Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:12]2[O:11][CH:10]([C:13]([O:15]CC)=[O:14])[O:9][C:8]=2[CH:7]=[C:6]([C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)=[O:19])[C:5]=1[Cl:26]>O.C(O)C>[Cl:3][C:4]1[C:12]2[O:11][CH:10]([C:13]([OH:15])=[O:14])[O:9][C:8]=2[CH:7]=[C:6]([C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)=[O:19])[C:5]=1[Cl:26]
Reactant: CCOC(=O)C1Oc2cc(C(=O)c3ccnn3C)c(Cl)c(Cl)c2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1nccc1C(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
A solution of 0.36 g of sodium hydroxide in 15 ml of water is added to a suspension of 1.86 g of ethyl 4,5-dichloro-6-(1-methyl-5-pyrazolylcarbonyl)-1,3-benzodi oxole-2-carboxylate in 35 ml of ethanol and the mixture is stirred at room temperature for 0.5 hour. The reaction mixture is concentrated to remove ethanol and adjusted to pH 1 with aqueous 10% hydrochloric acid. The resultant crystals are collected by filtration, washed successively with water and isopropyl ether and dried to give 1.66 g of 4,5-dichloro-6-(1-methyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylic acid. Yield: 97%
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18](OC)=[O:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][NH:23][CH3:24]>CO>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18]([N:23]([CH3:24])[CH3:22])=[O:19])(=[O:8])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CNC
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Solvent: CO
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Temperature: 35 °C
Yield: 76.8 %

Procedure:
115 g of N-tert.-butyl-2-methoxycarbonyl-5-nitro-benzenesulfonamide (Example c) in 1500 ml of methanol are gassed with about 200 g of dimethylamine. The mixture is stirred at about 35° C. for one week. The solution is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is washed successively with dilute hydrochloric acid, saturated NaHCO3 solution and saturated NaCl solution. After drying over MgSO4, the organic phase is concentrated. 92 g of N-tert.-butyl-2-dimethylaminocarbonyl-5-nitro-benzensulfonamide are obtained: m.p.: 138-141° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:2]2.[Cl:27][CH2:28][C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[O:30]>C(OCC)(=O)C>[Cl-:27].[F:26][C:21]1[CH:20]=[C:19]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:11][C:9]([CH:3]2[CH:4]3[CH2:5][CH2:6][N+:1]([CH2:28][C:29](=[O:30])[C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)([CH2:8][CH2:7]3)[CH2:2]2)=[O:10])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: O=C(OC(c1ccccc1)c1ccc(F)c(F)c1)C1CN2CCC1CC2
Reactant: O=C(CCl)c1cccs1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)C(C(=O)OC(c1ccccc1)c1ccc(F)c(F)c1)C2)c1cccs1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To a solution of (3,4-difluorophenyl)(phenyl)methyl quinuclidine-3-carboxylate (65 mg, 0.18 mmol) in ethyl acetate (3 ml), 2-chloro-1-(thiophen-2-yl)ethanone (29.2 mg, 0.18 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue was taken up with diethyl ether and filtered to give 3-(((3,4-difluorophenyl)(phenyl)methoxy)carbonyl)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (20 mg, mixture of diastereoisomers).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:35])[CH2:14]/[C:15](=[CH:19]\[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:24]([CH3:34])[CH:23]=1)/[C:16]([OH:18])=[O:17])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1(N)CCCCC1>CO.O>[CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:35])[CH2:14][C@@H:15]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:24]([CH3:34])[CH:23]=1)[C:16]([OH:18])=[O:17])([CH3:10])([CH3:11])[CH3:9]
Reactant: Cc1cc(CC/C=C(\CC(=O)OC(C)(C)C)C(=O)O)ccc1-c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: NC1CCCCC1
Solvent: O
Solvent: CO
Product: Cc1cc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)O)ccc1-c1ccccc1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 64.1 %

