Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2ccc(Br)cc2)c1
Temperature: 75 °C
Yield: 39.5 %

Procedure:
To a magnetically stirring solution of 3-cyanophenyl boronic acid (0.62 g, 4.24 mmol) and 1-bromo-4-iodobenzene (1.0 g, 3.53 mmol) in anhydrous DMF (7.0 mL), under argon at room temperature, was added 2M sodium carbonate solution (7.0 mL) followed by Pd(PPh3)4 (0.21 g, 0.18 mmol). The resulting mixture was heated to 75° C. overnight. The resulting dark reaction mixture was cooled to room temperature filtered to remove the solids and the resultant filtrate was poured into water (50 mL) and extracted with EtOAc (2×25 mL). The organics were washed with water (50 mL) and brine (50 mL) then dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (5% EtOAc in Hexanes) to yield the intermediate bromide as a white solid (0.36 g, 33%). 1H NMR (CDCl3): δ 1H NMR (CDCl3) δ: 7.43 (d, J=7.4 Hz, 2H), 7.53-7.67 (m, 4H), 7.76-7.84 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:11][C:10](=O)[CH2:9][C:8](=[O:13])[CH2:7]2)=[CH:2]1.C([O-])(=O)C.[NH4+:18]>C(O)C>[NH2:18][C:10]1[CH2:11][CH:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:7][C:8](=[O:13])[CH:9]=1
Reactant: O=C1CC(=O)CC(c2ccsc2)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2ccsc2)C1
Yield: 95.7 %

Procedure:
A mixture of 5-(3-thienyl)cyclohexane-1,3-dione (10.5 g) and ammonium acetate (13.1 g) in ethanol (200 ml) was refluxed for 16 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 ml). The resulting crystals were filtered, washed with water and toluene, and dried to give 1-amino-5-(3-thienyl)cyclohexen-3-one (10 g) as pale yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24].[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 54.9 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), isoamylamine (0.234 g, 2.69 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, and dissolve it in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate to give the title compound (0.484 g, 54.9%): TOF MS ES+ 345.2 (M+H)+, HRMS calcd for C18H25N4O3 345.1927 (M+H)+, found 345.1938, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=10.1 min, 95.4% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH2:15]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.O>[CH2:15]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][C:28]([C:29]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=4[O:13][CH3:14])[N:1]=3)=[CH:31][CH:32]=2)[CH2:23][CH2:24]1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN1CCN(c2ccc(C=O)cc2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCN1CCN(c2ccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)cc2)CC1
Temperature: 155 °C
Yield: 13 %

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (6) (1.19 mmol) in DMA (10 mL) was added 4-(4-butylpiperazin-1-yl)benzaldehyde (5) (1.09 mmol), NaHSO3 (1.30 mmol), and p-TsOH (0.10 mmol). The resulting solution was heated to 155° C. for 4 hours and cooled to room temperature. The solution was diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel eluting with 10% to 50% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the compound 7 (0.06 g, 13%). 1H NMR (300 MHz, DMSO-d6): δ 11.76 (s, 1H), 8.09 (d, J=8.9 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.17-3.42 (m, 4H), 2.39-2.58 (m, 4H), 2.23-2.37 (m, 2H), 1.37-1.56 (m, 2H), 1.26-1.37 (m, 2H), 0.84-0.94 (m, 3H). APCI MS m/z 423 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](C=O)=[CH:5][C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.[C:27]([C:32]1C=CC=C[C:33]=1P(=C)(C1C=CC=CC=1)C1C=CC=CC=1)([O:29][CH2:30][CH3:31])=[O:28].C(OCC)C>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:27](=[O:28])[CH:32]=[CH:33][C:4]1[C:3]([O:2][CH3:1])=[CH:16][C:15]2[CH:14]3[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)[CH:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:7][C:6]=2[CH:5]=1)[CH3:31]
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1C(=O)OCC
Reactant: COc1ccc(C2Cc3cc(C=O)c(OC)cc3C3CCCCC23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C=Cc1cc2c(cc1OC)C1CCCCC1C(c1ccc(OC)cc1)C2
Yield: 74.6 %

