Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:28][CH:29]=1)[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]>CCOCC.[Cl-].[Zn+2].[Cl-]>[OH:3][CH:4]([C:25]1[N:26]=[C:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:28][CH:29]=1)[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1csc(-c2ccccc2)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a suspension (50 ml) of zinc chloride (3.41 g, 25 mmol) in ether was added sodium borohydride (1.89 g, 50 mmol) at room temperature, and the mixture was stirred as it was for 2 hrs. Insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-oxo-3-(2-phenyl-1,3-thiazol-4-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate (6.01 g, 12.5 mmol) in ether (40 ml) under ice-cooling, and the mixture was stirred as it was for 1 hr. The reaction was quenched with 1N hydrochloric acid. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1, 4:1) to give ethyl 3-hydroxy-3-(2-phenyl-1,3-thiazol-4-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate (4.61 g, 76%) as a colorless transparent oil.
Reaction SMILES: C1(S([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:15][CH:14]=2)(=O)=O)C=CC=CC=1.O[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:23]1([S:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][O:10][C:30]3[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=3)=[CH:18][CH:17]=2)(=[O:21])=[O:22])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=S(=O)(OCCc1ccc(OS(=O)(=O)c2ccccc2)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCCc2ccc(OS(=O)(=O)c3ccccc3)cc2)cc1
Yield: 65.4 %

Procedure:
20 g (48 mmole) 4-[phenylsulfonyloxy]phenethyl 1-benzenesulfonate, 11.7 g (95 mmole) p-hydroxybenzaldehyde and 13.27 g (96 mmole) potassium carbonate in 100 ml acetonitrile were refluxed over night. The precipitate was filtered off and the filtrate was evaporated in vacuo. Dichloromethane was added, the solid material was filtered off and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate:petroleum ether (1:2) as eluent to give 12 g (yield 65%) of 4-[2-(4-formylphenoxy)ethyl]phenyl 1-benzenesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]([C:21]2[C:22]([OH:30])=[N:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=2)=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl.[NH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:37][O:36][C:34](=[O:35])[CH2:33][NH:32][C:27]([C:24]1[N:23]=[C:22]([OH:30])[C:21]([C:19](=[O:20])[NH:18][CH:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:26][N:25]=1)=[O:28]
Reactant: COc1ccc(C(NC(=O)c2cnc(C(=O)O)nc2O)c2ccc(OC)cc2)cc1
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)CNC(=O)c1ncc(C(=O)NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of compound 2-17-e (2.5 g, 6.1 mmol), methyl 2-aminoacetate hydrochloride (0.92 g, 7.3 mmol), TBTU (2.4 g, 7.3 mmol), DIPEA (1.6 g, 12.2 mmol) in DMSO (15 mL) and stirred at the ambient temperature overnight. Ice-water was then added to the reaction mixture and filtered. The cake was purified by column chromatography with DCM:MeOH=100:1˜50:1 to obtain the product, 2-17-f, (630 mg, 22%). LC-MS: (M+H)+ 481.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1.C1CNC(=O)C1.[Br:26][Br-]Br>CO.C(Cl)Cl>[Br:26][CH2:14][C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH2:5][C:4]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:2]([Cl:1])[CH:3]=2)[CH:8]=1)=[O:15]
Reactant: CC(=O)c1cccc(OCc2ccc(Cl)c(Cl)c2)c1
Agent: O=C1CCCN1
Solvent: ClCCl
Solvent: CO
Product: O=C(CBr)c1cccc(OCc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-[3-(3,4-Dichloro-benzyloxy)-phenyl]-ethanone (30 g) was dissolved in MeOH:DCM (2:1, 300 mL) and pyrolidone hydrotribromide (75 g) was added portion wise and stirred at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated in vacuo and poured into saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (2×200 mL). The organic extracts were combined and washed with brine and concentrated in vacuo. Then this residue was dissolved in DCM (75 mL) and product was precipitated by slow addition of methanol (75 mL), filtered and dried in vacuum (29 g). 1H NMR (400 MHz, CDCl3): 7.62-7.54 (m, 3H), 7.47 (d, 1H), 7.42 (t, 1H), 7.25-7.30 (m, 1H), 7.18-7.23 (m, 1H), 5.07 (s, 2H), 4.44 (s, 2H).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.BrC1C(C)=NC2C(N=1)=CC(Cl)=CC=2.[C:27]([C:29]1[N:33]([CH3:34])[N:32]=[C:31]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[N:30]=1)#[CH:28].C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:28]#[C:27][C:29]1[N:33]([CH3:34])[N:32]=[C:31]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[N:30]=1)[C:11]([CH3:12])=[N:10]2
Reactant: C#Cc1nc(N2CCCC2)nn1C
Reactant: Cc1nc2cc(Cl)ccc2nc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: Cc1nc2ccc(Cl)cc2nc1Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc2cc(Cl)ccc2nc1C#Cc1nc(N2CCCC2)nn1C
Temperature: 25 °C
Yield: 5.4 %

