Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]([NH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[CH2:37](Br)[CH:38]=[CH2:39]>CCCCCC.ClCCl.O>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]([NH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:39][CH:38]=[CH2:37])[CH:25]=[CH:24]2)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc2[nH]ccc2c1)c1nc2ccc(Cl)cc2n1Cc1ccccc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: ClCCl
Product: C=CCn1ccc2cc(NC(=O)c3nc4ccc(Cl)cc4n3Cc3ccccc3)ccc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To 0.66 g of 1-benzyl-6-chloro-2-(indol-5-ylaminocarbonyl)benzimidazole was added 50 ml of dimethylformamide, further added 170 mg of oily sodium hydride, said mixture was stirred under nitrogen gas atmosphere at 60° C. for 1 hour. Under cooling at 0° C., 0.14 ml of allyl bromide was added to the reaction mixture, and stirred at room temperature overnight, then water was added thereto and extracted with ethyl acetate, the extract was washed with water and an aqueous solution saturated with sodium chloride. The washed extract was dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: 10% n-hexane/dichloromethane), recrystallized from ethyl acetate-ethanol, there was obtained 0.35 g of 1-benzyl-6-chloro-2-(1-allylindol-5-ylaminocarbonyl)benzimidazole as in the form of colorless needle crystals.
Reaction SMILES: [S:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])(=[O:3])=[O:2].C1(CC[Cl:25])C=CC=CC=1>>[S:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][Cl:25])=[CH:11][CH:10]=1)(=[O:7])=[O:8])([CH3:4])(=[O:2])=[O:3]
Reactant: C=Cc1ccc(S(=O)(=O)NS(C)(=O)=O)cc1
Reactant: ClCCc1ccccc1
Product: CS(=O)(=O)NS(=O)(=O)c1ccc(CCCl)cc1

Procedure:
A procedure similar to that described in Example I was used to prepare the N-mesyl-4-vinylbenzenesulfonamide using phenyl ethyl chloride as a starting material and producing as an intermediate N-mesyl-4-(2-chloroethyl)benzenesulfonamide. Analysis of obtained vs. theoretical values for the intermediate are as follows: melting point: 149°-151° C.; neutralization equivalent: 302.05 (theory 297).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C([O:11][C@@H:12]1[C@@H:17]([O:18]C(=O)C)[C@H:16]([O:22]C(=O)C)[C@@H:15]([CH2:26][O:27]C(=O)C)[O:14][C@H:13]1[O:31][C:32]1[C:36]([CH2:37][C:38]2[CH:43]=[CH:42][C:41](/[CH:44]=[CH:45]/[C:46](O)=[O:47])=[CH:40][CH:39]=2)=[C:35]([CH:49]([CH3:51])[CH3:50])[NH:34][N:33]=1)(=O)C.C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1OC1C(CC2C=CC(/C=C/CC(O)=O)=CC=2)=C(C(C)C)NN=1)(=O)C>>[C:3]([C:2]([NH:1][C:46](/[CH:45]=[CH:44]/[C:41]1[CH:42]=[CH:43][C:38]([CH2:37][C:36]2[C:32]([O:31][C@@H:13]3[O:14][C@H:15]([CH2:26][OH:27])[C@@H:16]([OH:22])[C@H:17]([OH:18])[C@H:12]3[OH:11])=[N:33][NH:34][C:35]=2[CH:49]([CH3:51])[CH3:50])=[CH:39][CH:40]=1)=[O:47])([CH3:7])[CH3:6])(=[O:4])[NH2:5]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)C(N)=O
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(/C=C/C(=O)NC(C)(C)C(N)=O)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 26 using 2-amino-2-methylpropionamide and 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazole instead of ammonium chloride and 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole, respectively.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1B(O)O)=[O:16]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[C:17]([CH:15]=[O:16])=[CH:22][C:21]([O:23][CH3:24])=[CH:20][CH:19]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: Brc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccc(Br)cc2)c(C=O)c1
Temperature: 90 °C
Yield: 56 %

Procedure:
