Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[O:14]1>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:16]1[C:17](=[O:19])[O:18][C:13]([CH3:21])([CH3:12])[O:14][C:15]1=[O:20])([O-:3])=[O:2]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C(=Cc2cccc([N+](=O)[O-])c2)C(=O)O1

Procedure:
5-(3-Nitrobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione can be obtained in the following manner: a solution of 30.2 g of 3-nitrobenzaldehyde and 2,2-dimethyl-1,3-dioxane-4,6-dione in 400 cm3 of dimethylformamide is stirred for 18 hours at a temperature near to 20° C. The reaction mixture is diluted with 500 cm3 of ethyl acetate, washed five times with water, dried over magnesium sulphate, filtered and concentrated to dryness (1.2 kPa) to give an oil. This oil is crystallized in 100 cm3 of ethanol to give 26 g of 5-(3-nitrobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione in the form of a solid melting at 128° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl[CH:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N:28]1[C:27]2[CH:23]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[C:2]3[NH:10][CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH2:24][CH2:25][C:26]=2[CH:31]=[CH:30][CH:29]=1
Reactant: ClC1CCc2cccnc21
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2C2CCc3cccnc32)CC1
Yield: 68.3 %

Procedure:
A mixture of ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidine-carboxylate (0.0289 mol), 7-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.0289 mol) and potassium carbonate (0.0867 mol) in acetonitrile (250 ml) was stirred and refluxed for 48 hours and then brought to room temperature. The reaction was carried out again using the same quantities. The mixtures were combined, poured out into H2O and extracted with EtOAc. The organic layer was separated, washed with H2O, dried (MgSO4), filtered and the solvent was evaporated. The residue (25 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH NH4OH 97/3/0.5; 20-45 μm). Two fractions were collected and their solvents were evaporated, yielding 8 g of ethyl 4-[[1-(6,7-dihydro-5H-1-pyrindin-7-yl) 1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (interm. 22).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([CH2:27][S:28][C:29]3[S:30][CH:31]=[C:32]([CH3:34])[N:33]=3)=[C:23]([Cl:26])[CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:18]2[CH2:17][CH2:16][NH:15][CH2:21][CH2:20][C:19]=2[C:22]=1[CH2:27][S:28][C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1
Reactant: Cc1csc(SCc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1csc(SCc2c(Cl)ccc3c2CCNCC3)n1
Reaction time: 8 h
Yield: 98.3 %

Procedure:
Add TFA (19 mL) to a solution of 3-tert-butoxycarbonyl-7-chloro-6-(4-methyl-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.395 g, 0.93 mmol) in anhydrous DCM (19 mL) at room temperature and stir under nitrogen overnight. Concentrate the reaction mixture in vacuo and purify by SCX chromatography (10 g) eluting with DCM and then DCM/2M ammonia in methanol (1:1). Purify again by chromatography on silica gel (40 g) eluting with DCM/2M ammonia in methanol (1:0 to 9:1 gradient over 30 min; 35 mL/min) to obtain 7-chloro-6-(4-methyl-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.297 g, 99%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]([NH2:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH:11]([NH:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a cold solution of 2-fluoro-nitrobenzene (31.8 g, 0.225 mol) in ethanol (300 mL) cooled in an ice bath was added isopropylamine (54.0 mL, 0.634 mol), followed by the addition of a solution of potassium carbonate (31.1 g, 0.225 mol) in water (120 mL). The mixture was stirred at 0° C. for 1 h, then refluxed for 6 h. The reaction was terminated by cooling the mixture to ambient temperature, and evaporating it under reduced pressure yielding an orange residue. The residue was partitioned between ethyl ether (800 mL) and a brine solution (300 mL). The organic layer was dried and filtered, to provide the title intermediate (39 g) as an orange liquid. 1H-NMR (CDCl3, 300 MHz): δ (ppm) 8.06 (d, 1H), 7.30 (t, 1H), 6.74 (d, 1H), 6.48 (t, 1H), 3.73 (hept, 1H), 1.20 (d, 6H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][C:19]=1[C:20]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:21]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for example 9 from 1-(4-trifluromethylphenyl)piperazine (ABCR F07741NB, [30459-17-7] and 2-chloro-5-(methylsulfonyl)-benzoic acid (CAS: 89938-62-5); MS (m/e): 464.3 (M+NH4+).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C@@:8]12[C:24](=O)[CH2:23][CH2:22][C@H:21]1[C@H:20]1[C@@H:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=3[CH2:18][CH2:19]1)[CH2:10][CH2:9]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH2:1]=[C:24]1[CH2:23][CH2:22][C@H:9]2[C@H:10]3[C@H:11]([CH2:20][CH2:21][C@:8]12[CH3:7])[C:12]1[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=1[CH2:18][CH2:19]3
