Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:32]=[CH:31][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH:59]2[CH2:61][O:60]2)=[CH:53][CH:52]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][NH:20][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:61][C@H:59]([OH:60])[CH2:58][O:57][C:54]4[CH:55]=[CH:56][C:51]([OH:50])=[CH:52][CH:53]=4)=[CH:32][CH:31]=3)[CH2:13][CH2:14]2)=[O:19])=[CH:28][CH:27]=1)[CH3:30]
Reactant: CCc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=CO
Product: CCc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 28.4 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(4-ethylphenethyl)-1-piperidinecarboxamide formate (0.60 g, 1.3 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.55 g, 1.3 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.295 g, 0.369 mmol).
Reaction SMILES: C([S:5][C:6]([CH3:9])([CH3:8])[CH3:7])(C)(C)C.Cl>[Cl-].[Zn+2].[Cl-].CS(C)=O>[C:6]([S:5][S:5][C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)SC(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CS(C)=O
Product: CC(C)(C)SSC(C)(C)C
Yield: 85 %

Procedure:
When a mixture of 10 ml of di-t-butyl sulfide and 10 ml of dimethyl sulfoxide was heated at 300° F. (149° C.) for about 40 minutes in the presence of catalytic amounts of zinc chloride and hydrochloric acid, gas-liquid chromatography indicated an 85 percent yield of di-t-butyl disulfide. The identity of the product was confirmed by mass spectrometry and infrared spectroscopy.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24](Br)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC([N:42]1[C:46](B(O)O)=[CH:45][CH:44]=[N:43]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[NH4+].[Cl-]>O1CCOCC1.C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:46]5[CH:45]=[CH:44][NH:43][N:42]=5)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nccc1B(O)O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(Br)ccn4c3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(-c5cc[nH]n5)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 105 °C

Procedure:
To a solution of {1-[4-(7-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (200 mg, 0.38 mmol), and 1-(tert-butoxycarbonyl)pyrazole-5-boronic acid (164 mg, 0.77 mmol, 2 equiv) in dioxane (4 mL) under argon was added [1,1-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) CH2Cl2 complex (63 mg, 0.77 mmol, 20 mol %), Na2CO3 (123 mg, 1.16 mmol, 3 equiv) and water (0.5 mL). The resulting mixture was heated at 105° C. for 8 h in a microwave apparatus. The reaction mixture was mixed with water (10 mL), a saturated aqueous NH4Cl solution (10 mL) and CH2Cl2 (25 mL) with vigorous stirring at room temperature for 30 min. The organic phase was washed with a saturated aqueous NaCl solution (25 mL), dried (Na2SO4 anh), and concentrated under reduced pressure.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:5]([NH:13][CH2:2][C:3]#[N:4])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCc1ccccc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCNCCc1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Chloro-acetonitrile (1.5) eq was added to a solution of phenethylamine (1 eq) and K2CO3 (2 eq) in CH3CN. The mixture was stirred at 60° C. for 4 hrs. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography gave the expected compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:65]=[CH:64][CH:63]=[CH:62][C:4]=1[C:5]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[O:34][PH:35]([O:37][CH2:38][C@H:39]1[O:43][C@@H:42]([N:44]2[CH:52]=[C:50]([CH3:51])[C:48](=[O:49])[NH:47][C:45]2=[O:46])[CH2:41][C@@H:40]1[O:53]C(=O)C1C=CC=CC=1)=[O:36])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO.C(N)(C)(C)C>[CH3:1][O:2][C:3]1[CH:65]=[CH:64][CH:63]=[CH:62][C:4]=1[C:5]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[O:34][PH:35]([O:37][CH2:38][C@H:39]1[O:43][C@@H:42]([N:44]2[CH:52]=[C:50]([CH3:51])[C:48](=[O:49])[NH:47][C:45]2=[O:46])[CH2:41][C@@H:40]1[OH:53])=[O:36])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccccc1C(OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[PH](=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1OC(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CC(C)(C)N
Product: COc1ccccc1C(OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[PH](=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O)(c1ccccc1)c1ccccc1

