Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C2C(=CC=CC=2)C(CC2C=NC(OC)=CC=2)=C(C)N=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][C:34]2[CH:35]=[N:36][C:37]([Cl:40])=[CH:38][CH:39]=2)=[C:25]([CH3:41])[N:24]=1.[F:42][C:43]([F:52])([F:51])[C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47].Cl.O1CCOCC1>CO>[F:42][C:43]([F:51])([F:52])[C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH:47][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][C:34]2[CH:35]=[N:36][C:37]([Cl:40])=[CH:38][CH:39]=2)=[C:25]([CH3:41])[N:24]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1nc(Cl)c2ccccc2c1Cc1ccc(Cl)nc1
Agent: COc1ccc(Cc2c(C)nc(Cl)c3ccccc23)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(Nc2cccc(C(F)(F)F)c2)c2ccccc2c1Cc1ccc(Cl)nc1

Procedure:
Analogously to example 36, 0.70 g (2.3 mmol) of 1-chloro-4-[(6-methoxy-pyridin-3-yl)-methyl]-3-methylisoquinoline (contains traces of 1-chloro-4-[(6-chloro-pyridin-3-yl)-methyl]-3-methylisoquinoline as an impurity) in 15 ml of methanol are mixed with 741 mg (4.6 mmol) of 3-trifluoromethyl-aniline and 0.58 ml of 4 N HCl/dioxane and reacted for 18 h at 70° C. Extraction and column chromatography (SiO2, methylene chloride/diethylether 50:1→EtOAc→EtOAc/EtOH 10:1) yield 1-(3-trifluoromethyl-anilino)-4-[(6-chloro-pyridin-3-yl)-methyl]-3-methylisoquinoline 45a (m.p. 137° C.; FAB-MS: (M+H)+−=428), followed by 1-(3-trifluoromethyl-anilino)-4-[(6-methoxy-pyridin-3-yl)-methyl]-3-methylisoquinoline 45b (m.p. 136-137° C.; FAB-MS: (M+H)+=424), and finally 1-(3-trifluoromethyl-anilino)-4-[(6-hydroxy-pyridin-3-yl)-methyl]-3-methylisoquinoline 45c (m.p. 250-252° C.; FAB-MS: (M+H)+=410). The latter can also be obtained by demethylation (1. Me3SiI/CHCl6, 2. hydrolysis) from the 6-methoxy-pyridine derivative.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:16]C1C=CC(CCl)=CC=1.[Mg].C(OCC)(=O)C(OCC)=O>>[Cl:16][C:6]1[CH:5]=[CH:4][C:3]([CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:2][CH:7]=1
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Reactant: ClCc1ccc(Cl)cc1
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1ccc(Cl)cc1
Yield: 74 %

Procedure:
The title compound was prepared as described for B4 using 4-chlorobenzyl chloride (1.250 g, 7.76 mmol), magnesium (0.208 g, 8.54 mmol) and diethyl oxalate (2.269 g, 15.53 mmol). The product was isolated in the form of colorless oil in 74% yield and used instantly in next step.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[C:12]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O:11][CH2:10][C@@H:9]1[CH:18]=O>[O-]S([O-])(=O)=O.[Cu+2].C(Cl)Cl>[O:8]1[C:12]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O:11][CH2:10][C@@H:9]1/[CH:18]=[N:7]\[S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=C[C@H]1COC2(CCCCC2)O1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C\[C@H]1COC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.1 %

