Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([CH:28]([CH:30]2[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]2)[OH:29])[CH:25]=[CH:24][CH:23]=1>>[O:37]=[S:33]1(=[O:36])[CH2:34][CH2:35][CH:30]([CH:28]([OH:29])[C:26]2[N:27]=[C:22]([NH:1][C:2]3[S:3][C:4]([C:10]4[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=4[F:20])=[CH:5][C:6]=3[C:7]([NH2:9])=[O:8])[CH:23]=[CH:24][CH:25]=2)[CH2:31][CH2:32]1
Reactant: O=S1(=O)CCC(C(O)c2cccc(Br)n2)CC1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(O)C4CCS(=O)(=O)CC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 with 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.14 g, 0.47 mmol) and (6-bromopyridin-2-yl)(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methanol (0.15 g, 0.46 mmol) as the starting materials.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[C:10]([OH:22])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3]1.N1C=CC=CC=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].O>C(OC(=O)C)C.C1CCCCC1>[O:23]=[S:2]1(=[O:1])[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])=[C:10]([O:22][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3]1
Reactant: O=S1(=O)Cc2cccnc2C(O)=C1c1ccccc1C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OC1=C(c2ccccc2C(F)(F)F)S(=O)(=O)Cc2cccnc21
Yield: 15.7 %

Procedure:
To a solution of 6,6-Dioxo-7-(2-trifluoromethyl-phenyl)-5,6-dihydro-thiopyrano[4,3-b]pyridin-8-ol (1.92 g, 5.61 mmol) prepared according to the above Example 1 in methylenehloride (70 ml) was added at 0° C. pyridine (1.77 g, 22.4 mmol), followed by pivaloylchloride (0.744 g, 6.17 mmol). After stirring at room temperature for 16 h methylenehloride and water was added, the organic phase separated and concentrated. Chromatography over silica with ethylacetate/cyclohexane gave 380 mg colourless crystals (0.88 mmol).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CCC([O-])(C)C.[K+].C1(C)C=CC=CC=1.[NH:33]1[CH:37]=[CH:36][CH:35]=[CH:34]1.Cl[CH2:39][N:40]1[CH2:44][CH:43]([CH2:45][CH2:46][CH3:47])[CH2:42][C:41]1=[O:48]>CCOCC>[CH2:45]([CH:43]1[CH2:44][N:40]([CH2:39][N:33]2[CH:37]=[CH:36][CH:35]=[CH:34]2)[C:41](=[O:48])[CH2:42]1)[CH2:46][CH3:47]
Reactant: CCCC1CC(=O)N(CCl)C1
Reactant: c1cc[nH]c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCC1CC(=O)N(Cn2cccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.8 %

Procedure:
18-Crown-6 (0.158 g, 0.2 eq, 0.6 mmol) is dissolved in absolute ether (20 ml). A 1.7 M solution of potassium tert-amylate in toluene (1.93 ml, 1.1 eq, 3.28 mmol) is added dropwise in a flow of argon. The reaction mixture is stirred for 15 min at room temperature. Pyrrole (0.2 g, 1 eq, 2.98 mmol) is added. The reaction mixture is cooled to −15° C., and a solution of 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.603 g, 1.15 eq, 3.43 mmol) in absolute ether (5 ml) is added dropwise. The resulting solution is stirred for 16 h at 20° C. The contents of the flask are partitioned between 10 ml of water and 30 ml of ethyl acetate. The organic layer is separated. The aqueous one is subjected to additional extraction with ethyl acetate (2×20 ml). The combined extracts are dried with anhydrous Na2SO4 and evaporated. Purification by chromatography on silicagel (dichloromethane/acetone) afford 0.091 g of 4-propyl-1-(1H-pyrrol-1-ylmethyl)pyrrolidin-2-one x264.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[S:21]([CH3:24])(=[O:23])=[O:22])[C:3]=1[CH3:25].[CH3:26][C:27]1([CH3:42])[C:31]2=[N:32][CH:33]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:35]=[C:30]2[NH:29][CH2:28]1>C1(C)C=CC=CC=1>[CH3:26][C:27]1([CH3:42])[C:31]2=[N:32][CH:33]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:35]=[C:30]2[N:29]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[S:21]([CH3:24])(=[O:23])=[O:22])[C:3]=2[CH3:25])[CH2:28]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(N3CC(C)(C)c4ncc(N5CCOCC5)cc43)c2C)c1

