Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(O)=[O:2].C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.Cl.[NH2:37][C:38]1[C:46]([NH2:47])=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([NH2:42])=[O:41].C(O)(C)C>N1C=CC=CC=1.CN(C=O)C>[NH2:37][C:38]1[C:39]([C:40](=[O:41])[NH2:42])=[CH:43][CH:44]=[CH:45][C:46]=1[NH:47][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3cccc(C(N)=O)c3N)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-(4-carboxyphenyl)-piperidine-1-carboxylate (1 g) in pyridine (3 mL) and DMF (3 mL) at 40° C. was stirred for 30 minutes, treated with carbonyl diimidazole (CDI, 0.55 g), stirred for 1 hour, treated with 2,3-diaminobenzamide dihydrochloride (synthesized as described in U.S. Pat. No. 6,737,421, 0.73 g), stirred for 1 hour at ambient temperature, treated with isopropanol, (10 mL), cooled for 18 hours at 0° C. and filtered. The filtrant was dissolved in water (10 mL), treated with 50% aqueous NaOH (0.26 mL), stirred for 3 hours at ambient temperature and filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:44][C:45]1[CH:46]=[CH:47][C:48]2[CH2:54][CH2:53][CH2:52][C:51]([C:55]([O:57][CH3:58])=[O:56])=[C:50]([CH3:59])[C:49]=2[CH:60]=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:44][C:45]2[CH:46]=[CH:47][C:48]3[CH2:54][CH2:53][CH2:52][C:51]([C:55]([O:57][CH3:58])=[O:56])=[C:50]([CH3:59])[C:49]=3[CH:60]=2)=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)C1=C(C)c2cc(N)ccc2CCC1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C1=C(C)c2cc(NC(=O)c3ccc(Cl)cn3)ccc2CCC1
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of 5-chloropicolinic acid (354 mg, 2.248 mmol) in dichloromethane (5 mL) was added HATU (940 mg, 2.473 mmol) and DIPEA (0.589 mL, 3.37 mmol). After stirring for 10 min, methyl 2-amino-9-methyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate from preparation J, step J1 (260 mg, 1.124 mmol) was added. The mixture was stirred at rt for 4 h. Ethyl acetate (100 mL) was added and the organic layer was washed with water. After concentration of the organic layer, the residue was purified using silica gel column chromatography (hexanes-100% EtOAc) to give methyl 2-(5-chloropicolinamido)-9-methyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate (345 mg, 0.930 mmol, 83% yield). LCMS (M+H)+=371.3. 1H NMR (400 MHz, chloroform-d) δ 9.84 (s, 1H), 8.56 (dd, J=2.4, 0.6 Hz, 1H), 8.25 (dd, J=8.4, 0.6 Hz, 1H), 7.88 (dd, J=8.4, 2.4 Hz, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.63 (dd, J=8.0, 2.3 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 3.82 (s, 3H), 2.55 (t, J=6.5 Hz, 2H), 2.44 (s, 3H), 2.18-2.08 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([CH3:33])=[C:14](C(OCC)=O)[C:15]=3[NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)(=[O:20])=[O:19])[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].C(O)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([CH3:33])=[CH:14][C:15]=3[NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)(=[O:19])=[O:20])[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2scc(-c3cccc(Br)c3)c2c1NS(=O)(=O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: O=CO
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(Br)c3)csc2n1
Temperature: 150 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
A mixture of ethyl 3-(3-bromophenyl)-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 52) (1.4 g, 2.474 mmol) in DMSO (25 mL) and aqueous NaOH (5M) (1.979 mL, 9.90 mmol) was heated at 150° C. for ca. 1 h. After cooling to RT, the mixture was diluted with water (20 mL) and acidified to ca. pH 4 with formic acid. The mixture was then extracted with ethyl acetate (30 mL×3) and the combined organics dried and concentrated. Water (30 mL) was added to the residue and a yellow precipitate crashed-out which was filtered and rinsed with water (15 mL×3). The yellow solid was dried and subsequently taken-up in diphenyl ether (15.74 mL, 99 mmol) and heated at 200° C. for ca. 1.5 h and then allowed to stand at RT overnight. The mixture was purified by chromatography on silica, eluting with a gradient of 0-100% ethyl acetate in cyclohexane followed by 10% MeOH in DCM, to give the title compound (820 mg). LCMS (A) m/z: 494/496 [M+1]+, Rt 1.31 min (acidic).