A solution of 1,4-dibromobenzene (5.11 g, 21.67 mmol), potassium carbonate (6.91 g, 50.0 mmol) and 2-formyl-4-methoxyphenylboronic acid (3 g, 16.67 mmol) in DME (75 mL) and water (15 mL) (in a pressure vessel) was sparged with nitrogen for 15 min. Pd(Ph3P)4 (0.578 g, 0.500 mmol) was added and then the reaction was heated to 90° C. overnight. The reaction was cooled to r.t. and evaporated on rotovap. The residue was diluted with EtOAc and washed with water then brine, dried over MgSO4, filtered and evaporated to give the crude material. The crude material was purified by flash chromatography on the Biotage (5-15% EtOAc:Hex) to give 4′-bromo-4-methoxybiphenyl-2-carbaldehyde (2.72 g, 9.34 mmol, 56% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 3.91 (s, 3H) 7.18-7.26 (m, 3H) 7.34 (d, J=824 Hz, 1H) 7.52 (d, J=2.75 Hz, 1H) 7.54-7.70 (m, 2H) 9.94 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cccc(CO)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: N#Cc1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
3-(Hydroxymethyl)benzonitrile (5.00 g; 37.6 mmoles) and 3,4-Dihydro-2H-pyran (3.77 mL; 41.4 mmoles) were dissolved in methylene chloride (25 mL) under nitrogen and the solution was cooled to 5° C. p-Toluenesulfonic acid monohydrate (74 mg; 0.37 mmoles) was added and the mixture was stirred for 2 hours at 25° C. The reaction mixture was diluted with methylene chloride (25 mL). The solution was washed with aqueous sodium bicarbonate solution (30 mL) and aqueous sodium chloride solution (30 mL). The solution was dried over sodium sulfate and filtered. The solvent was removed under vacuum to give the product, 3-[(tetrahydro-2H-pyran-2-yloxy)methyl]benzo-nitrile (7.34 g; 89%) as an oil. 1H NMR (400 MHz) CDCl3 δ 7.68–7.70 (1H, m), 7.54–7.61 (2H, m), 7.42–7.48 (1H, m), 4.82 (1H, d, J=12.5 Hz), 4.72 (1H, t, J=3.3 Hz), 4.53 (1H, d, J=12.5 Hz), 3.84–3.92 (1H, m), 3.53–3.60 (1H, m), 1.60–1.95 (6H, m).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[O:11]=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1>CCCCCC.C1COCC1>[OH:11][C:12]1([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: c1cscn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
1.600 M of n-Butyllithium in hexane (1.0×10−1 mL) was added to 1,3-thiazole (0.958 mL, 0.0135 mol) in THF (20 mL) at −78° C. After 30 minutes, tert-butyl 3-oxopyrrolidine-1-carboxylate (2.50 g, 0.0135 mol) in THF (10 mL) was added, and the mixture was slowly warmed to room temperature overnight. The reaction was quenched with water, and the reaction mixture was extracted with ethyl acetate, dried with MgSO4, filtered and concentrated. The residue was purified by flash column (50% EtOAc/hexanes to pure EtOAc) to give the desired product (2.57 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[S:7])=[O:4].[C:8]1([NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:14][C:9]1[C:8]([NH2:15])=[CH:13][CH:12]=[CH:11][CH:10]=1)=[S:7])=[O:4]
Reactant: Nc1ccccc1N
Reactant: COC(=O)N=C=S
Solvent: c1ccccc1
Product: COC(=O)NC(=S)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-(o-aminophenyl)-3-thioallophanate is prepared by dissolving 11.7 parts of methoxycarbonyl isothiocyanate in 50 parts of benzene and adding this to 10.8 parts of o-phenylenediamine in 200 parts of benzene at 10° - 15°C. After stirring for one hour at room temperature, 13.7 parts of methyl 4-(o-aminophenyl)-3-thioallophanate is recovered by filtration, m.p. 187°C.(D).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4](/[N:12]=[C:13]2\C(Cl)=NSS\2)[CH:3]=1.[CH2:19]([NH2:24])[CH2:20][CH2:21][CH2:22][NH2:23].N#N>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[N:23]3[CH2:22][CH2:21][CH2:20][CH2:19][NH:24][C:13]3=[N:12]2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Br)cc1/N=c1/ssnc1Cl
