Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:10]3[CH2:9]2)[CH:5]=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30][CH2:31][CH3:32])=[CH2:29])CCC>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.C1(C)C=CC=CC=1>[CH2:31]([O:30][C:28]([C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:10]3[CH2:9]2)[CH:5]=[N:6][CH:7]=1)=[CH2:29])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(Br)c3)C[C@@H]2C1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1
Temperature: 90 °C
Yield: 45.1 %

Procedure:
The product from Example 64A (107 mg, 0.29 mmol) and tributyl-(1-ethoxyvinyl)stannane (157 mg, 0.43 mmol) were combined in a 100 mL conical flask with toluene (4 mL). Tetrakis(triphenylphosphine)palladium(0) (19.7 mg, 0.017 mmol) was added, and the mixture was heated under nitrogen at 90° C. for 22 h. The black mixture was cooled to room temperature, applied to a column of silica gel and eluted with hexanes-EtOAc (1:1) to provide the titled compound as an amber gum (contaminated with triphenyl phosphine oxide, 47 mg, 47% pure, 21% yield). MS(DCI/NH3) m/z 360 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].Cl>ClCCl>[C:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 63.9 %

Procedure:
A solution of 4-hydroxybenzoic acid (6.91 g) and pyridine (12.1 ml) in dichloromethane (100 ml) was cooled to an ice-water temperature, and hereto was added dropwise pivaloyl chloride (13.26 g). The mixture was stirred at same temperature for 1.5 hours, and thereto was added a 10% aqueous hydrochloric acid solution (50 ml). The organic layer was washed with H2O (100 ml) and brine, and dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 ml)-H2O (15 ml), and the mixture was stirred at 50° C. for 17.5 hours. After being cooled to an ice-water temperature, the mixture was basified with a saturated aqueous sodium hydrogen carbonate solution (about 100 ml). After being stirred at room temperature for 4 hours, the mixture was acidified with a 36% aqueous hydrochloric acid solution at an ice-water temperature. The resultant mixture was extracted with ethyl acetate (100 ml), and the organic layer was dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1-9:1) and triturated with diisopropyl ether to give 4-pivaloyloxybenzoic acid (7.10 g) as a colorless solid. ESI-Mass m/Z 221 (M−H). 1H-NMR (DMSO-d6) δ 1.31 (s, 9H), 7.23 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.7 Hz, 2H), 10.03 (brs, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:27])[CH:6]=[C:7]([CH3:26])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:34][C:35]([Cl:39])=[CH:36][CH2:37]Cl>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([O:27][CH2:37][CH:36]=[C:35]([Cl:39])[Cl:34])[CH:6]=[C:7]([CH3:26])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCc1cc(O)cc(C)c1OCCCNC(=O)c1ccc(C(F)(F)F)cc1
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(C)c1OCCCNC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
To a mixture of 0.66 g of 3-ethyl-5-methyl-4-(3-(4-(trifluoromethyl)benzamido)propyloxy)phenol, 0.29 g of potassium carbonate and 20 ml of N,N-dimethylformamide was added dropwise a mixed solution of 0.28 g of 1,1,3-trichloropropene and 5 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was poured into ice water and extracted twice with 50 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give crude crystals. The crude crystals were ground and washed with n-hexane, which afforded 0.48 g of 3-ethyl-5-methyl-1-(3,3-dichloro-2-propenyloxy)-4-(3-(4-(trifluoromethyl)benzamido)propyloxy)benzene (58% yield), m.p., 92.2° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[C:4]([O:13][CH3:14])[CH:3]=1.[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[CH2:8]2)=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COc1cc(Br)ccc1OC1CNC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(Br)ccc1OC1CN(C2CCC2)C1
Reaction time: 8 h
Yield: 56.6 %

