Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>CN(C)C=O.C1COCC1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([Cl:20])=[O:17])[CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2cc(C(=O)Cl)ccc2c1
Temperature: 25 °C

Procedure:
Into a 0.25 L, 3-necked roundbottom flask, fitted with a magnetic stirbar, addition funnel, and reflux condenser were added 6-acetoxy-2-naphthoic acid (30.0 g, 130 mmol), THF (135 mL) and dimethylformamide (approx. 20 drops). Thionyl chloride (18.6 g, 156 mmol) was added slowly dropwise to the reaction mixture over 15 minutes. The reaction mixture was heated to reflux for 2.5 hours under nitrogen and allowed to cool to room temperature overnight.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([NH:19][C:20](=[O:30])[C:21]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=1[CH3:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[C:15]([CH:17]=O)[CH:16]=2)=[CH:8][CH:7]=1.[CH3:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[CH:34]=1.[Li+].[OH-].Cl>ClC(Cl)C.C(OCC)(=O)C>[CH3:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH2:17][C:15]2[CH:16]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([NH:19][C:20](=[O:30])[C:21]4[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])[C:3]([OH:2])=[O:31])=[CH:7][CH:8]=3)[S:13][CH:14]=2)[CH:34]=1
Reactant: Cc1ccnc(N)c1
Reactant: COC(=O)C(Cc1ccc(-c2cc(C=O)cs2)cc1)NC(=O)c1c(C)cc(C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: Cc1ccnc(NCc2csc(-c3ccc(CC(NC(=O)c4c(C)cc(C)cc4C)C(=O)O)cc3)c2)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 33.5 %

Procedure:
99 mg of (18) were dissolved in/ml of dichloroethane and 37 mg (1.5 eq.) of 4-methylpyridin-2-ylamine and 240 mg (5 eq.) of NaHB(OAc)3 were added. The solution was stirred for 2.5 h. After pouring in ethyl acetate the organic layer was washed with saturated NaHCO3, brine and dried over Na2SO4. The crude product was redissolved in 6 ml of 1,4-dioxane and 1 ml of water. The solution was cooled to 0° C. and 3 eq. of LiOH*H2O were added. The solution was neutralized after 6 h with 1 M HCl and concentrated in vacuo. The product was purified by HPLC to give 39.1 mg of (19) as TFA salt.
Reaction SMILES: [C:1]([C:3]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[C:4](OC)[CH3:5])#[N:2].C(=O)(O)O.[NH2:25][C:26]([NH2:28])=[NH:27].O>CN(C)C(=O)C>[NH2:27][C:26]1[N:28]=[C:1]([NH2:2])[C:3]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:20])[F:19])=[C:4]([CH3:5])[N:25]=1
Reactant: N=C(N)N
Reactant: COC(C)=C(C#N)CCCc1ccccc1C(F)(F)F
Agent: O=C(O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc(N)nc(N)c1CCCc1ccccc1C(F)(F)F
Yield: 40.6 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 7.6 grams (0.027 mole) of 3-cyano-2-methoxy-6-(2-trifluoromethylphenyl)-2-hexene and 12.2 grams (0.068 mole) of guanidine carbonate in 35 mL of N,N-dimethylacetamide was heated at about 150° C. for 40 hours. After this time, the reaction mixture was poured into 300 mL of water. The resultant solid was collected by filtration, and was then slurried in 100 mL of diethyl ether. The solid was again collected by filtration and was subjected to column chromatography on silica gel. Elution was accomplished using 10% methanol in methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.4 grams of 2,4-diamino-5-[3-(2-trifluoromethylphenyl)propyl]-6-methyl-pyrimidine, mp 151°-158° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]([NH2:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CO.[Pt]=O>[CH2:12]([NH:24][CH:6]1[CH2:7][C:2]([CH3:11])([CH3:1])[NH:3][C:4]([CH3:10])([CH3:9])[CH2:5]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: CCCCCCCCCCCCN
Agent: O=[Pt]
Solvent: CO
Product: CCCCCCCCCCCCNC1CC(C)(C)NC(C)(C)C1
Reaction time: 3 h