Procedure:
Prepared according to procedure Y using 4-chloro-5,7-difluoro-3-methyl-2-(5-methyl-2-(methylsulfonyl)phenyl)quinoline (60.0 mg, 0.160 mmol) and 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine in toluene to give 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-(5-methyl-2-(methylsulfonyl)phenyl)quinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 7.99-8.17 (1H, m), 7.43-7.64 (3H, m), 7.22-7.31 (1H, m), 7.07 (1H, ddd, J=11.9, 8.9, 2.4 Hz), 6.00 (1H, d, J=2.2 Hz), 4.03 (1H, d, J=9.0 Hz), 3.66-3.87 (4H, m), 3.61 (1H, d, J=8.8 Hz), 2.97-3.16 (7H, m), 2.52 (3H, s), 1.96 (3H, s), 1.42-1.60 (6H, m). Mass Spectrum (ESI) m/e=579.2 (M+1).
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)O.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C)C=O.C(Cl)(Cl)Cl>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: O[C@@H](CBr)c1cccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)[C@@H](CBr)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.7 %

Procedure:
To a stirred solution of 1.54 g (7.61 mmol) of (R)-2-bromo-1-pyridin-3-yl-ethanol in 20 ml of dry N,N-dimethylformamide at room temperature was added 1.55 g (22.83 mmol) of imidazole followed by 1.72 g (11.4 mmol) of tert-butyldimethylsilyl chloride. The mixture was stirred at room temperature for about 18 hours and then an additional 1.55 g (22.83 mmol) of imidazole and 1.72 g (11.4 mmol) of tert-butyldimethylsilyl chloride were added, and the mixture was stirred at room temperature for about an additional 24 hours. The mixture was poured into 200 ml of water and extracted with ethyl acetate (2×200 ml). The organic extracts were combined, washed successively with water (1×40 ml), brine (1×40 ml), then dried over magnesium sulfate and concentrated in vacuo to furnish an oil. Chromatography on silica gel eluting with ethyl acetate:hexanes (2:3, v/v) provided 1.41 g (58% yield) of the desired title compound as a clear oil, αD=−51.5 (c=0.60, chloroform). Chiral HPLC analysis of the product on 4.6×250 mm Chiralcel® OD column (Chiral Technologies; Exton, Pa.) eluting with hexanes:isopropyl alcohol (7:3, v/v) at 1.0 ml/minute revealed an enantiomeric excess of 91.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.Cl.[C:26](=N)(OCC)[CH3:27].C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:17]([CH2:18][CH2:19][C:20]([F:21])([F:23])[F:22])[C:26]([CH3:27])=[N:15][C:14]=4[CH:16]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: CCOC(C)=N
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NCCC(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2cc(-c3nc4cc(Cl)ccc4o3)ccc2n1CCC(F)(F)F
Yield: 79.7 %

Procedure:
To a solution of 5-chloro-2-(2-(3,3,3-trifluoropropyl)aminoanilin-5-yl)benzoxazole (see Working Example 138-1) (200 mg, 0.562 mmol) in ethanol (5 mL) was added ethyl acetimidate hydrochloride (104 mg, 0.843 mmol), and this was heated to reflux for 5 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with chloroform. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude crystals that were washed with diethyl ether to yield the title compound (170 mg, 80% yield) as light green crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23]>>[C:22]([C:21]1[CH:20]=[C:19]([CH2:18][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH:26]=[CH:25][CH:24]=1)#[N:23]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: N#Cc1cccc(CBr)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cccc(C#N)c1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(bromomethyl)benzonitrile: 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 1H), 7.45 (m, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.21 (s, 1H), 7.12 (d, J=8.1 Hz, 1H), 6.69 (s, 1H), 5.40 (s, 2H), 2.43 (s, 3H); MS (ES) m/z 340 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:17][CH:18]2[CH2:22][CH2:21][CH:20]([O:23]C3CCCCO3)[CH2:19]2)[C:10]([NH:12][C:13]([NH:15][CH3:16])=[O:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:17][CH:18]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]2)[C:10]([NH:12][C:13]([NH:15][CH3:16])=[O:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(=O)NC(=O)C(CC1CCC(OC2CCCCO2)C1)c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CNC(=O)NC(=O)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 86.2 %