Procedure:
To a stirred solution of 2-bromo-6-chloro-3-methylquinoxaline with 3-bromo-6-chloro-2-methylquinoxaline (250 mg, 485 μmol, Eq: 1.00) and 5-Ethynyl-1-methyl-3-pyrrolidin-1-yl-1H-[1,2,4]triazole (94.1 mg, 534 μmol, Eq: 1.1) at room temperature in N,N-dimethylformamide (7.5 ml) under an argon atmosphere were added triethylamine (98.2 mg, 135 μl, 971 μmol, Eq: 2), copper (I) iodide (4.62 mg, 24.3 μmol, Eq: 0.05) and bis(triphenylphosphine)palladium (II) chloride (17.0 mg, 24.3 μmol, Eq: 0.05). The mixture was purged with argon before it was stirred over weekend at room temperature (dark sol.). The mixture was stirred over an additional night at 80° C. The crude material was applied on silica gel and purified by column chromatography. After separation of the isomers by preparative HPLC gave 6-chloro-3-methyl-2-(2-methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-ylethynyl)-quinoxaline (9.3 mg, 5.4%) as a yellow solid. MS: m/z=353.5 (M+H+)
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][CH:58]1[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][OH:66])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:57][CH:58]5[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][OH:66])[CH2:60][CH2:59]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCN(CCO)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(CCO)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino piperidine 1-ethanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-2.07 (m, 12 H) 2.38 (t, J=6.32 Hz, 2 H) 2.89 (d, J=11.37 Hz, 2 H) 3.27-3.34 (s, 3 H) 3.49 (q, J=6.06 Hz, 2 H) 3.65-3.83 (m, 1 H) 3.93 (s, 2 H) 3.97-4.14 (m, 2 H) 4.37 (t, J=5.31 Hz, 1 H) 4.76 (t, J=7.83 Hz, 1 H) 7.48 (d, J=8.0 Hz, 1 H), 7.49 (br. s., 1 H) 7.96 (s, 1 H) 8.12 (d, J=7.83 Hz, 1 H)), 8.26 (s, 1 H) 8.27 (d, J=8.0 Hz, 1 H). [M+H] calculated for C28H37F2N7O4, 574; found 574.
Reaction SMILES: O.[NH2:2][NH2:3].C(O)(=O)C.O.[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:11][C:10]=1[C:18]1[C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=O)[C:22]=2[CH:21]=[CH:20][CH:19]=1>CO.ClCCl>[NH:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[C:18]1[C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[N:2][NH2:3])[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=C1c2ccccc2-c2c1cccc2-c1nc2ccncc2[nH]1
Reactant: NN
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: NN=C1c2ccccc2-c2c1cccc2-c1nc2cnccc2[nH]1
Temperature: 52.5 °C