Procedure:
Combine 3-Methoxy-9-(4-methoxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthrene-2-carbaldehyde (1.77 g, 5.13 mmol), carboethoxy-methylene triphenylphosphorane (03.19 g, 9.03 mmol) in toluene (53 ml) and reflux 15 hours. Remove solvent in vacuo, slurry with diethyl ether and chromatograph the residue from the concentrated filtrate on silica gel with 20% ethyl acetate/hexanes, then 25% ethyl acetate/hexanes to yield the titled compound (1.61 g, 76%). MS m/z 421(M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].[CH2:9]([O:16][C:17](ON1C(=O)CCC1=O)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([O:16][C:17]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](CCO)C(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6 g (50.4 mmol) of L-homoserine were largely dissolved in 50 ml of DMF and treated at 0° C. in portions with 12.56 9 (50.4 mmol) of N-(benzyloxycarbonyloxy)succinimide. The mixture was stirred at 0° C. for 1 h, then at RT for 48 h. The solvent was distilled off and the residue was partitioned between EA and a saturated NaCl solution. The organic phase was washed with saturated NaCl solution, with 5% strength citric acid and again with saturated NaCl solution, dried, filtered and concentrated. The crystalline residue was stirred in ether, filtered off with suction, and washed with ether and pentane. Yield: 9.55 g (75%).
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]([CH2:17][CH3:18])[CH2:14][O:15][CH3:16])[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:7]1[C:6]2[C:2]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)=[CH:3][N:4]([CH:13]([CH2:17][CH3:18])[CH2:14][O:15][CH3:16])[C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Reactant: CCC(COC)n1cc(I)c2c(OC)nccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(COC)n1cc(-c2ccc(C#N)cc2)c2c(OC)nccc21
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(1-methoxybutan-2-yl)-1H-pyrrolo[3,2-c]pyridine (200 mg) obtained in Step A-2 of Example 17 in DMF (4 mL)/water (0.40 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (191 mg), tetrakis(triphenylphosphine)palladium(0) (64.2 mg) and potassium carbonate (154 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (40.0 mg).
Reaction SMILES: F[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].CCN(CC)CC.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.Cl>O>[CH:22]1([NH:25][C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=2[C:4]([OH:6])=[O:5])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)c1c(F)ccc([N+](=O)[O-])c1NC1CC1
Temperature: 25 °C
Reaction time: 28 h
Yield: 71.2 %

Procedure:
To a solution of 2,6-difluoro-3-nitrobenzoic acid (1.0 g, 4.92 mmol) in IMS (5 mL) and water (5 mL) were added Et3N (1.23 mL, 8.86 mmol) and cyclopropylamine (360 μL, 5.17 mmol). The reaction mixture was stirred at RT for 28 h. The pH of the solution was adjusted to 1 by addition of 1M aqueous HCl. A precipitate formed and this solid was collected by filtration, washing with water to afford the title compound (841 mg, 71%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.78 (1H, s), 8.28 (1H, dd, J=9.45, 5.85 Hz), 6.49 (1H, m), 2.84 (1H, m), 0.85 (2H, m), 0.68 (2H, m)
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([NH:26][CH3:27])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([N:26]([CH3:27])[S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:28][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CNc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (1.0 g, 4.53 mmol) was treated with 4-(benzyloxy)-N-methylaniline (1.45 g, 6.8 mmol) and DIPEA (0.59 g, 4.53 mmol) using method A to give 4-(N-(4-(benzyloxy)phenyl)-N-methylsulfamoyl)benzoic acid as an off white solid. Yield: 716 mg (40%). 1H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.46-7.30 (m, 5H), 7.01-6.94 (m, 4H), 5.08 (s, 2H), 3.13 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[N:4]=1.[CH3:23][NH:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:25]([N:24]([CH3:23])[C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:21])([F:1])[F:22])=[N:4]2)=[CH:20][CH:19]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCNC
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: CCCCN(C)C(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid and N-methylbutylamine using a similar procedure to that described for Example 2.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:15])[CH2:11][N:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[NH:16]1C=CN=[CH:17]1>C(O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10](=[O:15])[CH2:11][N:12]2[CH:14]=[CH:17][N:16]=[CH:13]2)=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: CN(C)CC(=O)Cc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(Cc1ccc(F)cc1)Cn1ccnc1
Yield: 54.1 %