Procedure:
A stirred solution of (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-2-pentenoic acid cyclohexylamine salt (1.1 Kg, 2.3 mol) and [(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)ruthenium chloride (2.2 g, 2.4 mmol) in methanol (8.2 liters) and water (2.8 liters) was heated to 60° C., under hydrogen (60 p.s.i.), for 40 hours and then allowed to cool to 20-25° C. (enantiomeric excess=88%). The mixture was concentrated in vacuo to a volume of 3 liters and then ethyl acetate (5 liters) was added. The mixture was distilled at constant volume of ethyl acetate until water droplets appeared in the distillate. The mixture was then cooled to 20-25° C. and then demineralised water (2.9 liters) and citric acid (485 g, 2.5 mol) were added. The organic phase was separated and washed with demineralised water (1.1 liter) and then dried azeotropically by distillation at a constant volume of 8.25 liters. Methylethyl ketone (8.25 liters) was added and the mixture was warmed to 40° C. Cyclohexylamine (228 g, 2.28 mol) was added in one portion and the mixture was allowed to cool to 20-25° C., then was stirred for 16 hours. The mixture was filtered and the residue was washed with a mixture of ethyl acetate (55 ml) and methylethyl ketone (55 ml) and then dried in vacuo at 45° C. to leave the title compound as a colourless solid (0.71 Kg, 65% yield, enantiomeric excess=98.6%, 99% pure by HPLC).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C=O)C>[Cl:1][C:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ON=Cc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
N-chlorosuccinimide (5.50 g, 41.3 mmol) was added in portions to a solution of benzaldehyde oxime (5.0 g, 41.3 mmol) in DMF (34 ml) such that the temperature did not rise above 35° C. The mixture was stirred at ambient temperature for 2 hours and then cooled with an ice bath. Water was added and the aqueous mixture extracted with ether. The organics were combined, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation to give the title compound (6.43 g, 100%) as an oil. NMR (CDCl3): 7.4 (m, 3H), 7.8 (d, 2H), 8.9 (bs, 1H).
Reaction SMILES: [CH:1]([C:4]([C:7]([C:10]([CH2:13][OH:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[Na+].[CH2:17](Cl)[CH:18]=[CH2:19].O.C[S:23](C)=O>>[CH:1]([C:4]([C:7]([C:10]([CH2:13][O:14][CH2:19][CH2:18][CH2:17][SH:23])([F:11])[F:12])([F:9])[F:8])([F:6])[F:5])([F:2])[F:3]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: CS(C)=O
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)C(F)(F)C(F)(F)C(F)(F)COCCCS
Temperature: 25 °C
Reaction time: 5 h

Procedure:
50 g of H(CF2)4CH2OH was dissolved in 100 ml of dimethyl sulfoxide (DMSO). 22.4 g of sodium hydroxide was added with stirring, and then 33 g of allyl chloride was dded slowly at room temperature over 2 hours. Stirring was continued for 5 hours. After filtration of precipitates, the solution was heated on a water bath to remove unreacted allyl chloride. The solution was poured into a large amount of water to separate H(CF2)4CH2OCH2 --CH=CH2. A small quantity of BPO of the order of mg was added to H(CF2)4CH2OCH2 --CH=CH2, and then thiolacetic acid was added with stirring at room temperature over 2 hours. Unreacted thiolacetic acid was removed under reduced pressure. 100 cc of methanol and 10 g of sodium hydroxide were added, and reaction was carried out at 60° C. for 3 hours. After cooling to room temperature, the reaction product was poured into a large amount of water to give crude H(CF2)4CH2OCH2CH2CH2SH. Upon distillation, there was obtained a purified product having bp. 57° C./3 mmHg. The structure of this compound was confirmed by 1H--NMR.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]([N:22]1[C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[CH2:15]([N:22]1[C:26]([C:27]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:28])=[CH:25][C:24]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)c1cc(C(=O)Cl)n(Cc2ccccc2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)n(Cc2ccccc2)n1
Yield: 59 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0445 g, 0.189 mmol), 1-benzyl-3-(tert-butyl)-1H-pyrazole-5-carbonyl chloride (0.055 g; 0.189 mmol), and triethylamine (0.0663 mL; 0.472 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 16% of ethyl acetate in dichloromethane gave 0.0485 g (59%) of 1-benzyl-3-tert-butyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1H-pyrazole-5-carboxamide as a solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22](Cl)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Cl:25][C@@H:26]1[CH2:30][NH:29][C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12>O.O1CCOCC1>[Cl:25][C@@H:26]1[CH2:30][N:29]([C:22]([O:21][CH2:20][CH:18]2[C:19]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:16]3[C:17]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:23])[C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O[C@H]1CO[C@H]2[C@@H]1NC[C@H]2Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1C[C@@H](Cl)[C@H]2OC[C@H](O)[C@H]21
Reaction time: 1.08 h
Yield: 76 %