Procedure:
To a solution of (S)-2-methylpropane-2-sulfinamide (4.7 g, 39 mmol) and DCM (15 mL) at RT was added anhydrous CuSO4 (14 g, 85 mmol) followed by a solution of (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (6.0 g, 35 mmol) and DCM (20 mL). The reaction was stirred at RT for 3 d then filtered through CELITE, washed with DCM and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with hexane/EtOAc (9:1 to 7:1) to afford 4.7 g (49%) of (S,Z)—N—((S)-1,4-dioxaspiro[4.5]decan-2-ylmethylene)-2-methylpropane-2-sulfinamide (248).
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][C:33](=[O:36])[N:32]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39](B4OC(C)(C)C(C)(C)O4)[C:38]=3[CH3:52])[C:31]2=[O:53])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:39]1[CH:40]=[CH:41][CH:42]=[C:37]([N:32]2[C:33](=[O:36])[CH:34]=[CH:35][N:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)[C:31]2=[O:53])[C:38]=1[CH3:52])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)ccn(-c2ccc(F)cc2)c1=O
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1c(-c2c(Cl)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)ccn(-c2ccc(F)cc2)c1=O
Temperature: 90 °C
Yield: 48.7 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H -carbazole-1-carboxamide [Intermediate 3] (135 mg, 0.354 mmol), 1-(4-fluorophenyl)-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione [Intermediate 44] (164 mg, 0.389 mmol), and tetrakis(triphenylphosphine)palladium (20 mg, 0.018 mmol) in toluene (5.3 mL) and ethanol (1.8 mL) was bubbled with argon for several min. The mixture was treated with 2 M aqueous Na2CO3 (354 μl, 0.707 mmol), bubbled again with argon, and heated at 90° C. for 16 h. The cooled mixture was partitioned between EtOAc and water. The organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 25-100%), to give 3-chloro-4-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (103 mg, 49% yield). Mass spectrum m/z 579 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 11.52 (d, J=4.5 Hz, 1H), 8.29 (br. s., 1H), 8.13 (d, J=2.5 Hz, 1H), 7.91 (dd, J=7.9, 6.4 Hz, 1H), 7.85-7.80 (m, 1H), 7.64-7.54 (m, 3H), 7.53-7.45 (m, 2H), 7.36 (dt, J=11.9, 8.7 Hz, 2H), 7.25 (ddd, J=7.3, 4.3, 1.2 Hz, 1H), 7.03-6.83 (m, 1H), 6.73-6.47 (m, 1H), 5.97 (dd, J=7.9, 3.5 Hz, 1H), 5.04-4.92 (m, 1H), 1.75 (d, J=1.5 Hz, 3H), 1.47-1.33 (m, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40]2[N:44]([CH2:45][C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=3)[C:43]3[CH:53]=[CH:54][CH:55]=[CH:56][C:42]=3[N:41]=2)[CH2:35][CH2:34]1>ClCCl>[F:52][C:49]1[CH:50]=[CH:51][C:46]([CH2:45][N:44]2[C:43]3[CH:53]=[CH:54][CH:55]=[CH:56][C:42]=3[N:41]=[C:40]2[NH:39][CH:36]2[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][NH:30][C:11](=[O:13])[CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:34][CH2:35]2)=[CH:47][CH:48]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1c[nH]c2ccccc12)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a stirred mixture of 3.5 parts of 1H-indol-3-acetic acid, 4.05 parts of N,N-diethylethanamine and 260 parts of dichloromethane were added 5.1 parts of 2-chloro-1-methylpyridinium iodide and stirring was continued for 15 minutes at room temperature. Then there were added 7.2 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine and the whole was stirred for 1 hour at room temperature. The reaction mixture was poured onto water and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 4.5 parts (43%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-1H-indol-3-acetamide; mp. 193.6° C. (compound 77).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]([OH:15])=[C:7]([CH:11]=[CH:12][C:13]=2[OH:14])[C:8]([NH2:10])=[O:9])[CH2:3][CH2:2]1.I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:36]=[CH:35][C:24]2[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[O:28][C:23]=2[C:22]=1[CH2:37][CH2:38][CH3:39]>C(OCC)(=O)C.CCCCCC>[NH2:10][C:8]([C:7]1[CH:11]=[CH:12][C:13]([O:14][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:36]=[CH:35][C:24]3[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[O:28][C:23]=3[C:22]=2[CH2:37][CH2:38][CH3:39])=[C:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]=1[OH:15])=[O:9]
Reactant: NC(=O)c1ccc(O)c(CC2CC2)c1O
Reactant: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OC)CC2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CC2CC2)ccc2c1OC(CCC(=O)OC)CC2

