Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2].[F:16][CH:17]([F:21])[C:18](O)=[O:19].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([O:15][C:18](=[O:19])[CH:17]([F:21])[F:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCC(C2CCC(O)CC2)CC1
Reactant: O=C(O)C(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1CCC(C2CCC(OC(=O)C(F)F)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
In 30 ml of dichloromethane were dissolved 2.2 g (11 mmol) of 4-(4-ethylcyclohexyl)cyclohexanol, 1.9 g (20 mmol) of difluoroacetic acid, and 0.8 g (8 mmol) of triethylamine, and this solution was cooled down to 0° C. To this solution was added dropwise 15 ml of solution of 2.4 g (12 mmol) of dicyclohexylcarbodiimide (DCC) in dichloromethane, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 17 hours. After the crystals in the suspension thus obtained were filtered off, the solvent was distilled off under a reduced pressure. After the residue was purified by column chromatography on silica gel (eluent: heptane/toluene=1/1), the solvent was distilled off, and the residue was subjected twice to recrystallization to give 1.4 g (4.9 mmol) of difluoro-acetic acid 4-(4-ethylcyclohexyl)-cyclohexyl ester. Yield of this compound based on 4-(4-ethylcyclohexyl)cyclohexanol was 45%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:32]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)[C:6]#[N:7]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: COc1cc(C#N)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1O[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
4-Hydroxy-3-methoxybenzonitrile (12 g, 80.2 mmol) and triphenylphosphine (21 g, 80.2 mmol) were added portionwise to an ice-cold solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (15 g, 80.2 mmol) in tetrahydrofuran (225 mL). A solution of diisopropyl azodicarboxylate (16.2 g, 80.2 mmol) in tetrahydrofuran (100 mL) was then added dropwise and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was treated with hydrochloric acid (4M in dioxane, 250 mL). The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with water (100 mL), and the combined aqueous solution was washed with ethyl acetate (2×150 mL), basified to pH10 with solid potassium carbonate and extracted with ethyl acetate (2×250 mL). The combined organic solution was washed with brine (100 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a cream solid in 67% yield, 11.8 g. LRMS ESI m/z 219 [M+H]+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1([C:18]2[CH:53]=[CH:52][C:21]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:30][CH2:31][CH:32]([S:41][C:42]3[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=3)[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH:12]1([C:18]2[CH:53]=[CH:52][C:21]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:30][CH2:31][CH:32]([S:41]([C:42]3[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=3)=[O:9])[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCCCC(CCc1ccccc1OCc1ccc(C2CCCCC2)cc1)Sc1ccc(C(=O)OC)cc1
Solvent: ClCCl
Product: COC(=O)CCCCC(CCc1ccccc1OCc1ccc(C2CCCCC2)cc1)S(=O)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 47 mg (0.19 mmol) of metachloroperbenzoic acid were added to a solution of 113 mg (0.19 mmol) of methyl 4-{[1-(2-{2-[(4-cyclohexylbenzyl)oxy]phenyl}-ethyl)-6-methoxy-6-oxohexyl]sulfanyl}benzoate 187 in 25 ml of CH2Cl2. The mixture was stirred at 0° C. for 30 min, and the cooling bath was then removed and stirring, was continued at room temperature for 16 h. After the reaction had ended, the mixture was washed successively with saturated Na2SO3 solution, saturated Na2CO3 solution, saturated NaCl solution and water. The organic phases were dried over Na2SO4 and the solvent was removed. The product was purified chromatographically (silica gel, cyclohexane/ethyl acetate 2:1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[I:17]N1C(C)(C)C(=O)N(I)C1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([I:17])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Reactant: Cc1ccc(Cl)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c(I)cc(Cl)cc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 158.9 %

