Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[C:17]([C:18]([OH:20])=O)=[C:16]([N+:24]([O-:26])=[O:25])[C:15]=1[OH:27].[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>C1COCC1.CN(C=O)C>[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[C:17]([C:18]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([F:28])=[CH:30][CH:31]=2)=[O:20])=[C:16]([N+:24]([O-:26])=[O:25])[C:15]=1[OH:27]
Reactant: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Reactant: Nc1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Reaction time: 0.67 h
Yield: 65.2 %

Procedure:
CDI (2.2 g, 0.013 mol) was added to a stirred solution of 4,6-dichloro-3-hydroxy-2-nitrobenzoic acid (3.0 g, 0.012 mol) in anhydrous THF (30 mL) and DMF (2 mL). After 40 min, 4-fluoroaniline (4 mL, 0.042 mol) was added. The solution was heated under reflux overnight, cooled, and concentrated to a dark brown viscous oil. The oil was purified via SiO2-gel chromatography (dichloromethane/methanol, 19:1-9:1) to yield 4,6-dichloro-N-(4-fluorophenyl)-3-hydroxy-2-nitrobenzamide as a light brown oil (2.7 g, 65%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27](C)[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC(C(F)(F)F)=C([Cl:47])C=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([Cl:47])[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1C(F)(F)F
Reactant: FC(F)(F)c1ccc(Br)cc1Cl
Product: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1Cl
Yield: 98 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-((3-methyl-4-(trifluoromethyl)-phenyl)ethynyl)pyridazine (Intermediate 74) using 4-bromo-2-chloro-1-(trifluoro-methyl)benzene in 98% yield.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][C:12]2([C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH3:24])[CH:21]=3)[C:16](=[O:25])[O:15]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[C].[Pd]>[ClH:1].[CH2:23]([C:20]1[CH:21]=[C:22]2[C:17]([C:16](=[O:25])[O:15][C:12]32[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)=[CH:18][CH:19]=1)[CH3:24]
Reactant: CCc1ccc2c(c1)C1(CCN(Cc3ccccc3)CC1)OC2=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCc1ccc2c(c1)C1(CCNCC1)OC2=O
Reaction time: 1.5 h
Yield: 74.2 %

Procedure:
1′-benzyl-6-ethylspiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride(400 mg) was dissolved in methanol (10 mL) and 10% palladium carbon was added. The mixture was stirred under a hydrogen atmosphere for 1.5 hours. After the palladium carbon was removed by filtration, the filtrate was concentrated to give a residue, which was subjected to crystallization with methanol-ethyl ether to give the subject compound (222 mg).
Reaction SMILES: CC1NC(=O)C2C(=CC3CCC(N([C:20]4[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=4)CC#C)C=3C=2)N=1.FC(F)(F)C(O[C:34]1[C:39]([F:40])=[C:38]([F:41])[C:37]([F:42])=[C:36]([F:43])[C:35]=1[F:44])=O>>[N:24]1[CH:25]=[CH:20][CH:21]=[CH:22][C:23]=1[C:26]([O:28][C:34]1[C:35]([F:44])=[C:36]([F:43])[C:37]([F:42])=[C:38]([F:41])[C:39]=1[F:40])=[O:27]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: C#CCN(c1ccc(C(=O)O)nc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccn1
Yield: 98 %

Procedure:
Using analogous procedures to those described in Example 12, 5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridine-2-carboxylic acid was reacted with pentafluorophenyl trifluoroacetate to give the pentafluorophenyl pyridine-2-carboxylate which was in turn reacted with tri-tert-butyl L-γ-glutamyl-D-glutamate (European Patent Application No. 0509643, Example 1 thereof) to give tri-tert-butyl N-{5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridyl-2-carbonyl -L-γ-glutamyl-D-glutamate in 98% yield which was in turn hydrolysed with aqueous sodium hydroxide solution to give N-{5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridyl-2-carbonyl}-L-γ-glutamyl-D-glutamic acid in 68% yield, m.p. 196° C.;
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([O:16]CC3C=CC=CC=3)[CH:13]=[C:12]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:11]=2)=[N:4]1)[CH3:2]>[Pd].C1COCC1.C(O)C>[CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:11]=[C:12]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:13]=[C:14]([OH:16])[CH:15]=2)=[N:4]1)[CH3:2]
Reactant: CCn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)COC)c2)n1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCn1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)COC)c2)n1
Reaction time: 16 h