Procedure:
1.0 g of platinum oxide was added to a solution of 31.0 g of 2,2,6,6-tetramethyl-4-piperidone and 47.0 g of dodecylamine in 250 ml of methanol. The resulting mixture was then hydrogenated under a hydrogen atmosphere in a Parr hydrogenation apparatus at room temperature for 3 hours. After completion of the reaction, the platinum catalyst was filtered off, and then the solvent was distilled from the filtrate under reduced pressure to give an oily product. This product was purified by column chromatography through silica gel, eluted with a 20:3:1 by volume mixture of ethyl acetate, ethanol and triethylamine, to give the title compound as an oil. The Rf value of this product on thin layer chromatography was 0.34, using silica gel and a 20:3:1 by volume mixture of ethyl acetate, ethanol and triethylamine as the developing solvent.
Reaction SMILES: CN[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]([N:12]([SiH3:16])C(C)C)(C)C>>[C:3]1([CH2:9][NH:12][SiH3:16])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)N([SiH3])C(C)C
Reactant: CNc1ccccc1
Product: [SiH3]NCc1ccccc1
Reaction time: 24 h
Yield: 89.4 %

Procedure:
In a 500 ml Schlenk flask, 64.2 grams (g) (0.6 mol) N-methylaniline and 131 g (1.0 mol) di-isopropylaminosilane were stirred at ambient temperature under a nitrogen atmosphere for 24 hours. The relatively lower boiling point by-product di-isopropylamine was removed with vacuum at a pressure of 20 mmHg and room temperature (25° C.). The reaction mixture was stirred for another 24 hours. The end-product phenylmethylaminosilane (73.6 g, 89.5% yield) was obtained by vacuum distillation with a boiling point of 60° C. at 5 mm Hg. The end-product was characterized by mass spectroscopy (MS) which is provided in FIG. 1 and shows, among other things, peaks at 137, 122, 106, 91, and 77. The molecular weight of the phenylmethylaminosilane was 137.27.
Reaction SMILES: CC(C)(OC([NH:7][CH2:8][CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11])=O)C.Cl.O1CCOCC1>C(O)(=O)C>[ClH:31].[NH2:7][CH2:8][CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 0.25 h
Yield: 163.1 %

Procedure:
To a solution of 2.30 g (5.0 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxopropyl]hydrazide (7), prepared as described above in Example 7, in 8 mL of acetic acid (HOAc) was added 8 mL of 6.8N HCl/dioxane. After 15 minutes, the solvent was removed under H2O aspirator vacuum. The resulting residue was triturated with diethyl ether (Et2O). The resulting white solid was collected on a sintered glass funnel and dried in a vacuum oven at 70° C. for 16 hours. A yield of 1.62 g (81%) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9) was isolated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[Br:11].[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[Br:11]
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(N2CCC(O)CC2)cc1Br
Temperature: 90 °C
Yield: 75.6 %

Procedure:
A mixture of 2-bromo-4-fluoro-benzoic acid methyl ester (2.06 g, 8.84 mmol), 4-hydroxy piperidine (1.86 g, 18.4 mmol), and potassium carbonate (1.33 g, 9.62 mmol) in acetonitrile (25 mL) is heated to 90° C. for 17 h. The mixture is concentrated and partitioned between ethyl acetate and water. The solvent layers are separated and the aqueous layer is extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4), filtered, and concentrated under reduced pressure. The residue is purified on silica (120 g) using a gradient of 0% to 90% ethyl acetate in heptane to provide the title compound (2.10 g, 76%) LC-ES/MS m/z 314.0 (M+1)
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([OH:15])=O.[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([F:2])[CH:4]=2)[NH:8][CH:7]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cc1c[nH]c2ccc(F)cc12)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 70 %