Procedure:
To a solution of 5-chloro-2-methylbenzoic acid (10.0 g, 58.6 mmol) in sulfuric acid (75 mL, 1407 mmol) was added portionwise 1,3-diiodo-5,5-dimethylimidazolidine -2,4-dione (12.0 g, 31.6 mmol). The reaction turned very dark and quickly formed a thick suspension. The reaction was stirred for 2 h, at which time it was poured into ice water (˜500 mL) and stirred for 30 min to break up the solids. The precipitate was filtered off, washed with water, and dried under vacuum to give 5-chloro-3-iodo-2-methylbenzoic acid (17.3 g, 50.2 mmol, 86% yield) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.48 (br. s., 1H), 8.11 (d, J=2.27 Hz, 1H), 7.73 (d, J=2.27 Hz, 1H), 2.54 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C@H:26]([OH:39])[CH2:27][O:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH:43]([O:45][CH2:46][CH3:47])=[CH2:44].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[CH2:1]([N:8]([CH2:25][C@H:26]([O:39][CH:43]([O:45][CH2:46][CH3:47])[CH3:44])[CH2:27][O:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)(=[O:31])=[O:30])[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=COCC
Reactant: COC(=O)C[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)C[C@H](O)COS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)O[C@H](COS(=O)(=O)c1ccc(C)cc1)CN(Cc1ccccc1)[C@@H](CC(=O)OC)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-benzyl 4-methyl (2S)-2-[benzyl((2S)-2-hydroxy-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate (43.0 g, 0.0774 mol) in methylene chloride (600.0 mL, 9.360 mol) was added ethyl vinyl ether (14.8 mL, 0.155 mol) followed by pyridinium p-toluenesulfonate (1 g, 0.004 mol). The mixture was stirred at rt for 1 h, concentrated to dry and purified on silical gel (eluting with 0 to 20% EtOAc in hexane) to afford the ether compound (39.7 g, 81.7%). MS (ESI): (M+H)+=628.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].[C:12](Cl)(=O)C(Cl)=O>ClCCl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:12])=[O:7])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cccc(C(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Preparation H11, Step 1: 10 g (0.068 mol) of 3-cyano benzoic acid was taken in 150 ml of dry dichloromethane and cooled to 0° C. Added 50 ml of oxalyl chloride drop wise followed by 5 drops of dry DMF. The reaction mixture was stirred at RT overnight. Dichloromethane was removed and dry methanol (50 ml) was added and stirred at rt for 2 h. Excess methanol was removed and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with 10% of sodium bicarbonate, brine and concentrated to give methyl 3-cyanobenzoate (7 g) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([OH:8])[CH2:3]1.C(=O)(O)[O-].[Na+].Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([OH:8])[CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@@H]1CCC[C@H](O)C1
Reactant: ClCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O[C@H]1CCC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Temperature: 75 °C
Yield: 91.3 %

Procedure:
To a suspension of (1S,3R)-3-aminocyclohexanol (5 g, 43.4 mmol; prepared as described in Tetrahedron: Asymmetry 15 (2004) 2051-2056) and sodium bicarbonate (12.03 g, 143 mmol) in ethanol (100 mL) was added (chloromethyl)benzene (15.01 mL, 130 mmol) at room temperature. The reaction mixture was heated at 75° C. overnight. Upon completion of the reaction as indicated by LCMS and TLC the reaction mixture was filtered and the filtrate concentrated. The residue was then dissolved in DCM (250 mL) and washed with aqueous sodium hydroxide solution (1N, 2×100 mL) and brine (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel chromatography (0%-80% ethyl acetate in hexanes) to yield (1S,3R)-3-(dibenzylamino)cyclohexanol (11.70 g, 91%) as a thick yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.26-7.37 (m, 8H), 7.17-7.22 (m, 2H), 4.56 (d, J=4.30 Hz, 1H), 3.57 (s, 4H), 3.16-3.26 (m, 1H), 2.41 (tt, J=3.17, 11.86 Hz, 1H)), 1.99-2.06 (m, 1H), 1.72 (d, J=8.20 Hz, 2H), 1.63-1.69 (m, 1H), 1.18-1.28 (m, 2H), 0.98 (t, 2H); MS (ESI) m/z 296.4 [M+1]+.
