Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[CH2:2]([N+:8]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1C=[C:31]2[C:33]([O:35]C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)[C:30]2=CC=1)=[O:34].C(O)(=O)C=C>CO>[C:33]([O-:35])(=[O:34])[CH:31]=[CH2:30].[CH2:21]([N+:8]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: C=CC(=O)O
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: [OH-]
Solvent: CO
Product: C=CC(=O)[O-]

Procedure:
The AgOH is resuspended in 400 ml of methanol. The purified tetraalkylammonium iodide (0.1 moles or 48.2 g) (Aldrich Chemical Co., Milwaukee, Wis.) is dissolved separately in 100 ml. of methanol and added to the AgOH suspension. Almost immediately, the AgOh develops a greenish cast. The mixture is stirred for an hour and then filtered through a sintered-glass funnel. The filtrate now contains 0.1 moles of tetrahexylammonium hydroxide. A small amount of phenophthalein is added, turning the solution red indicating that the solution is basic. Acrylic acid is added until the red color disappears. The methanol is removed by evaporation in a rotary flash evaporator leaving tetrahexylammonium acrylate. The resulting tetrahexylammonium acrylate was found to be electrically conductive.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]3[N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[N:22]=[C:23]([CH3:24])[C:18]3=[C:17]([C:31](=O)[CH3:32])[CH:16]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCl.C(O)(=O)C>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([CH:31]([C:17]2[CH:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[F:34])[N:20]=[C:19]3[N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[N:22]=[C:23]([CH3:24])[C:18]=23)[CH3:32])[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2F)nc2c1c(C)nn2C1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(C)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 40 °C
Reaction time: 8 h
Yield: 16.8 %

Procedure:
A mixture of 1-[6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-ethanone (390 mg), acetic acid (25 μL), piperazine-1-carboxylic acid tert-butyl ester (158 mg) and sodium triacetoxy borohydride (270 mg) in dichloromethane (7.5 mL) was stirred at 40° C. overnight. Then additional triacetoxy borohydride (90 mg) was added. The reaction mixture was concentrated in a membrane pump vacuum, and the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) giving 4-{1-[6-(4-Benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester (90 mg). This material was dissolved in methanol (5 mL), purged with argon, then with hydrogen and palladium (10% on charcoal, 8 mg) was added. The reaction mixture was stirred at 40° C. until the reaction was complete (according to HPLC/MS). The catalyst was filtered off and the filtrate was concentrated in a membrane pump vacuum. The residue was taken up in THF (2 mL), and conc. hydrochloric acid (1 mL) was added. The solution was stirred at r.t., then the solvents were evaporated and the residue was purified by preparative HPLC (C18 column, acetonitrile/water gradient) giving 3-fluoro-4-[3-methyl-4-(1-piperazin-1-yl-ethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol (30 mg, 9%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34]>>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: Fc1ccc(OCCCBr)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc(F)cc3F)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.796 g of 1-(3-bromopropoxy)-2,4-difluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.13 (1:2 EtOAc-heptane); Rt=5.12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]1=2.C(N(C(C)C)CC)(C)C.O>C(Cl)Cl>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([N:15]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3[CH:22]=[CH:23][CH:24]=[CH:25][C:16]2=3)(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])([O-:14])=[O:13]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.9 %

Procedure:
To 4-chloro-3-nitrobenzenesulfonyl chloride (1.0 g, 3.9 mmol) in dry DCM (10 mL), was added 2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.57 g, 3.9 mmol). Diisopropylethylamine (1.3 mL, 7.8 mmol) was added and the mixture was stirred at ambient temperature for 16 hrs. DCM (20 mL) and 30 mL of water were added. The DCM layer was separated, washed with brine (20 mL×2), dried over MgSO4 and evaporated to give 1-(3-nitro-4-chloro-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine 4-1 as a yellow solid (1.3 g, 85% yield). MS: 367 (M+H)+; tR=2.98 min (method 1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[N:25]=[CH:24][N:23]([CH3:26])[N:22]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:34])[NH:12][C:11]([C:21]2[N:25]=[CH:24][N:23]([CH3:26])[N:22]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(CBr)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Yield: 39.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(1-methyl-1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (5 g, 12 mmol) was reacted with NBS (2.1 g, 12 mmol) in chloroform (150 mL) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (2.4 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[O:26][CH2:27][CH:28]([CH3:29])[CH3:30])#[N:24]
Reactant: CC(C)COc1ccc(N)cc1C#N
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(OCC(C)C)c(C#N)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
1-(4-Fluorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g), 5-amino-2-isobutoxybenzonitrile (1.7 g), triethylamine (2.7 g) and diethyl cyanophosphate (2.2 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (1.2 g), melting point: 177–178° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:51]1([CH2:57][NH:58][CH2:59][CH:60]=[CH2:61])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C.C(OCC)(=O)C>[O:12]=[C:10]([N:58]([CH2:57][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:59][CH:60]=[CH2:61])[CH2:9][N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Reactant: C=CCNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCN(Cc1ccccc1)C(=O)CN(Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-N-(phenylmethyl)glycine (D88, 1.06 g, 4.0 mmol), DIPEA (1.38 ml, 8.0 mmol) and TBTU (1.61 g, 5.0 mmol) in dry DMF (8 ml) was stirred at room temperature for 30 min. Then N-(phenylmethyl)-2-propen-1-amine (D87, 647 mg, 4.4 mmol) was added and stirring was continued for another 2 h. After reaction was completed, ethyl acetate was added and the organic layer was washed with water and brine. The residue was purified via flash chromatography to give the title compound (1.50 g, 95%). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.4-7.2 (m, 10H), 5.8-5.5 (m, 1H), 5.2-5.0 (m, 2H), 4.7-4.3 (m, 4H), 4.1-3.7 (m, 4H), 1.5 (s, 9H); MS: (ES/+) m/z: 295 [M-BOC+], C24H30N2O3 requires 394.
Reaction SMILES: C([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[N:9][CH:8]=[CH:7][CH:6]=2)C.O.[OH-].[Li+]>CO.O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([S:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][N:4]2[C:5]3[C:10](=[N:9][CH:8]=[CH:7][CH:6]=3)[C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:3]2)=[CH:26][CH:27]=1
Reactant: CCc1c(C(=O)O)c(=O)c2ncccc2n1Cc1ccccc1Sc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(Cc2ccccc2Sc2ccc(Cl)cc2)c2cccnc2c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.6 %