Procedure:
A solution of product from step B (7.80 g, 36.6 mmol) in ethanol (30 ml) and water (30 ml) containing imidazole (12.4 g, 183.0 mmol) was heated under reflux for 6 hrs. The mixture was allowed to cool and partitioned between dichloromethane (100 ml) and water (100 ml), the organic phase was washed with brine (5×100 ml) separated and dried (MgSO4). Evaporation of the residue left a yellow oil. This was purified by chromatography (Biotage flash 40, 90 g, SiO2 cartridge) eluting with a gradient of 0-5% methanol/dichloromethane to give 1-(4-fluorophenyl)-3-(imidazol-1-yl)propanone as a yellow oil 4.32 g (54%).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11](OS(C(F)(F)F)(=O)=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3c(OC(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(N4CCOCC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in the example 363 was used, starting from Trifluoro-methanesulfonic acid 1-isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl ester and Morpholine to give 5 mg of (1-Isopropoxy-6-morpholin-4-yl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 368 (MH+).
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)=[O:4].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].O>CN(C)C=O>[Cl:11][C:10]1[C:5]([C:3](=[O:4])[CH:2]([N:18]2[C:17](=[O:19])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:24])[CH3:13])=[N:6][CH:7]=[C:8]([Cl:12])[CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(Br)C(=O)c1ncc(Cl)cc1Cl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)c1ncc(Cl)cc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
To 5.00 g of 2-bromo-1-(3,5-dichloropyridin-2-yl)-1-propanone in 20 ml of N,N-dimethylformamide, 3.27 g of potassium phthalimide was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was mixed with 50 ml of water and extracted with ethyl acetate (50 ml×2), and the resulting organic layers were combined, washed with water (30 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 2.02 g of the desired crude product as brown crystals. The crystals were used in the next step without further purification.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Br:18])[CH:12]=1)[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.ClCl.[OH-].[Na+]>C(O)(=O)C>[CH3:2][N:3]([CH2:10][C:11]1[CH:16]=[C:15]([Cl:1])[C:14]([OH:17])=[C:13]([Br:18])[CH:12]=1)[CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: Cl
Reactant: CN(Cc1ccc(O)c(Br)c1)C1CCCCC1
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(Cc1cc(Cl)c(O)c(Br)c1)C1CCCCC1
Temperature: 0 °C

Procedure:
3.6 gm of N-methyl-N-cyclohexyl-3-bromo-4-hydroxy-benzylamine hydrochloride were dissolved in 50 ml of 90% acetic acid and admixed with a solution of 0.85 gm of chlorine in 15 ml of glacial acetic acid while cooling with ice water. After stirring for a short time, the solution was poured into a mixture of ice and 10 N sodium hydroxide solution and extracted three times with methylene chloride. The organic phase was evaporated to dryness. The residue was purified by means of column chromatography over silicgel with ethyl acetate as the eluant, yielding N-methyl-N-cyclohexyl-3-bromo-5-chloro-4-hydroxy-benzylamine, m.p. 136°-138° C., of the formula ##STR24## after recrystallization from ethanol/ether.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[CH3:11])[N:7]=[C:6]([NH:14][C@H:15]([CH2:17][CH3:18])[CH3:16])[CH:5]=1.[OH-].[Li+].Cl>CO>[C@@H:15]([NH:14][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:13])([F:12])[CH3:11])[N:7]=1)[C:3]([OH:19])=[O:2])([CH2:17][CH3:18])[CH3:16]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(C(C)(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(C(C)(F)F)n1
Yield: 95 %

Procedure:
Dissolve (S)-2-sec-butylamino-6-(1,1-difluoroethyl)-isonicotinic acid methyl ester (200 mg, 0.73 mmol) in methanol (3 mL). Slowly add 1 N lithium hydroxide (1.0 mL) and stir overnight at room temperature. Acidify the mixture to about pH=6 by 5 N HCl and concentrate to near dryness. Dilute with ethyl acetate (20 mL) and wash the organic layer with saturated aqueous sodium chloride. Dry (magnesium sulfate) and concentrate to give the title compound as a solid (95%).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C[O:20][C:21]1[CH:41]=[CH:40][C:24]2N=C(NC(=O)CC(=O)C3C=CC=CC=3)[S:27][C:23]=2[CH:22]=1>>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH2:22][C:21](=[O:20])[C:41]1[S:27][CH:23]=[CH:24][CH:40]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Product: CCOP(=O)(OCC)C(CCC(=O)c1cccs1)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I) ,and 2-acetylthiophene (II, 0.76 ml); MS (m/e) 426, 381, 315, 289, 261, 152 and 111; IR (neat) 1663, 1518, 1478, 1443, 1416, 1392, 1368, 1355, 1250, 1164 and 1142 cm-1 ; NMR (CDCl3) 7.77, 7.62, 7.12, 4.2, 3.32, 2.58, 2.36 and 1.33 67 ; CMR (CDCl3) 192, 144, 133.5, 135.5, 128, 62, 38, 32.5 (t), 20.5 and 16 δ.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][CH:3]=[C:2]1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(O)C>[C:13]1([NH:19][N:20]=[CH:6][C:5]2[S:1][C:2]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)=[CH:3][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: NNc1ccccc1
Solvent: CC(C)O
Product: C(=NNc1ccccc1)c1ccc(-c2cccs2)s1
Temperature: 25 °C

