Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[S:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:14]=1>>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:14]=[C:10]([O:1][CH2:2][C:3]3([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]3)[S:11][CH:12]=2)=[CH:16][CH:17]=1
Reactant: OCC1(CO)CCC1
Reactant: Cc1ccc(-c2csc(Cl)n2)cc1
Product: Cc1ccc(-c2csc(OCC3(CO)CCC3)n2)cc1

Procedure:
The title compound was prepared using the same experimental procedure as in example 25a from [1-(hydroxymethyl)cyclobutyl]methanol and 2-chloro-4-(4-methylphenyl)-1,3-thiazole. 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J=8 Hz, 2H), 7.16 (d, J=8 Hz, 2H), 6.78 (s, 1H), 4.62 (s, 2H), 3.77 (t, J=7 Hz, 1H), 3.60 (d, J=7 Hz, 2H), 2.35 (s, 3H), 2.04-1.90 (m, 6H). GC-MS m/z 290 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11])=[CH2:2].[CH3:13][S:14]([C:17]1[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11])[O:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[N:22][CH:21]=1)=[CH2:2]
Reactant: C=Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 25 h
Yield: 78.8 %

Procedure:
A mixture of 2-ethenyl-4-fluoro-1-nitrobenzene (9.6 g), 6-(methylsulfonyl)pyridin-3-ol (10.0 g), potassium carbonate (8.3 g), and N,N-dimethylformamide (90 mL) was stirred at 60° C. for 25 hr. The reaction solution was concentrated under reduced pressure, to the obtained residue was added an aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous citric acid solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (14.5 g, yield 79%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:17]([F:18])=[C:16]([O:19][CH3:20])[C:12](C(O)=O)=[C:11]([O:21][CH3:22])[C:10]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClC1C=CC=CC=1>[CH2:1]([NH:8][C:9]1[C:10]([F:23])=[C:11]([O:21][CH3:22])[CH:12]=[C:16]([O:19][CH3:20])[C:17]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)c(NCc2ccccc2)c(F)c(OC)c1C(=O)O
Solvent: Clc1ccccc1
Product: COc1cc(OC)c(F)c(NCc2ccccc2)c1F
Temperature: 25 °C
Yield: 94.3 %

Procedure:
4-(Benzylamino)-3,5-difluoro-2,6-dimethoxybenzoic acid (9.1 g, 28.1 mmol) was treated with chlorobenzene (45 mL) and the solution heated to reflux under nitrogen where it was maintained for 16 hours. The solution was cooled to room temperature and extracted with saturated, aqueous sodium bicarbonate solution (2×5 mL) followed by water. The organic layer was concentrated under reduced pressure to an oil that crystallized on standing. This was recrystallized from heptane (10 mL) and toluene (5 mL), the mixture cooled to −10° C., filtered and the crystals washed with heptane (10 mL) and vacuum dried at 35° C. to give N-benzyl-2,6-difluoro-3,5-dimethoxyaniline (7.4 g, 26.5 mmol). mp: 65° C.–66° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][NH2:11]
Reactant: COCCOCc1cccc(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOCc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2-Methoxy-ethoxymethyl)-benzonitrile (2.58 g, 13.5 mmol) was dissolved in 50 mL tetrahydrofuran. Lithiumaluminium hydride (660 mg, 17.5 mmol) was added portionwise at 0° C. The reaction mixture was stirred at room temperature overnight and quenched by sequential addition of 0.66 mL water, 0.66 mL 15% sodium hydroxide solution and 1.98 mL water. The solid was filtered off and the filtrate was evaporated. The title compound was obtained as a yellow liquid (2.63 g, 97%), MS: m/e=196.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[C:32]([O:36][C:37](=[O:39])[NH2:38])([CH3:35])([CH3:34])[CH3:33].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(=O)C.O1CCOCC1>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:39])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CC(C)(C)OC(N)=O
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Yield: 25.6 %