Reactant: NCCCCN
Agent: N#N
Solvent: C1CCOC1
Solvent: O
Product: O=c1c2ccc(Br)cc2nc2n1CCCCN2
Temperature: 25 °C

Procedure:
To a stirred solution of (E)-methyl 4-bromo-2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzoate (100 mg, 0.27 mmol, 1 eq) in THF was added butane-1,4-diamine (0.027 mL, 0.27 mmol, 1 eq) dropwise under N2 and the reaction was heated at reflux for 3 hours. After it was cooled to rt, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was purified by silica gel chromatography. MS (ESI): 294, 296 (MH+).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CCO.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:3]([C:4]#[N:5])=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([CH3:10])[CH:9]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)c(C#N)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(C)c([N+](=O)[O-])cc2C#N)cc1
Temperature: 80 °C
Yield: 24.9 %

Procedure:
A mixture of 2-bromo-4-methyl-5-nitro-benzonitrile (522.0 mg, 2.17 mmol), 4-methoxyphenyl boronic acid (329.0 mg, 2.17 mmol) and 2 N aqueous potassium carbonate (6.56 mL, 13.1 mmol) in EtOH (6 mL) and toluene (3 mL) was degassed with N2 for 5 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (180.0 mg, 0.22 mmol), and degassed with N2 for an additional 5 minutes. The reaction mixture was sealed and heated to 80° C. for 3 hours. The reaction was cooled to room temperature and the layers were separated. The organic layer was filtered and the solids were air dried to give the title compound (145 mg). The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (25-75% EtOAc/heptane) to give the title compound (337 mg). The two lots of the title compound were combined (482 mg, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1 H), 7.78 (s, 1 H), 7.63 (d, J=8.78 Hz, 2 H), 7.14 (d, J=8.59 Hz, 2 H), 3.85 (s, 3 H), 2.64 (s, 3 H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10]Br>>[CH:1]1([NH:7][CH2:2][CH2:1][NH:7][CH:10]2[CH2:9][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCBr
Reactant: NC1CCCCC1
Product: C1CCC(NCCNC2CCCCC2)CC1
Yield: 78.3 %

Procedure:
N,N′-Dicyclohexyl-1,2-diaminoethane (18.1 g, yield=83%) was prepared as in Synthesis Example 1-1, using cyclohexylamine (83.3 g, 0.840 mol) and 1,2-dibromoethane (19.3 g, 0.103 mol).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:14])[NH:7][C:8]([CH:11]2[CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:15]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16]1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:14])[C:5]([CH:2]([NH:1][C:19]([CH:15]3[CH2:18][CH2:17][CH2:16]3)=[O:20])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CCC1
Reactant: CCC(N)c1nnc(C2CC2)[nH]c1=O
Product: CCC(NC(=O)C1CCC1)c1nnc(C2CC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 250 mg (1.29 mmol) 6-(1-aminopropyl)-3-cyclopropyl-1,2,4-triazin-5(4H)-one, 150 mg (1.29 mmol) cyclobutanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([S:14](=[O:29])(=[O:28])[N:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=2)[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].BrC(Br)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>O1CCCC1>[CH2:26]([C:23]1[CH:22]=[CH:21][C:20]([N:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[S:14]([C:11]2[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:5]([CH:10]=2)[C:6]([O:8][CH3:9])=[O:7])(=[O:28])=[O:29])=[CH:25][CH:24]=1)[CH3:27]
Reactant: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(C)=O)c(C(=O)OC)c2)cc1
Reactant: C1COCCN1
Agent: O=C(Br)Br
Solvent: C1CCOC1
