Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:37][C:38]([NH:41][S:42]([C:45]1[S:49][C:48](Br)=[CH:47][CH:46]=1)(=[O:44])=[O:43])([CH3:40])[CH3:39].CCCCCC>C1(C)C=CC=CC=1.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>[C:38]([NH:41][S:42]([C:45]1[S:49][C:48]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=3)[CH:23]=2)=[CH:47][CH:46]=1)(=[O:43])=[O:44])([CH3:40])([CH3:37])[CH3:39]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(F)c(F)c3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.9 %

Procedure:
A stirred mixture of 4-(3,4-difluoro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.13) (0.21 g, 0.34 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.11 g, 0.37 mmol), tetrakis(triphenylphosphine)palladium (0.024 g, 0.02 mmol) in toluene (3 ml) was heated under reflux conditions for 15 h, hexane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield 5-{1-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.24 g) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[OH:11])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C)C=O>[CH2:18]([O:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]=[O:2])[C:7]#[N:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(C=O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Formyl-3-hydroxybenzonitrile (4.0 g) and potassium carbonate (3.76 g) were suspended in N,N-dimethylformamide (20 mL). To the reaction mixture was added benzylbromide (3.6 mL), and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give the title compound (3.0 g).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC[N:11]1[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]=[C:13]([CH3:19])[C:12]1=[O:20]>N1C=CC=CC=1>[C:5]([O:4][CH2:1][CH2:2][N:11]1[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]=[C:13]([CH3:19])[C:12]1=[O:20])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(C)c(=O)n(CCO)c1C
Solvent: c1ccncc1
Product: CC(=O)OCCn1c(C)c(C)nc(C)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.8 %

Procedure:
Acetic anhydride (2 ml) was added under ice-cooling to compound 026 (0.91 g, 5 mM) dissolved in pyridine (10 ml), and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and dilute aqueous K2CO3 was added thereto, the resultant mixture being extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (Florisil, 60 g) packed with benzene and eluted with benzene-ethyl acetate (5:1) to obtain compound 061 (0.58 g, yield: 51.8%).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH4+].[Cl-]>C1COCC1>[CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A mechanically stirred solution of the resultant compound from Example 64 (10 g, 56.4 mmol) in dry THF (200 ml) under an atmosphere of nitrogen was treated with n-butyl-lithium in hexanes (1.05 equiv, 22.6 ml, 56.4 mmol, 2.5M) at -78° C. After stirring for an additional 20 min at -78° C., hydrocinnamoyl chloride (9.4 ml, 62 mmol, 1.1 equiv) was added and the reaction was allowed to warm to room temperature with stirring over 2 h. The clear reaction mixture was poured into 100 ml of saturated NH4Cl. The organic layer was removed and the resulting aqueous layer extracted three times with dichloromethane. The combined organic extracts were washed once with brine, dried (anhydrous sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude solid. This material was recrystallized from hot ethyl acetate/hexane at 0°-5° C. overnight. First crop yielded 12.9 g, mp 99°-100° C. Second crop afforded 3.6 g. Total yield 16.5 g (95%).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O-:13])=O)[C:6]([O:8]CC)=[O:7])C.[Cl:14][C:15]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH2:19][NH:20]2.C(O)C.[OH-].[Na+]>O>[Cl:14][C:15]1[C:16]2=[C:21]3[N:20]([CH2:19][CH2:18][CH2:17]2)[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11](=[O:13])[C:22]3=[C:23]([Cl:25])[CH:24]=1
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Reactant: Clc1cc(Cl)c2c(c1)NCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c3c(c(Cl)cc(Cl)c3c1=O)CCC2
Temperature: 140 °C
Yield: 67.8 %

Procedure:
3.1 g of ethyl ethoxymethylenemalonate was added to 2.7 g of 5,7-dichloro-1,2,3,4-tetrahydroquinoline and the mixture was heated on an oil bath at 110° C. during which time distillation of ethanol was observed. After heating the mixture at the same temperature as above for 30 minutes, 30 g of polyphosphoric acid was added thereto followed by heating at 140° C. for 30 minutes. After completion of the reaction, the reaction mixture was poured into 100 ml of water and the resulting mixture was rendered neutral with a 40% aqueous sodium hydroxide solution to precipitate light brown crystals. Without further purification the crystals were mixed with 100 ml of a 10% aqueous sodium hydroxide solution and the mixture was heat-refluxed for 40 minutes during which time the crystals were dissolved to form a uniform solution. The solution was treated with activated carbon while hot and filtered. The filtrate was allowed to cool and adjusted to a pH of 2 to obtain 2.7 g of 8,10-dichloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as light yellow crystals having a melting point of 300° to 304° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1S([O-])(=O)=O.[Na+].[NH2-:15].[Na+].N>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[NH2:15]
Reactant: [NH2-]
Reactant: Cc1cc(C)c(C)c(S(=O)(=O)[O-])c1
Agent: N
Agent: [Na+]
Product: Cc1cc(C)c(C)c(N)c1
Yield: 78.4 %