Procedure:
A mixture of 2,2′-bithiophene-5-carboxaldehyde (5.0 g, 0.0257 mole, obtained from TCI Europe nv, Boerenveldseweg 6, 2070 Zwijndrecht) and 10 ml of 2-propanol was added to a 100 ml, 2 neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. Heat was applied until all 2,2′-bithiophene-5-carboxaldehyde entered into solution. After all 2,2′-bithiophene-5-carboxaldehyde was dissolved, a hot solution of phenylhydrazine (3.05 g, 2.78 ml, 0.0309 mole, obtained from Aldrich) in 3 ml of 2-propanol was added to the 2,2′-bithiophene-5-carboxaldehyde solution. After the reaction mixture was refluxed for 6 hours, the mixture was cooled to room temperature. The crystals formed were filtered off, and then washed with a mixture of 2-propanol and hexane in 1:1 ratio by volume. The yield of the product, 2,2′-bithiophene-5-carboxaldehyde N-phenylhydrazone, was 6.95 g (94.9%). The product was recrystallized from 2-propanol and dried at 60° C. in a vacuum oven for 6 hours. The melting point of the product was found to be 156-158° C. An infrared absorption spectrum of the product was characterized by the following absorption wave numbers (KBr window, cm−1): 3306 (NH); 3104, 3061 (CHaromatic); 1599 (C═C, C—N). A 1H-NMR spectrum (300 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 7.77 (s, 1H, CH═N); 7.30-7.00 (m, 9H, Ph, Ht, NH); 6.95 (d, 1H, Ht); 6.87 (t, 1H, 4-H Ph). An elemental analysis yielded the following results in weight percent: C, 63.50; H, 4.16; N, 9.97, which compares with the following calculated elemental weight percent for a compound with the formula C15H12N2S2: C, 63.35; H, 4.25; N, 9.85.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([OH:17])=O)[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C@@H:26]1[NH:31][CH2:30][CH2:29][N:28]([C:32]2[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:27]1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:31]3[CH2:30][CH2:29][N:28]([C:32]4[C:37]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:27][C@@H:26]3[CH3:25])=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H]1CN(c2ncccc2C(F)(F)F)CCN1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Product: C[C@H]1CN(c2ncccc2C(F)(F)F)CCN1C(=O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1

Procedure:
In analogy to example 73, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was converted to the acid chloride and subsequently reacted with (S)-3-methyl-1-(3-trifluoromethyl-pyridin-2-yl)-piperazine to give the title compound as a colorless solid. MS: 580.3 ([M+H]+)
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O1CCCC1.C([Li])CCC.[CH2:20]1[CH2:30][CH2:29][C:23](=[C:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)[CH2:22][CH2:21]1>O>[CH:24]1([C:23]2([CH:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)[CH2:29][CH2:30][CH2:20][CH2:21][CH2:22]2)[CH:25]=[CH:26][CH:27]=[CH:28]1
Reactant: C1=CC(=C2CCCCC2)C=C1
Reactant: C1=Cc2ccccc2C1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C1=CC(C2(C3C=Cc4ccccc43)CCCCC2)C=C1
Reaction time: 3 h
Yield: 68.8 %

Procedure:
Indene (5.8 g, 50 mmole) was placed in a 250 ml round bottom flask with 50 ml of THF (tetrahydrofuran). 34.3 ml (1.6 M, 55 mmole) of n-butyl lithium (n-BuLi) was added into the solution under an ice bath. The mixture turned orange red. The ice bath was removed and the mixture was stirred for 3 hours. 6.7 g of 6,6-pentamethylenefulvene (46 mmole) was added gradually to the mixture. After stirring for 24 hours, 1 ml of water was added to the mixture to terminate the reaction. The reaction mixture was stripped under vacuum to remove solvent, washed with 100 ml of pentane, and filtered to remove the salt. The crude product (i.e., filtrate) was purified by column chromatography (the packing was 20 g of silica gel, the eluent was 100% pentane). The solution was then concentrated under reduced pressure to obtain a pale yellow liquid (8.3 g, yield=69%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[N-:12]=[N+]=[N-].[Na+].CCOC(C)=O>C1C=CC=CC=1.OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:12][CH2:6][CH2:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2cc(Br)ccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C1NCCc2cc(Br)ccc21

Procedure:
To a rapidly stirred solution of 5-bromo-1-indanone (Aldrich) (15.0 g, 71.1 mmol) in benzene (200 mL) and H2SO4 (38 mL) was added NaN3 portionwise over 20 minutes. The mixture was diluted EtOAc, washed with water then brine, dried and evaporated. Chromatography of the residue (silica gel; hexane/EtOAc 1:1) afforded the title compound as a solid.