Procedure:
Dissolve 3-(4-bromo-2-methoxy-phenoxy)-azetidine (1.84 g, 7.13 mmol) in dichloroethane (80 mL). Add cyclobutanone (1.86 mL, 25 mmol), sodium triacetoxyborohydride (3.02 g, 14.3 mmol) and acetic acid (0.82 mL, 14.3 mmol). Stir the mixture overnight, then add saturated sodium bicarbonate and extract three times using dichloromethane. Dry the combined organic portions over sodium sulfate, filter, and concentrate. Purify by silica gel chromatography using a 0-3% gradient of methanol/dichloromethane to give 1.26 g (56%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[OH-].[NH4+:15].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:15])(=[O:12])=[O:11]
Reactant: CCc1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 0.25 h

Procedure:
To a solution of 2-chloro-5-ethylbenzenesulfonyl chloride (0.41 g, 1.7 mmol, the product of Step A) in tetrahydrofuran (30 mL) was added 30% ammonium hydroxide (0.41 mL, 3.5 mmol) dropwise. The reaction mixture was stirred for 15 minutes, during which time a suspension formed. To this mixture water (10 mL) was added, and the tetrahydrofuran was evaporated under reduced pressure to precipitate a solid. The solid was dissolved in diethyl ether, dried over magnesium sulfate, and concentrated under reduced pressure. Diethyl ether and hexane were added to precipitate a solid. The solid was isolated by filtration to afford 190 mg of the title compound. 1H NMR (CDCl3) δ 7.95 (s, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 5.08 (br s, 2H), 2.71 (q, 2H), 1.25 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:41]=[CH:40][CH:39]=[CH:38][C:20]=1[O:21][C:22]1[C:36]([OH:37])=[CH:35][C:25]2[NH:26][C:27]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)=[N:28][C:24]=2[CH:23]=1>[Cu]=O.CN1CCCC1=O>[F:18][C:19]1[CH:41]=[CH:40][CH:39]=[CH:38][C:20]=1[O:21][C:22]1[C:36]([O:37][C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[CH:35][C:25]2[NH:26][C:27]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)=[N:28][C:24]=2[CH:23]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: Oc1cc2[nH]c(-c3cnccn3)nc2cc1Oc1ccccc1F
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Fc1ccccc1Oc1cc2nc(-c3cnccn3)[nH]c2cc1Oc1ccc(C(F)(F)F)nc1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
16 mg of 5-bromo-2-trifluoromethyl-pyridine, 50 mg of cesium carbonate and 10 mg of copper(II) oxide were added to an N-methylpyrrolidinone (1 ml) solution of 21 mg of 5-(2-fluorophenoxy)-6-hydroxy-2-pyrazin-2-yl-1H-benzimidazole obtained in Example 251 (step 1), and the reaction liquid was stirred at 130° C. for 5 hours. The deposit was separated through filtration, and the solution was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.N1C=CC=CC=1.[Li+].[BH4-].Cl>C1COCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
3.69 g (0.009 mol) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]methylcarbamate, 6 ml of THF and 7.3 ml of pyridine are introduced, in order, into a 50 ml three-necked round-bottomed flask. The mixture is placed under nitrogen and 10 ml of a freshly prepared 2 M LiBH4 solution (0.02 mol) in THF are added dropwise. After stirring for 30 minutes at room temperature, the mixture is heated under reflux for 16 hours. The reaction medium is poured over 32 ml of a 1 N HCl solution and the THF is evaporated under vacuum. The precipitate obtained is filtered. After drying, the crude product (2.75 g) is chromatographed on 95 g of silica gel, eluting with a heptane/ethyl acetate=3/7 mixture. 2.45 g (66%) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]methylcarbamate are obtained.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[C:5]([F:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[F:9][C:5]1[C:6]([I:8])=[CH:7][C:2]([NH:11][NH2:12])=[N:3][CH:4]=1
Reactant: Fc1cc(I)c(F)cn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1cc(I)c(F)cn1
Temperature: 50 °C
Reaction time: 19 h
Yield: 35 %