Procedure:
In a 10-ml round-bottomed flask, dissolve 100 mg of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-one, obtained in Example 1, in 3 ml of methanol, then add successively 96 μL of hydrazine hydrate and 57.6 μL of acetic acid, then heat at 50-55° C. for 3 hours. Pour the cooled reaction mixture into 10 ml of water. Filter the precipitate that formed, and dissolve again in a mixture of methanol and dichloromethane. After drying over sodium sulphate then concentrating under reduced pressure, purify the residue by crystallization in a minimum of diethyl ether. In this way we obtain 70 mg of N-[4-(1H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-ylidene]-hydrazine, as a mixture of the Z and E isomers, in the form of a beige powder with the following characteristics:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][N:14]1[C:21]2[N:17]([N:18]=[CH:19][CH:20]=2)[CH:16]=[CH:15]1)=[O:6])[CH:2]=[CH2:3].[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9][C@H:8]1[CH2:13][N:14]1[C:21]2[N:17]([N:18]=[CH:19][CH:20]=2)[CH:16]=[CH:15]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cn1ccn2nccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cn1ccn2nccc12

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-(imidazo[1,2-b]pyrazol-1-yl)methylpyrrolidine (3.16 g) in a mixture of ethyl acetate (60 ml) and triethylamine (2.27 ml) was dropwise added a solution of methanesulfonyl chloride (1.18 ml) in ethyl acetate (5 ml) with stirring under ice-cooling. The mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added water (50 ml) with stirring and the organic layer was separated. The organic layer was washed in turn with saturated aqueous sodium chloride, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (2:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl -2-(imidazo[1,2-b]pyrazol-1-yl)methyl-4-methanesulfonyloxypyrrolidine (3.06 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[C:4]([CH3:10])[C:3]=1[CH3:11].[H][H]>C(O)C.S(=O)(=O)(O)O.[Pd]>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:10])[C:3]=1[CH3:11]
Reactant: Cc1nc(Cl)c(C)c(Cl)c1C
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cnc(C)c(C)c1Cl
Yield: 78 %

Procedure:
200 g 4,6-dichloro-2,3,5-trimethylpyridine dissolved in 300 ml ethanol and 40 ml conc. sulphuric acid. 2 g 10% Pd/C was used as catalyst. The hydrogen pressure was 2 bar and the hydrogenation was stopped when 1 equivalent of hydrogen had been consumed. After evaporation of alcohol and dilution with water and adjustment of pH to 2.1 the water was extracted with toluene. The toluene contains all starting material and 6-chloro-2,3,5-trimethylpyridine and the water phase 4-chloro-2,3,5-trimethylpyridine and 2,3,5-trimethylpyridine. The pH of the water phase is adjusted to 4.6 and extracted with toluene (3x100 ml). All 4-chloro-2,3,5-trimethylpyridine is in the toluene layer and the 2,3,5-trimethylpyridine in the water. Evaporation of the toluene gave 4-chloro-2,3,5-trimethylpyridine in 78% yield (liquid). NMR: 2×3H, 2,3; 3H, 2,5(s); 1H, 8,25(s). (CDCl3)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[Br:43])[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1.[C:44](Cl)(=[O:48])[CH:45]([CH3:47])[CH3:46]>>[Br:43][C:42]1[CH:41]=[CH:40][C:4]([CH2:5][O:6][CH:7]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:8]2)=[CH:3][C:2]=1[NH:1][C:44](=[O:48])[CH:45]([CH3:47])[CH3:46]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Br)c(N)c2)cc1
Reactant: CC(C)C(=O)Cl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Br)c(NC(=O)C(C)C)c2)cc1

Procedure:
Analogously to Example 18e, 4.30 g of tert-butyl 3-(3-amino-4-bromobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate are reacted with 0.78 ml of isobutyryl chloride. The title compound is obtained as a colourless oil. Rt=6.12.
Reaction SMILES: [NH2:1][C:2]1[N:11]([CH2:12][CH3:13])[C:10]2[N:9]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=3)[CH:7]=[CH:6][C:5]=2[C:4](=[O:26])[C:3]=1[C:27](=[O:30])[NH:28][CH3:29].C1COCC1.CO.O.[OH-].[Li+].Cl>O>[NH2:1][C:2]1[N:11]([CH2:12][CH3:13])[C:10]2[N:9]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)[CH:7]=[CH:6][C:5]=2[C:4](=[O:26])[C:3]=1[C:27](=[O:30])[NH:28][CH3:29]
Reactant: CCOC(=O)Cc1ccc(-c2ccc3c(=O)c(C(=O)NC)c(N)n(CC)c3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(-c3ccc(CC(=O)O)cc3)nc21
Temperature: 70 °C
Yield: 97.6 %