Reactant: CC(C)(C)[O-]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (100.03 g, 0.28001 mol) and potassium t-butoxide (31.42 g, 0.2800 mol) in anh. dimethylsulfoxide (DMSO, 320 mL) under argon was stirred in an oil bath (68°-81° C.) 1 h, after which estrone (15.14 g, 55.99 mmol) in anh. DMSO (320 mL) was added via syringe. See FIG. 17. Stirring was continued 1 h and the reaction allowed to cool. The mixture was poured into 800 mL of ice-1N hydrochloric acid and then extracted three times with 400 mL aliquots of ether. The combined organic extracts were washed with 350 mL of saturated sodium bicarbonate+400 mL of brine, dried over sodium sulfate, and flash filtered through a 58 mm high×84 mm dia. column of silica gel (200-40 mesh). Product continued eluting with additional ether. Concentration of appropriate fractions under reduced pressure and three-fold recrystallization from aqueous ethanol gave very fine white needles (11.47 g, 42.73 mmol, 76%), m.p. 134°-136° C., homogeneous to TLC (20% ethyl acetate/hexanes on silica gel, Rf 0.45). (NA-1994A-242B)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[C:4]2[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:3]=12.C(N(CC)C(C)C)(C)C.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.[Cl-].[Li+]>CN1CCCC1=O>[CH3:42][C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][CH:30]([NH:29][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[C:4]3[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:3]=23)[CH2:31][CH2:32]1)=[O:37])([CH3:40])[CH3:41]
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C

Procedure:
A solution of ethyl 4-chloro-1,6-diethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (14.8 g, 52.6 mmol, e.g. which can be as prepared in Intermediate 3, first or alternative preparation thereof) in N-methyl-2-pyrrolidinone (140 ml) was treated with N,N-diisopropylethylamine (22.9 ml, 131 mmol) followed by 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (11.6 g, 57.9 mmol, commercially available e.g. from AstaTech) and the mixture was heated at 120° C. for 24 hours. The reaction mixture was cooled and poured into aqueous lithium chloride solution (5% LiCl, 1 L) and the aqueous phase was extracted with ethyl acetate (3×250 ml). The combined organic extracts were dried (Na2SO4) and the solvent was evaporated. The residue, an oil, was purified by column chromatography using a column of silica gel (ART9385, 500 ml) made up in 4:1 hexane:ethyl acetate, eluting with 4:1 hexane:ethyl acetate (500 ml) and then 2:1 hexane:ethyl acetate until the product eluted. The fractions containing the product were pooled and the solvent was evaporated to give the title compound (18.55 g) as an oil which solidified on standing. LCMS m/z 446 [MH+]; TRET=3.69 min.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10](C(OCC)C)[C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[F:30][C:31]([F:39])([F:38])[C:32]([C:34]([F:37])([F:36])[F:35])=[O:33].C(=O)(O)[O-].[Na+]>O1CCCC1.CCCCCC>[C:1]1([C:7]2[N:8]=[C:9]([C:32]([C:34]([F:37])([F:36])[F:35])([C:31]([F:39])([F:38])[F:30])[OH:33])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: CCOC(C)n1cnc(-c2ccccc2)c1-c1ccc(SC)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(-c2[nH]c(C(O)(C(F)(F)F)C(F)(F)F)nc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-phenyl-5-(4-methylthiophenyl)-1-(α-ethoxyethyl)imidazole (15.5 g, 0.05 mole) in 175 ml of dry tetrahydrofuran was added 7.95 ml (0.052 mole) of N,N-tetramethylethylenediamine. The reaction mixture was cooled to -78° and 45.9 ml of 1.6 M n-butyl lithium in hexane was added dropwise. After stirring the mixture an additional 15 minutes, hexafluoroacetone (12.2 ml) was condensed in a jacketed addition funnel and added dropwise. The mixture was stirred for 1 hour with continued cooling and then 200 ml of saturated aqueous sodium bicarbonate solution was added dropwise. The reaction was warmed to room temperature, and the organic layer was separated. The solvent was evaporated in vacuo and the residue was stirred in 300 ml