Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[N:16]1([C@@H:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=3[F:33])[CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([C@@H:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:10](=[O:12])[C:9]4[CH:13]=[CH:14][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=4[CH3:15])=[CH:28][C:27]=3[F:33])[CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCCCOc1ccc(C(=O)O)c(C)c1
Reactant: Nc1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CC[C@@H](N4CCCC4)C3)c(F)c2)c(C)c1

Procedure:
4-Butoxy-2-methyl-benzoic acid was reacted with (R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-fluorophenylamine according to Method P. In this way the product was obtained with molecular weight 439.58 (C26H34FN3O2); MS (ESI): 440 (M+H+).
Reaction SMILES: C(O[CH:5]1[O:13][C@H:12]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[Cl:19])(=O)C.[BrH:20]>ClCCl.C(O)(=O)C>[C:9]([O:8][C@@H:7]1[C@@H:12]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:13][CH:5]([Br:20])[C@@H:6]1[Cl:19])(=[O:11])[CH3:10]
Reactant: Br
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](Cl)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1OC(Br)[C@H](Cl)[C@@H]1OC(C)=O

Procedure:
3,5-Di-O-acetyl-2-chloro-2-deoxy-α,β-D-ribofuranosyl acetate (the compound described by J. P. Schaumberg et al., in "J. Org. Chem.," 50, pp. 1651-1656, 1985) represented by the following formula (N) ##STR52## where Ac is acetyl group is dissolved in dichloromethane. To the resulting solution is added 30% hydrogen bromide in acetic acid to effect the reaction at room temperature overnight. The resulting reaction solution is concentrated and the remaining acetic acid is removed by azeotropic distillation with toluene, to yield 3,5-di-O-acetyl-2-chloro-2-deoxy-α,β-D-ribofuranosyl bromide [compound (O)] as a syrup.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[C:10]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=[CH:7][C:6]=1[N+:21]([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:5]=2[CH:4]=[CH:3][NH:21]3)=[O:20])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2C=CN(C)C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2cccc3[nH]ccc23)cc1
Yield: 73.5 %