Procedure:
Proceeding as in Example 1, but substituting 2-(5-fluoro-1H-indol-3-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 212, (S)-3-(benzyloxy)-2-(2-(5-fluoro-1H-indol-3-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (78 mg, 70%). 1H-NMR (400 MHz, DMSO-D6): σ 10.98 (s, 1H), 10.17 (s, 1H), 8.37 (d, 1H), 7.63-7.57 (m, 2H), 7.39-7.16 (m, 9H), 7.05-6.95 (m, 4H), 6.93-6.86 (m, 1H), 4.75-4.67 (m, 1H), 4.50 (s, 2H), 3.70-3.53 (m, 4H). MS (EI) for C32H27F2N3O4. found 555.9 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@H:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].[C:40]1(=[O:50])[O:45][C:43](=[O:44])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12>>[C:40]([O:21][C@@H:13]([CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:6]([NH:22][C:23](=[O:39])[CH2:24][CH:25]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[O:32][C:33]3[C:38]2=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:7]=1)[CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)(=[O:50])[C:41]1[C:42](=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:43]([OH:45])=[O:44]
Reactant: CC(C)(C)c1ccc(CC[C@H](O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: O=C1OC(=O)c2ccccc21
Product: CC(C)(C)c1ccc(CC[C@@H](CC2CCCCC2)OC(=O)c2ccccc2C(=O)O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Example 54, but using (S)-N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 102) and phthalic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like material.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[C:41]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[C:41]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1cccc(F)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(F)c1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 46 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with (2-fluoro-6-methoxyphenyl)boronic acid (137 mg, 0.81 mmol), sodium carbonate (86 mg, 0.81 mmols) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, dichloromethane-ethyl acetate) to give 50 mg (46% yield) of the title compound. Purity 87%.
Reaction SMILES: [OH-:1].[Na+].Cl[P:4]1(=[O:22])[O:9][CH:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:7]([CH3:21])([CH3:20])[CH2:6][O:5]1.Cl>O>[OH:1][P:4]1(=[O:22])[O:9][CH:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:7]([CH3:21])([CH3:20])[CH2:6][O:5]1
Reactant: CC1(C)COP(=O)(Cl)OC1c1ccc2ccccc2c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)COP(=O)(O)OC1c1ccc2ccccc2c1
Temperature: 101 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Sodium hydroxide (14.9 g, 0.373 mol) was dissolved in water (150 ml). To this solution was added little by little 2-chloro-5,5-dimethyl-4-(2-naphthyl)-1,3,2-dioxaphosphorinane-2-one (38.6 g, 0.124 mol) with heating to 100 to 102° C. and stirring for 30 min. The solution was stirred at the same temperature for 20 min, and the reaction solution was cooled to 45° C. Concentrated hydrochloric acid (37 ml) was added thereto to adjust the solution to acidic. The solution was stirred at 15° C. for 30 min. The crystals were collected by filtration, washed with water and then ether, and dried under reduced pressure at 60° C. to give the title compound as pale ocher crystals having the melting point of 237 to 238° C. (33.87 g, yield 93.2%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:6][N:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2cccc([N+](=O)[O-])c2)cn1
Temperature: 140 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
A mixture of 6-methylpyridin-3-ol (17.6 g, 161 mmol), 1-fluoro-3-nitrobenzene (25.0 g, 177 mmol), potassium carbonate (66.8 g, 483 mmol) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 13 hr, 120° C. for 5 hr and 140° C. for 4 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (28.6 g, 77%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4(O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]([O:30][Si](C)(C)C)=[C:27]([CH3:29])[CH3:28]>ClCCCl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:27]([CH3:29])([CH3:28])[C:26]([O:25][CH3:24])=[O:30])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: OC1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)C(C)(C)C1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCCCC1
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
To a solution of 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexanol (500 mg, 1.6 mmol) in DCE (20 mL) was added 1-methoxy-2-methyl-1-trimethylsiloxy-propene (935 uL, 4.8 mmol) followed by TiCl4 (1.7 mL of 1.0 M in DCM). Within 10 min, the reaction was complete. The reaction was quenched with MeOH and then extracted from brine containing dilute HCl with EtOAc×4. The organic layers were dried over MgSO4, filtered, concentrated and purified on SiO2 using 25% EtOAc in hexanes to give 635 mg (100%) of methyl 2-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexyl)-2-methylprop-anoate MS found: (M+H)+=395.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:23])[N:10]=2)=[CH:5][CH:4]=1.[O:24]=[C:25]1[N:29]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:28]2[CH:36]=[CH:37][CH:38]=[CH:39][C:27]=2[NH:26]1>CO.C1COCC1>[Cl:23][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:33]3[CH2:32][CH2:31][CH:30]([N:29]4[C:28]5[CH:36]=[CH:37][CH:38]=[CH:39][C:27]=5[NH:26][C:25]4=[O:24])[CH2:35][CH2:34]3)=[CH:4][CH:5]=2)[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CBr)cc2)nc1Cl
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 6-[4-(bromomethyl)phenyl]-2-chloro-5-phenylnicotinonitrile (1-5; 0.078 g, 0.203 mmol) in MeOH (1 mL) and THF (1 mL) was added 4-(2-keto-1-benzimidazolinyl)-piperidine (0.066 g, 0.305 mmol) and DIEPA (0.131 g, 1.02 mmol). The mixture was stirred at rt overnight and concentrated. The residue was treated with aqueous Na2CO3 solution (5 mL, 2 M) and extracted with CH2Cl2 (3×10 mL). The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (3-5% MeOH in CH2Cl2) to give 2-chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl]-5-phenylnicotinonitrile (1-6). 1H-NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.31-7.37 (m, 4H), 7.25-7.29 (m, 4H), 7.17-7.19 (m, 2H), 7.05-7.09 (m, 3H), 4.31-4.36 (m, 1H), 3.54 (s, 2H), 2.97-2.99 (m, 2H), 2.41-2.47 (m, 2H), 2.12-2.17 (m, 2H), 1.78-1.80 (m, 2H). LRMS m/z (M+H) Calcd: 520.0, found: 520.0.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)(=O)=O.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[F:30][C:21]([F:20])([F:29])[C:22]1[CH:23]=[CH:24][C:25]([S:28][CH:6]2[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:10][CH2:11]2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCC(Sc2ccc(C(F)(F)F)cc2)CC1
Temperature: 130 °C
Yield: 43 %