Procedure:
Dinucleoside monophosphate 3 (20 mg; 20 μmol) was dissolved in 2 mL of 1:1 CH3OH-t-butylamine. The reaction mixture was maintained at 40°-45° C. for 2 days, then concentrated under diminished pressure. The residue was purified by preparative silica gel TLC; development was with 9:1 CH2Cl2 -CH3OH. Dinucleoside monophosphate 4 was isolated as an off-white gummy solid following lyophilization, yield 15 mg (84%); silica gel TLC Rf 0.50 (10:1 CH2Cl2 -CH3OH); 1H-NMR (CDCl3, (CH3)4Si) & 0.8-0.9 (m), 1.2-1.35 (m), 1.32 (s), 1.81 (s), 2.1-2.9 (m), 3.00 (m), 3.4-4.3 (m), 3.71 (s), 4.4 (m), 4.6 (m), 5.04 (m), 6.07 (t), 6.35 (m), 6.78 (d), 7.2-7.4 (m), 7.50 (s) and 8.46 (br s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:19]([CH3:25])[C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=3)[C:16](=O)[C:15]3[C:14]([C:27]([O:29]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:33][NH2:34]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:33][NH:34][C:27](=[O:29])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:19]([CH3:25])[C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nc(C)c(C)n1C)C(c1ccc(F)cc1)N2
Solvent: CO
Solvent: O
Product: Cc1nc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(F)cc2)n(C)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-4-oxo-3-(1,4,5-trimethyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg) in 85% hydrazine monohydrate (85%, 3 mL) and methanol (5 mL) was stirred at room temperature for 2 days. The result suspension was filtered and washed the water (20 mL) and methanol (5 ml) to obtain a white solid. The solid was dried in vacuum at 50° C. to afford the title compound (90 mg, yield 65%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.91-1.96 (d, J=18 Hz, 6H), 3.25 (s, 3H), 4.59-4.62 (d, J=10.8 Hz, 1H), 4.92-4.95 (d, J=10.8 Hz, 1H), 7.09-7.15 (m, 3H), 7.22 (s, 1H), 7.36-7.38 (d, J=7.6 Hz, 1H), 7.43-7.46 (m, 2H), 7.54-7.58 (t, J=8 Hz, 1H), 12.13 (s, 1H); LC-MS (ESI) m/z: 390 (M+1)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[O:59](C1C=CC(C(Cl)=O)=CC=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][C:5]([O:59][C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)=[CH:6][CH:7]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Oc5ccccc5)cc4)cc3)cc2C1=O
Yield: 76 %

Procedure:
The compound of example 149 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-phenoxy benzoyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([F:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[N+:10]([O-])([OH:12])=[O:11]>>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH2:1][CH3:2])([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CCc1cccc(F)c1
Product: CCc1cc(F)ccc1[N+](=O)[O-]

Procedure:
3-ethyl-fluorobenzene was reacted with nitric acid to obtain 4-nitro-3-ethyl-fluorobenzene which was reacted with N-hydroxy-phthalimide to form 0-(4-nitro-3-ethyl-phenoxy)-phthalimide which was reacted to form 0-(4-nitro-3-ethylphenyl)-hydroxylamine melting at 55°-56° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[C:13]([NH2:21])[C:14]([NH2:20])=[CH:15][CH:16]=3)[CH2:11]2)=[CH:5][CH:4]=1.[C:24](O)(=[O:28])[C:25](O)=[O:26]>Cl>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[CH:15][C:14]4[NH:20][C:25](=[O:26])[C:24](=[O:28])[NH:21][C:13]=4[C:12]=3[CH2:11]2)=[CH:7][CH:8]=1
Reactant: Nc1ccc2c(c1N)CN(Cc1ccc(C(F)(F)F)cc1)CC2
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1[nH]c2ccc3c(c2[nH]c1=O)CN(Cc1ccc(C(F)(F)F)cc1)CC3
Temperature: 25 °C