Procedure:
A solution of 1-{2-(3,4-dichloro-phenyl)-3-[3-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionyl}-3-methyl-urea (150.7 mg, 0.33 mmol) in ethanol (3.4 mL) was treated with pyridinium p-toluenesulfonate (8.54 mg, 0.03 mmol). The reaction mixture was heated to 60° C. for 18 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 methylene chloride/methanol) afforded 1-[2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-propionyl]-3-methyl-urea (102.2 mg, 83.7%) as a white solid: mp 82-84° C.; FAB-HRMS m/e calcd for C16H20Cl2N2O3 (M+H)+ 359.0929. found 359.0936.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[O:41][CH3:42])[CH2:33][O:32][C:31]4=[O:43])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[O:41][CH3:42])[CH2:33][O:32][C:31]4=[O:43])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: COc1ccccc1[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)c(F)c3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Reaction time: 18 h
Yield: 32.9 %

Procedure:
A mixture of (S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-methoxyphenyl) oxazolidin-2-one (0.0424 g, 0.071 mmol) in DCM (1 mL) was treated with trifluoroacetic acid (0.5 mL) at ambient temperature. The mixture was stirred for 18 hours. The solvent was concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was further extracted with EtOAc and DCM. The combined organic extracts were washed with brine, dried, and concentrated, and the crude material was purified by column chromatography (silica, 10% MeOH/dichloromethane) to afford the title compound (0.011 g, 33%) as a yellow solid. MS (APCI+) m/z 472 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Br:23])=[O:5])[CH3:2].[BH3-]C#N.[Na+].CCOC(C)=O.O>ClCCCl.[Zn+2].[I-].[I-]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Br:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1C(=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
To a solution of 3-benzoyl-7-bromo-1H-indole-2-carboxylic acid ethyl ester (2.4 g, 6.45 mmol) in 1,2-dichloroethane (80 ml) was added NaBH3CN (3.24 g, 51.6 mmol) and ZnI2 (6.18 g, 19.4 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was poured into a mixture of EtOAc/H2O. The organic layer was separated and washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and the resulting residue was purified by flash chromatography to give 3-benzyl-7-bromo-1H-indole-2-carboxylic acid ethyl ester as yellow solid (696 mg, 30%). 1H NMR (CDCl3, 300 MHz) δ: 1.39 (t, 3H, J=7.13 Hz), 4.43 (q, 2H, J=7.13 Hz), 4.49 (s, 2H), 6.98 (t, 1H, J=7.8 Hz), 7.22 (m, 5H), 7.46 (d, 1H, J=7.60 Hz), 7.54 (d, 1H, J=8.10 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([Br:14])[CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([CH3:21])=[CH2:20]>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:20][C:19]([CH3:21])=[CH2:18])[C:11](=[O:13])[CH3:12])=[C:6]([Br:14])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1Br
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)CN(C(C)=O)c1ccc(C(C)=O)cc1Br
Reaction time: 1 h
Yield: 105.7 %

Procedure:
N-(4-Acetyl-2-bromophenyl)acetamide (25 g, 0.1 mole) in dry DMF (250 ml) was treated with sodium hydride (60%, 4.5 g, 0.11 mole) at 25° C. under argon with stirring for 1 h. 3-Bromo-2-methylpropene (1.1 ml, 0.11 mole) was added and the mixture stirred for a further 16 h. The mixture was concentrated in vacuo and partitioned between water and Et2O. The organic phase was dried and concentrated in vacuo to give the title compound (32.8 g, 100%).
Reaction SMILES: CS([C:5]1[C:6]2[CH2:16][CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:7]=2[N:8]=[C:9]([NH2:11])[N:10]=1)(=O)=O.C(O[C:29]([N:31]1[CH2:35][CH2:34][CH:33]2[CH2:36][NH:37][CH2:38][CH:32]12)=O)C1C=CC=CC=1>C(O)=O.CO.[OH-].[OH-].[Pd+2]>[CH3:29][N:31]1[CH2:35][CH2:34][C@@H:33]2[CH2:36][N:37]([C:5]3[C:6]4[CH2:16][CH2:15][CH2:14][C:13]5[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=5[C:7]=4[N:8]=[C:9]([NH2:11])[N:10]=3)[CH2:38][C@H:32]12
Reactant: O=C(OCc1ccccc1)N1CCC2CNCC21
Reactant: CS(=O)(=O)c1nc(N)nc2c1CCCc1ccccc1-2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: CN1CC[C@@H]2CN(c3nc(N)nc4c3CCCc3ccccc3-4)C[C@@H]21