Procedure:
To a suspension of 0.87 g (2.1 mmol) of the compound obtained from step 2.4 in a 1/1/1 mixture of THF/methanol/water (12 ml) is added 0.134 g (3.2 mmol) of lithium hydroxide in a single portion. The reaction mixture is heated at 70° C. for 3 hours, and then cooled to room temperature. Water (10 ml) is added and the medium is acidified with HCl solution (1N) to pH 2, and the precipitate formed is isolated by filtration and dried over P2O5. 0.78 g of product is obtained in the form of a white powder. Yield=96%. Melting point 260° C. MH+: 381.1 (tr: 6.74 min., condition 1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C@@:18]([CH3:28])([S:24]([CH3:27])(=[O:26])=[O:25])[C:19]([O:21]CC)=[O:20])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Li+].Cl>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C@@:18]([CH3:28])([S:24]([CH3:27])(=[O:25])=[O:26])[C:19]([OH:21])=[O:20])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)[C@@](C)(CCn1cc(C#Cc2cccc(C#N)c2)cn1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@](CCn1cc(C#Cc2cccc(C#N)c2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of ethyl (2R)-4-{4-[(3-cyanophenyl)ethynyl]-1H-pyrazol-1-yl}-2-methyl-2-(methylsulfonyl)butanoate (0.415 g, 1.04 mmol) in THF-H2O (20 mL:10 mL) was added lithium hydroxide (0.249 g, 10.4 mmol, 10 eq). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was then acidified with 1M HCl and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to give (2R)-4-{4-[(3-cyanophenyl)ethynyl]-1H-pyrazol-1-yl}-2-methyl-2-(methylsulfonyl)butanoic acid (0.360 g, 93% yield) as a white solid. LC-MS M+H+372.1.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:13][CH:11]([S:8]([NH:7][CH:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])(=[O:10])=[O:9])[CH3:12]
Reactant: CC(C)S(=O)(=O)NC1CCCC1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCCC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.3 %

Procedure:
Scheme IA, step C: Into a 250 mL single neck flask, (2-hydroxycyclopentyl)[(methylethyl)sulfonyl]amine (1.5 g, 7.24 mmol), pyridinium chlorochromate (2.34 g, 1.5 eq) and methylene chloride (100 mL) were mixed together and stirred for 4 hours at room temperature under a nitrogen atmosphere. The solution was then filtered over a Celite® mat and the resulting filtrate was washed once with water, dried over potassium carbonate, and concentrated under reduced vacuum to yield 1.31 g as an oil. This material was purified via silica gel chromatography employing the Chromatotron® and using a 4000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 4:1 to yield the intermediate title compound (450 mg, 30%) as a slowly crystallizing oil. Ion spray M.S. 204 (M*−1). Analysis calculated for C8H15NO3S: Theory: C, 46.81; H, 7.37; N, 6.82. Found: C, 46.08; H, 7.12; N, 6.58.
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]1([CH2:15][CH2:16][C:17]#[CH:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:19]([C:22]1[S:23][C:24]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[C:25]([CH3:27])[N:26]=1)=[N+:20]=[N-:21]>>[CH2:31]([NH:30][C:28]([C:24]1[S:23][C:22]([N:19]2[CH:18]=[C:17]([CH2:16][CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:21]=[N:20]2)=[N:26][C:25]=1[CH3:27])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#CCCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(CCc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 20 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 4-phenyl-1-butyne to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 20% yield: mp 167-170° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 7.37-7.19 (m, 10H), 6.15 (t, J=6.0 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H), 3.14-3.02 (m, 4H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.6, 153.3, 148.5, 140.5, 137.5, 128.9, 128.5, 128.3, 127.8, 126.3, 124.0, 118.6, 44.3, 35.0, 27.2, 17.4; MS (ES+) m/z 404.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC(F)=CC=3)C=2)=[O:7])=[CH:4][N:3]=1.C[C@H]1CNC[C@@H](C)N1>>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:26]=[CH:27][CH:2]=[N:3][CH:4]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1)c1ccc(Cl)nc1
Agent: C[C@@H]1CNC[C@H](C)N1
Product: NC(=O)c1cccnc1