Reaction SMILES: [C:1]([CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:3])[CH3:2].[BH4-].[Na+].Cl>CO>[OH:3][CH:1]([CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: COC(=O)C(Cc1ccccc1)C(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Cc1ccccc1)C(C)O
Yield: 99.7 %

Procedure:
Methyl 2-acetyl-3-phenylpropionate (60 g) is dissolved in methanol (300 ml), and thereto is added portionwise sodium boro hydride (2.9 g) with stirring under ice cooling, and the mixture is stirred under ice cooling from 2 hours. The reaction mixture is adjusted to pH 1 with 10% hydrochloric acid, and methanol is distilled off under reduced pressure. The residue is extracted with ethyl acetate. The extract is washed with diluted aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and ethyl acetate is distilled off under reduced pressure to give methyl 2-(1-hydroxyethyl)-3-phenylpropionate (60.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:11]
Reactant: COc1cc2ncnc(N)c2cc1OC
Reactant: O=C=Nc1c(Cl)cccc1Cl
Product: COc1cc2ncnc(NC(=O)Nc3c(Cl)cccc3Cl)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 3, 2,6-dichlorophenyl isocyanate was reacted with 4-amino-6,7-dimethoxyquinazoline (European Patent Application No. 30156, Chemical Abstract volume 95, abstract 187290) to give the title compound; NMR Spectrum: (DMSOd6) 3.96 (s, 3H), 7.31 (m, 2H), 7.38 (t, 1H), 7.5 (d, 2H), 7.6 (d, 2H), 8.43 (s, 1H), 8.7 (s, 1H), 10.61 (s, 1H), 12.09 (s, 1H); Mass Spectrum M+H+ 393 & 395.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][S:4][N:3]=1.[CH3:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C=O)C>[CH3:13][CH:14]1[CH2:19][CH2:18][N:17]([C:2]2[C:6]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[N:5][S:4][N:3]=2)[CH2:16][CH2:15]1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC1CCNCC1
Solvent: CN(C)C=O
Product: CC1CCN(c2nsnc2-c2cccnc2)CC1

Procedure:
A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (10.80 g, 4 mmol) and 4-methylpiperidine (1.96 g, 20 mmol) in DMF (10 ml) was heated at 100° C. for 3 h. After evaporation water was added to the residue and extracted with ether. The combined and dried organic phases were evaporated and the residue purified by column chromatography (SiO2, eluent: ethyl acetate/methylene chloride (1:2)). Yield: 0.8 g (77%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][NH:12]2)=[CH:7][CH:6]=1)=[O:4].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25]>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][N:12]2[S:24]([C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[O:16][CH3:15])(=[O:26])=[O:25])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)NCCC2
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(C)ccc1OC)CCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (23.00 g, 0.12 mol) in dichloromethane (0.70 L) and pyridine (0.10 L) was treated with 2-methoxy-5-methyl-benzenesulfonyl chloride (31.78 g, 0.14 mol) and the mixture stirred at room temperature for 18 hours. The reaction mixture was then washed with 0.5 N HCl (0.40 L), water (2 times 0.40 L) and brine (0.25 L) and the organic phase dried over sodium sulphate and evaporated. The residue was sonicated in ether/dichloromethane 95:5 and the precipitate filtered and dried under vacuum. 1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester was obtained as an off-white solid, 42.05 g (93%), MS (ISP): m/e=376.4 (M+H).
Reaction SMILES: CN(C=O)C.Br[C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[CH:13][CH:14]=2)[N:9]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=2)[CH:8]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=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.O.C(OCC)(=O)C>[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=4)=[CH:13][CH:14]=3)[N:9]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=3)[CH:8]=2)=[CH:45][CH:44]=1
Reactant: CSc1nccc(-n2cc(Br)c3ccc(-c4cccc([N+](=O)[O-])c4)cc32)n1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(-c3ccnc(SC)n3)c3cc(-c4cccc([N+](=O)[O-])c4)ccc23)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
DMF (2 mL) was added to a mixture of 3-bromo-1-(2-(methylthio)pyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (130 mg, 0.295 mmol), K3PO4 (188 mg, 0.885 mmol) and 4-methoxyphenylboronic acid (90 mg, 0.59 mmol) and then the dissolved gas was removed. After adding Pd(PPh3)4 (68 mg, 0.055 mmol), the mixture was stirred at 100° C. for 4 hours. After adding ethyl acetate and water and then filtering using a diatomite pad, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (silica gel, EA:Hx=1:4-1:1). The target compound (96 mg) was obtained as white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:9]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:10]=1[O:11][CH:12]([CH:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])=[O:8].C(O)(=O)C>CN(C=O)C>[CH:17]([C:12]1([C:13]([O:15][CH3:16])=[O:14])[C:7](=[O:8])[C:9]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:10]=2[O:11]1)([CH3:19])[CH3:18]