Procedure:
10% Palladium on carbon (1.9 g, 50% wet) was added under argon to N-(1-ethyl-1H-pyrazol-3-yl)-3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzamide (19.1 g, 46.7 mmol) in dry THF (100 mL) and ethanol (100 mL). The reaction mixture was degassed, placed under a hydrogen balloon and stirred for 16 hours. The mixture was filtered through diatomaceous earth and the filtrate was evaporated to give a brown oil. The residue was purified by column chromatography on silica, eluting with 40-65% ethyl acetate in hexanes, to give the desired product as a clear oil which crystallised on standing (11.35 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:42])[CH2:10][C:11]1[CH:41]=[CH:40][CH:39]=[CH:38][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:37]=[CH:36][C:26]([CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:25][CH:24]=2)[N:16]=1>C(Cl)Cl>[NH2:28][CH2:27][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:17]2[N:16]=[C:15]([CH2:14][CH2:13][C:12]3[CH:38]=[CH:39][CH:40]=[CH:41][C:11]=3[CH2:10][C:9]([NH2:8])=[O:42])[C:20]([CH3:21])=[CH:19][N:18]=2)=[CH:37][CH:36]=1
Reactant: Cc1cnc(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(CN)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl 4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)benzylcarbamate (A114) (0.043 g, 0.090 mmol) in DCM (3 mL) and the resulting solution stirred at room temperature for 4 hours. The volatiles were removed in vacuo then 2 M aqueous K2CO3 (5 mL) and water (15 mL) were added to the residue. The resulting suspension was sonicated for 1 minute, filtered and the filter cake dried to give the title compound 27 as a light tan solid (0.028 g, 82%); 1H NMR (300 MHz, d6-DMSO) δ 9.30 (s, 1H), 8.16 (s, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.43 (s, 1H), 7.12-7.27 (m, 6H), 6.93 (s, 1H), 3.64 (s, 2H), 3.49 (s, 2H), 3.34 (brs, 2H), 3.02-3.07 (m, 2H), 2.85-2.90 (m, 2H), 2.06 (s, 3H). LCMS-B: rt 4.666 min; m/z 376 [M+H]+.
Reaction SMILES: C[O:2][CH:3]1[CH:7]([CH:8]=O)[CH2:6][CH:5](OC)O1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH:3]([C:7]1[CH:6]=[CH:5][N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:15][CH:14]=2)[CH:8]=1)=[O:2]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: COC1CC(C=O)C(OC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(C=O)c2)cc1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
A solution of 33.6 g (210 millimoles) of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde in 200 ml of glacial acetic acid was added dropwise to 40.6 g (200 millimoles) of 6-(4-aminophenyl)-4,5-dihydro-5-methylpyridazinone in 400 ml of glacial acetic acid at 80° C. After 2 hours, the reaction mixture was poured into saturated NaHCO3 solution and extracted with CH2Cl2. The extract was washed with water and saturated NaCl solution and dried over Na2SO4, the solvent was stripped off in a rotary evaporator, and the residue was then recrystallized from dimethylformamide (DMF)/water. 44.2 g of 6-[p-(3-formylpyrrol-1-yl)-phenyl]-4,5-dihydro-5-methylpyridazinone of melting point 191°-192° C. were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]([N:9]=[C:10]=[S:11])[CH:8]=1)#[N:2].[NH3:18]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]([NH:9][C:10]([NH2:18])=[S:11])[CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCOCC2)c(N=C=S)c1
Reactant: N
Solvent: CCO
Product: N#Cc1ccc(N2CCOCC2)c(NC(N)=S)c1