Procedure:
A solution of sodium carbonate (155 mg, 1.46 mmol) in water (2.5 mL) then a solution of 9-fluorenylmethoxycarbonyl chloride (189 mg, 0.73 mmol) in 1,4-dioxane (1.5 mL) was added whilst stirring to a solution of aminoalcohol (77) in 1,4-dioxane (1 mL). The mixture was stirred for 65 minutes then water (20 mL) was added and the product extracted into dichloromethane (3×10 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 10:90 to 50:50 gave alcohol (78) (194 mg, 76%) as a white solid. TLC (Rf=0.45, EtOAc:heptane 1:1), analytical HPLC single main peak, Rt=15.51 min., HPLC-MS 386.1/388.1 [M+H]+, 408.1/410.1 [M+Na]+; [α]D23.0−7.46° (c=2.01, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers 1:1; 1.15 (0.5H, s, OH), 3.05 (0.5H, t, J=9.58 Hz, FmocNCH2), 3.09 (0.5H, s, OH), 3.23 (0.5H, t, J=10.38 Hz, FmocNCH2), 3.43 (0.5H, d, J=4.37 Hz, FmocNCH), 3.53 (0.5H, brs, OCH2CHOH), 3.62 (0.5H, dd, J=10.20 and 1.92 Hz, OCH2CHOH), 3.75 (0.5H, dd, J=10.21 and 4.53 Hz, OCH2CHOH), 3.84-3.97 (2H, m, 1×FmocNCH2, 0.5×OCH2CHOH and 0.5×CHCl), 4.02 (0.5H, dd, J=9.96 and 4.65 Hz, OCH2CHOH), 4.06-4.12 (0.5H, m, CHCl), 4.15-4.26 (1.5H, m, Fmoc CH and 0.5×FmocNCH), 4.39-4.46 (1.5H, m, 0.5×OCH2CHOH, 0.5×Fmoc CH2 and 0.5×CHCHCl), 4.50 (0.5H, dd, J=10.64 and 6.70 Hz, Fmoc CH2), 4.67 (0.5H, t, J=4.29 Hz, CHCHCl), 4.75 (0.5H, dd, J=10.86 and 3.69 Hz, Fmoc CH2), 4.82 (0.5H, dd, J=10.82 and 3.97 Hz, Fmoc CH2), 7.30-7.81 (8H, aromatic CH); δC (125 MHz, CDCl3) 47.22/47.41 (Fmoc CH), 50.55/50.93 (FmocNCH2), 54.60/55.28 (CHCl), 65.94/67.60 (Fmoc CH2), 69.08/69.56 (FmocNCH), 75.00/75.35 (OCH2CHOH), 76.23/76.86 (OCH2CHOH), 81.27/81.84 (CHCHCl), 119.87/119.92/120.09/124.42/124.46/124.82/124.88/127.10/127.50/127.51/127.89/127.96/127.98/128.53 and 128.65 (aromatic CH), 141.24/141.36/141.44/143.44/143.57/143.83 and 143.84 (aromatic quaternary), 153.41/154.42 (Fmoc C═O).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[NH:2]2.[H-].[Na+].Cl[C:13]1[CH:22]=[N:21][C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=2)[N:14]=1>C1COCC1.CN(C=O)C>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:25][CH3:26])[N:14]=[C:13]([N:2]1[C:3](=[O:9])[CH:4]3[CH2:7][CH2:8][CH:1]1[CH2:6][CH2:5]3)[CH:22]=[N:21]2
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Reactant: O=C1NC2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2ncc(N3C(=O)C4CCC3CC4)nc2cc1OC
Temperature: 80 °C
Yield: 34.9 %

