Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]#[N:25])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].CN(C)C=O>C(OCC)(=O)C.[Cl-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc2c(Cl)ccc(OCC#N)c2c(C)c1Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2c(Cl)ccc(OCc3nnn[nH]3)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of [8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-yloxy]acetonitrile (0.10 g), sodium azide (0.026 g), ammonium chloride (0.022 g) and N,N-dimethylformamide (1.5 mL) was heated by microwave irradiation at 100° C. for 45 minutes. The mixture was diluted with ethyl acetate (20 mL) and saturated aqueous sodium chloride solution (20 mL). The resulting precipitate was collected by filtration, washed with water and ethyl acetate and dried to afford title compound as a white solid, 0.14 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[C:10]([OH:15])=[N:11][CH:12]=[CH:13][N:14]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:23]([O:30][C:31](ON1C(=O)CCC1=O)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:30][C:31]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[C:10]([OH:15])=[N:11][CH:12]=[CH:13][N:14]=2)[CH2:3][CH2:2]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1nccnc1NCC1CCNCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(CNc2nccnc2O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-[(piperidin-4-ylmethyl)-amino]-pyrazin-2-ol from Step 1 above (0.287 g, 1.021 mmol) in DMF (5 mL) was added triethylamine (0.356 mL, 2.55 mmol), followed by N-(benzyloxycarbonyloxy)succinimide (0.305 g, 1.23 mmol). The resulting reaction mixture was stirred at rt for 15 min, then partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the crude product purified by flash column chromatography (50% EtOAc hexane to 5% MeOH EtOAc) to give an oil which solidified on standing. M.S (M+1): 343.24.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[F:55][C:56]([F:66])([F:65])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[OH:64].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:62]1[CH:61]=[CH:60][C:59]([OH:64])=[C:58]([CH2:57][C:56]([F:65])([F:66])[F:55])[CH:63]=1
Reactant: Oc1ccccc1CC(F)(F)F
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Br)cc1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 187.3 %

Procedure:
Tetrabutylammonium tribromide (6.56 g) was dissolved in chloroform (50 ml) and added dropwise to a solution of 2-(2,2,2-trifluoroethyl)phenol (2.4 g) in chloroform (50 ml). The reaction mixture was stirred at room temperature for 2 hrs, after which time 5% sodium thiosulfate solution (100 ml) was added and the resultant stirred for 30 mins. The mixture was then partitioned between dichloromethane (100 ml) and 1N HCl (200 ml). The organics were separated and dried over magnesium sulfate. The solvent was then removed in vacuo, the crude residue was then purified by column chromatography on silica gel eluting with 90:10 hexanes:ethyl acetate to afford the title compound as a yellow oil (3.24 g). 1H NMR (CDCl3): δ 3.50 (q, J=21.48 Hz 2H), 6.70 (d, J=2.54 Hz, 1H), 7.32 (d, J=2.54 Hz, 1H), 7.45 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:35])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=4)[CH2:23][C:22](=[O:35])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc([N+](=O)[O-])c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-(3-nitro-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K42) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (719 mg).
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[OH:21][CH2:22][C:23]1[C:28]([CH3:29])=[C:27]([OH:30])[C:26]([CH3:31])=[CH:25][N:24]=1.[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[O:19]1[C:20]2[C:12]([C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([OH:5])([C:7]([F:9])([F:10])[F:8])[CH2:6][N:24]3[CH:25]=[C:26]([CH3:31])[C:27](=[O:30])[C:28]([CH3:29])=[C:23]3[CH2:22][OH:21])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: Cc1cnc(CO)c(C)c1O
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cn(CC(O)(CC(C)(C)c2cccc3c2OCC3)C(F)(F)F)c(CO)c(C)c1=O
Temperature: 85 °C
Yield: 22.6 %