Reactant: COC(=O)C(Oc1c(C=O)cccc1OC)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C1(C(C)C)Oc2c(OC)cccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
Potassium t-butoxide (5.62 g) was dissolved in DMF (150 ml) and the obtained solution was cooled to 0° C. To this solution, methyl 2-(2-formyl-6-methoxyphenoxy)isovalerate (11.10 g) solution in DMF (50 ml) was added dropwise for 40 minutes, and the resulting solution was stirred for another 30 minutes. Acetic acid (4 ml) was added to the reaction solution and the solution was concentrated. The resultant was poured into water layer (300 ml) and extracted twice with ethyl acetate (150 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the obtained residue was dissolved in dichloromethane (250 ml). To this solution, Celite (70 g) and pyridinium dichromate (23.55 g) were added and the solution was stirred at room temperature for 19 hours. Isopropyl alcohol (20 ml) was added to the reaction solution and the solution was stirred for 15 minutes. Ether (200 ml) was added to the solution and the solution was filtered through Celite, followed by washing the obtained precipitate with ether (100 ml twice). The filtrate was concentrated and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1-3/1) using silica gel to obtain the desired compound (7.26 g, yield: 66%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of 2-(4-cyanophenyl)4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole (2.5 g, 7.3 mmol) [See Ex. 1 above] in THF (50 mL) was added LiAlH4 (7.3 mL of 1M solution in THF, 7.3 mmol), and the resulting mixture was heated at reflux for 2 h, at which time tlc analysis indicated that the reaction was incomplete. Additional LiAlH4 (4.0 mL, 4.0 mmol) was added and heating was continued for 30 min. The mixture was allowed to cool, then poured into 2.5N NaOH and extracted with THF. The organic extract was washed with saturated aqueous NaCl and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 9:1 CHCl3 /MeOH, followed by 90:10:1 CHCl3 /MeOH/NH3. The material that was isolated was triturated with Et2O to afford the title compound (1.5 g, 60%): mp 214°-215° C.
Reaction SMILES: [C:1]([CH:5]([N:10]([C:23](=[O:35])[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([CH3:32])=[C:26]([O:33][CH3:34])[CH:25]=1)[NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH3:21])[CH2:6][CH2:7][CH2:8]C)([CH3:4])([CH3:3])[CH3:2].[C:36](OCC)(=O)C>CCCCCC>[C:1]([CH:5]([N:10]([C:23](=[O:35])[C:24]1[CH:25]=[C:26]([O:33][CH3:34])[C:27]([CH3:32])=[C:28]([O:30][CH3:31])[CH:29]=1)[NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH2:21][CH3:36])[CH2:6][CH2:7][CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(N(NC(=O)c1cccc(OC)c1C)C(=O)c1cc(OC)c(C)c(OC)c1)C(C)(C)C
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC(N(NC(=O)c1cccc(OC)c1CC)C(=O)c1cc(OC)c(C)c(OC)c1)C(C)(C)C

Procedure:
RG-115852, 3,5-dimethoxy-4-methyl-benzoic acid N-(1-tert-butyl-pentyl)-N′-(3-methoxy-2-methyl-benzoyl)-hydrazide. 1H NMR (CDCl3, 500 MHz), δ (ppm): 7.05 (t, 1H), 7.0 (s, 1H), 6.85 (d, 1H), 6.65 (s, 2H), 6.25 (d, 1H), 4.7 (d, 1H), 3.89 (s, 3H), 3.78 (s, 6H), 2.10 (s, 3H), 1.86 (s, 3H), 1.3-1.6 (br m, 6H), 1.06, 0.99 (2s, 9H), 0.94 (t, 3H); TLC Rf=0.55 (1:1 ethyl acetate:hexane).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>CN(C=O)C>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][C:17]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[C:14]=2[C:15]#[N:16])=[CH:6][CH:5]=1
Reactant: N#Cc1c(F)cccc1F
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a cold (ice water) suspension of sodium hydride (316 mg; 7.9 mmol) in anhydrous DMF (10 mL) is added a solution of 4-bromobenzyl alcohol (1.48 g; 7.9 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 30 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1 g; 7.2 mmol) in anhydrous DMF (15 mL), and allowed to room temperature over 3 hours. The reaction mixture is poured into ice water with vigorous stirring and refrigerated overnight. The resulting precipitate is removed by filtration and dried under vacuum at 30° C. overnight to give 1.82 grams 2-(4-bromobenzyloxy)-6-fluorobenzonitrile.
