reactant: CON
Reactant: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)C(=O)CCCO2
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CON=C1CCCOc2cc(OC)c(CCN3CCC(n4ccc5ccc(C(N)=O)cc54)CC3)cc21
Temperature: 25 °C
Yield: 67.9 %

Procedure:
97 mg of 1-(1-(2-(8-methoxy-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamide was dissolved in a mixed solution consisting of 4 ml of methanol, 2 ml of tetrahydrofuran, and 2 ml of chloroform. Thereafter, 105 mg of methoxylamine hydrochloride and 103 mg of sodium acetate were added to the reaction solution, and the obtained mixture was then stirred at room temperature. At the midpoint of the reaction, 1 g of methoxylamine hydrochloride and 1 g of sodium acetate were further added thereto. After completion of the reaction, a 1 N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution, and chloroform were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was solidified from t-butyl methyl ether-ethyl acetate, so as to obtain 70 mg of the subject compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C@@H:33]([NH2:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C@@H:33]([NH:36][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Product: COc1ccc(F)cc1C(=O)c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)nc1N
Yield: 87.8 %

Procedure:
The same procedure was used as described in Example 9 starting from (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (400 mg, 1.18 mmol, Example 48) and (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (233 mg, 1.25 mmol, Astatech), to give (R)-3-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (447 mg). MS (M+H)+, 432.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:10]([O-:19])(=[O:18])C1C(=CC=CC=1)O.[Ag+:20]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O-:19])=[O:18])[C:4]=2[N:3]=[N:2]1.[Ag+:20]
Reactant: O=C([O-])c1ccccc1O
Reactant: c1ccc2[nH]nnc2c1
Agent: [Ag+]
Product: O=C([O-])c1cccc2[nH]nnc12

Procedure:
45 mL of a 20% aqueous solution of benzotriazole with a pH of about 6.5 were added with stirring to the aqueous dispersion of silver salicylate. A fine dispersion of silver benzotriazolate was obtained. The size of the silver benzotriazolate particles was ascertained by optical microscopy to be 1 to 2 μm.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:4]=1[N:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH3:6])=O.[C:21](=O)([O-])[O-].[K+].[K+].CI.CN(C=O)C.C(=O)(OC)OC.C[O-].[Na+].Cl>CN(C=O)C.CO.CCCCCC.C(OCC)(=O)C>[CH3:21][O:13][C:11]([C:10]1[CH2:9][CH2:8][CH2:7][N:5]([CH3:6])[C:4]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:3]=2[CH:1]=1)=[O:12]
Reactant: O=C([O-])[O-]
Reactant: CN(CCCCC(=O)O)c1ccc([N+](=O)[O-])cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Solvent: CCOC(C)=O
Product: COC(=O)C1=Cc2cc([N+](=O)[O-])ccc2N(C)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of 5-(2-formyl-4-nitro-N-methylanilino)pentanoic acid (3.0 g) in DMF (8.1 ml), potassium carbonate (1.6 g) and a solution of methyl iodide/DMF (1.8 g/1 ml) were added at room temperature, and the resulting mixture was stirred further for 2 hours. To the mixture, dimethyl carbonate (18 ml) and subsequently a solution of 28% sodium methoxide in methanol (5.0 g) were added and the resulting mixture was stirred at 50° C. for 2.5 hours. The mixture was allowed to cool to room temperature, and neutralized with 1N hydrochloric acid. After ethyl acetate extraction, the organic layer was washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was redissolved in hot isopropyl alcohol [IPA], and the solution was allowed to cool to room temperature, stirred at room temperature further for 1 hour, and at ice temperature for 0.5 hours. The precipitated crystal was collected by filtration, and washed with IPA. The crystal was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1 to 1/1), and subsequent concentration of the appropriate eluate gave yellow crystal of 8-nitro-1-methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylic acid methylester (2.3 g, yield 78%). mp. 127–129° C. 1H-NMR(CDCl3, δ, 300 MHz): 1.38–1.72(2H, m), 2.35–2.80(2H, m), 3.02(3H, s), 3.42–3.85(2H, m), 3.80(3H, s), 6.65(1H, d, J=9.4 Hz), 7.80(1H, s), 7.99–8.06(2H,m). Anal. Calcd for C14 H16 N2 O2: C,60.86; H,5.84; N,10.14. Found: C,60.79; H,5.81; N,9.98. IR (KBr, cm−1): 1708, 1255, 1191.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][CH2:29][C@H:30]1[CH2:34][O:33][C:32]([CH3:36])([CH3:35])[O:31]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C.C(#N)C>[I:25][CH2:28][CH2:29][C@H:30]1[CH2:34][O:33][C:32]([CH3:36])([CH3:35])[O:31]1
Reactant: II
Reactant: CC1(C)OC[C@H](CCO)O1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CC#N
Product: CC1(C)OC[C@H](CCI)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
Triphenyl phosphine (31.0 g, 118.21 mmol) and imidazole (8.05 g, 118.21 mmol) were dissolved in a mixed solution (400 ml) of diethyl ether-acetonitrile (3:1), iodine (30.0 g, 118.21 mmol) was added thereto under cooling on ice and the mixture was stirred at room temperature for 3 hours. The solution was cooled on ice again, a mixed solution (100 ml) of (4S)-(+)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (15 g, 98.51 mmol) in diethyl ether-acetonitrile (3:1) was added thereto and stirred at room temperature for 18 hours. A saturated sodium thiosulfate aqueous solution was added to the reaction solution under cooling on ice and stirred for a while. The solution was extracted with diethyl ether and the extract was washed with saturated sodium chloride solution. The solvent was removed under reduced pressure and the obtained residue was triturated by adding a mixed solvent of ether/hexane to remove the insoluble material by filtration. The filtrate was concentrated under reduce pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 23.1 g (92%) of the title compound in the form of a colorless clear oily product.
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)=O)CCC.CO.[NH3:31]>>[O:27]=[C:24]1[CH:25]=[CH:26][N:21]([C:17]2[C:16]([F:28])=[CH:15][C:14]([N:10]3[CH2:9][C@H:8]([C:6]([NH2:31])=[O:5])[O:12][C:11]3=[O:13])=[CH:19][C:18]=2[F:20])[CH2:22][CH2:23]1
Reactant: CCCCOC(=O)[C@H]1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Reactant: N
Solvent: CO
Product: NC(=O)[C@H]1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(5R)-3-[3,5-Difluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid butyl ester (Step 5, 200 mg, 0.50 mmol) is dissolved in a 2M solution of NH3 in MeOH (4 mL, 8 mmol). The resulting solution is stirred at room temperature for 3 h at which time the reaction mixture is concentrated under reduced pressure. The residue is washed with ether to give the title compound as an off white solid (139 mg, 82%), 1H NMR (300 MHz, DMSO) δ 7.89 (br s, 1H), 7.64 (br s, 1H), 7.54-7.38 (m, 3H), 5.07-4.98 (m, 2H), 4.26 (t, 1H), 4.01 (dd, 1H), 3.78 (t, 2H); MS for C15H13F2N3O4 m/z 338.4 (M+H)+.