Procedure:
To a suspension of 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran (30.0 mg) and 2-hydroxymethyl-3,5-dimethylpyridin-4-ol (32.2 mg) in anhydrous ethanol (0.25 mL) was added sodium ethoxide (21 wt. % solution in ethanol, 39.0 μL). After heating at 85° C. for 18 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 4% to 7% methanol-methylene chloride) to give the title compound as a white solid (10.4 mg), m.p. 160° C.-162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH2:15])[CH:4]=1.N1C=CC=CC=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:15][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:4]=1
Reactant: COc1ccc(-c2ccccc2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-c2ccccc2)c(NC(=O)C(C)(C)C)c1
Yield: 93 %

Procedure:
A magnetically stirred solution of 4-methoxybiphenyl-2-ylamine (25.27 g, 127 mmol) in CH2Cl2 (300 mL)/pyridine (300 mL) at 0° C. under nitrogen was treated with pivaloyl chloride via syringe (16.8 g, 17.2 mL, 139 mmol). The resultant suspension was stirred for 12 h at room temperature and concentrated in vacuo. The residue was digested with CH2Cl2 (300 mL), washed with 1 N HCl (2×300 mL), 1 N NaOH (2×300 mL), H2O (300 mL), brine (300 mL), dried (K2CO3), filtered, and concentrated in vacuo to give 33.6 g (93%) of a white solid: 1H NMR (300 MHz, CDCl3) δ 1.07 (s, 9H), 3.83 (s, 3H), 6.69 (dd, J=8.5, 2 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.29-7.47 (m, 5H), 7.53 (br s, 1H), 8.13 (d, J=2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4](=[N:6][OH:7])[NH2:5].[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O)([O-:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]1[N:5]=[C:19]([C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[O:7][N:6]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: NC(=NO)c1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2nc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
2,6-Dichlorobenzamidoxime (1.0 g) was dissolved in pyridine and m-nitrobenzoyl chloride (0.91 gm, 1.0 molar equivalent) was added. The solution was stirred at room temperature for 1 h under nitrogen, then heated at 90° C. for 4 h. The solution was cooled to room temperature, and poured into ice water. The pH of the solution was adjusted to approximately pH 10 with 2M aqueous sodium carbonate solution. The mixture was extracted with ether and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to dryness. The residue was dissolved in ethyl acetate. Addition of hexanes to the solution gave 3-(2,6-dichlorophenyl)-5-(3-nitrophenyl)-1,2,4-oxadiazole as a white solid (0.69 g). NMR (300 MHz, DMSO-d6): 8.52 (s, 1H), 8.38 (d, 1H), 8.18 (d, 1H), 7.78 (t, 1H), 7.57 ppm (m, 3H). LC-MS tr=38.2 min (Method W) MH++NA=359
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC[O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH:18]2[CH2:20][CH:15]1[CH2:16][CH2:17]2>CCOCC>[C:5]([O:4][CH2:1][CH2:2][O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH:18]2[CH2:20][CH:15]1[CH2:16][CH2:17]2)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: OCCOCCN1CC2CCC1C2
Solvent: CCOCC
Product: CC(=O)OCCOCCN1CC2CCC1C2
Reaction time: 3 h
Yield: 52 %

