Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:11][CH3:12])=[CH:6][C:5]=1[O:13][CH3:14].[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=2[N:21]=1.[C:31](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][O:2][C:3]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]2[N:11]([CH3:31])[C:12]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:30])([F:28])[F:29])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:10][C:8]=2[CH:9]=1)=[O:15]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CNc1cc(OC)c(C(=O)OC)cc1N
Solvent: ClCCCl
Product: COC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1OC
Yield: 50.5 %

Procedure:
6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (80 mg) was prepared by following General Procedure D starting from 5-amino-2-methoxy-4-methylamino-benzoic acid methyl ester (95 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (82 mg), 1,1′-thiocarbonyldiimidazole (90 mg), and EDC (108 mg). LC/MS: m/z 453.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.24, (s, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.71 (d, 1H), 7.36 (d, 1H), 7.24 (s, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.64 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH2:3][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5]1.[C:12]1(C)C=C(C)C=C(C)C=1.Cl>CO>[CH3:12][O:9][C:8](=[O:10])[CH2:7][C:4]1([CH2:3][C:2](=[O:1])[CH3:11])[CH2:6][CH2:5]1
Reactant: CC(=O)CC1(CC(=O)O)CC1
Reactant: Cc1cc(C)cc(C)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CC1(CC(C)=O)CC1

Procedure:
To a solution of 4.9 g crude [1-(2-oxo-propyl)-cyclopropyl]-acetic acid (31 mmole) in 73.5 ml methanol are added 1 ml of mesitylene (GC standard) and 2.5 ml of conc. hydrochloric acid. The mixture is heated to reflux for 1 hour and then concentrated to dryness. 40 ml of water are added to the residue and the resulting mixture is extracted with 100 ml of methyl tert-butyl ether in two portions. The combined organic phases are concentrated to dryness. The resulting crude product is directly used in the next step (spiro[2.5]octane-5,7-dione).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17].O>ClCCl.CC(O)C>[OH:17][CH2:16][C:15]([NH:14][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[CH3:1])([CH3:19])[CH3:18]
Reactant: CC(C)(N)CO
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1c(C(=O)NC(C)(C)CO)cccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A solution of 2-methyl-3-nitrobenzoyl chloride, 0.2 mol, (U.S. Pat. No. 4,065,477) in dichloromethane is added to 0.4 mol of 2-amino-2-methyl-1-propanol (Aldrich Chemical Company) with ice cooling. The mixture is allowed to stand overnight, water added and the solid filtered to give 20.8 g. The organic layer is washed with water, separated and evaporated to give 28.1 g. The two crops of material are combined and dissolved in 2-propanol. The 2-propanol solution is concentrated to give 40.2 g of N-(2-hydroxy-1,1-dimethylethyl)-2-methyl-3-nitrobenzamide; mp 144°-145° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=O)=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:29])([F:28])[F:27])([CH3:3])[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C([BH3-])#N.[Na+].[Cl:41]C(Cl)C>CO.C(O)(=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH2:24][N:30]2[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]2)=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:28])([F:29])[F:27])([CH3:3])[CH3:2].[ClH:41]
Reactant: CC(C)Oc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C(F)(F)F
Reactant: O=C(O)C1CNC1
Reactant: CC(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2onc3c2CCc2cc(CN4CC(C(=O)O)C4)ccc2-3)cc1C(F)(F)F
Product: Cl
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 18 %