Procedure:
In a 200-ml autoclave were placed 11.2 grams (0.05 mole) of anydrous sodium 2,3,5-trimethylbenzene sulfonate, 5.2 grams (0.13 mole) of sodium amide and 60 ml liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 160° C for 9 hours. The reaction pressure in the autoclave was 140 atm. during the reaction. After the ammonia was removed, 10 ml of water was added to the reaction mixture for hydrolysis. The product was extracted with ether and the ether was distilled off to produce crude 2,3,5-trimethyl aniline. The recrystallization thereof from petroleum ether gave 5.3 grams of 2,3,5-trimethyl aniline having a melting point of 36° C. Yield was 78.8%.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][C:9]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:10]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([NH:8][C:9]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:10]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:2]=[N:3][C:4]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(Nc2cc(Cl)cnc2Br)c(C(=O)OC(C)(C)C)c1
Product: Cc1ccc(Nc2cnc(-c3ccccc3)c(Cl)c2)c(C(=O)OC(C)(C)C)c1

Procedure:
Obtained (0.005 g, 3% of yield) following the procedure described in Example 8 (step A) starting with 0.230 g (0.58 mmol) of Intermediate 20A and 0.106 g (0.87 mmol) of phenylboronic acid.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].CO.C1COCC1.[CH3:14][C@H:15]1[CH2:20][NH:19][C@H:18]([CH3:21])[CH2:17][N:16]1[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24](F)[CH:23]=1>[Cl-].[Na+].O>[CH3:14][C@H:15]1[CH2:20][NH:19][C@H:18]([CH3:21])[CH2:17][N:16]1[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([O:4][CH3:2])[CH:23]=1
Reactant: C[C@@H]1CN(c2ccc(C#N)c(F)c2)[C@@H](C)CN1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2C[C@@H](C)NC[C@@H]2C)ccc1C#N
Reaction time: 0.5 h

Procedure:
A 1.35 g portion of potassium tert-butoxide and 0.48 ml of methanol were added to 5 ml of THF, and the mixture was stirred for 30 minutes. Next, this was mixed with 934 mg of trans-4-(2,5-dimethylpiperazin-1-yl)-2-fluorobenzonitrile synthesized in Reference Example 14 and stirred at room temperature for 2 days. This was mixed with saturated brine and extracted with ethyl acetate, the organic layer was washed with water, and then the solvent was evaporated and the resulting mixture was subjected to a silica gel column chromatography and eluted with ethyl acetate-methanol-28% aqueous ammonia (9:1:0.1, v/v/v) to obtain 900 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16]Br)[CH:3]=1.C(=O)([O-])[O-:19].[Ca+2]>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16][OH:19])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc2cc(Br)cc(CO)c2nc1OC

Procedure:
11.5 g (31.85 mmol) of 7-bromo-5-bromomethyl-2,3-dimethoxy-quinoxaline are suspended at 20° C. in 100 ml of dioxane. 16.4 g (164 mmol) of calcium carbonate in 100 ml of water are then added and the mixture is heated at reflux for 24 hours. The dioxane is concentrated by evaporation and 300 ml of dichloromethane are added. The salt is filtered off, the organic phase is washed with brine and concentrated by evaporation and the residue is chromatographed on silica gel with ethyl acetate and hexane (1:1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:43])[CH2:40][O:41][CH3:42]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:39](=[O:43])[CH2:40][O:41][CH3:42])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCC(=O)N(C)OC
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Product: COCC(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(Cl)c1F

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N,2-dimethoxy-N-methylacetamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][O:29][C:30]2[CH:31]=[C:32]([NH2:35])[NH:33][N:34]=2)[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([CH2:28][O:29][C:30]2[CH:31]=[C:32]([NH:35][C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([CH:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:17][CH:16]=3)[NH:33][N:34]=2)[CH:21]=[C:20]([O:19][CH3:18])[CH:25]=1
Reactant: COC(=O)c1ccc(C2CCN(C)CC2)cc1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(C4CCN(C)CC4)cc3)[nH]n2)cc(OC)c1
Yield: 46.7 %