Procedure:
To a light brown solution of ethyl 1-(2-(4-chlorophenylthio)benzyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (26) (203 mg, 0.450 mmol) in methanol (20 mL) was added the solid lithium hydroxide monohydrate (189 mg, 4.5 mmol) at room temperature. The resulting light brown solution was stirred for 15 h at room temperature at which time LCMS analysis indicated the absence of starting material. Then, it was diluted with water and the methanol was removed under vacuum. The resulting light brown solids were difficult to dissolve in 1.0N NaOH and water, but it was dissolved in dimethylformamide (approx. 10 mL) and the solution was diluted with water (approx. 100 mL). Then, the resulting basic aqueous solution was neutralized with 1.0N HCl. The resulting solids were collected by filtration and washed with water and hexanes. After air drying, 102 mg of 1-(2-(4-chlorophenylthio)benzyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (27) (53.6% yield) was isolated as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](Cl)=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.[NH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([NH:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1
Reactant: NN1CCCCC1
Reactant: O=C(Cl)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NN1CCCCC1)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
Part D: Crude 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carbonyl chloride (919 mg, ˜2.39 mmol), 1-aminopiperidine (0.469 g, 4.69 mmol) and triethylamine (0.363 g, 3.59 mmol) are dissolved in dichloromethane and stirred for one hour at room temperature. The mixture is washed with a saturated aqueous NaHCO3 solution (3×20 mL), dried over Na2SO4 and concentrated in vacuo and further purified by column chromatography (ethyl acetate, silicagel) to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide (356 mg, 26% yield (based on ethyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate). Mass Spectrometry (MS): 449.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]CC)=[O:26])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[K+].C(O)C.O.Cl>O>[CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)OCC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)O)cc1

Procedure:
A mixture of 6.0 g. of ethyl (4-hexadecylaminophenyl)acetate, 7.0 g. of potassium hydroxide and 100 ml. of ethanol-water (9:1) is heated to reflux for 4 hours. While hot, the mixture is adjusted to pH 7 with conc. hydrochloric acid. The mixture is diluted with water cooled and filtered. Recrystallization of the precipitate yields (4-hexadecylaminophenyl)acetic acid.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[CH:17]=[N:16][CH:15]=[N:14][C:13]=2[NH:12][CH:11]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH:24]=O.C(O)(=O)C.C([BH3-])#N>C(O)C>[F:1][C:2]1[N:7]=[C:6]([NH:8][CH2:24][C:23]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[CH:17]=[N:16][CH:15]=[N:14][C:13]=2[NH:12][CH:11]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: Nc1ccc(Cc2c[nH]c3ncncc23)c(F)n1
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(CNc2ccc(Cc3c[nH]c4ncncc34)c(F)n2)cc(OC)c1OC