Procedure:
A solution of 2,5-difluoro-4-iodopyridine (1.35 g, 5.602 mmol) in ethanol (7 mL) was treated with hydrazine hydrate (2.75 mL) and the mixture was stirred at 50° C. for 19 hours. The mixture was concentrated in vacuum and the resulting solid triturated with water, filtered, rinsed with more water and dried to yield the title compound (0.57 g, 35%) that was used in the following steps without further purification.
Reaction SMILES: CO.[BH4-].[Na+].[N+:5]([N:8]1[C:12]2=[C:13]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:14]3[CH:15]=[CH:16][C:17]([N:52]=3)=[C:18]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:19]3[N:23]([N+:24]([O-])=O)[C:22]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[C:28]4[N:39]=[C:31]([C:32]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[C:9]1[CH:10]=[CH:11]2)[CH:30]=[CH:29]4)=[CH:21][CH:20]=3)([O-])=O>[Pd].ClCCl>[NH2:24][N:23]1[C:19]2=[C:18]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:17]3[CH:16]=[CH:15][C:14]([N:52]=3)=[C:13]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:12]3[N:8]([NH2:5])[C:9]([C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:31]4[N:39]=[C:28]([C:27]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)=[C:22]1[CH:21]=[CH:20]2)[CH:29]=[CH:30]4)=[CH:10][CH:11]=3
Reactant: O=[N+]([O-])n1c2ccc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc(c(-c4ccccc4)c4nc(c2-c2ccccc2)C=C4)n3[N+](=O)[O-])C=C1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nn1c2ccc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc(c(-c4ccccc4)c4nc(c2-c2ccccc2)C=C4)n3N)C=C1
Yield: 96.2 %

Procedure:
A 2-l three-necked round bottomed flask was fitted with a condenser and a dropping funnel to add solid material. To this flask was added anhydrous dichloromethane (850-ml) and methanol (420-ml). To this organic solution was added 10% palladium on carbon (14.0 g), the mixture was stirred under an argon blanket, and then cooled in an ice bath. Sodium borohydride (4.0 g, mol) was added in small portions over about 30-min. Next the dinitrotetraphenylporphyrin (7.0 g, 0.01 mol) and solid sodium borohydride (14.0 g) were added in small portions over about 60-min. The reaction mixture was stirred under argon for 30 min. The reaction mixture was filtered through a layer of CELITE® (diatomateous earth of Johns Manville, Denver, Colo.) in a Buchner funnel and washed repeatedly with dichloromethane. The solvent was completely removed under reduced pressure to produce a crude residue. The residue was redissolved in dry dichloromethane to separate insoluble CELITE®, and filtered. The solvent was removed under reduced pressure and dried to produce a purified residue (6.2 g). This residue was flash chromatographed over silica using dichloromethane as eluent. The product obtained (0.6 g, 9.6% yield) was free of impurities. See FIG. 4.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:20]=O)=[C:9]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[C:10]=1[CH2:11]C)=[O:5])C.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:39]=[C:38]3[C:34]([CH2:35][C:36](=[O:40])[NH:37]3)=[CH:33][CH:32]=2)[CH:28]=[CH:29][CH:30]=1)[CH3:23]>N1CCCCC1.C(O)C>[C:15]([CH2:14][CH2:13][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:20]=[C:35]1[C:34]2[C:38](=[CH:39][C:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH2:22][CH3:23])[CH:26]=3)=[CH:32][CH:33]=2)[NH:37][C:36]1=[O:40])([OH:17])=[O:16]
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1CC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C(=O)O)c(C)c2CCC(=O)O)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
A mixture of 5-formyl-4-(2-ethoxycarbonylethyl)-3-ethyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 6-(3-ethoxyphenyl)-2-oxindole (304 mg), and piperidine (2 drops) in ethanol (5 mL) were held at 90° C. overnight. The precipitate that formed was filtered, washed with ethanol. The precipitate, an orange solid, was stirred with potassium hydroxide (4 pellets) in ethanol (3 mL) at 90° C. for 2.5 hours. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 370 mg of 4-(2-Carboxyethyl)-5-[6-(3-ethoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH:10]=[CH2:11])=[CH:4][CH:3]=1.Br[CH2:14]Br.Cl>CCOCC.[Zn].[Cu]Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[CH2:9][CH:10]2[CH2:14][CH2:11]2)=[CH:6][CH:7]=1
Reactant: BrCBr
Reactant: C=CCC(O)c1ccc(Cl)cc1
Agent: Cl[Cu]
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Product: OC(CC1CC1)c1ccc(Cl)cc1
Yield: 44 %

