Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]([F:16])([F:15])[C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.Cl[C:18]1[C:23]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:22]([CH3:31])[N:21]=[N:20][C:19]=1[CH3:32]>C(OCC)(=O)C>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]2[C:18]([N:12]3[CH:13]=[CH:14][C:10]([C:9]([F:16])([F:15])[F:8])=[N:11]3)=[C:19]([CH3:32])[N:20]=[N:21][C:22]=2[CH3:31])=[CH:29][CH:28]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: Cc1nnc(C)c(-c2ccc(Cl)cc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nnc(C)c(-n2ccc(C(F)(F)F)n2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.5 %

Procedure:
87 mg of sodium hydride (55% oil dispersion) was added to 5 ml of DMF, and to this was added 0.27 g of 3-trifluoromethylpyrazole, and the mixture was stirred for 5 hours at room temperature. To the resultant mixture was added 0.25 g of 4-chloro-5-(4-chlorophenyl)-3,6-dimethylpyridazine, and the mixture was stirred for 3 hours on an oil bath of 80° C. To the reaction mixture was added ethyl acetate, and the mixture was washed with brine four times. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.57 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.27 g of 5-(4-chlorophenyl)-4-(3-trifluoromethyl-1-pyrazolyl)-3,6-dim ethylpyridazine (hereinafter, described as compound (4) of the present invention.).
Reaction SMILES: [CH3:1][NH:2][CH3:3].ClCCl.[CH3:7][O:8][C:9]([C:11]1[C@H:12]2[CH2:29][C@@H:28]3[O:30][C@:27]3(C)[C@@H:13]2[C@H:14]([O:17][C:18](OC2C=CC=CC=2)=[O:19])[O:15][CH:16]=1)=[O:10]>CCCCCC.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:11]1[C@H:12]2[CH2:29][C@@H:28]3[O:30][C@@H:27]3[C@@H:13]2[C@H:14]([O:17][C:18](=[O:19])[N:2]([CH3:3])[CH3:1])[O:15][CH:16]=1)=[O:10]
Reactant: COC(=O)C1=CO[C@@H](OC(=O)Oc2ccccc2)[C@@H]2[C@@H]1C[C@@H]1O[C@]21C
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)C1=CO[C@@H](OC(=O)N(C)C)[C@H]2[C@H]3O[C@H]3C[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
5 ml of a 50% aqueous dimethylamine solution were added to a dichloromethane solution containing 198 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(phenoxycarbonyloxy) cyclopenta [c] pyrane-4-carboxylic acid methylester described in Example 10 followed by stirring for 10 minutes at room temperature. The reaction mixture was then extracted with dichloromethane. After washing the organic phase with brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the hexane-ethyl acetate eluate in the form of (1S,4aS,6S,7R,7aR)-1-(dimethylcarbamoyloxy)-6,7-epoxy-1,4a,5,6,7,7a-hexahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (140 mg, yield: 83%). The physicochemical properties of this compound are described in Table 7. Compound No. 31.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1csc(NC2CCCCC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1csc(NC2CCCCC2)n1

Procedure:
The reaction described in Preparation 15 was repeated, but using 19 g of ethyl 2-cyclohexylaminothiazole-4-carboxylate, 4.2 g of lithium aluminum hydride and 250 ml of tetrahydrofuran, giving the title compound as pale yellow needles.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C:5](=O)[C@H:4](CCCCCCC(O)=O)[C@H:3]1[CH2:17][CH2:18][C:19](=[O:28])[C:20]([F:27])([F:26])[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24].[C:29]([OH:32])(=[O:31])[CH3:30]>>[F:27][C:20]([F:26])([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25])[C:19](=[O:28])[CH2:18][CH2:17][C@@:3]1([C@@H:30]([CH2:4][CH2:3][CH2:2][CH2:6][CH3:5])[C:29]([OH:32])=[O:31])[C:2](=[O:1])[CH:6]=[CH:5][CH2:4]1
Reactant: CC(C)CCC(F)(F)C(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Reactant: CC(=O)O
Product: CCCCC[C@@H](C(=O)O)[C@@]1(CCC(=O)C(F)(F)CCC(C)C)CC=CC1=O
Temperature: 70 °C