Reaction SMILES: C([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25]/[CH:26]=[C:27](\[CH3:34])/[CH2:28][CH2:29][C:30]([O:32]C)=[O:31])C.[OH-:35].[Li+]>CO>[OH:35][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Product: CC(=CCc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2)CCC(=O)O

Procedure:
A solution of methyl (E) 6-(1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-toluenesulfonyloxylisobenzofuran-5-yl)-4-methyl-4-hexenoate (3.16 g) and lithium hydroxide (1.2 g) in 1:1 aqueous methanol (40 ml) was heated at 62° C. for 18 hours. The solution was acidified and extracted with ethyl acetate. The extract was dried and evaporated and the residue chromatographed on silica gel, eluting wth ethyl acetate/hexane/acetic acid to afford (E) 6-(1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, m.p. 141°-142° C. (t-butylmethylether).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:23][C:9]2[C:10]3[CH2:11][CH2:12][N:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:15][C:16]=3[S:17][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[K+]>CCO>[CH2:21]([O:20][C:18]([N:13]1[CH2:12][CH2:11][C:10]2[C:9]3[NH:23][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=3[S:17][C:16]=2[CH2:15][CH2:14]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cc2sc3c(c2[nH]1)CCN(C(=O)OCC)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1CCc2sc3cc(C(=O)O)[nH]c3c2CC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 94.8 %

Procedure:
To a stirred solution of the product from step (e) (3.45 g, 10.26 mmol) in EtOH (120 ml) was added 2M KOH (50 ml). The reaction mixture was heated to 50° C. for 6 hours and then allowed to cool to RT. The reaction mixture was then stirred at RT for an additional 12 hours. The MeOH was then evaporated in vacuo and the remaining aqueous mixture was diluted with additional water (50 ml). The aqueous mixture was washed with EtOAc (2×). The aqueous mixture was then acidified with 2M HCl to pH 2 and extracted with DCM (3×). The combined DCM extracts were dried (Na2SO4), decanted, and solvent evaporated in vacuo to give the sub-titled compound as a tan solid (3.0 g) that was used without further purification. MS: ESI (positive): 308 (M+H), ESI (negative): 307 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]2[CH:12]([NH:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([NH2:26])[CH:22]=4)[N:17]=3)[CH2:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]2[CH:12]([NH:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([NH:26][C:35](=[O:36])[CH2:34][N:31]5[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]5)[CH:22]=4)[N:17]=3)[CH2:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COCCOc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CO2
Reactant: CN1CCN(CC(=O)O)CC1
Product: COCCOc1cccc2c1C(Nc1ccc3cc(NC(=O)CN4CCN(C)CC4)ccc3n1)CO2

Procedure:
The title compound was prepared from rac-N2-[4-(2-methoxy-ethoxy)-2,3-dihydro-benzofuran-3-yl]-quinoline-2,6-diamine (Example 174) (200 mg, 0.4 mmol) and commercially available (4-methyl-piperazin-1-yl)-acetic acid (68 mg, 0.6 mmol) in accordance with the general method 14 described in example 119 and was obtained as an off-white solid (160 mg, 76%); MS: m/e=492.3 (M+H+).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>[OH-].[K+].C(O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])=[CH:23][CH:22]=1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc(Br)cc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 80.2 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.40 g, 1.6 mmol) was reacted with 4-bromobenzaldehyde (0.433 g, 2.3 mmol) in 2 mL of 4% KOH in ethanol to afford 0.543 g (81%) of the title compound as a coarse white solid, mp 152-153° C.: CI-MS m/e 423, 425 (M+);
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([C:7]([NH:9][NH:10][C:11](=[O:30])[C@H:12]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[C:18]=2[CH3:29])[C@@H:13]([OH:15])[CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:33][C:34]([Si:37](Cl)([CH3:39])[CH3:38])([CH3:36])[CH3:35].N1C=CN=C1>CN(C=O)C>[Si:37]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[C:18]=1[CH3:29])[C:11]([NH:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:32][CH:31]=1)=[O:30])([C:34]([CH3:36])([CH3:35])[CH3:33])([CH3:39])[CH3:38]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O)ccc(C#N)c1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
The crude material 4-cyano-N′-((2R,3S)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxybutanoyl)benzohydrazide (507 mg, 1.14 mmol) was added to DMF (30 mL), followed by addition of TBDMS-Cl (686 mg, 4.55 mmol) and imidazole (619 mg, 9.10 mmol) at 0° C. The solution was allowed to stir at 0° C. for 30 min and then at room temperature for overnight. The reaction was quenched with the addition of 200 mL brine and extracted with EtOAc. The resulting crude material was chromatographed to give the desired product (390 mg)1H NMR(400 MHz, acetone-d6, δ in ppm): 9.6 (br s), 7.92 (d, J=9 Hz, 2H), 7.8 (d, J=9 Hz, 2H), 7.56 (d, J=9 Hz, 1H), 6.92 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.51 (m, 1H), 4.16 (m, 1H), 2.25 (m, 3H), 1.24 (d, J=6 Hz, 3H), 0.82 (s, 9H), 0.05 (s, 6H), 0.00 (s, 3H).