Procedure:
Crude 4-(4-chlorophenyl)but-1-en-4-ol from the previous reaction (85.37 g, approximately 92% pure, approximately 430 mmol), zinc dust (121.5 g, 1.86 mol), copper(I) chloride (18.69 g, 187 mmol) and dibromomethane (163.6 g, 936 mmol) in dry ether (250 ml) were heated under reflux for 3 hours in a sonic bath and then poured into 2M hydrochloric acid. The mixture was extracted with ether and the extract washed with 2M hydrochloric acid and brine, dried and evaporated in vacuo. Chromatography [SiO2, hexane-ethyl acetate (90:10)] gave 1-(4-chlorophenyl)-2-cyclopropylethanol (37.24 g, 44% from 4-chlorobenzaldehyde).
Reaction SMILES: [O:1]=[C:2]([CH3:23])[CH2:3][CH2:4][C:5]1([CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([Cl:18])[C:9]([Cl:17])=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=O.C(O)C.[OH-].[Na+]>O>[Cl:17][C:9]1[C:10]([O:15][CH3:16])=[CH:11][C:12]2[CH2:13][CH2:14][C:5]3([CH2:20][CH2:21][CH3:22])[C:6]([C:7]=2[C:8]=1[Cl:18])=[CH:23][C:2](=[O:1])[CH2:3][CH2:4]3
Reactant: CCCC1(CCC(C)=O)CCc2cc(OC)c(Cl)c(Cl)c2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)CC2
Temperature: 25 °C
Reaction time: 96 h
Yield: 52.7 %

Procedure:
2-(3-Oxobutyl)-7,8-dichloro-6-methoxy-2-propyl-1-tetralone (700 mg), ethanol (25 ml), water (6 ml) and 10N sodium hydroxide solution (200 μl) were combined and stirred at room temperature for 96 hours. The reaction mixture was evaporated in vacuo at 30° C. treated with water, extracted two times with 100 ml of ether, washed with water, brine dried over MgSO4, evaporated in vacuo, and chromatographed on 25 g of SiO2 (ethyl acetate-hexane; 1:2) to give 350 mg of 3,4-Dichloro-6,7,8,8a,9,10-hexahydro-2-methoxy-6-oxo-8a-propylphenanthrene which was used in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][N:4]=[CH:3]1.[CH3:9][C:10]([S@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11]>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[CH3:9][C:10]([S@:13](/[N:15]=[CH:7]/[C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)=[O:14])([CH3:12])[CH3:11]
Reactant: Cn1cncc1C=O
Reactant: CC(C)(C)[S@](N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: Cn1cncc1/C=N/[S@](=O)C(C)(C)C
Yield: 51.1 %

Procedure:
A solution of 1-methyl-1H-imidazole-5-carbaldehyde (1.46 g, 13.26 mmol), (R)-2-methylpropane-2-sulfinamide (2.893 g, 23.87 mmol), and tetraethoxytitanium (10.89 g, 47.73 mmol) in THF (100 mL) was heated to 65° C. for 12 h. The reaction was cooled and poured onto water. The solids were filtered off, and the filtrate was extracted with EtOAc. The layers were separated, and the organic layer was concentrated. The resulting residue was purified by SiO2 eluting with a DCM/MeOH gradient (1.5 to 2% MeOH) to afford 1.444 g (51.1%) of (R,E)-2-methyl-N-((1-methyl-1H-imidazol-5-yl)methylene)propane-2-sulfinamide (128).
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[C:40]([C:48]1[CH:53]=[CH:52][C:51]([CH2:54][N:55]3[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]3)=[CH:50][CH:49]=1)[NH:41][C:42]2=[O:47]>C(Cl)Cl>[C:1]([N:58]1[CH2:59][CH2:60][N:55]([CH2:54][C:51]2[CH:50]=[CH:49][C:48]([C:40]3[NH:41][C:42](=[O:47])[C:43]4[C:38]([CH:39]=3)=[C:37]([CH3:36])[CH:46]=[CH:45][CH:44]=4)=[CH:53][CH:52]=2)[CH2:56][CH2:57]1)(=[O:3])[CH3:2]
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCNCC4)cc3)cc12
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(Cc2ccc(-c3cc4c(C)cccc4c(=O)[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.8 %