Procedure:
198 g (1.94 moles) of acetic anhydride are added to 286 g (1.55 moles) of N-(2-hydroxyethoxyethyl-)2-azabicyclo[2.2.1]heptane (XV) in the absence of moisture such that the temperature is maintained between 50° and 60° C. The mixture is kept boiling for three hours. After cooling 200 ml of ether are added. The product is neutralized with soda solution, is washed until it is neutral, and--after the ether is withdrawn--it is distilled under high vacuum. The main fraction weighs 185 g and contains 99% (XXI). This corresponds to a yield of 52% of theoretical.
Reaction SMILES: Br[C:2]1[C:15]([CH:16]2[C@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:20]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:19]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:18]([CH2:46][O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[O:17]2)=[CH:14][C:13]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH2:63][CH3:64])=[CH:58][CH:57]=2)=[C:12]([Cl:65])[C:3]=1[O:4][CH2:5][C:6](N(OC)C)=[O:7].[Li]CCCC>C1COCC1.[NH4+].[Cl-]>[Cl:65][C:12]1[C:3]2[O:4][CH2:5][C:6](=[O:7])[C:2]=2[C:15]([CH:16]2[C@H:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@@H:20]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:19]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C@@H:18]([CH2:46][O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[O:17]2)=[CH:14][C:13]=1[CH2:55][C:56]1[CH:57]=[CH:58][C:59]([O:62][CH2:63][CH3:64])=[CH:60][CH:61]=1
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCC(=O)N(C)OC)c2Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 2-(2-bromo-6-chloro-5-(4-ethoxybenzyl)-3-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenoxy)-N-methoxy-N-methylacetamide (1.02 g, 1.06 mmole) in THF (15 mL) was added nBuLi (1.3 mL, 3.18 mmole, 2.5M in hexane) at −78° C. The resulting solution was warmed up to rt and stirred overnight, diluted with a saturated NH4Cl and extracted with ethyl acetate. The organic layer was washed with water then brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus to yield the title compound (429 mg, 49%) as a yellow gum.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:11]([C:12]([NH:14]C(=O)C2C=CC=CC=2)=[S:13])[N:10]=[C:9]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[S:8]1)=[N+:2]=[N-:3].NN>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:11]([C:12](=[S:13])[NH2:14])[N:10]=[C:9]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NC(=O)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole-3-carbonothioyl)benzamide (0.737 g, 1.41 mmol) in 20 mL of anhydrous THF was added hydrazine (0.088 mL, 2.82 mmol). The reaction was stirred at room temperature for 3 hours, then concentrated in vacuo. The residue was purified by flash column chromatography (10-20% ethyl acetate/hexanes) to afford the desired product as a pale yellow foam, 0.504 g, 85%.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].CN(C=O)C.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([O:4][CH2:3][CH2:2][N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][CH2:6][O:7][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCNCCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COCCN(CCOCc2ccccc2)Cc2ccccc2)cc1
Reaction time: 8 h

Procedure:
Diethanolamine (42.0 g., 0.4 mole) is stirred under nitrogen in 800 ml. of dry DMF at 0° C. and 50% NaH in mineral oil (57.6 g., 1.2 mole) is added in small portions. After the sodium hydride has reacted, benzyl bromide (205.3 g., 1.2 mole) is added dropwise. The mixture is allowed to come to room temperature while stirring overnight. The reaction mixture is poured into water and is extracted with ether. The ether solution is extracted with dilute HCl. The acid extract is basified with NaOH and extracted with ether. Crude product is recovered by drying, filtering and evaporating the ether. The residual liquid (138.4 g.) is subjected to distillation at 290° C. and 0.01 mm. to remove volatile impurities. This gives 114.4 g. of amber oil.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[CH2:28][CH2:27][CH2:26]2.Br[CH2:35][C:36]([O:38][CH3:39])=[O:37]>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[CH:28]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:27][CH2:26]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: COC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)CC1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of LDA, prepared from diisopropylamine (0.84 ml) and n-butyl lithium (3.44 ml, 1.6M in hexane) in 10 ml of THF at -78° was added dropwise a solution of 6-methoxy-1-tetralone (0.88 g, 5.0 mmol) in 5 ml of THF in an atmosphere of nitrogen. To the stirred solution at -78° was then added methyl bromoacetate (0.5 ml, 6.0 mmole) and the mixture was allowed to warm to room temperature. Aqueous work-up and extraction with ether gave, after chromatography on silica gel, the title compound, m.p. 110`-112°.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]1=[O:27]>>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][CH:17]=[C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:27])=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCN2CCCC2)cc1
Yield: 63.5 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (767 mg, 1.2 equiv.) and 3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 3.11 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (690 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)=[O:28])[CH:5]=[C:6]2[C:10]=1[N:9](C(C1OC=CC=1)=O)[N:8]=[C:7]2/[CH:18]=[CH:19]/[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.N>C(O)C.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)=[O:28])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[CH:18]=[CH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1cc(F)c2c(c1)c(/C=C/c1cccnc1)nn2C(=O)c1ccco1)c1ccco1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(Nc1cc(F)c2[nH]nc(C=Cc3cccnc3)c2c1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
208 mg of furan-2-carboxylic acid{7-fluoro-1-(furan-2-carbonyl)-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol-5-yl}-amide was suspended in 20 mL ethanol, added with 5 mL of concentrated aqueous ammonia and stirred at room temperature overnight. The reaction solution was added with saturated brine, extracted with ethyl acetate, and the organic phase was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated, purified by LC-MS and the obtained crystals were suspended in ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate, and the organic phase was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, to afford 96.2 mg of the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:13][C:14]([F:37])([F:36])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23][C:24]2[CH:35]=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([N:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:36])[F:37])=[CH:21][CH:20]=1)[S:23][C:24]1[CH:35]=[CH:34][CH:33]=[CH:32][C:25]=1[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: CC(C)OC(=O)c1ccccc1SNc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1ccccc1SN(C(=O)NC(=O)c1ccccc1Cl)c1ccc(OC(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
A solution of 2-chlorobenzoyl isocyanate (2.7 g) in dry toluene (5.0 ml) was added to a stirred suspension of isopropyl 2-[[[4-(trifluoromethoxy)phenyl]amino]thio]benzoate (3.7 g) in the same solvent (20.0 ml) at room temperature. After 18 hours, a cake of crystals had formed. The reaction mixture was cooled to -5° C. and filtered, washing the crystals with cold toluene followed by light petroleum. After drying at 40° C. under vacuum, the pure product was obtained as colourless crystals (4.8 g). Melting point 143°-144° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Cl:12])[CH:6]=1)C.[NH2:14][NH2:15]>>[Cl:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[OH:11])[C:4]([NH:14][NH2:15])=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1ccc(O)c(Cl)c1
Product: NNC(=O)c1ccc(O)c(Cl)c1
Yield: 69 %