Procedure:
2-Azabicyclo[2.2.2]octan-3-one (228 mg, 2.3 mmole) is dissolved in a mixture of THF/DMF (5 mL/3 mL) and treated with NaH (60%, 184 mg, 4.6 mmole). The resulting mixture is heated at 60° C. for 0.5 hour before addition of 2-chloro-6,7-dimethoxyquinoxaline (344 mg, 1.5 mmole). After being heated at 80° C. overnight, the reaction mixture is concentrated. The residue is chromatographed on silica gel (50% ethyl acetate/hexane) to give 164 mg (23%) of a yellow solid (m.p. 158-159° C.).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:24]([C:25]2[N:30]=[CH:29][N:28]=[C:27]([O:31][C:32]3[C:37]4[N:38]=[C:39]([NH2:41])[S:40][C:36]=4[CH:35]=[CH:34][CH:33]=3)[CH:26]=2)=[CH:23][CH:22]=[C:21]([C:42]([F:45])([F:44])[F:43])[N:20]=1.C(=O)([O-])[O-].[K+].[K+].[C:52](OC(=O)C)(=[O:54])[CH3:53]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:24]([C:25]2[N:30]=[CH:29][N:28]=[C:27]([O:31][C:32]3[C:37]4[N:38]=[C:39]([NH:41][C:52](=[O:54])[CH3:53])[S:40][C:36]=4[CH:35]=[CH:34][CH:33]=3)[CH:26]=2)=[CH:23][CH:22]=[C:21]([C:42]([F:45])([F:43])[F:44])[N:20]=1
Reactant: CC1CCCCN1CCCNc1nc(C(F)(F)F)ccc1-c1cc(Oc2cccc3sc(N)nc23)ncn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4NCCCN4CCCCC4C)ncn3)cccc2s1
Temperature: 90 °C

Procedure:
A mixture of 4-(6-(2-(3-(2-methylpiperidin-1-yl)propylamino)-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yloxy)benzo [d]thiazol-2-amine trifluoroacetic acid salt, Example 80, (29 mg, 0.052 mmol), potassium carbonate (35 mg, 0.253 mmol) and acetic anhydride (2 mL) was heated at 90° C. in a microwave synthesizer for 10 min. to give MS (ESI, pos. ion.) m/z: 658 (M+1). The reaction mixture was dissolved in DCM (10 mL), filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Prodigy 5μ ODS-3 100 Å column, gradient: 20-100% CH3CN (0.1% TFA)/H2O (0.1% TFA) over 15 min) to give the title compound as a light-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 700 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[C:13](=[O:23])[O:14][C:15]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=2[CH:17]=1>Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[C:13](=[O:23])[O:14][C:15]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=2[CH:17]=1)=[O:5]
Reactant: Nc1cc2ccc(O)cc2oc1=O
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Product: O=C(Nc1cc2ccc(O)cc2oc1=O)c1ccccc1Cl
Reaction time: 1 h
Yield: 54.8 %

