Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(F)ccc1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 28 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a stirred solution of 2,5-difluorotoluene (0.544 g, 4.25 mmol, Aldrich, used as received) in conc. H2SO4 (5.0 mL) at 0° C., KNO3 (0.430 g, 4.25 mmol) was added in one portion. The resulting pale yellow solution was warmed to 28° C. and stirred at that temperature overnight. It was then poured into ice (25 g) and extracted with ethyl acetate (40 mL). The extract was dried over Na2SO4 and evaporated to afford 0.555 g (91%) of the title compound as a light red oil; 1H NMR (CDCl3): 2.369 (d, 3H, J=1.8 Hz), 7.127 (dd, 1H, J1 =8.1 Hz, J2 =6.0 Hz), 7.734 (dd, 1H, J1 =8.4 Hz, J2 =6.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]4[O:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]4)=[CH:18][CH:17]=3)=[O:14])[N:10]=[N:9]2)=[N:6][CH:7]=1.[ClH:35].CCOCC>O1CCOCC1>[ClH:35].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C@@H:22]4[O:27][CH2:26][CH2:25][NH:24][CH2:23]4)=[CH:20][CH:21]=3)=[O:14])[N:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cn(-c4ccc(Br)cn4)nn3)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1)c1cn(-c2ccc(Br)cn2)nn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
(S)-tert-Butyl 2-(4-(1-(5-bromopyridin-2-yl)-1H-1,2,3-triazole-4-carboxamido)phenyl)morpholine-4-carboxylate (63 mg, 0.12 mmol) was dissolved in dioxane (0.5 ml) and a solution of HCl in dioxane (4 M, 0.36 ml, 1.44 mmol) was added. The reaction mixture was stirred for 2 hours at 60° C. After cooling, ether was added, the solid was filtered off, washed with ether and dried in vacuo at 60° C. to afford (S)-1-(5-bromopyridin-2-yl)-N-(4-(morpholin-2-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (48 mg, 87%) as a white solid. MS (ISP): 429.4 ({79Br} [M−H]+), 431.5 ({81Br} [M−H]+).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][O-:4].[Na+].[H-].[Na+].[CH2:10]([O:12][C:13]([C:15]1[C:20]([Br:21])=[C:19](CC)[N:18]=[C:17](S(C)(=O)=O)[N:16]=1)=[O:14])[CH3:11]>C(O)C(F)(F)F>[CH2:10]([O:12][C:13]([C:15]1[C:20]([Br:21])=[CH:19][N:18]=[C:17]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[N:16]=1)=[O:14])[CH3:11]
Reactant: [O-]CC(F)(F)F
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)nc(CC)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: OCC(F)(F)F
Product: CCOC(=O)c1nc(OCC(F)(F)F)ncc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of sodium trifluoroethoxide, prepared from trifluoroethanol (2 ml) and sodium hydride (37 mg, 0.84 mmol) at 0-5° C., was added dropwise a solution of ethyl 5-bromo-2-(methylsulfonyl)pyrimidine-4-carboxylic acid ethyl ester (200 mg, 0.65 mmol; example 126, step 1) dissolved in trifluoroethanol (2 ml) at the same temperature. The ice bath was removed after 15 min and the mixture was stirred at r.t. for 4 h. The reaction mixture was poured into ethyl acetate (20 ml) and extracted with potassium hydrogen sulfate (10%, 10 ml). The organic phase was washed with water and brine and the aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried and evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as colorless oil (186 mg, 87%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:38][CH3:39])=[C:35]([OH:37])[CH:36]=1>>[CH3:39][O:38][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][NH:28][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:16]=3)[CH:26]=[CH:25][N:24]=2)=[CH:36][C:35]=1[OH:37]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Reactant: COc1ccc(CCN)cc1O
Product: COc1ccc(CCNc2nccc(-c3cccc(NC4CCNCC4)c3)n2)cc1O

Procedure:
Intermediate 7 was coupled with 5-(2-Amino-ethyl)-2-methoxy-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 420. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H) 7.0-7.6 (m, 8H) 4.95 (m, 1H) 3.89 (m, 1H) 3.7 (m, 1H) 3.4 (m, 2H) 2.9-3.3 (m, 5H) 2.2-2.3 (m, 2H) 1.95 (m, 2H) 1.6-1.8 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:15][CH2:16][CH3:17].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:15][CH2:16][CH3:17]
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(=O)O)cc(OCC)c1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of methyl 4-bromo-3,5-diethoxybenzoate (3 g) in a mixture of THF (25 ml) and MeOH (10 ml) was added aqueous 1N NaOH (20 ml) and the reaction mixture was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure, the residue was diluted with H2O and diethylether. The aqueous layer was acidified with 1N HCl aq., the mixture was extracted with CHCl3 and dried over sodium sulphate. After filtration and concentration, the residue was dried in vacuo to give the crude title compound as a colorless solid. Thus obtained crude product was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:12][C:13]1[C:22]([C:23](=[O:26])[CH2:24][CH3:25])=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>>[C:1]1([CH2:7][CH2:8][C:9]([O:12][C:13]2[C:22]([C:23](=[O:26])[CH2:24][CH3:25])=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)c1cccc(C(=O)OC)c1O
Reactant: O=C(Cl)CCc1ccccc1
Product: CCC(=O)c1cccc(C(=O)OC)c1OC(=O)CCc1ccccc1