of ethanol and 300 ml of 2N aqueous hydrochloric acid. The ethanol was removed in vacuo and the reaction mixture was basified to pH=8 with saturated aqueous potassium carbonate. The product was extracted into ether, washed with 10% aqueous sodium bicarbonate and dried over anhydrous potassium carbonate. After concentration in vacuo, the residue was purified by flash chromatography on silica gel (85:15 hexane/ethyl acetate) followed by trituration with petroleum ether to afford 12.3 g of 4-phenyl-5-(4-methylthiophenyl)-α,α-bis(trifluoromethyl)-1H-imidazole-2-methanol, m.p. 119°-121°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].C(#N)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([Br:1])=[C:3]([CH:6]=1)[CH:4]=[O:5])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc(Br)c(C=O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(Br)c(C=O)cc1OCc1ccccc1
Temperature: 50 °C
Yield: 83 %

Procedure:
2-Bromo-5-hydroxy-4-methoxybenzaldehyde (25 g, 0.108 mol) and K2CO3 (30 g, 0.216 mol) were added to acetonitrile (250 mL) and flushed with Ar. Benzyl bromide (20 g, 0.12 mol) was added and the mixture was heated under Ar for 20 h at 50° C. After cooling, the mixture was poured into water (200 ml) and extracted with CH2Cl2 (300 mL). The CH2Cl2 was washed with water (3×100 mL), dried and concentrated. Recrystallization with isopropanol: water (3:1) gave 28.8 g (83%) of 2 as a light brown solid. 1H-NMR (400 MHz, CDCl3) dH 3.96 (3H, s, OCH3), 5.16 (2H, s, CH2Ph), 7.07-7.48 (7H, m, ArH+CH2Ph), 10.16 (1H, s, CHO).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4ccc(C)cc4nc3OC)CC2)c1
Yield: 88 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 88%). MS(ESI) m/z 438 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[Br:36][CH2:37][CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:36][CH2:37][CH2:38][O:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(OCCBr)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
To a solution of tert-butyl 4-((4-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (4 g, 8.14 mmol), 1,2-dibromoethane (2.1 mL, 24.42 mmol) in acetone (20 mL) was added potassium carbonate (4.50 g, 32.6 mmol). The resulting solution was stirred for 16 h at reflux. Add another 4 eq of potassium carbonate and 3 eq of 1,2-dibromoethane. The mixture was refluxed for another 7 hs. After cooling to rt, the white solid was filtered and washed with actone. The filtrate was concentrated and purified by Biotage eluting with 20-33% ethyl acetate in hexane to give tert-butyl 4-((4-((4-(2-bromoethoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (2.91 g, 60%) as white solid.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(O)N1
Reactant: CCCCCO
Product: CCCCCOC1CCC(=O)N1

Procedure:
2.5 g of 5-hydroxy-pyrrolidin-2-one and 1.25 g of Amberlite IR 120H are heated to 65° C. for 3 hours in 55 cm3 of 1-pentanol. The resin is filtered off, and the remainder is distilled under reduced pressure at a temperature of 22° C./24° C. under 0.5 mbar. The residue is chromatographed on silica (eluent: ethyl acetate), and 2.68 g of the expected product is obtained. m.p. 42°-43° C.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[OH:2][CH:3]1[CH2:6][N:5]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH2:4]1
Reactant: OC1CNC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)N1CC(O)C1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
To a stirred mixture of 3-hydroxyazetidine hydrochloride (10.0 g, 91.3 mmol), benzoyl chloride (12.8 g, 91.3 mmol) in 3:2 water/ethyl acetate (500 mL) was added potassium carbonate (63.1 g, 456.5 mmol) at room temperature. After 16 h the organic layer was separated and concentrated under reduced pressure. The resulting residue was dissolved in 2:1 THF/methanol (150 mL) and stirred with 1.0 N sodium hydroxide (50.0 mL) at room temperature. After 1 h the reaction mixture was concentrated under reduced pressure, the resulting residue was partitioned between ethyl acetate and water and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure to provide (3-hydroxyazetidin-1-yl)(phenyl)methanone (13.5 g, 83%) as a colorless gum-like substance.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[BH4-].[Na+]>CO>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=Cc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2cccc(CO)c2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