Procedure:
The compound of Example 66 and the compound of Example 3 are coupled under the conditions outlined in Example 60. Chromatography of the crude phenolic ester on silica gel using ethyl acetate/hexane (3:7) as eluant affords the product.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([S:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[CH:18][C:17]([CH2:27][N:28](C)[C:29](=O)OC(C)(C)C)=[CH:16]2)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1.Cl>ClCCl.O1CCOCC1>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]1[N:15]([S:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][C:3]([N:2]([CH3:1])[CH3:38])=[O:37])(=[O:14])=[O:13])[CH:16]=[C:17]([CH2:27][NH:28][CH3:29])[CH:18]=1
Reactant: CN(C)C(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)N(C)C)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl ((1-((3-(2-(dimethylamino)-2-oxoethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 9c (54 mg, 0.10 mmol) was dissolved in 4 mL of dichloromethane, and the reaction solution was cooled in an ice bath, followed by dropwise addition of a solution of hydrogen chloride in 1,4-dioxane (4 N, 4 mL). After removing the ice bath, the reaction solution was stirred at room temperature for 3h. A saturated sodium bicarbonate solution was added dropwise until the pH of the reaction solution was 7 to 8, 5 mL of water were added, and then the reaction solution was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N,N-dimethylacetamide 9 (20 mg, a yellow solid) in 45% yield.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:58]([CH:61]2[CH2:63][CH2:62]2)(=[O:60])=[O:59])=[C:10]([CH2:12][N:13]([CH3:57])[C:14]([CH:16]([NH:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][C:40]=2[F:41])[C:37]([N:42]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[N:36][CH:35]=[CH:34]3)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([C@@H:25]([CH3:28])[CH2:26][OH:27])=[CH:19][C:18]=2[F:29])=[O:15])[CH:11]=1>C(#N)C.C(Cl)Cl>[C:45]([O:44][C:43]([N:42]([C:37]1[C:38]2[C:33](=[CH:32][C:31]([NH:30][C@H:16]3[C:14](=[O:15])[N:13]([CH3:57])[CH2:12][C:10]4[CH:11]=[C:6]([CH:7]=[CH:8][C:9]=4[S:58]([CH:61]4[CH2:62][CH2:63]4)(=[O:59])=[O:60])[NH:5][C:1](=[O:2])[O:27][CH2:26][C@H:25]([CH3:28])[C:20]4[C:21]([O:23][CH3:24])=[CH:22][C:17]3=[C:18]([F:29])[CH:19]=4)=[C:40]([F:41])[CH:39]=2)[CH:34]=[CH:35][N:36]=1)[C:50](=[O:51])[O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:49])([CH3:47])([CH3:48])[CH3:46]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(C(Nc2cc3ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3cc2F)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)c(F)cc1[C@@H](C)CO
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc2c(F)cc1[C@@H](C)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1cc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
Phosgene (87 mg, 0.176 mmol) was added dropwise to a solution of 25D (148 mg, 0.176 mmol) in acetonitrile (2.5 mL)/CH2Cl2 (2.5 mL) at 0° C. The mixture was stirred at rt for 30 min. Ar was bubbled though the solution (10 min) to remove excess phosgene, and then the mixture was added to a solution of TEA (0.123 mL, 0.881 mmol) in CH2Cl2 (25 mL) at 40° C. over 5 h. The reaction was stirred at rt overnight, quenched with H2O (1 mL) and MeOH (5 mL) and then concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 100% ethyl acetate in hexane over 15 min using a 12 g silica gel cartridge). The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 25E (20 mg, 0.023 mmol, 13.11% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:28])[NH:18][C:19]3[C:24]\2=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(O)(=O)C>[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:28])[NH:18][C:19]3[C:24]\2=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)/[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 31 from (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone and acetic anhydride in glacial acetic acid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:38]([S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41])[CH3:39]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:46]3[CH2:45][CH2:44][N:43]([S:40]([CH2:38][CH3:39])(=[O:41])=[O:42])[CH2:48][CH2:47]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)CC)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-ethanesulfonyl-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C35H44Cl2N5O4S [(M+H)+] 700.2486, observed 700.2486.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3].[C:20](O)(=[O:22])[CH3:21].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[C:20]([C:8]1[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[CH:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][C:7]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:22])[CH3:21]
Reactant: CC(=O)O
Reactant: C=CCOc1cc(CC(=O)OC)cc(OCC=C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C=CCOc1cc(CC(=O)OC)c(C(C)=O)c(OCC=C)c1
Temperature: 4 °C
Reaction time: 3.5 h
Yield: 70.4 %