Procedure:
In a 2 mL microwave vial, 6-fluoro-5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-ylamine (68, 9.72 mg, 0.04 mmol) and 3,4,5-trimethoxy-benzaldehyde (69, 15.7 mg, 0.08 mmol) were dissolved in 600 μL of 95:5 ethanol:acetic acid, and silica supported cyanoborohydride (50 mg, 1 mmol/g, 0.05 mmol) was added. The reaction was irradiated for 10 minutes at 160° C. in a microwave. The vial was centrifuged to condense the silica and the supernatant was removed by pipette into another vial. The residual silica was rinsed with 500 μL of ethanol, centrifuged and the supernatant added to the first supernatant. The solvents were removed under vacuum and the resulting material dissolved in dimethyl sulfoxide for purification by HPLC. Samples were purified on Phenomenex C18 column (50 mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H+]+=424.3.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:9][N:10]1[CH2:11][CH2:12][CH:13]([C:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:24])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccnc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](Cc1cccnc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {(R)-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-pyridin-3-ylmethyl-ethyl}-carbamic acid tert-butyl ester (0.149 g, 0.34 mmol) in dichloromethane (2 ml) is added trifluoroacetic acid (0.5 ml) and the reaction mixture stirred at ambient temperature for 1 hour. The reaction mixture is evaporated and the residue takeup in hydrochloric acid (1M), the solution basified with sodium hydroxide solution (4M) and the precipitate extracted into dichloromethane. The dichloromethane was dried over magnesium sulphate and evaporated to afford [1-((R)-2-amino-3-pyridin-3-yl-propyl)-piperidin-4-yl]-(4-fluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 1.63-1.85 (m 4H), 1.88-2.00 (m 1H), 2.08-2.32 (m 5H), 2.50 (dd J 13.5 7.9 1H), 2.67 (dd J 13.5 4.9 1H), 2.78-2.98 (m, 2H), 3.04-3.20 (m, 2H), 7.04 (t J 8.8 2H), 7.17 (dd J 6.9 4.9 1H) 7.48 (d J 7.9 1H), 7.88 (dd, J 8.8 5.4 2H), 8.33-8.45 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[O:19]([C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC(C1C(C)=C2C(NC3C=CC(SC4N(C)C=CN=4)=C(Cl)C=3)=C(C#N)C=NN2C=1)=O)C.CN(C=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:31][N:30]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(Oc2ccccc2)cn1
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Agent: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2c1C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cn3)c2c1C
Yield: 50.8 %

Procedure:
Compound 429 (21 mg, 51%) was prepared from 4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (Example 1D) (26 mg, 0.1 mmol) and 429C (210 mg, 1.0 mmol) by a route analogous to that used for the preparation of compound 426, DMF (1 ml) was used as solvent instead of THF. 429 is a yellow solid and has a retention time of 6.24 min (standard LC1 method, 8 min run). MS Found: (M+H)+=414.2
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[OH:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[OH:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:16]=[CH:15][CH:14]=[C:4]([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Reactant: OB(O)c1cccc(O)c1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2cccc(O)c2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 2 using tert-butyl N-(3-bromobenzyl)carbamate instead of tert-butyl N-(4-bromobenzyl)carbamate and 3-hydroxyphenylboronic acid instead of 3-benzyloxyphenylboronic acid.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([Sn:7](Cl)(Cl)[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6].[Cl].[Cl].[Cl].C([Sn])CCC>C1(C)C=CC=CC=1>[CH2:3]([Sn:7](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6]
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Reactant: [OH-]
Agent: CCCC[Sn]
Agent: [Cl]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCC[Sn](=O)CCCC
Temperature: 75 °C
Yield: 97 %

Procedure:
The same apparatus as used in Example 1 was employed. To the flask were continuously fed 1,300 g of 16% aqueous sodium hydroxide solution and 5,504 g of a toluene solution which had been prepared by dissolving, in 3,592 g of toluene, 1,912 g of di-n-butyltin dichloride containing 1.5% tri-n-butyltin chloride and 1.0% mono-n-butyltin trichlorine. The above feeding was performed with stirring and heating at 75° C., to conduct hydrolysis for 60 minutes. The resulting reaction mixture overflowed was allowed to stand, thereby splitting into three distinct phases. The specific gravities of the upper, intermediate and lower phases were 00.6, 1.1 and 1.2, respectively. These three phases were separated from one another and then subjected to the same treatments as in Example 4. As a result, the lower phase gave 1,520 g of di-n-butyltin oxide having a purity of 99.8% and an average particle diameter of 80 μm; the intermediate phase gave 2.6 g of mono-n-butyltin oxide having a purity of 95.9%; and the upper phase gave 5.9 g of bis(tri-n-butyltin) oxide having a purity of 95.6%. The total yield based on the starting material was 99.2%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH:23]([N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:15])[C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25]
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)C(Nc1ccccc1)c1ccccc1Cl
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)OC(C)(C)C)c2ccccc2Cl)c1
Yield: 39.1 %

Procedure:
The procedure is as in Example 1, but using 2.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 3.2 g of tert-butyl (RS)-2-anilino-2-(2-chlorophenyl)acetate and 0.72 cm3 of thionyl chloride as starting materials. The product obtained is purified by chromatography on 100 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter [eluent: dichloromethane/methanol (99/1 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 10-cm3 fractions. Fractions 7 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue obtained is recrystallized from a mixture of acetonitrile and isopropyl ether (10/90 by volume). 2 g of tert-butyl (RS)-2-(2-chlorophenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 181° C. are then obtained.
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:9][CH2:8][NH:7][C@H:6]1[CH3:10])([CH3:4])[CH3:3].[Cl:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>>[Cl:11][C:12]1[CH:19]=[C:18]([N:7]2[CH2:8][CH2:9][C@H:5]([C:2]([OH:1])([CH3:4])[CH3:3])[C@@H:6]2[CH3:10])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(Cl)c1

Procedure:
Using compound 1 and 2-chloro-4-fluorobenzonitrile as starting materials, the title compound was obtained by the same manner as shown in Example 1.