Procedure:
A solution of 32 g. (0.098 mole) of 2-(2-dimethylaminoethenyl)-3-(4-methoxybenzoyl)nitrobenzene in 200 ml of ethyl acetate was treated with 5 g of 10% palladium-on-charcoal, and the starting material reduced with hydrogen under 50 p.s.i.g. The mixture was then filtered, the filtrate taken to dryness, and the residue recrystallized from ethyl acetate to give 18.1 g of 4-(4-methoxybenzoyl)indole. Another sample, similarly prepared by reduction of the starting material with Raney nickel in ethanol, afforded material having m.p. 148°-152° C.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:35])[CH:15]=2)[C:10]([Cl:36])=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[Cl:36][C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=4)=[N:22][C:21]=3[CH3:35])=[CH:13][CH:12]=2)[N:8]([CH2:7][C:6]([OH:37])=[O:5])[CH:9]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2c(Cl)cn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2c(Cl)cn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], (3-chloro-6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with LiOH to obtain (3-chloro-6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid as light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>ClCCl.Cl>[OH:20][C:17](=[C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])[CH2:18][CH3:19]
Reactant: CCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.41 g, 30.0 mmol) and pyridine (4.85 mL, 60.0 mmol) in dichloromethane (24 mL) at 0° C. under argon is added propionyl chloride (2.95 mL, 33.0 mmol). The mixture is stirred at 0° C. for 1 h and at room temperature for 1 h before being diluted with 2 N HCl (40 mL) and extracted with dichloromethane (80 mL). The extract is washed (brine) and dried. Solvent is removed at reduced pressure to give 5.57 g (93%) of 2 as a yellow solid, mp 43-46° C. IR 3345, 2856, 1715, 1456 cm−1; 1H NMR (CDCl3) δ 1.29 (t, J=7.5 Hz, 3H, CH2CH3), 1.76 (s, 6H, CH3, CH3), 3.14 (q, J=7.5 Hz, 2H, CH2CH3), 15.42 (bs, 1H, OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:8][C:7]([O:9][CH3:10])=[CH:6][CH2:5][CH:4]=1.C([Li])(C)(C)C.[I-].[Ba+2].[I-].[CH2:19](Cl)[CH:20]=[C:21]([CH3:23])[CH3:22]>C1COCC1.CCCCC>[CH3:1][O:2][C:3]1[CH:8]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[C:7]([O:9][CH3:10])=[CH:6][CH2:5][CH:4]=1
Reactant: COC1=CCC=C(OC)C1
Reactant: CC(C)=CCCl
Agent: [Ba+2]
Agent: [I-]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COC1=CCC=C(OC)C1CC=C(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A portion of barium iodide dihydrate was dried over 12 h at 150° C. under 6 mmHg vacuum in a 250-mL round-bottom flask to yield activated barium iodide (8.38 g, 21.4 mmol, 1.1 equiv.), which was taken up in THF (125 mL). Meanwhile, a THF (50 mL) solution of 1 (2.73 g, 19.5 mmol, 1 equiv.) was cooled to −78° C. in a 500-mL round-bottom flask, and a pentane solution of tert-butyllithium (1.63 M, 13.1 mL, 21.4 mmol, 1.1 equiv.) was added over 5 min. After stirring the resulting clear yellow solution at −78° C. for 1 h, the THF slurry of activated barium iodide was transferred via cannula to this solution over 15 min. After stirring the resulting yellow-tan slurry an additional 30 min at −78° C., a THF (2 mL) solution of 3 (2.4 mL, 21.4 mmol, 1.1 equiv.) was added, and the slurry was allowed to warm over 2.25 h. The reaction was then quenched with water and extracted thrice with EtOAc. The organic extracts were combined, washed twice with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting clear oil was slowly loaded onto a SiO2 plug and eluted with 98:2 hexane:EtOAc. The eluent was concentrated in vacuo to afford 2.90 g (13.3 mmol, 68% yield) of 11 as a clear, colorless oil. TLC Rf 0.77 (9:1 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 4.99 (t, J=7.4 Hz, 1H), 4.68 (dd, J=4.6, 3.0 Hz, 2H), 3.53 (s, 6H), 2.94-2.91 (m, 1H), 2.78 (ddt, J=20.7, 6.0, 3.0 Hz, 1H), 2.72 (dq, J=20.7, 4.6 Hz, 1H), 2.41 (dd, J=7.4, 4.7 Hz, 2H), 1.64 (s, 3H), 1.55 (s, 3H). 13C NMR (125 MHz; CDCl3): δ 154.5, 132.8, 120.6, 91.9, 54.4, 41.3, 28.5, 26.1, 24.7, 17.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:21])=O>N1C=CC=CC=1.C1C=CC=CC=1>[Cl:21][CH2:5][C:4]1[CH:7]=[C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:9]=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(Oc2ccccc2Cl)cc1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(Oc2ccccc2Cl)cc1CCl

Procedure:
A mixture of 2-methoxy-5-(2-chlorophenoxy)benzyl alcohol (8 g), thionyl chloride (4.4 ml) and pyridine (3 drops) in dried benzene (60 ml) was treated in a similar manner to that of Example 3-(6) to give oily 2-chlorophenyl 3-chloromethyl-4-methoxyphenyl ether (8.5 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:11])=[CH:5][NH:6]2.[CH3:12][N:13]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2]>[CH3:11][C:4]1[C:3]2[C:2]([C:12]#[N:13])=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][CH:5]=1
Reactant: Cc1c[nH]c2cccc(Br)c12
Reactant: CN1CCCC1=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1c[nH]c2cccc(C#N)c12
Temperature: 140 °C
Yield: 59 %