Procedure:
An acetic acid (10 ml) solution of 7-[(1R,2R,3R)-3-hydroxy-2-(4,4-difluoro-7-methyl-3-oxooctyl)-5-oxocyclopentyl]heptanoic acid (6-1) (0.533 g) prepared as described in Example 2 was heated overnight at 70° C. The crude product obtained after the usual work up was chromatographed on silica gel eluted with a mixed solvent of dichloromethane and methanol (20/1) to yield the compound (6-2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[NH:13][C:12]3[CH:22]=[CH:23][CH:24]=[CH:25][C:11]2=3)=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=1.[BH4-].[Na+].[CH3:29]O>>[CH3:29][N:3]1[CH:2]([CH3:1])[CH2:7][C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[NH:13][C:12]3[CH:22]=[CH:23][CH:24]=[CH:25][C:11]2=3)=[O:9])=[CH:5][CH:4]1[CH3:26]
Reactant: CO
Reactant: Cc1cc(C(=O)N2c3ccccc3NC(=O)c3ccccc32)cc(C)n1
Agent: [BH4-]
Agent: [Na+]
Product: CC1C=C(C(=O)N2c3ccccc3NC(=O)c3ccccc32)CC(C)N1C
Yield: 25 %

Procedure:
Prepared analogously to Example 7(c) from 5,10-dihydro-5-[(2,6-dimethyl-4-pyridinyl)carbonyl]-11H-dibenzo[b,e][1,4]diazepin-11-one methoiodide and sodium borohydride in methanol in a yield of 25% of theory. After purification by column chromatography on silica gel using dichloromethane/methanol (ratio by volume 9:1) as a eluent and recrystallizing from diisopropylether/methanol, the light beige crystals melted at 124°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:35])=[CH:7][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C(=O)c1ccc(SCCOc2ccc3ccccc3c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(S(=O)CCOc2ccc3ccccc3c2)cc1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A solution of 4-[[2-(2-naphthalenyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid methyl ester (2.56 g) in dichloromethane (75 mL) was chilled in ice and 85 % metachloroperbenzoic acid (1.42 g) was added. The mixture was stirred cold for 1 hour, diluted with saturated sodium bicarbonate solution, and extracted with dichloromethane. The dried (Na2SO4) was filtered, evaporated and the residue was crystallized from dichloromethane-hexane to give 2.2 g of rac.-4-[[2-(2-naphthalenyloxy)ethyl]sulfinyl]-alpha-oxobenzeneacetic acid methyl ester, mp 129°-130° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[C:19]#[CH:20])[CH3:16].CCN(CC)CC>CN(C=O)C.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.[Cu]I>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:2]([C:20]#[C:19][CH:18]([O:21][CH2:22][CH3:23])[O:17][CH2:15][CH3:16])=[CH:7][N:6]=1
Reactant: CCC(CC)Nc1nc(Cl)ncc1Br
Reactant: C#CC(OCC)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(C#Cc1cnc(Cl)nc1NC(CC)CC)OCC
Temperature: 55 °C
Yield: 37.2 %

Procedure:
To a mixture of (5-bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (420 mg, 1.5 mmol) and propargylaldehyde diethyl acetal (0.32 mL, 2.25 mmol) in DMF (6 mL) is added PdCl2(PPh3)2 (105 mg, 0.15 mmol) and CuI (28 mg, 0.15 mmol), followed by Et3N (0.42 mL, 3 mmol). The mixture is degassed, and heated at 55° C. for 16 h. After cooling to room temperature, the reaction mixture is diluted with EtOAc, washed with water and brine. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, EtOAc/heptane 5:95 to 40:60) to give 182 mg of [2-chloro-5-(3,3-diethoxy-prop-1-ynyl)-pyrimidin-4-yl]-(1-ethyl-propyl)-amine as a light brown oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].C(O[C:18]1[C:22]([NH2:23])=[C:21]([S:24]([CH3:27])(=[O:26])=[O:25])[S:20](=[O:28])[N:19]=1)C>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:18]2[C:22]([NH2:23])=[C:21]([S:24]([CH3:27])(=[O:26])=[O:25])[S:20](=[O:28])[N:19]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CCOC1=NS(=O)C(S(C)(=O)=O)=C1N
Solvent: CC#N
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)C(S(C)(=O)=O)=C2N)o1
Reaction time: 15 h