Procedure:
4-[(tert-Butoxycarbonyl)amino]cyclohexyl methanesulfonate (0.7 g, 2.39 mmol), 4-(trifluoromethyl)thiophenol (1.28 g, 7.16 mmol) and K2CO3 (1.32 g, 9.54 mmol) was dissolved in THF (21 ml) and the reaction mixture was heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was diluted with water (300 ml) and extracted with EtOAc (2×150 ml). The combined organic phases were dried over Na2SO4, filtrated and evaporated. The residue was purified by silica gel column chromatography using a 85:15 mixture of heptane:EtOAc to give the title compound (0.386 g, 43%) as a 50:50 mixture of cis and trans isomers. 1H-NMR (CDCl3, 500 MHz): δ 7.55-7.50 (m, 4H), 7.45-7.40 (m, 4H), 4.70-4.23 (m, 2H), 3.69-3.36 (m, 3H), 3.16-3.05 (m, 1H), 2.13-2.04 (m, 4H), 1.95-1.64 (m, 9H), 1.54-1.40 (m, 1H), 1.45 (ds, 18H), 1.30-1.15 (m, 2H); 13C-NMR (CDCl3, 125 MHz): δ 155.4, 141.1, 140.7, 130.5, 129.9, 128.6, 128.5, 128.2, 126.0, 125.9, 125.9, 125.9, 125.4, 123.2, 79.5, 49.1, 47.9, 44.8, 43.8, 33.4, 32.0, 29.2, 29.1, 28.6.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]2[NH:18][C:6]([C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:19][C:14]=2[CH:13]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(N)c(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2nc3cc(C)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
4-Methylbenzoyl chloride (2.17 mL, 2.54 g, 16.4 mmol) in dichloromethane (25 mL) was added dropwise to a stirred, cooled (0° C.) solution of 4-methyl-1,2-benzenediamine (2.0 g, 16.4 mmol) and triethylamine (4.57 mL, 3.32 g, 33 mmol) in dichloromethane (25 mL) and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, acetic acid (40 mL) was added and the mixture was stirred at 100° C. for 24 h. The solvent was evaporated under reduced pressure, water (100 mL) was added and the pH was adjusted to 7.0 with aqueous sodium carbonate (10%). Ethyl acetate (50 mL) was added, the layers were separated and the aqueous layer was extracted with ethyl acetate (4×35 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol, heated to reflux and allowed to cool. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound (1.17 g, 32%). 1H NMR (360 MHz, CDCl3) δ 7.92 (2H, d, J 8.2 Hz), 7.52 (1H, d, J 8.1 Hz), 7.38 (1H, d, J 1.0 Hz), 7.27 (2H, d, J 8.2 Hz), 7.08 (1H, dd, J 8.1, 1.0 Hz), 2.47 (3H, s), and 2.40 (3H, s). m/z (ES+) 223 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1C=O.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12]>C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CO>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:10]([O:13][CH3:14])[O:11][CH3:12]
Reactant: COC(OC)OC
Reactant: O=Cc1ccccc1Br
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: COC(OC)c1ccccc1Br
Yield: 94.4 %

Procedure:
To a 500 mL round bottom flask equipped with a reflux condenser were added 2-bromobenzaldehyde (102.5 g, 0.554 mol, Aldrich), trimethyl orthoformate (64.9 mL, 0.594 mol, Aldrich), 10-camphor sulfonic acid (1.25 g, 5.40 mmol, Aldrich), and methanol (100 mL). The reaction was heated at reflux for 14 hrs and concentrated in vacuo. The residue was taken up in 500 mL of ether, washed with 200 mL each of sat. aqueous sodium bicarbonate, water, and sat. aqueous NaCl, dryed over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was distilled through a 27 cm Vigrew column (b.p. 78-82° C./1.2 mmHg), affording a clear colorless oil (120.8 g, 94%). 1H-NMR (300 MHz, CDCl3) δ3.37 (s, 6H), 5.54 (s, 1H), 7.18 (dt, 1H, J=1.7, 8.1 Hz), 7.31 (dt, 1H, J=1.2, 7.5 Hz), 7.54 (dd, 1H, J=1.2, 8.1 Hz), 7.59 (dd, 1H, J=1.7, 7.5 Hz). Mass spectrum (EI+) m/e 230, 232 (M+), 199, 201 (bp).