Procedure:
To 3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 14C, 0.06 g, 0.149 mmol) in methanol (2 mL) and dichloroethane (2 mL) was added azetidine-3-carboxylic acid (0.018 g, 0.179 mmol) followed by 5 drops of acetic acid. The contents were heated at 70° C. for 1 h. The reaction mixture was then cooled to room temperature and sodium cyanoborohydride (0.011 g, 0.179 mmol) was added in one portion at room temperature. The turbid reaction mixture became clear after 15 min. at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting white solid was partitioned between dichloromethane (20 mL) and water (10 mL). The cloudy dichloromethane layer was separated, washed with brine (2×10 mL), dried over sodium sulfate and concentrated. To the resulting semi-solid was added methanol (3 mL) and the contents were triturated and filtered. The solid was combined with the filtrate and subjected to prep. HPLC. Fractions corresponding to the product were collected and concentrated. To the solid was added acetonitrile (2 ml) and 2 mL of 6N hydrochloric acid (aq). The contents were heated at 70° C. for 30 min. The reaction mixture was concentrated, azeotroped with THF (2×2 mL) and freeze dried using acetonitrile (0.5 mL) and water (1 mL) to yield 1-((3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, hydrochloric acid (0.017 g, 0.027 mmol, 18% yield) as a pale yellow solid. LC/MS M+1=487.1; 1H NMR (400 MHz, MeOD) δ ppm 7.95-8.03 (3H, m), 7.45-7.58 (2H, m), 7.39 (1H, d, J=8.8 Hz), 4.31-4.53 (6H, m), 3.67-3.79 (1H, m), 3.04-3.15 (4H, m), 1.40 (6H, d, J=6.2 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13]C(N)=O>C1(C)C=C(C)C=C(C)C=1.P(O)(O)O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(N)=O
Agent: OP(O)O
Solvent: Cc1cc(C)cc(C)c1
Product: NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
334 g (2.0 mol) of 4-nitrobenzoic acid, 120 g (2.0 mol) of urea and 2.0 g of phosphorous acid are heated in 1000 ml of mesitylene with stirring at from 158° C. to 163° C. for 8 h. After cooling to 25° C. the solid is filtered off with suction and washed with 200 ml of mesitylene. The filter cake is introduced into 1000 ml of water, the mixture is adjusted to a pH of 12 using aqueous sodium hydroxide solution, and is subjected to steam distillation. Subsequently the solid is filtered off with suction and dried at 100° C. 301.2 g of 4-nitrobenzamide are obtained, having a melting point of from 191° to 194° C. This corresponds to a yield of 90.7% of theory. By acidification of the aqueous mother liquor to pH 2, 12.5 g of 4-nitrobenzoic acid (3.7% of theory) are obtained which can be employed again in a subsequent batch.
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[N+:27]([O:30][CH:31]([CH2:35][O:36][N+:37]([O-:39])=[O:38])[CH2:32][CH2:33]O)([O-:29])=[O:28].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([O:10][CH2:33][CH2:32][CH:31]([O:30][N+:27]([O-:29])=[O:28])[CH2:35][O:36][N+:37]([O-:39])=[O:38])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Reactant: O=[N+]([O-])OCC(CCO)O[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC/C(=C(\C(=O)OCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 1.72 g of (2Z)-4-(acetyloxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid in 30 mL of CH2Cl2 at 0° C. was added 750 mg of 3,4-bis(nitrooxy)butyl alcohol, 560 mg of DMAP and 880 mg of EDCI. The mixture was stirred at RT for 2 h then quenched by addition of NH4Cl sat., extracted with EtOAc, washed with NaHCO3 sat., brine and dried over sodium sulfate. Purification by flash chromatography afforded 930 mg of the titled compound as a white solid. 1H NMR (acetone-d6, 500 MHz): δ 7.77 (d, 2H), 7.43 (d, 2H), 7.17-7.15 (m, 3H), 7.08 (dd, 2H), 5.56-5.52 (m, 1H), 5.22 (s, 2H), 4.95 (dd, 1H), 4.69 (dd, 1H), 4.47-4.41 (m, 2H), 3.05 (s, 3H), 2.32-2.19 (m, 2H), 1.89 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:19])[CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:27]([O:29][CH3:30])=[O:28]>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[N:6]([C:27]([O:29][CH3:30])=[O:28])[C@@H:7]([CH3:19])[CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: COC(=O)Cl
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2cc(Br)ccc2N1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: COC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A 100-mL round bottom flask fitted with nitrogen inlet and magnetic stir bar was charged with (S)-tert-butyl 7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (4.95 g, 15.13 mmol), 1,2-dichloroethane (50 mL), and pyridine (2.45 mL, 30.3 mmol). The reaction was cooled to 0° C. and methyl chloroformate (1.758 ml, 22.69 mmol) was added slowly. The reaction mixture stirred at 0° C. for 30 min and was then warmed to room temperature. After 2 h the reaction was diluted with 1,2-dichloroethane (20 mL) and washed with 1 M aqueous HCl solution (25 mL). The organic was concentrated under reduced pressure to afford (S)-4-tert-butyl 1-methyl 6-bromo-2-methyl-2,3-dihydroquinoxaline-1,4-dicarboxylate (5.83 g, 100%) as an amber oil. The material was used without further purification. MS (ESI, pos. ion) m/z 385 [M+1]+.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH2:13][O:14]C(=O)C)[CH2:10][C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[O-].[Na+]>CO>[Si:1]([N:8]1[CH:11]([CH2:12][CH2:13][OH:14])[CH2:10][C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OCCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CCO
Reaction time: 2 h
Yield: 45.3 %