Procedure:
Ethyl-3-chloro-4-hydroxybenzoate (4.95 g, 25 mmol) was reacted with hydrazine as described for the preparation of intermediate 22b to afford the product as white crystals (3.15 g, 69%). 1H NMR (400 MHz, DMSO-d6, δ in ppm) 10.71 (br s, 1H), 9.64 (br s, 1H), 7.83 (d, J=2.1 Hz, 1H), 7.65 (dd, J=2.1, 8.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 4.43 (br s, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[CH3:30].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:32][CH2:33][N:34]([CH2:21][CH2:20][CH2:19][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:35][CH2:36]2)[CH:27]=[CH:28][C:29]=1[CH3:30]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccc(C)c(C)c4)CC3)nn2-c2ccccc2)cc1

Procedure:
118 mg (85%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(3,4-dimethylphenyl)piperazine (53 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)[CH:20]=[CH:21][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)[CH:18]=3)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)sc2ccc(Cl)cc12
Yield: 39.4 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-chloro-3-methyl-benzothiophene-2-sulfonyl chloride (15 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) giving 8 mg (40%) of the title product. MS (ESI+) calcd for C16H12ClN5O2S2 405.012094, found 405.012744.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.Br[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: OP(O)CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CP(=O)(O)CCCCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 71.6 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (2.0 g, 0.01 mole) in chloroform (40 ml) was added triethylamine (3.2 ml, 0.022 mole) and cooled in an ice bath to 0° C. Trimethyl silyl chloride (2.8 ml, 0.022 mole) was added to the above solution dropwise, followed by benzyl bromoacetate (1.6 ml, 0.011 mole). The ice bath was removed and the mixture stirred at room temperture for 5 hours and poured into 10% aqueous HCl (30 ml) and crushed ice (20 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil (3.5 g) was dissolved in 30 ml ether; hexane was added dropwise to get a turbid solution and left at room temperature overnight to complete the crystallization. The resulting product was cooled in the freezer for 2 hours, filtered and the solid was washed very thoroughly with hexane (50 ml), ether (50 ml) and again very thoroughly with hexane (50 ml), ether (50 ml) in that order. The solid was vacuum dried to get 2.48 g (71%) of title compound, m.p. 68°-70° C. TLC: Silica gel, CH2Cl2 :MeOH:HOAc (20:1:1) shows a single spot at Rf =0.25.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[CH3:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCCCCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: COCCCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 74.2-75.0° C. and MS: m/e=312 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and 5-methoxy-pentylamine.