Procedure:
To a solution of 2-[(5-dimethylaminomethyl-2furanyl)methylthio]ethylamine (440 mg, 2 mmol) in acetonitrile (6 ml) there was added 3-ethoxy-4-amino-5-methylsulfonylisothiazole-1-oxide (480 mg, 2 mmol). This mixture was stirred under a nitrogen atmosphere for 15 hours as product slowly crystallized out. Precipitate was collected by filtration, washed with acetonitrile, diethyl ether and air dried to give 650 mg, of title compound, mp 134°-137°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:35])[CH:9]([C:23]1[NH:24][C:25](=[O:34])[C:26]([OH:33])=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1)[CH2:10][CH2:11][C:12]([CH3:22])([CH3:21])[CH2:13][O:14]C1CCCCO1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([O:5][C:6]([N:8]([CH3:35])[CH:9]([C:23]1[NH:24][C:25](=[O:34])[C:26]([OH:33])=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1)[CH2:10][CH2:11][C:12]([CH3:22])([CH3:21])[CH2:13][OH:14])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1nc(C(CCC(C)(C)COC2CCCCO2)N(C)C(=O)OC(C)(C)C)[nH]c(=O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(C(CCC(C)(C)CO)N(C)C(=O)OC(C)(C)C)[nH]c(=O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the crude methyl 2-[1-[(tert-butoxycarbonyl)(methyl)amino]-4,4-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)pentyl]-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (32 g) and 1 g of p-toluenesulfonic acid monohydrate was dissolved in methanol (100 mL) and stirred at room temperature for 2 hours. The reaction was quenched with 3 mL of saturated NaHCO3 and concentrated. The residue was taken up in 500 mL of EtOAc, washed with saturated NaHCO3 and dried over Na2SO4. Removal of solvents under reduced pressure gave the title product as a brown foam: MS (ES+): 314.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH3:19])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 79.1 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) in N,N-dimethylformamide (1.3 mL) was added potassium carbonate (269 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. Iodoethane (305 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=80/20→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (187 mg) as a pale-yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10](S)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO.[Ni]>[C:1]1([C:7]2[N:11]=[CH:10][NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Sc1nc(-c2ccccc2)n[nH]1
Agent: [Ni]
Solvent: CCO
Product: c1ccc(-c2nc[nH]n2)cc1
Yield: 89.2 %

Procedure:
3-phenyl-1,2,4-triazole-5-thiol (1.80 g, 10.2 mmol) and Raney Ni (rinsed with EtOH 3×, 3 g) in 30 mL EtOH was refluxed for 1.5 h. The mixture was filtered and concentrated. The crude yellow oil was redissolved in EtOAc and filtered through 1″ SiO2, then concentrated to afford 1.32 g of Intermediate 17.1 as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30]>CN1C(=O)CCC1.CS(C)=O.CO>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:27]3[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: O=C1CNCCN1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCNC(=O)C3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol) and piperazin-2-one (30 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 20-45% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a orange solid (17 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 3.43 (br. s., 2 H) 4.08 (t, J=5.18 Hz, 2 H) 4.27 (s, 2 H) 6.38 (d, J=2.27 Hz, 1 H) 7.41 (s, 1 H) 7.60 (d, J=8.59 Hz, 2 H) 8.00 (d, J=8.34 Hz, 2 H) 8.11 (d, J=2.27 Hz, 1 H) 8.23 (br. s., 1 H) 10.93 (s, 1 H). ESI-MS: m/z 395.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[I:11]I.[O-]S([O-])(=S)=O.[Na+].[Na+].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:9]([I:11])=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: II
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(I)c1Cl
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 20 %