Procedure:
To a solution of 230 (454 mg, 2.16 mmol) in NMP (4.5 mL) under argon atmosphere was added Zn(CN)2 (252 mg, 2.16 mmol), zinc powder (27 mg, 0.43 mmol), Pd2(dba)3 (0) (293 mg, 0.32 mmol), and dppf (358 mg, 0.65 mmol). The solution was heated at 140° C. for 18 h, the mixture was cooled and partitioned between EtOAc (100 mL) and H2O (30 mL). The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to dryness in vacuo. The residue was purified by SiO2 chromatography eluting with 10% EtOAc/petroleum ether to afford 200 mg (59%) of 3-methyl-1H-indole-4-carbonitrile (232) as white solid: MS (ESI) m/z=157.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:12]2[C:13]([C:18](O)=[O:19])=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](=[N:14][N:15]([CH3:17])[CH:16]=3)[C:18]2=[O:19])[CH:3]=1
Reactant: Cn1cc(C(Nc2cc(Cl)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C(=O)O)n1
Solvent: ClCCl
Solvent: CO
Product: Cn1cc2c(n1)C(=O)N(c1cc(Cl)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)(4-chlorophenyl)methyl)-1-methyl-1H-pyrazole-3-carboxylic acid (Step 10.4). tR: 3.65 min (HPLC 1); tR: 0.82 min (LC-MS 2): ESI-MS: 389/391 [M+H]+ (LC-MS 2); Rf=0.56 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.45 (s, 3H) 3.98 (s, 3H) 6.21 (s, 1H) 7.26 (d, J=8.4 Hz, 2H) 7.38 (d, J=8.4 Hz, 2H) 7.79 (s, 1H) 7.90-8.04 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH:22]=O.N1CCCCC1>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:14]1[NH:15][C:16]2[C:21]([C:13]=1[CH3:12])=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: Cc1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ccc2c(c1)C(=Cc1[nH]c3ccccc3c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of 5-methyl-2-oxindole (59 mg), 3-methylindole-2-carbaldehyde (56 mg) and piperidine (30 mg) in ethanol (1 mL) was held in a sealed tube at 90° C. overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 72 mg (74%) of 5-methyl-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O-:24])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH2:36])(=[O:35])=[O:34]>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:36][C:23]([NH:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:4]2[CH:5]=[C:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:7]=[C:3]2[CH2:1][CH3:2])=[CH:19][CH:18]=1)=[O:24])(=[O:35])=[O:34]
Reactant: NS(=O)(=O)c1ccccc1F
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)[O-])cc1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccccc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate and 2-fluorobenzenesulfonamide. MS (ESI) n/z 500 [M+H]+, 498 [M−H]−, 1H-NMR (CDCl3) δ 1.23 (3H, t, J=6.0 Hz), 2.71 (2H, q, J=6.0 Hz), 2.84 (2H, t, J=6.0 Hz), 3.44-3.52 (2H, m), 6.58 (1H, br), 7.18-7.30 (7H, m), 7.37 (2H, t, J=9.0 Hz), 7.59-7.65 (1H, m), 7.78 (2H, d, J=6.0 Hz), 7.84-7.90 (2H, m).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[S:12][C:13](Br)=[N:14][N:15]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O1CCOCC1>[Br:10][C:11]1[S:12][C:13]([N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[N:14][N:15]=1
Reactant: Brc1nnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2nnc(Br)s2)CC1
Temperature: 120 °C
Yield: 77.1 %

Procedure:
DIPEA (430 μL, 2.460 mmol) was added to a stirred solution of 2,5-dibromo-1,3,4-thiadiazole (300 mg, 1.230 mmol) and tert-butyl piperazine-1-carboxylate (275 mg, 1.476 mmol) in dioxane (4 mL). The reaction mixture was heated at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered under vacuum, rinsed with dioxane, and the filtrate was concentrated in vacuo to afford the crude product as an orange oily residue. The crude material was purified by preparative HPLC under neutral conditions (ammonium formate modified) to afford the title compound as a yellow solid (331 mg, 77% yield). LC-MS: Rt 1.18 min; MS m/z 351.1 [M+2]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.38-3.55 (m, 8H), 1.41 (s, 9H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[CH3:29][N:30]1[C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([S:39](Cl)(=[O:41])=[O:40])[C:33]=2[CH:32]=[CH:31]1>>[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][N:23]([S:39]([C:34]4[CH:35]=[CH:36][CH:37]=[C:38]5[C:33]=4[CH:32]=[CH:31][N:30]5[CH3:29])(=[O:40])=[O:41])[CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1
Reactant: Cn1ccc2c(S(=O)(=O)Cl)cccc21
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc5c4ccn5C)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and 1-methyl-1H-indole-4-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[OH:12])=O.C=O.[CH:23]([NH2:25])=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:25]=[CH:23][O:12][C:11]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20]
Reactant: NC=O
Reactant: O=C(c1ccc(Cl)cc1Cl)C(O)c1ccc(Cl)cc1Cl
Agent: C=O
Solvent: O
Product: Clc1ccc(-c2ncoc2-c2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 205 °C