Procedure:
N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(1-methylpiperidin-4-yl)benzamide was prepared following the procedure as for Example 159, but starting from methyl 4-(1-methylpiperidin-4-yl)benzoate (0.25 g, 1.07 mmol), 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.267 g, 1.07 mmol) and 2M trimethylaluminium in toluene (2.14 ml, 4.29 mmol). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 8% 2.5M NH3/MeOH in DCM. Pure fractions were evaporated to dryness, redissolved in DCM, triturated with ether and evaporated to dryness to afford the title compound (0.225 g, 46.5%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ 1.69 (1H, d), 1.73 (2H, d), 1.77 (1H, s), 1.95-2.02 (2H, m), 2.21 (3H, s), 2.88 (2H, d), 3.76 (6H, s), 5.09 (2H, s), 5.62 (1H, s), 6.45 (1H, s), 6.60 (2H, s), 7.41-7.42 (2H, m), 7.89-7.91 (2H, m), 10.85 (1H, s), 11.58 (1H, s). MS: m/z 451 (MH+).
Reaction SMILES: [F:1][C:2]1[C:10]([CH2:11][C:12]2[N:16]3[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[C:9]([F:24])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:25].Cl.[NH:27]([C:29]([NH2:31])=[O:30])[NH2:28]>CO>[F:1][C:2]1[C:10]([CH2:11][C:12]2[N:16]3[N:17]=[C:18](/[C:21](=[N:28]/[NH:27][C:29]([NH2:31])=[O:30])/[CH3:22])[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[C:9]([F:24])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:25]
Reactant: CC(=O)c1ccc2ncc(Cc3c(F)cc4c(cnn4C)c3F)n2n1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2ncc(Cc3c(F)cc4c(cnn4C)c3F)n2n1
Yield: 62.6 %

Procedure:
A solution of 1-(3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (45 mg, 0.099 mmol, 75% pure) and hydrazinecarboxamide hydrochloride (22 mg, 0.198 mmol) in 10 mL MeOH was stirred at room temperature overnight. Solvent was evaporated and the residue was dissolved in a small amount of MeOH. Precipitates formed and was filtered to give the title compound as a white solid (25 mg, 0.062 mmol). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.95 (s, 1H), 8.62 (d, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 8.0 (s, 1H), 7.54 (d, 1H), 6.85 (broad, 2H), 4.48 (s, 2H), 4.0 (s, 3H), 2.3 (s, 3H). LCMS (method B): [MH]+=398.9, tR=2.17 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([C:14]2[CH:31]=[CH:30][C:17](/[CH:18]=[CH:19]/[C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25]C)=[O:24])=[CH:16][C:15]=2[CH3:32])=[CH:12][C:11]([C:33]([OH:36])([CH3:35])[CH3:34])=[N:10]1.O.O.[OH-].[Li+].CO>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13]([C:14]2[CH:31]=[CH:30][C:17](/[CH:18]=[CH:19]/[C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([OH:25])=[O:24])=[CH:16][C:15]=2[CH3:32])=[CH:12][C:11]([C:33]([OH:36])([CH3:34])[CH3:35])=[N:10]1
Reactant: COC(=O)c1cccc(/C=C/c2ccc(-c3cc(C(C)(C)O)nn3-c3c(Cl)cccc3Cl)c(C)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(/C=C/c2cccc(C(=O)O)c2)ccc1-c1cc(C(C)(C)O)nn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
To a solution of (E)-methyl 3-(4-(1-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylstyryl)benzoate (180 mg of impure material from previous step, 0.35 mmol) in THF (2.0 mL) was added H2O (0.4 mL) followed by lithium hydroxide monohydrate (25.3 mg, 0.6 mmol). After stirring for 1 hour at ambient temperature a biphasic mixture had formed, and LC/MS analysis of the reaction showed no reaction. a small amount of MeOH was added to homogenize the mixture, and the reaction was then heated to 50° C. in an oil bath. After 2 hours stirring at 50° C., LC/MS analysis showed the reaction to be complete. Heating was discontinued, and after stirring at ambient temperature overnight, the reaction was quenched by the addition of 5% aqueous citric acid, and EtOAc. The layers were separated and the aqueous was extracted with EtOAc (3×). Combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a clear film. This material was purified by reverse phase preparative HPLC eluting with a gradient of MeCN/H2O with 0.05% TFA. The major peak from the HPLC was concentrated under reduced pressure to remove most of the solvents, and the resulting acidic aqueous was extracted with CH2Cl2 (3×). The combined organic extracts were washed with H2O until the washings were no longer acidic (2×), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (E)-3-(4-(1-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylstyryl)benzoic acid (45.4 mg, 26% yield) as a white powder. 1H NMR (400 MHz CDCl3): δ 821 (1H, s), 7.98 (1H, d, 7.69 (1H, d), 7.45 (1H, t), 7.39 (1H, d), 7.37-7.31 (2H, m), 7.23 (1H, m), 7.15 (1H, m), 7.12-7.07 (2H, m), 7.06 (1H, m), 6.46 (1H, s), 2.45 (3H, s), 1.71 (6H, s). MS(ES): 529 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.P(Cl)(Cl)([Cl:10])=O.O[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16](=[O:24])[C:15]=1[C:25]([N:27]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26]>>[Cl:10][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16](=[O:24])[C:15]=1[C:25]([N:27]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2c(O)c3ccccc3[nH]c2=O)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2c(Cl)c3ccccc3[nH]c2=O)cc1
Temperature: 65 °C
Yield: 67 %