Procedure:
The title compound was prepared using the procedure described in Example 1F, substituting the product from Example 3A for the product from Example 1C, and substituting the product from Example 15B for the product from Example 1E. The resulting intermediate was refluxed for 16 hours in 4.4% formic acid in methanol with the presence of Pd(OH)2 (5% mol). The mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting with 3% (9:1 MeOH: NH4OH) in dichloromethane to provide the title compound. 1H NMR (CDCl3) δ 1.71-1.84 (m, 1H), 2.04-2.10 (m, 1H), 2.15-2.20 (m, 3H), 2.31-2.40 (m, 1H), 2.38 (s, 3H), 2.51-2.56 (m, 1H), 2.64 (t, J=6.44 Hz, 2H), 2.83 (m, 2H), 3.14-3.21 (m, 1H), 3.60-3.77 (m, 4H), 4.85 (s, 2H), 7.18-7.21 (m, 1H), 7.31-7.34 (m, 2H), 7.73-7.77 (m, 1H). MS (M+H)+ m/z 336.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:20]([C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=1)#[N:21]
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccnc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 52.2 %

Procedure:
A mixture of methyl thiosalicylate (0.65 g, 3.9 mmol), 2,4-dicyanopyridine (0.50 g, 3.9 mmol), triethylamine (0.81 ml, 5.8 mmol) and toluene (2.0 ml) was refluxed for 2.5 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from acetone-chloroform to give the titled compound (0.54 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]=[CH2:12])[C:7]([O:13][CH3:14])=[CH:6][C:3]=1[CH2:4][OH:5].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.O.N>O1CCCC1.O>[CH2:10]([C:8]1[C:7]([O:13][CH3:14])=[CH:6][C:3]2[CH2:4][O:5][C:16](=[O:18])[NH:1][C:2]=2[CH:9]=1)[CH:11]=[CH2:12]
Reactant: C=CCc1cc(N)c(CO)cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1cc2c(cc1OC)COC(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 126.2 %

Procedure:
677 mg of 2-amino-5-methoxy-4-(2-propenyl)benzylalcohol was dissolved in 20 ml of tetrahydrofuran under nitrogen atmosphere. Thereafter, 0.52 g of triphosgene and 1.46 ml of triethylamine were added to the reaction solution while cooling on ice. The obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, while cooling on ice, water and ammonia water were added to the reaction solution until foaming was terminated. The reaction solution was diluted with ethyl acetate and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) and then reprecipitated from ethyl acetate, so as to obtain 485 mg of the subject compound.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([NH:13][CH:14]([C:17]2[C:18](=[O:27])[NH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:21][N:22]=2)[CH2:15][CH3:16])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:23]([C:20]1[NH:19][C:18](=[O:27])[C:17]2=[C:14]([CH2:15][CH3:16])[N:13]=[C:11]([CH:8]3[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]3)[N:22]2[N:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CCC(NC(=O)C1CCC(C(C)(C)C)CC1)c1nnc(C(C)(C)C)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCC(C(C)(C)C)CC2)n2nc(C(C)(C)C)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 377 mg (1.00 mmol) crude 4-tert-butyl-N-[1-(3-tert-butyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclohexanecarboxamide, 184 mg (1.20 mmol) phosphoric trichloride are stirred at reflux for 3 hours, proportionate amounts of the solvents are used. The resulting mixture is separated into the pure cis- and trans-isomers via silica gel chromatography with eluent cyclohexane/ethylacetate 10/1, 5/1.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH2:27][C:28]2[C:29]([CH3:34])=[N:30][CH:31]=[CH:32][CH:33]=2)[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1>C(O)C.Cl>[Cl:25][C:23]1[CH:24]=[C:19]([S:18][C:12]2[N:11]([CH2:27][C:28]3[C:29]([CH3:34])=[N:30][CH:31]=[CH:32][CH:33]=3)[C:10]([CH2:9][OH:8])=[N:14][C:13]=2[CH:15]([CH3:17])[CH3:16])[CH:20]=[C:21]([Cl:26])[CH:22]=1
Reactant: Cc1ncccc1Cn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Cn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
In a mixture of 15 ml of ethanol and 20 ml of 36% hydrochloric acid was dissolved 609 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(2-methylpyridin-3-ylmethyl)-1H-imidazole (118a), and the mixture was stirred at 90° C. for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. An aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crystals were washed with diethyl ether, filtered, and 500 mg of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-4-isopropyl-1-(2-methylpyridin-3-ylmethyl)-1H-imidazole (119a)was obtained (yield 99%). mp 136° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:25]1([C@@H:31]([NH2:33])[CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH:25]1([C@@H:31]([NH:33][C:2]2[S:3][C:4]3[CH:10]=[C:9]([CH2:11][N:12]4[C:16]5[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=5[N:14]=[CH:13]4)[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Reactant: C[C@H](N)C1CCCCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncn(Cc3ccc4nc(N[C@@H](C)C5CCCCC5)sc4c3)c2cc1OC
Temperature: 100 °C
Yield: 53.8 %