Reaction SMILES: C(O[C:4](=[O:24])[CH:5]([OH:23])[CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])C.[CH2:25]([CH2:27][NH2:28])[OH:26]>C(O)C>[OH:26][CH2:25][CH2:27][NH:28][C:4](=[O:24])[CH:5]([OH:23])[CH:6]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CCOC(=O)C(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Reactant: NCCO
Solvent: CCO
Product: O=C(NCCO)C(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Yield: 58 %

Procedure:
3 g of ethyl-3-phenyl-2-hydroxy-3-(2-nitrophenoxy)-propionate was refluxed with 5.4 ml of ethanolamine in 50 ml of anhydrous ethanol for 20 hours. The solvent was removed under reduced pressure, the residue was taken up with water and the solid collected by filtration. After crystallization from ethyl acetate, 1.8 g of N-(2-hydroxyethyl)-3-phenyl-2-hydroxy-3-(2-nitrophenoxy)-propionamide was obtained, m.p. 166°-188° C. Yield 58%.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[Cl:18]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([Cl:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc(C(=O)O)c1N
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)cc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.1 %

Procedure:
To a mixture of 1.67 g of 2-amino-3-methoxybenzoic acid and 100 ml of N,N-dimethylformamide was added 1.3 g of N-chlorosuccinimide at room temperature, and the resulting mixture was stirred at room temperature for 10 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 1.2 g of 2-amino-5-chloro-3-methoxybenzoic acid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=O>>[CH3:29][N:27]([CH3:28])[C:25](=[O:26])[C:24]1[CH:30]=[CH:31][CH:32]=[C:22]([CH2:20][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:23]=1
Reactant: CN(C)C(=O)c1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CN(C)C(=O)c1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-formyl-N,N-dimethylbenzamide was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N,N-dimethyl-3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]benzamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[N:17]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[C:26](=[O:29])(O)[O-:27].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:16]1[C:21]([NH:22][C:26]([O:27][CH2:15][C:12]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=2)=[O:29])=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[N:17]=1)[S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCOC(=O)C(c1nc(OC)ccc1N)S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(c1nc(OC)ccc1NC(=O)OCc1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 9.45 g (0.026 m) of [3-amino-6-methoxy-pyridin-2-yl]-[toluene-4-sulfonyl]-acetic acid ethyl ester dissolved in 150 mL of methylene chloride is added 150 mL of saturated sodium bicarbonate followed by 5.56 mL (0.038 m) of carbo-benzyloxy chloride. The reaction mixture is stirred for 20 hours at room temperature. The water layer is separated from the organic layer and the organic layer is dried (Na2SO4) and evaporated to yield 15.73 grams of [3-benzyloxycarbonylamino-6-methoxy-pyridin-2-yl]-[toluene-4-sulfonyl]-acetic acid ethyl ester as a yellow solid. 1H NMR (CDCl3) δ 7.8 (m, 1H), 7.6 (m, 1H), 7.3 (m, 10H), 6.7 (m, 1H), 5.2 (m, 3H), 4.0 (m, 2H), 3.3 (s, 3H), 3.1 (m, 2H), 1.1 (m, 3H). TLC (7/3 hexanes/ethyl acetate) Rf=0.6. Step 5:
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.Br[CH2:31][CH:32]1[CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:32]1([CH2:31][O:1][C:2]2[C:3](=[O:29])[C:4]([C:18]3[N:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:21]=[CH:20][CH:19]=3)=[N:5][N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=3)[CH:7]=2)[CH2:34][CH2:33]1
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(OCC2CC2)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.1 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), (bromomethyl)cyclopropane (0.048 mL, 0.50 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 20 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/1) and crystallized from MeOH to give the title compound (103 mg, 91% yield) as colorless prisms: mp 72-78° C.; 1H NMR (300 MHz, CDCl3): δ ppm 0.32-0.47 (2H, m), 0.60-0.76 (2H, m), 1.26-1.39 (1H, m), 4.06 (2H, d, J=7.2 Hz), 7.04 (1H, dd, J=2.3, 8.3 Hz), 7.18 (1H, s), 7.33-7.46 (7H, m), 7.55 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=1.9 Hz), 7.99 (1H, s). LC-MS (ESI) m/z 453 [M+H]+. Anal. Calcd for C24H0F3N4O2.0.5H2O: C, 62.47; H, 4.37; N, 12.14. Found: C, 62.19; H, 4.41; N, 12.15.