Procedure:
A mixture of [3-(4-bromobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.40 g), carbamic acid tert-butyl ester (0.19 g), tris(dibenzylideneacetone)dipalladium(0) (0.073 g), Xantphos (0.014 g), cesium carbonate (0.58 g) and 1,4-dioxane (5.0 mL) was heated at 100° C. for 10 hours. The mixture was cooled to room temperature, acidified by the addition of glacial acetic acid and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 10:1 by volume) gave title compound as a yellow gum (0.11 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:24][CH3:25])[C:17]=3[C:21]([CH3:23])=[CH2:22])[CH:12]=2)([OH:10])[CH:7]([CH3:9])[CH3:8])[N:3]=[CH:2]1>CO.[C].[Pd]>[NH:1]1[CH:5]=[C:4]([C:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:24][CH3:25])[C:17]=3[CH:21]([CH3:23])[CH3:22])[CH:12]=2)([OH:10])[CH:7]([CH3:9])[CH3:8])[N:3]=[CH:2]1
Reactant: C=C(C)c1c(OC)ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc12
Agent: [Pd]
Solvent: CO
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.7 %

Procedure:
1-(1H-Imidazol-4-yl)-1-[6-methoxy-5-(propen-2-yl)naphthalen-2-yl]-2-methyl-1-propanol (0.509 g) was dissolved in methanol (40 ml). To the solution was added 10% palladium carbon (0.260 g), and the mixture was stirred at room temperature for 5 h under hydrogen atmosphere (3 atoms). The catalyst was filtered off, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, dichloromethane:methanol=50:1→20:1) to give the titled compound (0.234 g) as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:21]=[C:22]2[C:27](=O)[O:26][C:24](=[O:25])[C:23]2=[CH:29][CH:30]=1>CC#N>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([N:1]3[C:27](=[O:26])[C:22]4[C:23](=[CH:29][CH:30]=[C:20]([CH3:19])[CH:21]=4)[C:24]3=[O:25])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: CC#N
Product: Cc1ccc2c(c1)C(=O)N(C1CCN(CCc3c[nH]c4ccccc34)CC1)C2=O
Yield: 27.4 %

Procedure:
4-Amino-1-[2-(indol-3-yl)ethyl]piperidine (1.22 g, 5 mmol) was dissolved in warm methyl cyanide (50 cm3) and a solution of 4-methylphthalic anhydride (0.81 g, 5 mmol) in methyl cyanide (10 cm3) was added dropwise with stirring to precipitate a white solid. The suspension was stirred overnight then the solid collected and heated in acetic anhydride (40 cm3) for 2 hours on a steam bath. The acetic anhydride was evaporated. The residue was dissolved in very dilute aqueous acetic acid and the solution basified by addition of conc. ammonia to give a gum. The mother liquor was decanted and the gum recrystallised from ethanol to give crystals of the title compound (0.53 g, 27.3%).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:41])[C@@H:17]([O:19][C:20]1[CH:40]=[CH:39][C:23]([CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=3)[C:27]([CH3:37])=[C:26]2[CH3:38])=[CH:22][CH:21]=1)[CH3:18]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:34]([C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[N:25]([CH2:24][C:23]2[CH:39]=[CH:40][C:20]([O:19][C@@H:17]([CH3:18])[C:16]([O:15][CH3:14])=[O:41])=[CH:21][CH:22]=2)[C:26]([CH3:38])=[C:27]3[CH3:37])=[O:35])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C(O)(=O)C>[C:28]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:13][CH2:12]2)=[CH:20][CH:19]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CN2CCC(C(c3ccccc3)c3ccccc3)CC2)cc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CN2CCC(C(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 8 parts of 4-{[4-(diphenylmethyl)-1-piperidinyl]methyl}benzenamine in 50 parts of acetic acid is added 5 parts of acetic anhydride. The resultant mixture is heated to the boiling point under reflux and maintained thereat for 10 minutes, then stripped of solvents by vacuum distillation. The residue is combined with 10 volumes of water. The resultant mixture is made alkaline with concentrated ammonium hydroxide. The mixture thus obtained is extracted with dichloromethane. The dichloromethane extract is dried over anhydrous potassium carbonate and then stripped of solvent by vacuum distillation. The residue, recrystallized from benzene, affords N-acetyl-4-{[4-(diphenylmethyl)-1-piperidinyl]methyl}benzenamine melting at approximately 182°-183°. The product has the formula ##STR5##
Reaction SMILES: Cl[CH2:2][CH:3]([NH:8][C:9]([C:11]1[C:19]2[N:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:17]([O:38][CH2:39][CH3:40])=[N:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[C:41]([O-:44])(=[S:43])[CH3:42].[K+]>CC#N>[CH2:39]([O:38][C:17]1[N:18]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:19]2[C:11]([C:9]([NH:8][CH:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:43][C:41](=[O:44])[CH3:42])=[O:10])=[CH:12][CH:13]=[CH:14][C:15]=2[N:16]=1)[CH3:40]
Reactant: CCOc1nc2cccc(C(=O)NC(CCl)CC(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC#N
Product: CCOc1nc2cccc(C(=O)NC(CSC(C)=O)CC(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 90 °C