Procedure:
This compound was prepared in three steps according to the method described for Intermediate XC (first step) and Intermediate LXXX (second and third steps). In the first step, 3-phenylpropionyl chloride was used instead of 2-furancarbonyl chloride and methyl 2-hydroxy-3-propionylbenzoate was used instead of the ethyl homolog, yielding methyl 2-(3-phenylpropionyloxy)-3-propionylbenzoate. This compound was used without purification for the second step. The title compound melted at 107.5°-109° C. after crystallization from ethanol.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][CH2:30][N:7]2[C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: c1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(CCn2c3c(c4cccnc42)CN2CCCC2C3)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (70 mg, 0.328 mmol) in DMF (1 mL) was added a suspension of NaH (40.0 mg, 0.986 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (287 mg, 0.986 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 2 h at RT. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography (MeOH-DCM) to yield 11-(2-(6-methylpyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:24][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3ccc(F)cc3o2)c1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2ccc(F)cc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-6-fluorobenzoxazole (552 mg, 2.0 mmol) and propylamine (492 μL, 6.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:26][C:12]([F:11])([F:25])[C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][N:22]([C:2]3[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=3)[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N2CCN(c3cccc(C(F)(F)F)c3)CC2)nc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
A mixture of 6-chloro-3-pyridinecarboxamide (0.11 mol), 1-[3-(trifluoromethyl)-phenyl]-piperazine (0.1 mol) and sodium carbonate (0.22 mol) in DMF (300 ml) was stirred at 120° C. overnight. The mixture was poured out into ice water (600ml) and stirred for 1 hour. The precipitate was filtered off and dried Part of this fraction (4 g) was taken up in DCM and an aqueous NaHCO3 solution. The mixture was separated into its layers. The aqueous layer was extracted three times with DCM. The combined organic layer was dried, filtered and the solvent was evaporated till a small volume. The precipitate was filtered off and dried, yielding 3.2 g of 6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-3-pyridinecarboxamide (intermediate 3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Nc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1
Yield: 17 %

Procedure:
A mixture composed of 500 mg of N-(4-bromophenyl)methane-sulfonamide, 334 mg of 4-methoxyphenyl boronic acid, 55.5 mg of tetrakis-triphenylphosphinepalladium, 2 ml of a 2 M aqueous solution of sodium carbonate, 4 ml of toluene, and 1 ml of ethanol was heated under. reflux for 5 hours in an atmosphere of nitrogen. After the reaction mixture was poured into a saturated aqueous solution of sodium chloride, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified by silica gel column chromatography (using a 7:1 mixture of chloroform and tetrahydrofuran as the eluent) to obtain 94 mg of N-(4′-methoxybiphenyl-4-yl)methanesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:20][O:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:21][C:22]1[CH:26]=[CH:25][N:24]([CH2:27][C:28]([CH3:31])([OH:30])[CH3:29])[N:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:20][O:19][CH2:18]2)[C:13]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH2:27][C:28]([OH:30])([CH3:29])[CH3:31])[N:23]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(CC2COC2)C(=O)O)cc1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2COC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 24 h
Yield: 39.2 %

Procedure:
A reaction of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-oxetan-3-yl-propionic acid (0.18 g, 0.56 mmol), 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 0.1 g, 0.64 mmol), and triethyl amine (0.17 ml, 1.24 mmol) in methylene chloride (15 mL) was cooled to 0° C. To this solution was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.25 g, 0.56 mmol). The reaction was allowed to warm to 25° C. and stirred for 24 h. After this time, the reaction was concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 3% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-oxetan-3-yl-propionamide (0.1 g, 40%) as a 1:1 enantiomeric reaction as a white gummy solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.01-2.15 (m, 1H, CH of CH2), 2.32-2.47 (m, 1H, CH of CH2), 2.75-2.91 (m, 1H, CH), 3.31 (s, 3H, SO2CH3), 3.69-3.79 (m, 1H, ArCHCO), 3.85 (s, 2H, NCH2), 4.16-4.30 (m, 2H, 2×OCH of 2×OCH2), 4.47-4.57 (m, 2H, 2×OCH of 2×OCH2), 4.65 (s, 1H, OH), 6.44 (d, J=2.4 Hz, 1H, Ar), 7.52 (d, J=2.4 Hz, 1H, Ar), 7.57 (dd, Jo=8.3 Hz, Jm=1.4 Hz, 1H, Ar), 7.70 (d, Jm=1.4 Hz, 1H, Ar), 8.00 (d, Jo=8.3 Hz, 1H, Ar), 10.77 (s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][O:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[O:10][CH2:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCCBr
Reactant: COc1cc(C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCCOc1ccc(C)cc1OC