Procedure:
A stirred mixture of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole from Example 2 (80 mg, 0.198 mmol), (S)-(+)-1-cyclohexylethylamine (50 mg, 0.396 mmol) and DIEA (77 mg, 0.594 mmol) in anhydrous DMA (2 mL) was heated at 100° C. for 72 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (S)—N-(1-cyclohexylethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine (48 mg, 54%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.62 (s, 1H), 7.29 (m, 1H), 7.12-7.23 (m, 3H), 5.40 (s, 2H), 3.76 (2×s, 6H), 1.55-1.79 (m, 6H), 1.32 (m, 1H), 0.93-1.22 (m, 8H). LCMS (ESI) m/z 451 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([C:13]1[N:17]=[CH:16][NH:15][N:14]=1)(=[O:12])=[O:11].[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([C:13]1[N:17]=[CH:16][N:15]([C:20](=[O:21])[N:19]([CH3:18])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:14]=1)(=[O:11])=[O:12]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Cc1cc(C)c(S(=O)(=O)c2nc[nH]n2)c(C)c1
Product: Cc1cc(C)c(S(=O)(=O)c2ncn(C(=O)N(C)c3ccccc3)n2)c(C)c1

Procedure:
3-(2,4,6-Trimethylphenyl)sulfonyl-1H-1,2,4-triazole and N-methyl-N-phenylcarbamoyl chloride were employed to synthesize the title compound as in Example 22.
Reaction SMILES: [CH2:1]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[C:10]([Cl:11])=[C:9]([CH3:12])[NH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].F[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][C:19]=1[C:29]([N:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32]1)=[O:30]>>[Cl:11][C:10]1[C:6]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][N:8]([C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][C:19]=2[C:29]([N:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32]2)=[O:30])[C:9]=1[CH3:12]
Reactant: CCOC(=O)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Reactant: CCCCN(CCCC)c1n[nH]c(C)c1Cl
Product: CCCCN(CCCC)c1nn(-c2ccc(C(=O)OCC)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 26.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, N,N-dibutyl-4-chloro-5-methyl-1H-pyrazol-3-amine (160 mg, 0.66 mmol) and ethyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 1D, 258 mg, 0.79 mmol) were converted to the title compound (98 mg, 27%). 1H NMR (CDCl3, 2:1 mixture of amide rotamers) δ 8.19 (d, J=8.1 Hz, 1H), 8.12 (d, J=1.7 Hz, 1H), 7.40 (d, J=8.33 Hz, 1H), 7.08-7.30 (m, 3.5H), 6.92 (d, J=7.5 Hz, 0.5H), 4.95 (d, J=17.1 Hz., 0.5H), 4.68 (d, J=17.10 Hz, 0.5H), 4.31-4.53 (m, 2.5H), 4.12 (d, J=4.1 Hz, 0.5H), 3.51-3.76 (m, 1.5H), 3.03-3.36 (m, 4.5H), 2.75-3.03 (m, 2H), 2.58 (s, 2H), 2.47 (s, 1H), 1.33-1.51 (m, 7H), 1.13-1.30 (m, 4H), 0.77-0.96 (m, 6H); MS(ESI+) m/z 551.4 (M+H)+.