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(=O)CN3CCOCC3)c(C(=O)OC)c2)cc1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
A solution of phenyltrimethylaminotribromide (100 mg, 0.266 mmol) in tetrahydrofuran (THF) (0.5 mL) was added dropwise over 5 minutes, to a solution of methyl 2-acetyl-5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)benzoate (105 mg, 0.251 mmol) in THF (1.5 mL) at room temperature, under nitrogen. The orange solution was stirred for 1 hour to give a yellow solution containing a white precipitate. Analysis showed major product to be the desired intermediate bromoketone. The precipitate was filtered off and the solution was treated with morpholine (0.066 mL, 0.754 mmol). The resulting suspension was stirred for 30 minutes and partitioned between ammonium chloride solution (10 mL) and ethyl acetate (2×5 mL). The dried (MgSO4) extract was evaporated to give the desired product (65 mg), as an orange gum, which was used directly in the next step. LCMS [LCMS1] Rt 1.06 min, m/z (ES+) 503 (M+H).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(O)C>[CH2:30]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCCCCCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1OC
Temperature: 80 °C

Procedure:
Vanillin (100 g; 0.657 mol) is dissolved in ethanol (500 ml), and dried K2CO3 (101.5 g; 0.73 mol) is added. Heating to 80° C. is then carried out and 1-bromododecane is added dropwise under a protective gas atmosphere. The suspension is heated at reflux for a further 16 hours. After cooling to 25° C., filtration is carried out, the residue is then washed several times with ethanol and the combined filtrates are concentrated to dryness by evaporation. The residue is dissolved in tert-butyl methyl ether. Washing is then carried out with 1M aqueous sodium hydroxide solution (3×200 ml) and water (1×200 ml), and the organic phase is dried over Na2SO4, filtered off and concentrated to dryness by evaporation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[CH2:20][CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH2:20][CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CCCC(O)(c2ccc(OCc3ccccc3)cc2)C1
Agent: Cl
Solvent: CCO
Product: CC1(C)C=C(c2ccc(OCc3ccccc3)cc2)CCC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
1-(4-Benzyloxy-phenyl)-3,3-dimethyl-cyclohexanol (5.08 g, 16.4 mmol) was dissolved in EtOH (80 mL) after which concentrated hydrochloric acid (8 mL) was added. This mixture was stirred at 50° C. for 1.5 hours. The solvent was removed under reduced pressure. Water (15 mL) was added. The mixture was basified with aqueous ammonia and extracted three times with EtOAc. The organic phase was dried and concentrated to provide the title compound as a yellow solid 4.43 g as a mixture of isomers.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[S:7])C=1.[CH2:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([NH2:34])=[C:29]([F:35])[CH:28]=3)[CH2:23][CH2:22]2)[CH2:17][CH2:16]1)[CH3:14]>ClCCl>[F:35][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][CH:21]([CH:18]3[CH2:17][CH2:16][CH:15]([CH2:13][CH3:14])[CH2:20][CH2:19]3)[CH2:22][CH2:23]2)[CH:32]=[C:31]([F:33])[C:30]=1[N:34]=[C:6]=[S:7]
Reactant: CCC1CCC(C2CCC(c3cc(F)c(N)c(F)c3)CC2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCC1CCC(C2CCC(c3cc(F)c(N=C=S)c(F)c3)CC2)CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
9.5 g of 1,1-thiocarbonyldiimidazole are added to 85 g of 4-(4′-ethylbicyclohexyl-4-yl)-2,6-difluorophenylamine in 100 ml of dichloromethane, and the mixture is stirred at RT. Conventional work-up gives 4′-(3,5-difluoro-4-isothiocyanatophenyl)-4-ethylbicyclohexyl, yield 59%, having the following properties: C 33 N 198.2 I; Δε 15.3; Δn 0.1930.