Procedure:
1-(t-butyldimethylsilyl)-4-(2-acetoxyethyl)-2-azetidinone (1.94 g, 7.15 mmol) is dissolved in anhydrous methanol (20 ml) cooled to 0° and a solution of NaOMe (0.36 mmol) in MeOH (0.5 ml) is added to the mixture stirred at 0° for 2 hours. HOAC (0.1 ml) is added the mixture is evaporated under vacuum and the residue is taken up in CH2Cl2 ; washed with water, 5% NaHCO3, dried and evaporated to a pale yellow oil. This is chromatographed on silica gel using EtOAc as eluant, to give 1-(t-butyldimethylsilyl)-4-(2-hydroxyethyl)-2-azetidinone 0.743 g (45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C@@H:12]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C@H:11]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH:10]([CH2:44][O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[O:9]2)=[CH:4][C:3]=1CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:76]([Br:80])(Br)(Br)Br>O1CCCC1>[Br:80][CH2:76][C:3]1[CH:4]=[C:5]([C@H:8]2[C@@H:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C@@H:12]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C@H:11]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH:10]([CH2:44][O:45][CH2:46][C:47]3[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=3)[O:9]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(COCC2O[C@@H](c3ccc(Cl)c(CO)c3)[C@@H](OCc3ccc(OC)cc3)[C@@H](OCc3ccc(OC)cc3)[C@@H]2OCc2ccc(OC)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COCC2O[C@@H](c3ccc(Cl)c(CBr)c3)[C@@H](OCc3ccc(OC)cc3)[C@@H](OCc3ccc(OC)cc3)[C@@H]2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of the product from step D (0.36 g, 0.46 mmol) in tetrahydrofuran (5.0 mL) at 0° C. was added triphenylphosphine (0.36 g, 1.38 mmol), followed by dropwise addition of a solution of carbon tetrabromide (0.46 g, 1.38 mmol) in tetrahydrofuran (5.0 mL). The reaction mixture was allowed to warm to room temperature and stirred for 8 hours. The reaction solution was then quenched by addition of methanol and stirred for 15 minutes at room temperature. The resultant mixture was concentrated to dryness and the residue obtained was purified by flash column chromatography (eluent: hexanes/ethyl acetate 95:5 to 60:40) to give (2S,3R,4R,5R)-2-(3-(bromomethyl)-4-chlorophenyl)-3,4,5-tris(4-methoxybenzyloxy)-6-((4-methoxybenzyloxy)methyl)tetrahydro-2H-pyran (0.31 g, partial pure) as a light yellow oil, which was used in the next step without further purification.
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1)([O-:9])=[O:8].[Br:21]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:21][CH2:19][CH2:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1
Reactant: CCCC(O)c1ccc([N+](=O)[O-])cc1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(CCCCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
Part A. Pyridine (0.66 mL, 8.21 mmol) was added slowly to an ice cooled solution of 4-nitrophenyl butanol (1.0 gm,5.13 mmol) and dibromotriphenylphosphorane (2.8 gm, 6.66 mmol) in 20 mL acetonitrile under a nitrogen atmosphere. The reaction solution was stirred for 1/2 hr and allowed to warm to ambient temperature and stir overnight. The reaction was concentrated invacuo to give a residue. The residue was filtered through a short plug of silica gel and then the product was purifed by flash chromatography on silica gel eluting methylene chloride:hexane (v:v, 50:50), to give 1-bromo-4-(4-nitrophenyl)butane as an oil 1.3 gm (98%) MS 275(M+NH4)+ 1 H NMR (CDCl3): 8.2(d, 2H), 7.4(d, 2H), 3.4(t, 2H), 2.8(t, 2H), 1.8-2.0(m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:17][CH2:16][CH2:15][N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:13]2)=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][NH:34][CH3:35]>O1CCCC1.C(#N)C>[CH3:33][N:34]([CH3:35])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:17][CH2:16][CH2:15][N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:13]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: CNC
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC(=O)CCl)cc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC(=O)CN(C)C)cc2)C1
Yield: 125.2 %

Procedure:
A solution of 2-chloro-N-{4-[(2S)-4-((1R)-1-phenylethyl)morpholin-2-yl]phenyl}acetamide (0.9 g, 2.5 mmol), potassium carbonate (1.72 g, 12.5 mmol), and dimethylamine hydrochloride (1.00 g, 12.5 mmol) in tetrahydrofuran (40 ml) and acetonitrile (80 ml) was stirred at 95° C. for 10 hours. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give N2,N2-dimethyl-N1-{4-[(2S)-4-((1R)-1-phenylethyl)morpholin-2-yl]phenyl}glycinamide (1.15 g, quant.) as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20]1>CS(C)=O>[CH2:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@@H:20]1[CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cl[C@H]1CCCN(CCc2ccccc2)C1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.8 %