Procedure:
A solution of the product from Example 16 (0.53 g, 1.32 mmol) in 3N HCl (50 mL) was treated with oxalic acid (0.25 g, 1.98 mmol) and refluxed for four hours. After cooling to room temperature, the precipitate was filtered, suspended in water (70 mL), heated to 80° C. and basifyed to pH 8. The solids were filtered, and dried to give the title compound in two crops [125 mg, mp=293-297° C. (dec.)] and [33 mg, mp=263-266° C. (dec.)] yielding 34%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C([Li])(C)(C)C.I[C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[C:7]([C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=2)=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccccc2)nc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2nc(-c3ccccc3)ccc2Cl)cc1
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution (50 ml) of 5-chloro-2-phenylpyridine (3.50 g) in tetrahydrofuran was added dropwise t-butyl lithium (1.7 M solution in pentane, 12.0 ml) under an argon atmosphere at −78° C., and the mixture was stirred for 1 hr. To this mixed solution was added a solution (15 ml) of zinc chloride (3.00 g) in tetrahydrofuran, and the mixture was stirred at 0° C. for 30 min. Then, ethyl 4-iodobenzoate (3.4 ml) and tetrakis (triphenylphosphine)palladium (1.15 g) were added. This mixture was stirred overnight at room temperature under an argon atmosphere, and poured into 0.5 M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1, volume ratio). Recrystallization from hexane-ethyl acetate gave ethyl 4-(3-chloro-6-phenyl-2-pyridyl)benzoate (3.86 g, yield 58%) as colorless crystals. melting point: 81–82° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[N:40]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:45]([N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:46])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:4])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Reactant: O=C(Cl)N1CCCC1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)N1CCCC1)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure D using 1-pyrrolidinecarbonyl chloride. The final product was obtained in 57% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]3)[CH:16]=[N:17][C:4]=2[CH:3]=1.[Cl-].[Li+].CC1(C)CCCC(C)(C)N1[Mg]Cl.[F:40][C:41]1[C:42]([CH:47]=[O:48])=[N:43][CH:44]=[CH:45][CH:46]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]3)[C:16]([CH:47]([C:42]3[C:41]([F:40])=[CH:46][CH:45]=[CH:44][N:43]=3)[OH:48])=[N:17][C:4]=2[CH:3]=1
Reactant: O=Cc1ncccc1F
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Agent: CC1(C)CCCC(C)(C)N1[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(C(O)c3ncccc3F)nc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (Preparative Example 3.1, Step 1) (1.2 g, 3.19 mmol) in THF (20 mL) was added 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (Aldrich, 1M in THF/toluene) (5.11 mL, 5.11 mmol) at −78° C., and the reaction was stirred at −78° C. for 2 hours under a nitrogen atmosphere. 3-fluoropicolinaldehyde (1.1 g, 9.59 mmol) dissolved in THF (4.0 mL) was added dropwise at −78° C., and the reaction was stirred for an additional 2 hours at −78° C. The reaction was quenched with aqueous saturated NH4Cl solution (50 mL) and extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column (0 to 100% EtOAc/hexanes) afforded {6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}(3-fluoropyridin-2-yl)methanol. MS APCl calcd. for C25H24Cl2FN5O [M+H]+ 500. found 500.
Reaction SMILES: C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.[CH:19]1([C:22]2[N:26]([CH3:27])[C:25]3[CH:28]=[C:29]([N:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:33]4=[O:39])[CH:30]=[CH:31][C:24]=3[N:23]=2)[CH2:21][CH2:20]1.[Br:40][C:41]1[CH:42]=[C:43]([CH2:47]O)[S:44][C:45]=1[Cl:46].C(P(CCCC)CCCC)CCC>C1COCC1>[Br:40][C:41]1[CH:42]=[C:43]([CH2:47][O:38][C:35]2[CH:36]=[CH:37][N:32]([C:29]3[CH:30]=[CH:31][C:24]4[N:23]=[C:22]([CH:19]5[CH2:20][CH2:21]5)[N:26]([CH3:27])[C:25]=4[CH:28]=3)[C:33](=[O:39])[CH:34]=2)[S:44][C:45]=1[Cl:46]
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1cc(Br)c(Cl)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Br)c(Cl)s4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
1,1-(Azodicarbonyl)dipiperidine (269 mg) was added to a solution of 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (4-bromo-5-chloro-2-thienyl)methanol (162 mg) and tributylphosphine (0.26 ml) in THF (5 ml) at room temperature. The mixture was stirred at 60° C. for 2 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) and preparative HPLC (L-Column 2 ODS, eluted with H2O in acetonitrile containing 0.1% TFA). The desired fraction was neutralized with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (12 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)=[O:20]>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[C:16]([NH:15][C:8]([C:3]4[N:4]([CH3:7])[N:5]=[CH:6][C:2]=4[Cl:1])=[O:10])[CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: Cn1ncc(Cl)c1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cn1ncc(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A dry 25 mL flask was charged with 4-Chloro-2-methyl-2H-pyrazole-3-carboxylic acid (0.139 g, 0.873 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.794 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 2 h. The reaction mixture was then allowed to cool to room temperature. The tan solids were filtered and washed with ˜3 mL of THF to afford the pure 4-Chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.264 g, 0.667 mmol, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:10][CH3:11])=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[N+:12]([CH2:15][CH2:16][CH3:17])([O-])=[O:13].C1(N=C=O)C=CC(N=C=O)=CC=1.O>C(N(CC)CC)C.C1C=CC=CC=1>[CH2:16]([C:15]1[CH:9]=[C:8]([C:6]2[CH:5]=[N:4][C:3]([S:10][CH3:11])=[C:2]([Cl:1])[CH:7]=2)[O:13][N:12]=1)[CH3:17]
Reactant: CCC[N+](=O)[O-]
Reactant: C#Cc1cnc(SC)c(Cl)c1
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1cc(-c2cnc(SC)c(Cl)c2)on1
Reaction time: 8 h
Yield: 479.8 %