Procedure:
A mixture of (+/−)-2,2′,4,4′-tetrachlorobenzoin (1.0 gm, 2.9 mmol) from Step A and paraformaldehyde (0.70 gm, 24 mmol) in formamide (20 mL) was heated to 200-210° C. for 3 hr. The reaction was cooled to rt, diluted with water, and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography, eluting first with 10% ethyl acetate in hexanes to afford 4,5-di-(2,4-dichlorophenyl)oxazole as a higher Rf byproduct and then with 75% ethyl acetate in hexanes to elute the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Al](Cl)(C)C.[CH3:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[C:17]([O:28][C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[CH:18]=[C:19]([C:24](OC)=[O:25])[CH:20]=2)[CH2:15]1>ClCCCl.C(Cl)Cl>[CH3:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[C:17]([O:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=3)[CH:18]=[C:19]([C:24]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)=[O:25])[CH:20]=2)[CH2:15]1
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)C(=O)N(C)C2
Agent: C[Al](C)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)C(=O)N(C)C3)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a solution of 5-methyl-2-aminopyridine (144 mg, 1.33 mmol) in DCE at 0° C. was added Al(CH3)2Cl drop-wise. The reaction was stirred at room temperature for 20 minutes followed by the addition of methyl 2-methyl-7-(4-(methylsulfonyl)phenoxy)-3-oxoisoindoline-5-carboxylate. After stirring the reaction at room temperature for 14 hours, it was diluted with CH2Cl2 and quench with potassium sodium tartrate tetrahydrate (20% w/w) (1 mL) slowly. The solution was washed with brine, dried over Na2SO4, and concentrated. The crude sample was introduced into a silica gel column and eluted with 5-10% MeOH/CHCl3 to provide the product (40 mg, 85% yield) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.33 (s, 3 H) 3.10 (s, 3 H) 3.19-3.33 (m, 3 H) 4.40 (s, 2 H) 7.19 (d, J=8.67 Hz, 2 H) 7.53-7.66 (m, 1 H) 7.82 (s, 1 H) 7.97 (d, J=8.67 Hz, 2 H) 8.10-8.17 (m, 1 H) 8.19 (s, 2 H) 8.81 (s, 1 H); LC-MS (ESI)+ m/z=452.00 (M+H)+.
Reaction SMILES: C(NC1C=CC([O:11][C:12]2[CH:13]=[C:14]([CH:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:28][C:29]5[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:38])[CH3:37])=[CH:31][CH:30]=5)[CH:24]=4)[O:19]3)[CH:15]=[CH:16][CH:17]=2)=NC=1)(=O)C.NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=C(O)C=CC=2)CC3)=NC=1.C(Cl)(C)=O>>[OH:11][C:12]1[CH:13]=[C:14]([CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][C:29]4[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:38])[CH3:37])=[CH:31][CH:30]=4)[CH:24]=3)[O:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)Nc1ccc(Oc2cccc(C3CCc4cc(Oc5ccc(NC(C)=O)cn5)ccc4O3)c2)nc1
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(O)c2)O3)nc1
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(O)c2)O3)nc1