Procedure:
2-Chlorobenzoyl chloride (23.0 mg, 0.291 mmol) was added to a mixture of 3-amino-7-hydroxy-2H-1-benzopyran-2-one (50.0 mg, 0.282 mmol), and the mixture was stirred at room temparature for 1 hour. 1N hydrochloric acid (10 ml) was added, and the mixture was stirred. The precipitated crystal was filtered and washed successively with water and diisopropyl ether to give the title compound as a light brown crystal (48.8 mg, 54.8%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4](O)=[O:5])[CH3:2].[C:9]1(=[O:22])N(CC=O)C(=O)[C:11]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:10]12.F[C:24](F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH:19]1[CH:20]=[CH:21][C:10]([CH2:9][O:22][C:24]2[CH:8]=[CH:7][C:3]([CH2:4][OH:5])=[CH:1][CH:2]=2)=[CH:11][CH:18]=1
Reactant: CCC(CC)C(=O)O
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: OCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
Phthalimidoacetaldehyde diethylacetate (5.3 g, 20 mmole) was dissolved in chloroform (100 mL) and a trifluoroacetic acid solution (50% aqueous, 80 mL) was added. The reaction mixture was stirred at room temperature for 12 hours. The chloroform layer was collected and dried over sodium sulfate. The filtrate was concentrated to give 3.75 g of the title compound (99% yield): TLC (Rf: 0.4; 40% EtOAc/Hexane), 1H NMR (DMSO-d6) δ 4.6 (s, 2 H, CH2), 7.8 (m, 4 H, Ar), 9.6 (s, 1 H, CHO). 13C NMR (DMSO-d6): δ 47.4 (CH2), 123.4 (Ar), 131.5 (Ar), 134.8 (Ar), 167.3 (CO), 196.8 (CHO).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I-].[K+].II>C(O)C.O.C(OCC)(=O)C>[C:14]1([S:20][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:10][CH2:11][CH2:12][OH:13])[NH:1][CH:2]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCCc1cccc2[nH]ccc12
Reactant: Sc1ccccc1
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: OCCCc1cccc2[nH]cc(Sc3ccccc3)c12
Temperature: 65 °C
Yield: 71.3 %

Procedure:
To a solution of 3-(1H-indol-4-yl)propan-1-ol (0.91 g, 5.19 mmol) and thiophenol (0.53 mL, 5.19 mmol) in absolute ethanol (30 mL) was added a solution of potassium iodide (0.862 g, 5.19 mmol) and iodine (1.318 g, 5.19 mmol) in ethanol (7.5 mL) and water (22.5 mL) over 5 minutes, and the reaction was then heated at 65° C. for 5.5 hours. The cooled reaction mixture was diluted with ethyl acetate (250 mL), washed with 5% aqueous Na2S2O3 solution (250 mL), water (250 mL) and brine (250 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford an off-white solid. Purification by flash chromatography (25 to 75% ethyl acetate/hexane) afforded a white solid. The product was recrystallized from 3:1 v/v hexane:ethyl acetate (60 mL) to afford the title compound as a white crystalline solid (1.048 g, 71%). MS (ES+) m/z 284.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(OC[CH:22]([N:26]=[N+:27]=[N-:28])[CH2:23][CH2:24][CH3:25])(=O)=O.N([CH2:32]CN1C=CC=C(OC)C1=O)=[N+]=[N-]>>[N:26]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:32][N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]1=[O:15])=[N+:27]=[N-:28]
Reactant: COc1cccn(CCN=[N+]=[N-])c1=O
Reactant: O=c1[nH]cccc1OCc1ccccc1
Reactant: CCCC(COS(C)(=O)=O)N=[N+]=[N-]
Product: [N-]=[N+]=NCCCCCn1cccc(OCc2ccccc2)c1=O
Yield: 63 %