Procedure:
A mixture of 3-chloro-5-ethynyl-2-methylthiopyridine (0.5 g, 2.72 mmol), 1-nitropropane (0.24 g, 0.27 mmol), 1,4-phenylenediisocyanate (1.3 g, 7.93 mmol) and triethylamine (5 drops) in benzene (20 mL) was heated under reflux with stirring for 8 hours, and allowed to stir at room temperature overnight. Water (1 mL) was added and the mixture stirred at room temperature for 2 hours. It was filtered through Celite, dried over anhydrous sodium sulphate and evaporated under reduced pressure. Recrystallisation of the residue from hexane gave the desired product (0.33 g, 48%) as a cream solid, melting point. 78-80° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:23][CH:24]([O:29][Si](C(C)(C)C)(C)C)[C:25]([F:28])([F:27])[F:26])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:43][O:44][C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:43][O:44][C:45]1[CH:51]=[CH:50][C:48]([NH:49][C:2]2[CH:3]=[C:4]([N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:21])([F:22])[CH:18]([F:20])[F:19])[CH:11]=3)[CH2:23][CH:24]([OH:29])[C:25]([F:26])([F:28])[F:27])[CH:5]=[CH:6][CH:7]=2)=[CH:47][CH:46]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Br)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)cc1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 74.2 %

Procedure:
A mixture containing N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl) dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy) benzenemethanamine (75 mg, 0.124 mmol), cesium carbonate (57.5 mg, 0.176 mmol), 4-methoxyaniline (18.6 mg, 0.151 mmol) tris(dibenzylideneacetone) dipalladium(0) (4.6 mg, 0.005 mmol), R-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.7 mg, 0.0075 mmol) and toluene (2.5 mL) was heated to 95° C. in a sealed vial for 48 h. Tetrabutylammonium fluoride (1 M, THF, 0.372 mL, 0.372 mmol) was added, and the reaction was stirred at 23° C. for 1.5 h. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give 49 mg (73%) of the desired 3-[[3-[(4-methoxyphenyl)amino]phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd for C25H23F7N2O3: 532.1597, found: 532.1592 [M]+. 1H NMR (CDCl3) δ 3.48-3.57 (m, 1H), 3.77 (s, 3H), 3.83 (dd, 1H), 4.33 (m, 1H), 4.59 (s, 2H), 5.87 (tt, 1H), 6.27 (m, 1H), 6.33 (bd, 1H), 6.86 (dd, 4H), 7.02-7.12 (m, 4H), 7.31 (t, 1H), 7.41 (m, 1H), 7.60 (m, 1H). 19F NMR (CDCl3) δ −137.201 (d, 2F), −88.515 (s, 2F), −79.120 (s, 3F).
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2>>[NH:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:12](=[O:13])[CH2:11][C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ccc2[nH]ncc2c1
Yield: 82.5 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.1 g) and 5-aminoindazole (0.067 g) to give the title compound as a white solid (0.12 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11].[OH:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[C:22](=[O:24])[CH3:23]>CC(C)=O>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([C:22](=[O:24])[CH3:23])=[C:14]([O:13][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:19]=1
Reactant: COc1ccc(C(C)=O)c(O)c1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(C)=O)c(OCC=C(C)C)c1

Procedure:
20.7 g of potassium carbonate and 23.2 ml of 1-bromo-3-methyl-2-butene were successively added to 300 ml of acetone containing 25 g of 2′-hydroxy-4′-methoxyacetophenone. The reaction solution was then heated to reflux. Approximately 6 hours later, 4.14 g of potassium carbonate and 4.63 ml of 1-bromo-3-methyl-2-butene were further added thereto, and the obtained mixture was heated to reflux. Approximately 34 hours later, the reaction solution was stood to cool, and then, it was filtered through celite. The filtrate was concentrated under a reduced pressure, and the residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain the subject compound. The reaction was further carried out using 2′-hydroxy-4′-methoxyacetophenone (25 g×2 times) under the above described conditions. The total amount of the subject compounds was 98.7 g.