Procedure:
A stirred solution of 2-methoxy-4-methylphenol (5.00 g, 36.2 mmol), 1-bromo-3-methoxypropane (7.06 g, 45.2 mmol) and anhydrous K2CO3 (7.50 g, 64.3 mmol) is refluxed overnight. After cooling, volatiles are removed under reduced pressure, the residue is taken up in water and extracted with AcOEt. The combined organics are washed with brine, dried (Na2SO4) and concentrated. After silica gel chromatography (hexane/AcOEt 3:1) the title compound is obtained as colorless liquid. TLC, Rf (hexane/AcOEt 2:1)=0.34. MS: 211.0 [M+H]+. 1H-NMR (CDCl3): δ 2.13 (m, 2H), 2.33 (s, 3H), 3.38 (s, 3H), 3.61 (m, 2H), 3.88 (s, 3H), 4.12 (m, 2H), 6.7-6.85 (m, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[NH:20][CH:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCOCC1
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 2-amino-4-(4-methyl-piperazin-1-yl)-benzoic acid tert-butyl ester (11.5 g, 39.5 mmol) in dichloromethane (340 mL) were added tetrahydro-pyran-4-one (4.5 mL, 49.3 mmol), trifluoroacetic acid (8.2 mL) and tetramethylammonium triacetoxyborohydride (15.57 g, 59.2 mmol). The mixture was stirred at room temperature for 2 hours then washed with 0.5N hydrochloric acid, with 0.5N NaOH and with a saturated solution of NaHCO3. The organic layer was dried over sodium sulfate and evaporated to dryness affording the title compound as a pale yellow solid (13.3 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[I-].[K+].[CH2:27]([NH2:30])[CH:28]=[CH2:29]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:30][CH2:27][CH:28]=[CH2:29])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: C=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
A stirred mixture of 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (0.004 mole), potassium iodide (0.67 g., 0.004 mole), allylamine (0.84 g., 0.012 mole) and tetrahydrofuran (100 ml.) is kept at ambient temperature (25° C.) for 18 hours and then concentrated in vacuo. The residue is mixed with water and extracted with methylene chloride. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is crystallized from ethyl acetate-Skellysolve B hexanes to give 8-chloro-1-[(allylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 39 8-Chloro-1-[(allylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [N:1]1[C:2](=[O:10])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.Br[C:12]1[CH:20]=[C:19]2[C:15]([C:16](=O)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.Cl>C(O)(=O)C>[CH:13]1[CH:12]=[CH:20][C:19]2[NH:18][C:17](=[O:21])/[C:16](=[C:3]3\[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[NH:1][C:2]\3=[O:10])/[C:15]=2[CH:14]=1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Reactant: O=C1C=c2ccccc2=N1
Agent: Cl
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2/C1=C1\C(=O)Nc2ccccc21
Temperature: 25 °C
Yield: 95 %

Procedure:
Separately adding 6-brome indolone (500 mg, 2.36 mmol), 6-bromoisatin (533 mg, 2.36 mmol of isatin), 15 mL glacial acetic acid and 0.1 mL HCl into a flask, heating and refluxing for 24 hours. Stop the reaction and cooling to room temperature, filtering to obtain a solid, and then washing the solid by water, ethanol, and ethyl acetate. Drying the final product in a vacuum drying box, get brown 6,6′-bidromo isoindigo, the yield was 95%.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:27][C:28]1([CH3:42])[O:33][C:32]2[CH:34]=[CH:35][C:36]([C:38]([OH:40])=O)=[CH:37][C:31]=2[C:30](=[O:41])[O:29]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:38]([C:36]3[CH:35]=[CH:34][C:32]4[O:33][C:28]([CH3:27])([CH3:42])[O:29][C:30](=[O:41])[C:31]=4[CH:37]=3)=[O:40])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCNCc1ccc(C#Cc2ccc(CCCC)cc2)cc1
Reactant: CC1(C)OC(=O)c2cc(C(=O)O)ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)C(=O)c1ccc2c(c1)C(=O)OC(C)(C)O2
Yield: 47.7 %