Procedure:
Adapting a protocol by Uchiyama et al (J. Am. Chem. Soc., 2002, 124, 8514-8515), which reference is incorporated herein by reference in its entirety, 2-chloro-4-fluorobenzonitrile (311 mg, 2.0 mmol) in dry THF (1.0 mL) was added dropwise to lithium di-t-butyl(2,2,6,6-tetramethylpiperidino)zinncate (4.0 mmol in 10 mL THF, Uchiyama et al J. Am. Chem. Soc., 1999, 121, 3539-3540, which is incorporated herein by reference in its entirety) at 0° C. and stirred at 0° C. for 3.5 h. Iodine (5.08 g, 20.0 mmol) was then added and the reaction was stirred at r.t. overnight. Na2S2O3 (1.0 M, 50 mL) and saturated aqueous NH4Cl (100 mL) were added, followed by extraction with dichloromethane (3×100 mL), drying of the combined organic layers over Na2SO4, filtering, and removal of the solvents in vacuo. The residue was passed through a pad of silica gel eluting with EtOAc/n-heptane (1:40), affording 112 mg (0.40 mmol) of 2-chloro-4-fluoro-3-iodobenzonitrile. This material was combined with nortropine (114 mg, 0.90 mmol), K2CO3 (186 mg, 0.134 mol) and DMSO (2.0 mL), and stirred at 130° C. for 1.5 h. The crude mixture thus obtained was diluted with n-heptane (10 mL), passed through a pad of silica gel using EtOAc/n-heptane (1:2), concentrated and purified by preparative TLC (EtOAC/n-heptane, 1:1) to give 1.5 mg (1.7%) of 195JP18 as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-n2cnc3ccccc32)c1
Agent: [Ni]
Product: Nc1cccc(-n2cnc3ccccc32)c1
Yield: 71 %

Procedure:
Reduction of 1-(3-nitrophenyl)benzimidazole (prepared by the method of M. A. Khan and J. B. Polya, J. Chem. Soc. (C), 1970:85-91) with Raney nickel as for Example 8, followed by chromatography on silica gel, eluting with EtOAc, gave Example 3 (71%), mp (EtOAc/hexane) 93-95° C.
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12]O>ClCCl>[CH3:1][CH:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11][NH:9]1
Reactant: CC(N)c1ccccc1
Reactant: OCCBr
Solvent: ClCCl
Product: CC1NCCc2ccccc21
Temperature: 52 °C
Reaction time: 50 h
Yield: 86.1 %

Procedure:
103.08 g(0.86 mole) of α-methylbenzylamine was dissolved in 110 ml of dichloromethane and 127.56 g(1.02 mole) of 2-bromoethanol was added thereto. This mixture was stirred at 52° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 109 g of the title compound, which had a pale yellow color.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH:9]=1)([O-])=O.[F:18][C:19]([F:36])([F:35])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>>[F:18][C:19]([F:35])([F:36])[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:1][C:4]3[CH:5]=[CH:6][C:7]4[N:8]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=4)[CH:9]=3)=[O:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cn2cc([N+](=O)[O-])ccc2n1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: CCOC(=O)c1cn2cc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)ccc2n1
Yield: 31.1 %

Procedure:
Operations similar to Example 1 were conducted using ethyl 6-nitroimidazo[1,2-a]pyridine-2-carboxylate (600 mg) and 4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid (700 mg), to provide ethyl 6-({[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-amino)imidazo[1,2-a]pyridine-2-carboxylate (360 mg) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13]C(=O)OC)=[CH:4][CH:3]=1.[OH-].[K+].O.NN>C(O)CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:7]=1
Reactant: COC(=O)NCCOCCc1ccc(F)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: NCCOCCc1ccc(F)cc1
Temperature: 25 °C