Procedure:
Triethylamine (5.73 mL, 41.2 mmol) was added to phosphorus oxychloride (60 mL), followed by 4-hydroxy-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (Example 74c) (6.11 g, 13.7 mmol). The reaction was heated at 65° C. for 4 hours, then cooled to room temperature and carefully poured into ice water (1200 mL). The solution was extracted dichloromethane (2×200 mL. The organic layers were combined and washed with water, dried over MgSO4, filtered and evaporated. The residue was dissolved in dichloromethane (18 mL) and poured into 200 mL of 30% hexanes in diethyl ether. The resultant precipitate was collected by filtration to give crude 4-chloro-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (4.25 g, 67%) which was used without further purification. MS 463 (MH+).
Reaction SMILES: [CH2:1]([C:11]1[C:18]2[S:17][C:16]3[CH:19]=[CH:20][S:21][C:15]=3[C:14]=2[S:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:22]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:22][C:12]1[S:13][C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[S:17][C:18]=2[C:11]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCc1csc2c1sc1ccsc12
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCc1c(Br)sc2c1sc1ccsc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
3-decanyldithieno[3,2-b:2′,3′-d]thiophene (91) (9.03 g, 0.027 mol) is dissolved in DMF (100 mL). To this solution, N-bromosuccinimide (NBS) (4.78 g, 0.027 mol) in DMF (50 mL) is added dropwise in the dark and under argon. The resulting mixture is stirred at 0° C. for about three hours or until GC/MS shows a single peak at 415. This solution is poured into water (500 mL) and the organic solution is extracted with hexane (3×100 mL). The combined organic solutions are washed with brine (2×50 mL) and water (50 mL). After drying over MgSO4, the hexane is evaporated. The crude product is purified by column chromatography and eluted with hexane to yield the target compound (10.1 g, 90.2% yield). 1HNMR (CD2Cl2): δ 7.39 (d, 1H), 7.29 (d, 1H), 2.74 (t, 2H), 1.74-1.33 (m, 16H), 0.89 (t, 3H). 13CNMR: 140.89, 140.63, 136.00, 131.55, 129.22, 126.58, 121.04, 108.89, 32.31, 29.94, 29.73 (overlap), 29.35, 28.49, 23.09, 14.27.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:24]>>[ClH:24].[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CCCCC(CC(=O)OCC)c1ccc2c(c1)CCN2C(C)=O
Agent: Cl
Product: CCCCC(CC(=O)O)c1ccc2c(c1)CCN2
Temperature: 85 °C

Procedure:
A suspension of ethyl (R/S) 3-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-heptanoate [3.95 g, Reference Example 11(b)] in aqueous hydrochloric acid (120 mL, 6M) was heated at 85° C. for 7 hours. After cooling to room temperature the mixture was evaporated. The residue was treated with toluene and the solvent evaporated under reduced pressure (repeated twice more). Final drying in a dessicator afforded the title compound (4.13 g) as an orange-brown oil. LC-MS: RT=3.36 minutes; M (ES+) 248 (MH+).
Reaction SMILES: [CH:1]1([C:8]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:12]=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[Na]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:12][CH2:11][CH:10]([C:8]([CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:30][CH2:29]1
Reactant: O=CCC(C(=O)C1CCCCCC1)c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: [Na]
Product: COc1ccccc1N1CCN(CCC(C(=O)C2CCCCCC2)c2ccccc2)CC1
Yield: 70.3 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-cycloheptanecarbonyl-3-phenylpropionaldehyde (2.52 mmol) and 1-(2-methoxyphenyl)piperazine (2.52 mmol) with sodium triacetoxyboranehydride (3.28 mmol) gave pure product 1-(2-methoxyphenyl)-4-[3-(cycloheptanecarbonyl)-3-(phenyl)propyl]piperazine (770 mg) in 70% yield. The di-hydrochloric acid salt was prepared as described above. m.p.=193-194° C.; MS (m/e): 434 (M+).