Procedure:
To a stirred solution of acetic acid (0.005 mL, 0.068 mmol) in CH2Cl2 (5 mL) was added TBTU (22 mg, 0.068 mmol) and N,N-diisopropylethylamine (0.036 mL, 0.20 mmol) and the reaction stirred for 10 min at RT. 5-Methyl-3-(4-piperazin-1-ylmethylphenyl)-2H-isoquinolin-1-one (23 mg, 0.068 mmol) was then added and the reaction stirred for 2 h at RT. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC-MS to afford 3-[4-(4-acetyl-piperazine-1-ylmethyl)-phenyl]-5-methyl-2H-isoquinolin-1-one as a white solid (2 mg, 9%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=O)[CH:28]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:10][C:9]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(4-Amino-2-phenylbenzoyl)methionine methyl ester hydrochloride (5.0 g, 12.7 mmol), prepared as in Example 192B, and 3-pyridinecarboxaldehyde (1.25 mL, 13.3 mmol) were dissolved in 100 mL 1% acetic acid in methanol. After 10 minutes, sodium cyanoborohydride (0.95 g, 15.9 mmol) was added. After stirring at room temperature 18 hours, the reaction mixture was evaporated and partitioned between 5% NaHCO3 and ethyl acetate. The organic layer was washed with 5% NaHCO3 and brine, dried over Na2SO4, and evaporated to provide [4-(3-pyridylmethylamino)-2-phenylbenzoyl]methionine methyl ester which was used without further purification. MS m/e 450 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.65 (m, 2H), 1.87 (m, 2H), 2.00 (s, 3H), 3.63 (s, 4H), 4.42 (s, 2H), 4.61 (m, 1H), 5.69 (d, J=7 Hz, 1H), 6.50 (d, J=3 Hz, 1H), 6.63 (m, 1H), 7.45 (m, 6H), 7.68 (m, 2H), 8.55 (m, 1H), 8.62 (d, J=3 Hz, 1H).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[CH:21](=[O:23])[CH3:22]>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[CH:21]([OH:23])[CH3:22]
Reactant: Fc1cncc(Br)c1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)c1c(F)cncc1Br
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
n-BuLi (1.6M in hexanes) (19.60 ml, 31.4 mmol) was added dropwise to a solution of diisopropylamine (4.84 ml, 34.0 mmol) in THF (87 ml) at −78° C. under N2. The resulting mixture was warmed up to −40° C. and stirred for 10 min and recoiled to −78° C. 3-bromo-5-fluoropyridine (4.6 g, 26.1 mmol) in 5 mL THF was added dropwise at this temperature. After 30 min, acetaldehyde (2.95 ml, 52.3 mmol) was added dropwise and the resulting mixture was stirred for 30 min at −78° C., and then for another 30 min at 0° C. The mixture was quenched with saturated NH4Cl solution and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The residue was purified via Biotage (SNAP50, 0-30% AcOEt/heptane, v/v) giving the title compound 4a (2.869 g, 50%) as yellow oil. LC-MS (M+1) 221.9, t=1.01 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(Br)ccc1OCc1ccccc1

Procedure:
A suspension of 2-benzyloxy-5-bromobenzaldehyde (14.5 g, 50.2 mmol) in absolute ethanol (250 ml) was treated with sodium borohydride (2.6 g, 68.8 mmol). The reaction was stirred and the temperature slowly rose to 33° C. After 1 hour the reaction mixture was evaporated and the residue dissolved in ethyl acetate and poured into a mixture of ice water (200 ml) and 1N HCl (25 ml). The organic layer was separated, washed with aqueous sodium hydrogen carbonate, brine, dried (Na2SO4) and evaporated to give 2-benzyloxy-5-bromobenzylalcohol as a pale yellow oil (14.85 g, quantitative).