Procedure:
Reaction of 3-benzyloxypyridine-2-one (0.50 g, 2.49 mmol) and 156d (0.62 g, 2.98 mmol) within 16 h as described for synthesis of 157a gave compound 157d (0.49 g, 63%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=8.0 Hz, 2H), 7.23 (m, 3H), 6.81 (m, 1H), 6.56 (m, 1H), 5.94 (m, 1H), 5.01 (s, 2H), 3.85 (m, 2H), 3.18 (m, 2H), 1.71 (m, 2H), 1.54 (m, 2H), 1.32 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 157.68, 148.47, 135.98, 128.60, 128.12, 127.53, 126.93, 115.09, 104.32, 70.27, 50.77, 49.21, 28.19, 28.06, 23.37. HRMS (EI) calcd for C17H20N4O2 [M]+ 312.1586. found 312.1589.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[CH:17]=[CH:16][N:15]3[CH:18]=[CH:19][N:20]=[C:14]3[CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)[CH:23]=[O:24]>>[C:6]1([C:12]2[CH:17]=[CH:16][N:15]3[C:18]([CH:23]=[O:24])=[CH:19][N:20]=[C:14]3[CH:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(-c2ccn3ccnc3c2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnc2cc(-c3ccccc3)ccn12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
An oven dried flask under N2 was charged with 2 ml of N,N-dimethylformamide and phosphorous oxychloride (0.048 ml, 0.52 mmol) was added dropwise. 7-Phenylimidazo[1,2-a]pyridine (1-4, 0.100 g, 0.515 mmol) was added and the reaction was heated to 90° C. After 4 h additional POCl3 (0.048 ml, 0.52 mmol) was added and the reaction was heated overnight. Another sample of POCl3 (0.048 ml, 0.52 mmol) was added and heating was continued. After 4 h more, the reaction was cooled to ambient temperature. The reaction was quenched with saturated aqueous NaHCO3 and extracted 3× with DCM. The extracts were dried over Na2SO4, filtered and concentrated.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][S:6]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[Cl:16])(=[O:8])=[O:7])#[N:2].O.[NH2:20][NH2:21]>C(O)C>[NH2:2][C:1]1[NH:21][N:20]=[C:4]([NH:5][S:6]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:16])(=[O:8])=[O:7])[N:3]=1
Reactant: NN
Reactant: CSC(=NC#N)NS(=O)(=O)c1cc(Cl)ccc1Cl
Solvent: O
Solvent: CCO
Product: Nc1nc(NS(=O)(=O)c2cc(Cl)ccc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.2 %

Procedure:
A mixture of 8.51 g (26.2 mmol) of N'-cyano-N-(2,5-dichlorophenylsulfonyl)-S-methylisothiourea and 10 ml (10 g, 0.20 mol) of hydrazine monohydrate in 85 ml of ethanol was heated at reflux for 30 minutes. After cooling to room temperature, the solid which separated was collected and suspended in 170 ml of H2O and the suspension was acidified with concentrated aqueous HCl. After stirring the suspension for 4 hours the solid was collected and dried in vacuo to yield 5.10 g (57 percent) of the desired product as a hydrochloride salt, mp 306°-308° C. IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[C:8](O)(=O)[CH3:9].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:18]([C:8]2[CH:9]=[CH:14][CH:13]=[CH:12][CH:17]=2)=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccccc1
Reactant: O=C1CSC(=S)N1
Reactant: CC(=O)O
Product: O=C1NC(=S)SC1=C(c1ccccc1)c1ccccc1

Procedure:
One hundred and ninety grams (1.05 mol) of diphenyl kerimine, 140 grams (1.05 mol) of rhodanine, 5 ml of acetic acid and 1500 ml of toluene were heated at reflux for 3 hours. Crystals formed upon cooling. The solvent was decanted, fresh toluene was added to the residue and the resulting suspension was filtered. The recovered crystals were recrystallized from methanol to provide 172.0 g of title product, m.p. 192°-194° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3Nc1ccc2[nH]ccc2c1

Procedure:
6-Bromo-N-(1H-indol-5-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (100 mg, 0.76 mmol) and 5-aminoindole (100 mg, 0.76 mmol) in a similar manner as described above to give 54 mg (37%) of a white solid; 1H-NMR (DMSO-d6): δ 11.08 (s, 1H), 10.61 (s, 1H), 7.55 (d, 1H), 7.23 (d, 1H), 7.14-7.11 (m, 2H), 7.10 (d, 1H), 6.84-6.83 (m, 1H), 6.65 (dd, 1H), 6.18-6.17 (m, 1H), 5.21 (d, 1H), 4.77-4.71 (m, 1H), 2.68-2.54 (m, 2H), 2.02-1.89 (m, 2H), 1.84-1.73 (m, 2H); MS m/z (M+1) 378, 380.