Procedure:
2-Ethoxy-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-4-carboxylic acid (1-chloromethyl-3-methylbutyl)amide (100 mg, 180 μmol) and potassium thioacetate (31 mg, 15 equiv) were dissolved in MeCN (5 mL) and heated at 90° C. overnight. The solvent was evaporated and the residue partitioned between water (10 mL) and EtOAc (10 mL). The aqueous phase was discarded, the organic layer washed with saturated aqueous NaCl, dried over NaSO4, decanted, and the solvent evaporated. The crude product (80 mg, 70%) was used without further purification. ESMS [M+H]+ calcd for C32H35N7O3S, 597.3. found 598.3.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([OH:20])C.C=O.C([O-])([O-])=O.[K+].[K+]>O>[OH:17][CH2:16][C:6]1([CH2:18][OH:20])[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[CH:10]=[CH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]1=2
Reactant: CCO
Reactant: O=CC1c2ccccc2C=Cc2ccccc21
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCC1(CO)c2ccccc2C=Cc2ccccc21
Yield: 40 %

Procedure:
A mixture of 11 g (0.05 mol) of 5H-dibenzo[a,d]cycloheptene-5-carboxaldehyde (prepared according to L. SALISBURY, J. Org. Chem., 1972, 37, 4075), 66 ml of ethanol, 16.2 ml (0.2 mol) of aqueous 37% formaldehyde solution, 11 ml of water and 6.6 g (0.05 mol) of K2CO3 is refluxed for 20 hours. The reaction medium is then poured into 1 liter of water with stirring and the mixture is extracted with CH2Cl2. The combined organic phases are dried over Na2SO4 and evaporated. The residual mass is triturated from 60 ml of absolute ethanol and disperses as a beige-coloured solid, which is filtered off and dried. 5 g of product are obtained (yield: 40%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([O-:31])=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(/C=C/C(=O)[O-])cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(/C=C/C(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of butyl ((E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate (0.50 g, 0.9 mmol) in tetrahydrofuran (10 ml)-methanol (10 ml) was added 1N sodium hydroxide (2 ml). The obtained mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.38 g, 84.4%) as crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])(=[O:35])=[O:34])[C:27]=2[F:44])[CH:5]=[CH:4][N:3]=1.[CH3:45][Zn]C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[F:43][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([F:42])[C:36]=1[S:33]([NH:32][C:28]1[C:27]([F:44])=[C:26]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:45])[N:7]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:35])=[O:34]
Reactant: C[Zn]C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nccc(-c2sc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (167 mg, 0.251 mmol) was dissolved into 1,4-dioxane (3 mL) and the solution was degassed for 10 min. PdCl2(dppf)-CH2Cl2 adduct (10.24 mg, 0.013 mmol) and dimethylzinc (0.251 mL, 0.501 mmol) were added to the reaction mixture. The reaction mixture was stirred at 80° C. for 1 h. The reaction was quenched with methanol (3 mL) and water (10 mL) and extracted with EtOAc (3×). The extract was dried over Na2SO4, filtered, and concentrated. The residue was purified using column chromatography (40% to 100% EtOAc/hexane) to give the title compound (120 mg). MS (ESI): 646.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([O:12]C)=[CH:4][CH:3]=1.COC.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([OH:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c2nc(C)sc12
Agent: COC
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nc2c(Cl)ccc(O)c2s1