Procedure:
A solution of N-{4-[(4-butylphenyl)ethynyl]benzyl}-1-hexanamine (144 mg, 0.41 mmol), 2,2-dimethyl-4-oxo-4H-1,3-benzodioxine-6-carboxylic acid (92 mg, 0.41 mmol), EDC.HCl (87 mg, 0.46 mmol), HOBT (61 mg, 0.46 mmol) and DIEA (105 μL, 0.62 mmol) in DCM (10 mL) was stirred at rt overnight. Then the reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3, a saturated aqueous solution of NH4Cl and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silicagel (EtOAc/c-Hex (20/80)) to give 108 mg (47%) of the title compound as a colorless oil. HPLC, Rt: 6.14 min (purity: 99.9%). 1H NMR (CD3Cl3) δ: 0.82 (m, 3H), 0.91 (t, J=7.3 Hz, 3H), 1.32-1.40 (m, 10H), 1.57 (m, 2H), 1.72 (s, 6H), 2.59 (t, J=7.6 Hz, 2H), 3.16-3.41 (m, 2H), 4.40-4.72 (m, 2H), 7.00 (m, 2H), 7.14 (d, J=8.3 Hz, 2H), 7.25 (m, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.61 (m, 1H), 8.03 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>C(O)C>[CH:6]1([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCCC1
Reactant: CC(O)CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CNC1CCCCC1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-amino-2-propanol (15 g, 0.199 mol) in ethanol (300 ml) was added cyclohexanone (31.4 mL, 0.299 mol). The reaction mixture was stirred at 0-10° C. for 10 minutes. Sodium borohydride (10.8 g, 0.285 mol) was added at 0° C., then stirred at rt for 15 minutes. The resultant reaction mixture was quenched with water, filtered through the Celite® reagent, and solvent was evaporated. The residue was dissolved in 2N HCl, washed with ethyl acetate; the pH of the aqueous layer was adjusted to 8 using saturated sodium bicarbonate solution. The compound was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, concentrated to dryness, and the crude material was subjected to column chromatography to obtain 1-(cyclohexylamino)propan-2-ol. Yield: 22 g (70.1%); 1H NMR (400 MHz, DMSO-d6) δ 8.25 (bs, 1 H), 5.25 (bs, 1 H), 3.95-3.91 (m, 1 H), 2.89-2.88 (dd, J=6, 9 Hz, 2 H), 2.71-2.66 (m, 1 H), 2.00-1.99 (m, 2 H), 1.75-1.72 (m, 2 H), 1.60-1.57 (m, 1 H), 1.36-0.93 (m, 8 H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH3:12])[CH2:5][P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8].C(NC1C=CC(S([N:26]=[N+:27]=[N-])(=O)=O)=CC=1)(=O)C>C1C=CC=CC=1.C1COCC1>[N+:26](=[C:5]([P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8])[C:4](=[O:3])[CH3:12])=[N-:27]
Reactant: COP(=O)(CC(C)=O)OC
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a suspension of 4.1 g of NaH (washed with hexane) in 110 mL of benzene and 25 mL of THF at 5° C., was added 15.5 g of dimethyl 2-oxopropylphosphonate (Formula 13) in 15 mL of benzene. The resulting solution was stirred at 5-10° C. for 1 hour. A solution of 24.7 g of 4-acetamidobenzenesulfonyl azide (Formula 14) in 25 mL of benzene and 50 mL of THF was then added and the mixture was stirred at room temperature for 2 hours. The yellow suspension was filtered through celite and washed with ethyl ether. The filtrate was concentrated to give 18 g of dimethyl 1-diazo-2-oxopropylphosphonate (Formula 15) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([CH2:13][OH:14])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1F.CN(C)C=[O:25]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]3[CH:6]([CH2:7][N:8]=[C:20]4[C:15]=3[CH:16]=[CH:17][CH:18]=[CH:19]4)[C:13](=[O:14])[O:25][C:9]2=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2F)c1CO
Solvent: O
Product: O=C1Oc2ccc(Cl)cc2C2=c3ccccc3=NCC12

Procedure:
Sodium hydride suspension (50% in mineral oil), 10 g, was washed with hexane and added to a solution of 20 g (0.066 mol) of the 6-chloro-4-(2-fluorophenyl)-3-hydroxymethylquinolin-2(1H)one in 350 ml of dimethylformamide. This mixture was stirred and refluxed under an atmosphere of nitrogen for 5 min. The cool reaction mixture was diluted with water and the product was precipitated by acidifying with 1N hydrochloric acid. It was collected, washed with water and recrystallized from dimethylformamide to yield final product with mp>350°.