Procedure:
Methyl 3,5-diallyloxyphenylacetate (40 g, 0.14 mol) obtained in Example 5, Step 1 was dissolved in trifluoroacetic acid (0.15 L). After the solution was cooled to 4° C., acetic acid (9.5 mL, 0.17 mol) and trifluoroacetic anhydride (40 mL, 0.28 mol) were added thereto, followed by stirring at 4° C. for 3.5 hours. The reaction mixture was gradually added to a saturated aqueous solution of sodium hydrogencarbonate for neutralization, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/20-1/6) to obtain methyl 2-acetyl-3,5-diallyloxyphenylacetate (30 g, 65%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH2-:10].[Na+].Cl>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccncc1
Reactant: [NH2-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCc1ccnc(N)c1
Temperature: 140 °C
Reaction time: 48 h
Yield: 50.7 %

Procedure:
To a solution of 4-propylpyridine (10.0 g, 82.5 mmol) in toluene (170 mL), sodium amide (6.4 g, 165 mmol) was added at room temperature, and the mixture was stirred at 140° C. for 2 days. Under ice-cold conditions, the reaction solution was added 6N aqueous solution of hydrochloric acid (30 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate/1% triethylamine), and the title compound (5.70 g (yield 51%)) was obtained as a red-brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:10](=[O:27])[N:11]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:12]=[CH:13][C:14]=2[N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:4][CH:3]=1.C[Sn](C)(C)[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.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>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:11]2[C:10](=[O:27])[C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)=[CH:3][CH:4]=3)=[C:14]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH:13]=[N:12]2)=[CH:21][CH:22]=1
Reactant: O=c1c(Oc2ccc(Br)cc2)c(-n2ccnc2)cnn1-c1ccc(Cl)cc1
Reactant: C[Sn](C)(C)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1c(Oc2ccc(-c3ccncc3)cc2)c(-n2ccnc2)cnn1-c1ccc(Cl)cc1

Procedure:
1.5 mmol of 4-(4-bromophenyl)oxy-2-(4-chlorophenyl)-5-(1H-imidazol-1-yl)-3(2H)-pyridazinone, 2.1 mmol of 4-trimethylstannylpyridine, 0.1 mmol of bis(triphenyl-phosphine)palladium dichloride and 1.3 mmol of ethyldiisopropylamine in 5 ml of dimethylformamide are heated at 100° C. for 5 hours. The solvent is removed in a rotary evaporator, and the residue is purified by chromatography on silica gel (elution with ethyl, acetate/methanol mixtures). 0.3 g (45% of theory) is obtained of m.p. 188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].CO[CH:15](O)[C:16]([F:19])([F:18])[F:17].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH:15]([C:16]([F:19])([F:18])[F:17])[O:12][C:9]([CH3:10])([CH3:11])[C:3]=2[CH:4]=1
Reactant: COC(O)C(F)(F)F
Reactant: CC(C)(O)c1cc(Br)ccc1N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CC1(C)OC(C(F)(F)F)Nc2ccc(Br)cc21
Temperature: 80 °C