Reaction SMILES: [F:1][C:2]1[C:3](=[NH:21])[N:4]([CH3:20])[C:5](=[O:19])[N:6](S(C2C=CC(OC)=CC=2)(=O)=O)[CH:7]=1.FC(F)(F)C(O)=O.CSC>>[F:1][C:2]1[C:3](=[NH:21])[N:4]([CH3:20])[C:5](=[O:19])[NH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(F)c(=N)n(C)c2=O)cc1
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)[nH]cc(F)c1=N
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A 25-mL screw capped vial was charged with 5-fluoro-4-imino-1-(4-methoxyphenylsulfonyl)-3-methyl-3,4-dihydropyrimidin-2(1H)-one (80.4 mg, 0.257 mmol), trifluoroacetic acid (TFA; 16.0 mL, 215 mmol), and dimethylsulfide (94 μL, 1.28 mmol). The resulting solution was allowed to stir at room temperature for 5.5 h and was then concentrated to dryness by rotary evaporation at 30° C. The crude material was then dissolved in a minimal amount of methanol (CH3OH; ˜2 mL) and loaded onto a 5-g normal phase solid load Isco cartridge, rinsing the source vial with CH3OH (3×1 mL). The solid cartridge was then dried under vacuum at room temperature. After drying, the product was purified by chromatography (4 g SiO2 column; 0 to 30% CH3OH in dichloromethane (CH2Cl2) gradient). The material thus obtained was determined to be the 4-methoxysulfonic acid salt of the desired product. The free base was obtained by dissolving the material in CH3OH (4 mL), adding MP-carbonate resin (345 mg, 3.03 mmol/g, 4.0 equiv), and allowing to stir at room temperature. After stirring for 20 h, the solid resin was filtered off and rinsed with CH3OH (3×1 mL). After concentration under high vacuum, 5-fluoro-4-imino-3-methyl-3,4-dihydropyrimidin-2(1H)-one (35.2 mg, 96%) was obtained as a 95% pure white solid: mp 181-184° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=4.1 Hz, 1H), 3.22 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 152.19 (s), 151.86 (d, J=27.3 Hz), 136.73 (d, J=221.0 Hz), 129.45 (d, J=26.0 Hz), 28.91 (s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)[CH:5]=[CH:6][C:7]=1[OH:8].CS(O[CH2:31][CH:32]1[CH2:35][C:34]([F:37])([F:36])[CH2:33]1)(=O)=O>>[F:36][C:34]1([F:37])[CH2:35][CH:32]([CH2:31][O:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[O:10][C:11]4[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=4[N:25]=3)=[CH:3][C:2]=2[F:1])[CH2:33]1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)c(F)c3)nc2cn1
Reactant: CS(=O)(=O)OCC1CC(F)(F)C1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4CC(F)(F)C4)c(F)c3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (3,3-difluorocyclobutyl)methyl methanesulfonate, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][N:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[N:29]=[C:30]([C:40]5[CH:39]=[N:38][C:37]([O:36][CH3:35])=[CH:42][CH:41]=5)[CH:31]=[CH:32][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: COc1ccc(B(O)O)cn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccc(OC)nc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-methoxypyridine-5-boronic acid.
Reaction SMILES: [CH2:1]([Si:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:40][C:41]([F:51])([F:50])[O:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH2:1]([Si:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10][CH:9]([C:12]([O:14][C:46]2[CH:45]=[CH:44][C:43]([O:42][C:41]([F:40])([F:50])[F:51])=[CH:48][CH:47]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC[Si]1(c2ccccc2)CCC(C(=O)Oc2ccc(OC(F)(F)F)cc2)CC1
Yield: 78.4 %

Procedure:
A mixture of 50 g of 4-n-pentyl-4-phenyl-4-silacyclohexanecarboxylic acid, 50.0 g of triphenylphosphine and 420 ml of carbon tetrachloride was agitated under reflux for 1 hour. Then, a mixture of 32.0 g of 4-trifluoromethoxyphenol and 100 ml of pyridine was added to the mixture, followed by further addition of 1.00 g of 4-dimethylaminopyridine and agitation at room temperature for 9 hours. The resultant reaction mixture was poured into dilute hydrochloric acid, followed by extraction with ethyl acetate. The ethyl acetate solution was washed with brine, dried and concentrated, followed by purification of the resultant residue with silica gel chromatography to obtain 60.8 g (yield: 78%) of (4-trifluoromethoxyphenyl) 4-n-pentyl-4-phenyl-4-silacyclohexanecarboxylate. The results of IR and NMR analyses are shown below.