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:20])[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[CH:3]=1.[Cu][C:24]#[N:25].O>CN(C=O)C>[C:24]([C:2]1[C:7]2[C:8](=[O:20])[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[CH:3]=1)#[N:25]
Reactant: N#C[Cu]
Reactant: COc1ccc(-c2coc3cc(OC)cc(Br)c3c2=O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2coc3cc(OC)cc(C#N)c3c2=O)cc1
Temperature: 120 °C
Yield: 98.7 %

Procedure:
A suspension of 5-bromo-7-methoxy-3-(4-methoxyphenyl)-4-oxo-4H-1 benzopyran (150 mg), copper(I) cyanide (55.5 mg) in DMF (4 mL) was heated at 120° C. for 3 h. The mixture was cooled, poured into cold water and extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate and brine, and dried over MgSO4. Evaporation of the solvents afforded the title compound (126 mg) as a white solid. 1H NMR (DMSO-d6): 8.52 (s, 1H), 7.67 (d, 1H, J=2.7 Hz), 7.54 (m, 3H), 7.01 (d, 2H, J=8.7 Hz), 3.97 (s, 3H), 3.80 (s, 3H); MS: 308 (MH+); HPLC tR: 2.29 min.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:19][CH:18]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][N:31]([CH3:33])[CH3:32])([OH:34])[C:5]2[C:4]([C:3]([NH:2][CH3:1])=[O:10])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:19][CH:18]=1
Reactant: CNC(=O)c1ccccc1
Reactant: CN(C)Cc1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1C(O)(c1ccc(Cl)cc1)c1ccccc1CN(C)C
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 19.7 g (0.146 mole) of N-methyl benzamide and 400 ml. dry tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5°C. Stirring is initiated and 204 ml. of 1.6 M. n-butyl lithium (~0.321 mole) in hexane is added dropwise over about 1 hour maintaining the temperature below 8°C. The resulting dilithio salt is stirred at 5°C. for an additional hour and then a solution of 40 g. (0.146 mole) of 4'-chloro-2-dimethylaminomethyl benzophenone in 500 ml. tetrahydrofuran is added dropwise over about 1 hour maintaining the temperature between -10 to 10°C. The resulting mixture is stirred at 5°C. for 1 hour longer and 150 ml. of saturated ammonium chloride is added maintaining the temperature at about 10°C. The layers are separated and the organic phase dried over ahydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is crystallized from ether to give α-(4-chlorophenyl)-α-(2-dimethylaminomethyl phenyl)-α-hydroxy-N-methyl-o-toluamide; m.p. 154°-156°C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O>[N:1]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=3)=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCOC(=O)c1coc(-c2ccc(CCl)cc2)n1
Reactant: c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc(-c2ccc(Cn3ncc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of indazole (0.244 g, 2.07 mmol) in DMF at 0° C. was treated with sodium hydride (0.076 g, 1.98 mmol), stirred for 10 minutes at room temperature, treated with ethyl 2-[4-(chloromethyl)phenyl]-1,3-oxazole-4-carboxylate (0.5 g, 1.88 mmol) and stirred at 80° C. overnight. The reaction mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated in vacuo to give a solid residue. The resultant residue was purified by column chromatography (silica, EtOAc:hexanes, 50%) to give ethyl 2-[4-(1H-indazol-1-ylmethyl)phenyl]-1,3-oxazole-4-carboxylate as white solid. The resulting solid (0.45 g, 1.29 mmol) was dissolved in 1:1 MeOH:THF treated with 1.0 M LiOH for 3 hours at 60° C. and concentrated in in vacuo. The resulting residue was diluted with water, treated with 1.0 M HCl and filtered to afford the title product 92% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 320 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.[N:18]#CBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:1]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1)#[N:18]
Reactant: Cc1ccc2onc(C3CCN(C)CC3)c2c1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc2onc(C3CCN(C#N)CC3)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
A suspension of 0.5 g of 3-(1-methyl-4-piperidyl)-5-methyl-1,2-benzisoxazole, 0.37 g of cyanogen bromide and 1.5 g of potassium carbonate in 50 ml of chloroform was heated under reflux for 48 hrs and stirred at room temperature for 48 hrs. The reaction was filtered, the solvent was removed and the residue was triturated with hexane to give a solid. The solid was recrystallized from hexane (three times) to give 0.178 g (37%) of product, mp, 125°-126°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:17]=[CH2:18])[CH:13]=2)[N:8]=1.Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12](/[CH:17]=[CH:18]/[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:13]=2)[N:8]=1
Reactant: C=Cc1ccc2nc(NCc3ccccc3OC)ccc2c1
Reactant: Brc1cccnc1
Product: COc1ccccc1CNc1ccc2cc(/C=C/c3cccnc3)ccc2n1

Procedure:
(2-Methoxy-benzyl)-(6-vinyl-quinolin-2-yl)-amine (240 mg, 0.828 mmol) was reacted with 3-bromopyridine (170 mg, 1.08 mmol) as described in example 2 step B. The title compound was obtained as a yellow waxy solid (100 mg, 33%), MS: m/e=368.0 (M+H+).