To the solution of (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-formylphenyl)thiophene-2-carboxamide) (875 mg) in methanol (15 mL), sodium borohydride (97.2 mg) was added. The mixture was then stirred at room temperature for 4 h. The residue was partitioned between water and chloroform. The extracts were dried over magnesium sulfate, filtered, and evaporated, and the residue was then purified by flash chromatography using 5-20% 3.5M methanolic ammonia/chloroform mixtures as the eluent to give the title compound (547 mg); MS (ES+) 343 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:12]2[CH2:27][CH2:26][C:15]3([CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)[CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1.[ClH:28]>O1CCOCC1.C(OCC)(=O)C>[ClH:28].[ClH:28].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:12]2[CH2:13][CH2:14][C:15]3([CH2:18][NH:17][CH2:16]3)[CH2:26][CH2:27]2)=[O:11])=[N:7][CH:8]=1
Reactant: COc1ccc(CC(=O)N2CCC3(CC2)CN(C(=O)OC(C)(C)C)C3)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(CC(=O)N2CCC3(CC2)CNC3)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
To a solution of tert-butyl 7-[(5-methoxypyridin-2-yl)acetyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (2-1a, 2.57 g, 6.85 mmol) in dioxane (5 mL) was added 4N HCl in dioxane (1.72 mL). The mixture was stirred at room temperature for 5 hours and heated at 45° C. overnight. The light-yellow mixture was concentrated to give a light-yellow sticky foam. The residue was suspended in ethyl acetate and evaporated to dryness (3×) to afford the title compound (2-1b, 1.86 g, 78%) MS (ES+) 276.4 (M+H)+. 1H NMR (CD3OD) δ 2.17-2.42 (m, 2H), 2.48 (d, 2H), 3.94-4.13 (m, 4H), 4.40 (d, 4H), 4.51 (s, 3H), 4.74 (s, 2H), 8.34 (d, 1H), 8.61-8.64 (m, 1H), 8.99-9.01 (m 1H).
Reaction SMILES: C1C(=O)N(O[C:9]([O:11][N:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:13]2=[O:14])=[O:10])C(=O)C1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][CH2:30][CH:31]2[C:43]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:37]3[C:32]2=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])=[CH:22][CH:21]=1>CC#N>[O:18]=[C:17]1[CH2:16][CH2:15][C:13](=[O:14])[N:12]1[O:11][C:9]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]([O:29][CH2:30][CH:31]2[C:43]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:37]3[C:32]2=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])=[CH:24][CH:25]=1)=[O:10]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Solvent: CC#N
Product: O=C(Nc1ccc(NC(=O)ON2C(=O)CCC2=O)cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
N,N′-Disuccinimidylcarbonate (16.20 g, 63.26 mmol, 1.1 eq) was added at room temperature to a stirred solution of N-(4-aminophenyl)(fluoren-9-ylmethoxy)carboxamide (20.00 g, 60.53 mmol, 1.0 eq) in CH3CN (1100 mL). After stirring overnight at room temperature, the reaction mixture was filtered to afford 28.50 g of the expected crude product as a white powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of sulfonamide VII (34 gm, 95.5 mmol) in THF and water (1:1), LiOH (20 gm, 47.66 mmol) was added and the resulting mixture was allowed to stir at 80° C. overnight. After completion of reaction, the crude mixture was washed with EtOAc. The aqueous layer was acidified with citric acid and filtered. Thus obtained solid was washed with Et2O and azeotroped by toluene, under reduced pressure to afford acid VIII (30 gm, 95.8% yield) which was taken forward for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:29][CH:30]=[CH2:31])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:35]I>CN(C=O)C.C1OCCOCCOCCOCCOC1>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:29][CH:30]=[CH2:31])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH3:35])=[CH:12][CH:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CCN(CCc1ccc(NS(=O)(=O)c2ccc(C(C)C)cc2)cc1)C(=O)OC(C)(C)C
Reactant: CI
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(CCc1ccc(N(C)S(=O)(=O)c2ccc(C(C)C)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
To a solution of allyl-{2-[4-(4-isopropyl-benzenesulfonylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (200 mg, 0.44 mmol) in DMF (5 ml), 15-crown-5, and sodium hydride (20 mg, 0.48 mmol) were added, and the mixture was stirred at room temperature for 30 min. Methyliodide (60 mg, 0.44 mmol) was added and the mixture was stirred for 3 h at room temperature. After concentration in vacuo the residue was partitioned between dichloromethane and saturated aqueous NaHCO3. The organic layer was washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure to give the product as a yellow oil (200 mg, 97%).