Procedure:
The product of step d) (8.0 g) was dissolved in ethylene glycol and to this was added potassium hydroxide (48 g) and hydrazine hydrate (8.3 ml). The stirred mixture was heated to 140° for 4 hours then allowed to cool to room temperature overnight. The mixture was then diluted with water and extracted with diethyl ether (×3). The combined organic extracts were washed with brine, dried (MgOS4) and filtered. The volatiles were removed in vacuo to give the subtitle compound (5.36 g).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])/[C:14](/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30]COC)[CH:25]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.O1CCOCC1.O>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])/[C:14](/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[C:15](/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)\[CH2:16][CH3:17])=[CH:8][CH:7]=1
Reactant: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1cccc(OCOC)c1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1cccc(O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of 4a (50 mg, 0.105 mmol) in MeOH (2 ml) was added 4N HCl in 1,4-dioxane (0.26 ml) under ice cooling, and the mixture was stirred at room temperature for 3 h. A solution of NaHCO3 in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residual was crystallized with AcOEt to give 5a (73%). 5a: colorless powder; 1H-NMR (CD3OD) δ 0.97 (3H, t, J=7.5 Hz), 2.36 (6H, s), 2.66 (2H, q, J=7.5 Hz), 2.79 (2H, t, J=5.4 Hz), 4.10 (2H, t, J=5.4 Hz), 6.52 (1H, dd, J=1.0, 8.1 Hz), 6.57 (1H, m), 6.64 (1H, m), 6.90 (1H, t, J=7.8 Hz), 6.94 (2H, d, J=9.1 Hz), 7.13-7.23 (5H, m), 7.53 (2H, d, J=9.1 Hz). HRMS calcd for C27H31N2O3 [M+H]+: 431.2335. Found: 431.2336.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[C:24]([F:46])=[CH:25][C:26]([Cl:45])=[C:27]([CH:44]=1)[O:28][C:29]1[N:34]=[C:33]2[S:35][C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])=[N:37][C:32]2=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][C:23]1[CH:44]=[C:27]([O:28][C:29]2[N:34]=[C:33]3[S:35][C:36]([NH:38][C:39]([CH:41]4[CH2:42][CH2:43]4)=[O:40])=[N:37][C:32]3=[CH:31][CH:30]=2)[C:26]([Cl:45])=[CH:25][C:24]=1[F:46])=[O:6]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c(Cl)cc1F
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)c(Cl)cc2F)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.4 %

Procedure:
2-Chloro-3-(1-cyano-1-methylethyl)benzoic acid (71.6 mg, 0.320 mmol) produced in Example C61(v) was dissolved in tetrahydrofuran (2 mL)/N,N-dimethylformamide (40 μL), oxalyl chloride (36 μL, 0.420 mmol) was added, and the mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[5-(5-Amino-2-chloro-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (79.8 mg, 0.211 mmol) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution (5 mL), and the mixture was extracted with ethyl acetate (5 mL×4). The organic layer was washed successively with water (5 mL) and saturated brine (5 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→10/90), and crystallized from diisopropyl ether/ethyl acetate to give the title compound (63.4 mg, 51%) as white crystals.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:15][C:16]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:17]([Cl:19])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[Cl:19][C:17]1[N:18]=[C:14]([C:11]2[CH2:10][CH2:9][N:8]([C:6]3[C:27]([C:29]([F:32])([F:31])[F:30])=[CH:11][CH:10]=[CH:9][N:8]=3)[CH2:13][CH:12]=2)[NH:15][C:16]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nc(Cl)c(-c3ccc(F)cc3)[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2[nH]c(C3=CCN(c4ncccc4C(F)(F)F)CC3)nc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[4-chloro-5-(4-fluoro-phenyl)-1H-imidazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester from step (b) above in 30% TFA in DCM (5 mL) was stirred at RT for 1 h. The solvents were removed, and the residue was stirred with sat. aqueous solution of NaHCO3 (10 mL) at RT for 0.5 h. The reaction mixture was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over MgSO4 and filtered. The filtrate was evaporated in vacuo to give the title compound, which was directly used in the next step without additional purification. MS (ESI, positive ion) m/z: 278 (M+1).