Procedure:
Reaction of 5-cyano-2-morpholinophenyl isothiocyanate (2.5 g) in ethanol (10 ml) with 25% aqueous ammonia solution (1 ml) at room temperature for 3 hours gave 1-(5-cyano-2-morpholinophenyl)thiourea (m.p. 193°-194° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:35])[CH2:9][CH2:10][CH2:11][N:12]([CH3:34])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27](OC(C)(C)C)=[O:28])=[CH:17][CH:16]=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(Cl)(=O)C(C)(C)C.[C:72]1([C:92]2[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=2)[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[NH:78][C:79](=[O:91])[O:80][CH:81]1[CH2:86][CH2:85][N:84]([CH2:87][CH2:88][NH:89][CH3:90])[CH2:83][CH2:82]1>C(Cl)Cl>[C:72]1([C:92]2[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=2)[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[NH:78][C:79](=[O:91])[O:80][CH:81]1[CH2:86][CH2:85][N:84]([CH2:87][CH2:88][N:89]([C:27](=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22][NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:13](=[O:14])[N:12]([CH2:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:35])[CH3:34])=[CH:16][CH:17]=2)[CH3:90])[CH2:83][CH2:82]1
Reactant: CN(CCCN(C)C(=O)c1ccc(NCCOCCC(=O)OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCOCCNc1ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 66.6 %

Procedure:
The compound (188 mg, 0.381 mmol) obtained in Example 28e was dissolved in methylene chloride (4 mL), trifluoroacetic acid (2 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. The solvent was evaporated under reduced pressure, and moisture was removed from the resulting residue azeotropically with toluene (×2). The resulting residue was dissolved in methylene chloride (4 mL), triethylamine (0.318 mL, 2.29 mmol) and di-tert-butyl dicarbonate (183 mg, 0.838 mmol) were added, and the mixture was stirred at room temperature for 18.5 hours. The solvent was evaporated under reduced pressure, the resulting residue was dissolved in methylene chloride (4 mL), triethylamine (79 μL, 0.572 mmol) and pivaloyl chloride (49 μL, 0.400 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 20 minutes. 1-[2-(Methylamino)ethyl]piperidin-4-yl biphenyl-2-ylcarbamate (296 mg, 0.838 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=50:1, v/v) to give the title compound (196 mg; yield, 66%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[N:40]1([CH2:44][C@@H:45]([NH:49][CH3:50])[CH2:46][CH2:47]C)[CH2:43][CH2:42][CH2:41]1>CN(C=O)C>[N:40]1([CH2:44][C@@H:45]([N:49]([CH3:50])[C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:46]([CH3:47])[CH3:11])[CH2:41][CH2:42][CH2:43]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCC[C@@H](CN1CCC1)NC
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@@H](CN1CCC1)N(C)C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
4-Chlorobenzoic acid (1.300 mL, 12.80 mmol) and TBTU (4.31 g, 13.44 mmol) was mixed in DMF (35 mL). The mixture was cooled to 0° C. and NMM (1.689 mL, 15.36 mmol) was dropwise added. After 10 min at 0° C. was (S)-1-(azetidin-1-yl)-N-methylpentan-2-amine (Compound J1) (2 g, 12.80 mmol) added. The resultant mixture was stirred at 0° C. for 30 min and at rt for 16 h. The mixture was concentrated and the residue dissolved in DCM (25 mL). The organic phase was washed with NaHCO3 (saturated, 2×50 mL), and brine (50 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (2.49 g, 66%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:39]=[CH:38][C:18]3[NH:19][C:20]([C:22]4[C:26]([NH:27][C:28](=[O:37])[C:29]5[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=5[F:36])=[CH:25][NH:24][N:23]=4)=[N:21][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOC(C)=O>CO>[F:35][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([F:36])[C:29]=1[C:28]([NH:27][C:26]1[C:22]([C:20]2[NH:19][C:18]3[CH:38]=[CH:39][C:15]([CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:16][C:17]=3[N:21]=2)=[N:23][NH:24][CH:25]=1)=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3[nH]c(-c4n[nH]cc4NC(=O)c4c(F)cccc4F)nc3c2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCNCC3)ccc2[nH]1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.7 %