Procedure:
6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)nicotinamide (0.15 mmol) was used in general procedure 3 with cis-2,6-dimethylpiperazine (0.77 mmol). The product was purified by RP-HPLC to give N-(4-fluorobenzamido)phenyl)-6-(3S-,5R)-3-5-dimethylpiperazine-1-yl)nicotinamide. MS (Q1) 482.3 (M)+
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])=[C:13]([CH3:16])[CH2:14]Br)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH3:18][CH:19]1[CH2:24][CH:23]([CH3:25])[CH2:22][NH:21][CH2:20]1>CCOCC>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])=[C:13]([CH3:16])[CH2:14][N:21]2[CH2:22][CH:23]([CH3:25])[CH2:24][CH:19]([CH3:18])[CH2:20]2)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CC1CNCC(C)C1
Reactant: CCC(C)(C)c1ccc(C(C)=C(C)CBr)cc1
Solvent: CCOCC
Product: CCC(C)(C)c1ccc(C(C)=C(C)CN2CC(C)CC(C)C2)cc1

Procedure:
62 G. of 3-(p-tert.-amyl-phenyl)-2,3-dimethyl-allyl bromide in 150 ml. of ether are added dropwise to a solution of 45.2 g. of 3,5-dimethylpiperidine in 200 ml. of absolute ether and the mixture is heated at reflux for 16 hours. The 3,5-dimethylpiperidine hydrobromide is removed by filtration and back-washed with ether. The ether solution is extracted with 2 N hydrochloric acid and made alkaline with 50% sodium hydroxide. The alkaline-aqueous solution is again extracted with ether, washed with water, dried over sodium sulfate and evaporated. By distillation, there is obtained pure 1-[3-(p-tert.-amylphenyl)-2,3-dimethyl-2-propenyl]-3,5-dimethylpiperidine having a boiling point of 155° C./0.04 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[CH3:10][C:11](=[O:14])[C:12]#[CH:13].C(NC(C)C)(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]#[C:12][C:11](=[O:14])[CH3:10])[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: C#CC(C)=O
Reactant: Clc1cc(Cl)cc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)C#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1,3-dichloro-5-iodo-benzene (3.44 g, 12.6 mmol) in THF (220 mL) was added PdCl2(PPh3)2 (904 mg, 1.29 mmol), 3-butyn-2-one (2.18 g, 32.0 mmol), copper(l)iodide (380 mg, 2 mmol) and diisopropylamine (44 mL). The reaction mixture was stirred at room temperature for 48 hours, filtered and evaporated. The residue was purified by column chromatography using methylene chloride:hexanes (1:1) as eluent. The desired 4-(3,5-dichloro-phenyl)-3-butyn-2-one product was isolated in 977 mg yield.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:13]N1C(=O)CCC1=O>CN1C(=O)CCC1.O>[Br:13][C:10]1[C:4]2[S:3][C:2]([Cl:1])=[N:6][C:5]=2[CH:7]=[CH:8][C:9]=1[O:11][CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2nc(Cl)sc2c1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc2nc(Cl)sc2c1Br
Yield: 120.6 %

Procedure:
To the solution of 2-chloro-6-methoxy-benzothiazole (200 mg, 1.0 mmol, 1.0 eq) in 5 mL of NMP was added N-bromosuccinimide (213 mg, 1.20 mmol, 1.2 eq) at room temperature. The reaction mixture was stirred at 75° C. for >24 hours with subsequent addition of NBS in small batches for reaction progress, thereafter the mixture was diluted with water (ca. 100 mL) and aqueous layer extracted with ethyl acetate (ca. 150 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure. Purification on ISCO using gradient 0%-50% ethyl acetate-hexane gave 336 mg of product as off white fluffy powder in 60% yields structure of which was confirmed by H+NMR. LC/MS (m/z) [279.9] (MH+)