Procedure:
A mixture of 2-(2-amino-5-bromo-phenyl)-propan-2-ol (5 g, 21.7 mmol), trifluoroacetaldehyde methyl hemiacetal (5 mL), and magnesium sulfate (10 g) in toluene (75 mL) was heated at 80° C. under nitrogen. After disappearance of the starting material, the reaction was filtered through a pad of silica gel and the filtrate dried over sodium sulfate and concentrated to give 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine as an amorphous solid: 1H-NMR (DMSO-d6) δ 7.31 (d, 1H, J=1.99 Hz), 7.19 (dd, 1H, J=8.73, 2.38 Hz), 6.88 (s, 1H), 6.74 (d, 1H, J=8.33 Hz), 5.32 (m, 1H), 1.52 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[C:11]([OH:12])=[CH:10][C:7]([C:8]#[N:9])=[C:6]([CH3:13])[CH:5]=1)(=[O:3])[CH3:2].[I:14]N1C(=O)CCC1=O>C(O)(=O)C.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]([CH3:13])[C:7]([C:8]#[N:9])=[C:10]([I:14])[C:11]=1[OH:12])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)c1cc(C)c(C#N)cc1O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(C)c(C#N)c(I)c1O
Temperature: 80 °C
Yield: 62.9 %

Procedure:
The 4-acetyl-5-hydroxy-2-methylbenzonitrile (6.7 g, 38 mmol) was dissolved in acetic acid (80 mL) and the N-iodosuccinimide (10.0 g, 46 mmol) was added. The reaction was heated to 80° C. in an oil bath and monitored by LC/MS. After heating for 4 hrs the reaction was complete. This was allowed to cool and was concentrated in vacuo to give a dark oil. The oil was taken up in ethyl acetate and washed with water, sodium bicarbonate (3×, until remained slightly basic), brine, dried over magnesium sulfate and concentrated to give the crude product as a dark oil. The product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give 4-acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile as pale yellow solid (7.2 g, 62%). LCMS calculated for C10H9INO2(M+H)+: m/z=301.9; found: 301.9.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]1[CH2:18][O:19][CH3:20])[CH3:2].[CH3:21]OC(C1OC=CC(=O)C=1OCC1C=CC=CC=1)C>>[CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]1[CH:18]([O:19][CH3:20])[CH3:21])[CH3:2]
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Reactant: COC(C)c1occc(=O)c1OCc1ccccc1
Product: CCn1ccc(=O)c(OCc2ccccc2)c1C(C)OC
Yield: 29.6 %

Procedure:
In an analogous procedure in the preparation of 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one using 2-(1 -methoxyethyl)-3-benzyloxy-pyran-4(1H)-one 3.12 g (12 mmol, 1 eq.) yielded the title compound (1.03 g, 29.6%) after purification by column chromatography on silica gel (eluant: 15% CH3OH/85% CHCl3) as a yellow oil.
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(OCC)=O)C.[Li+].CC([N-]C(C)C)C.[CH:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:46](=[O:56])[CH2:45]1)=O>C1COCC1>[C:22]1([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:13]2[CH:14]=[C:10]([CH:9]=[CH:42][CH:44]3[CH2:49][CH2:48][N:47]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:46](=[O:56])[CH2:45]3)[N:11]=[CH:12]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Reactant: O=CC1CCN(c2ccccc2)C(=O)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CC(C=Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCN1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The product from Step H is dissolved in THF and cooled to -78° C. under nitrogen. A solution of LDA in THF is added dropwise. The reaction is stirred at -78° C. for 1 h, then a solution of 4-formyl-1-phenyl-2-piperidinone from Step E is added, and the reaction warmed to room temperature overnight. The reaction is quenched with ammonium chloride solution, and extracted with ethyl acetate. The title compound is obtained after chromatography on silica gel