Procedure:
The title compound was prepared from 4-chloro-7-methoxy-2-methylbenzothiazole by cleavage of the methyl ether with pyridine hydrochloride as described in Preparation 1, m.p. 225° C. (decomposition), mass spec. m/z 200.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][N:3]=1.[O:17]1[CH2:22][CH2:21][CH2:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[O:17]1[CH:18]=[C:19]([C:2]2[C:10]3[C:5](=[CH:6][N:7]=[C:8]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[NH:4][N:3]=2)[CH2:20][CH2:21][CH2:22]1
Reactant: Ic1n[nH]c2cnc(-c3cccnc3)cc12
Reactant: CC1(C)OB(C2=COCCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C1=C(c2n[nH]c3cnc(-c4cccnc4)cc23)CCCO1
Temperature: 130 °C
Yield: 34.9 %

Procedure:
In a microwave tube was added 3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine from Example 4 (0.32 g, 1 mmol), 2-(5,6-dihydro-4H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.31 g, 1.5 mmol), 2 M Na2CO3 (2 mmol, 1 mL), PdCl2(dppf) (87 mg, 0.1 mmol) and dioxane (8 mL). The suspension was purged with N2 and heated under microwave radiation at 130° C. for 1 hour. It was then cooled to room temperature. Solvent was removed under reduced pressure. The residue was purified by SGC (Petrol/EtOAc:5/1 to 1/1) to give 281 as a yellow solid (97 mg, 35%). 1H NMR (400 MHz, DMSO) δ 9.19 (d, J=1.2 Hz, 1H), 9.07 (d, J=0.8 Hz, 1H), 8.53-856 (m, 2H), 8.45 (d, J=0.8 Hz, 1H), 7.71 (s, 1H), 7.47-7.49 (m, 1H), 4.08-4.10 (m, 2H), 2.59-2.61 (m, 2H), 1.98-2.0 (m, 2H). ESI MS m/z=279 (M+1)
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:30]1(C)C=CC=CC=1N1CCNCC1>>[C:4]1([CH3:30])[CH:3]=[CH:8][CH:7]=[CH:6][C:5]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18]2)[CH2:13][CH2:14]1
Reactant: O=c1c2ccccc2ncn1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: Cc1ccccc1N1CCNCC1
Product: Cc1ccccc1N1CCN(CCn2cnc3ccccc3c2=O)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 1c, using 1-o-tolylpiperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4](=[O:30])[CH2:3]1.Br[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:34]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:8]1[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4](=[O:30])[CH:3]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:34]=2)[C:2]1=[O:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1nc(CC2C(=O)N(CC(=O)OCc3ccccc3)c3ccccc3N(c3ccccc3)C2=O)c2ccccc21

Procedure:
To a stirring solution of benzyl (2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl)acetate (3.45 g, 8.62 mM) in 25 mL DMF at 0° C. was added 1.1 equiv. of 0.5 M solution of KN(TMS)2 in toluene. The resulting solution was stirred 10–30 min, then a solution of tert-butyl 3-(bromomethyl)-1H-indazole-1-carboxylate (2.95 g, 9.48 mM) in 15 mL DMF was added. The resulting solution was stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture was then poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer was separated, dried (MgSO4), and the solvents removed in vacuo. The resultant material was purified by silica gel flash column chromatography using methylene chloride/EtOAc 9/1 providing 4.4 g of white solid.
Reaction SMILES: C([N:8]1[C@@H:13]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:22])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:22][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:8]1
Reactant: C[C@H]1CCC[C@H](CCc2ccccc2)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CCC[C@H](CCc2ccccc2)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-(2-phenylethyl)piperidine (1.4 g, 5.50 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 65 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-(2-phenylethyl)piperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occured. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 148.3-151.0; 1HNMR (300 MHz) δ9.3, (s, 2H), 7.28-7.11 (m, 5H), 3.43 (s, 1H), 3.19 (s, 1H), 2.67-1.27 (m, 13H); 13C NMR (75 MHz) 140.0 (s), 128.3 (s), 126.1 (s), 50.9 (s), 47.9 (s), 32.1 (s), 31.5 (s), 28.5 (s), 26.4 (s), 17.2 (s), 16.5 (s). FT-IR (neat): 3410, 3075, 2944, 1590, 1494, 1454, 1435, 1336, 1122, 1029, 751, 701. Elemental Analysis for C14H22NCl: C, 70.11%; H, 9.27%; N, 5.84%. Found: C, 69.95%; H, 9.19%; N, 5.79%.