Procedure:
N-{6-[2-(3-Hydroxyphenyl)chroman-6-yloxy]pyridin-3-yl}acetamide was prepared as described for N-(6-{2-[3-(5-acetylaminopyridin-2-yloxy)-phenyl]-chroman-6-yloxy}pyridin-3-yl)acetamide in Example 57 starting from 3-[6-(5-aminopyridin-2-yloxy)chroman-2-yl]phenol using 1.2 eq. AcCl. 1H NMR (400 MHz, d6-DMSO) δ: 10.03 (s, 1H), 9.42 (s, 1H), 8.27 (d, 1H, J 2.6 Hz), 8.01 (dd, 1H, J 8.8, 2.6 Hz), 7.18 (t, 1H, J 8.0 Hz), 6.93 (d, 1H, J 8.8 Hz), 6.84-6.85 (m, 5H), 6.72 (d, 1H, J 8.9 Hz), 5.03 (d, 1H, J 8.2 Hz), 2.94 (m, 1H), 2.70 (m, 1H), 2.14 (m, 1H), 2.04 (s, 3H), 1.94 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:42])=[C:5]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]2C(=O)C3=CC=CC=C3C2=O)=[O:23])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN>C(O)C>[CH3:42][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[C:5]=1[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[O:23]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc(C(F)(F)F)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN)C1c1cccc(C(F)(F)F)c1
Yield: 29.9 %

Procedure:
A solution of 11.2 g of methyl 6-phthalimidohexyl 2,6-dimethyl-4-(m-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 10.1 g of hydrazine monohydrate in 330 ml of 95% ethanol (containing water of 5%) was refluxed for 4 hours under heating. After cooling the reaction solution, the solution was concentrated under reduced pressure. The residue was extracted with chloroform, and the extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Crude crystal were recrystallized from chloroform-ether to provide 2.6 g of 6-aminohexyl methyl 2,6-dimethyl-4-(m-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:13]([CH2:23]O)=[C:12]2[CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:41]1(=[O:51])[NH:45][C:44](=[O:46])[C:43]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:42]12.[K]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:13]([CH2:23][N:45]1[C:41](=[O:51])[C:42]3[C:43](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:44]1=[O:46])=[C:12]2[CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCc1c(CO)c(CC(C)C)nc2ccc(OCc3ccccc3)cc12
Agent: CS(=O)(=O)Cl
Agent: [K]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1c(CN2C(=O)c3ccccc3C2=O)c(CC(C)C)nc2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of [6-(benzyloxy)-4-butyl-2-isobutylquinolin-3-yl]methanol (1.43 g, 3.8 mmol) in tetrahydrofuran (20 ml) were added triethylamine (0.64 ml, 4.6 mmol) and methanesulfonyl chloride (0.36 ml, 4.6 mmol) and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in N,N-dimethylformamide (30 ml). Potassium phthalimide (1.41 g, 7.6 mmol) was added, and the mixture was stirred at room temperature for 6 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 2-{[6-(benzyloxy)-4-butyl-2-isobutylquinolin-3-yl]methyl}-1H-isoindole-1,3(2H)-dione (1.81 g, yield 94%) as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:28])[CH:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[H][H]>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:28])[CH:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)C(C(=O)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Product: COC(=O)C(c1ccccc1)C(O)CCCCNC(=O)OCc1ccccc1
Yield: 87.4 %

Procedure:
22.6 g (58.8 mmol) of methyl 7-(N-benzyloxycarbonylamino)-3-oxo-2-phenylheptanoate, 435 mg (0.39 mmol) of [RuI(p-cymene)(S)-BINAP]I, 72 mg (0.39 mmol) of tin chloride and 364 mg (1.56 mol) of camphor-10-sulfonic acid (hereinafter referred to as "CSA") were placed in a 500 ml autoclave. After air in the autoclave was replaced with nitrogen, 160 ml of methanol was added to the mixture. The nitrogen in the autoclave was replaced with hydrogen and then the mixed solution was reacted at 80° C. under a hydrogen pressure of 80 kg/cm2 for 40 hours. After the completion of the reaction was confirmed by means of HPLC, the reaction solution was concentrated under reduced pressure. The residue was then purified by means of SGIC (eluent: hexane/ethylacetate=2/1 by volume) to prepare the target compound as a colorless oil in an amount of 37.4 g at a yield of 87.4%. The products were analyzed using HPLC. As a result, the rate of the syn-form to the anti-form was 76.3:23.7 and the optical purity of each of the forms was 95.6% ee and 97.8% ee respectively. The analytical results on the target compound are given below.