Procedure:
Sixty-percent sodium hydride (608 mg, 15 mmols) was washed with petroleum ether, and then suspended in 50 ml of dimethyl sulfoxide. To the suspension were added 1.5 g (7.6 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 1 hour. To this reaction solution was added dropwise a solution of 3.2 g (14 mmols) of (S)-(+) -3-chloro-1-phenethylpiperidine[[α]D25=+10.9° (c=1.0, ethanol)] in 30 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 2.5 hours and at 45° C. for 6 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:2. This mixed solvent was distilled off under reduced pressure to give 3.5 g of (R)-(+)-5,11-dihydro-5-[1-phenethyl-2-pyrrolidinyl-methyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 91%.
Reaction SMILES: [C:1]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH3:4])=[O:2].Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]>C1C=CC=CC=1>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:27](=[O:28])[CH:26]=[CH:5][C:1]([O:3][CH3:4])=[O:2]
Reactant: O=C(CBr)c1ccccn1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COC(=O)C=CC(=O)c1ccccn1

Procedure:
A solution of 33.4 g of carbomethoxymethylene triphenylphosphine [Helv. Chim. Acta. 40, 1242 (1957)] in 500 ml of dry benzene under nitrogen is treated with 10 g of 2-(bromoacetyl)pyridine and heated at reflux temperature for 2 hours. The reaction mixture is cooled and filtered to remove carbomethoxymethyl triphenylphosphonium bromide. The filtrate, containing triphenylphosphine, is treated with methyl bromoacetate and heated at reflux temperature for 2 hours. Cooling and filtration removes additional phosphonium salt. The filtrate is concentrated in vacuo yielding the title compound.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2ccc(F)cc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccc(F)cc3)CC2)cc1
Yield: 45.4 %

Procedure:
0.5 g (0.00239 mol) of 1-(4-fluoro-benzyl)-piperidin-4-ol and 0.67 ml (0.00478 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.632 ml (0.00478 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.355 g (59%) of 1-(4-fluoro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a yellow oil. MS: me/e=328 (C2H23FNO2+).
Reaction SMILES: [CH3:1][S:2]([C:5]1(C(N)=O)[NH:9][N:8]=[CH:7][S:6]1)(=[O:4])=[O:3].[CH2:13]([N:15](CC)CC)C.O>C(Cl)(Cl)(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[S:6][C:7]([C:13]#[N:15])=[N:8][N:9]=1)(=[O:3])=[O:4]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)C1(C(N)=O)NN=CS1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1nnc(C#N)s1

Procedure:
A mixture of 20 ml titanium tetrachloride in 50 ml carbon tetrachloride was added dropwise at 0° to 5° C. upon stirring to 350 ml tetrahydrofuran. Subsequently, 2-methylsulfonyl-1,3,4-thiadiazole-2-carboxamide was added in batches at room temperature in an amount of 20.7 g. After continued stirring for 1 hour a solution of 50 ml triethylamine in 50 ml tetrahydrofuran was dropped into the mixture within a period of 60 minutes. The mixture was then reacted with 50 ml water, the total mixture was extracted with chloroform and the organic phase was dried over magnesium sulfate and the solvent was distilled off in a vacuum. The residue was taken up in acetic acid ethylester, subjected to boiling with activated carbon, filtered and concentrated. The residue was crystallized from chloroform/tetrahydrofuran (3:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])C)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:25]=1.[CH2:26]([N:28](CC)CC)C.CN=C=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([NH:28][CH3:26])=[O:24])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:25]=1
Reactant: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reactant: CCN(CC)CC
Agent: CN=C=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 25 °C

Procedure:
To a mixture of 2.03 g (6.53 mmole) of 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5 H-benzo[5,6]cyclohepta[1,2-b]pyridine and 1.0 mL of triethylamine in 30 mL of dry THF at -10° C. and under a nitrogen atmosphere was added dropwise over 10 minutes 0.40 mL (6.78 mmole) of methylisocyanate. The mixture was slowly warmed to room temperature. After 4 hours it was poured in water and extracted 3× with CH2Cl2. The organic portions were combined, dried over MgSO4, filtered and concentrated in vacuo to afford a product which was recrystallized from CH2Cl2 ethyl acetateexanes to give 1.70 g of the title compound as white crystals. (m.p. 194.5°-196° C.).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1.Cl>C(Cl)Cl.N1C=CC=CC=1.CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14]([NH:32][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 0 °C

Procedure:
Procedure-B: 2-(4-cyclopropanesulfonylphenyl)-2-(2,4-difluorophenoxy)acetic acid (obtained in step III) was dissolved in DCM. To this solution was added DMF and cooled to 0° C., followed by the addition of oxalyl chloride under stirring. To this mixture, a solution of 2-aminothiazole and pyridine in DCM was added drop wise at 0° C. and was stirred further for 4 h. at room temperature. The reaction mixture was poured into 1N aqueous HCl under stirring, organic layer was again washed with 1N HCl, followed by 5% brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to get the crude compound which was purified by flash chromatography to get the title product.