Procedure:
A mixture of 4-{2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazol-5-ylmethyl}-piperazine-1-carboxylic acid tert-butyl ester (84 mg), MeOH (3 mL) and saturated HCl/EtOAc (3 mL) was stirred at r.t. for 16 h and then reduced in vacuo azeotroping with toluene to give the title compound (21 mg) as a yellow solid. (LC/MS: Rt 1.60, [M+H]+ 438.09).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20]>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:11]1(=[O:20])[N:10]([CH2:9][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]12
Reactant: Oc1ccccn1
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1COc1ccccn1
Temperature: 80 °C
Reaction time: 14 h
Yield: 39.3 %

Procedure:
In 4 ml of benzene were suspended 0.095 g (1.0 mmol) of 2-hydroxypyridine and 0.14 g (0.5 mmol) of silver carbonate, N-bromomethylphthalimide [0.29 g (1.2 mmol)] was added at room temperature, and the mixture was stirred at 80° C. for 14 hours under heating. After cooling, the residue was filtered and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/hexane=10:1) to obtain powder. The powder was recrystallized from ethyl acetate to obtain 0.10 g of the desired compound (yield: 39.0%, colorless columns).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([CH:20]=O)[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[CH:35]([NH2:38])([CH3:37])[CH3:36].CC(O)=O.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([CH2:20][NH:38][CH:35]([CH3:37])[CH3:36])[CH2:16][CH2:15]2)=[O:7])=[CH:33][CH:34]=1
Reactant: O=C[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCCCC4)cc32)CC1
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NC[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCCCC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 12.2 %

Procedure:
A suspension of (E)-4-fluoro-N-(1-(cis-4-formylcyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (75 mg, 0.162 mmol) in MeOH (3.2 mL) was cooled to 0° C. under nitrogen atmosphere. To this mixture was added isopropylamine (0.208 mL, 2.432 mmol) followed by AcOH (0.056 mL, 0.973 mmol). The resulting mixture was stirred for 15 minutes. Solid sodium cyanoborohydride (15.28 mg, 0.243 mmol) was added in one portion, and the resulting mixture was stirred for 18 hours at RT. The reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with DCM (30 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (10-30% of 90/10/1 DCM/MeOH/NH4OH in DCM) to afford (E)-4-fluoro-N-(1-(cis-4-((isopropylamino)methyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (10 mg, 12.20% yield). MS m/z=506.2 [M+H]. Calc'd for C30H40FN5O: 505.3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Oc1ccc(-c2ccc(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Yield: 63.4 %

Procedure:
1-Bromomethyl-3-nitro-benzene (110 mg, 0.508 mmol), 2′,4′-difluoro-biphenyl-4-ol (110 mg, 0.533 mmol), and dried, finely ground potassium carbonate (74 mg, 0.533 mmol) in 10 mL acetone were refluxed under argon for 20 hrs. The reaction mixture was cooled, filtered, concentrated and re-dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated NaHCO3, dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography with a gradient of 0-20% ethyl acetate in hexanes to yield 0.11 g (63%) of 2,4-difluoro-4′-(3-nitro-benzyloxy)-biphenyl. LC-MS (ES) calculated for C19H13F2NO3, 341.32; found m/z 340.3 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30][CH:31]3CCOC3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].C(CC(NN)=O)#[N:37].O1CCC(CC(NN)=O)C1>>[C:31]([CH2:30][C:28]1[NH:29][C:25]([C:21]2[C:22]([CH3:24])=[CH:23][C:2]([CH3:1])=[C:3]([CH:20]=2)[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:10][CH2:11]2)=[O:5])=[N:26][N:27]=1)#[N:37]
Reactant: N#CCC(=O)NN
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: NNC(=O)CC1CCOC1
Product: Cc1cc(C)c(-c2nnc(CC#N)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using 2-cyanoacetohydrazide (compound 139.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 425 (M+H)+. 1H-NMR (300 Hz, CD3OD): δ 7.70 (d, J=8.4 Hz, 2H), 7.54-7.42 (m, 3H), 7.35 (s, 1H), 4.87-4.80 (m, 1H), 4.12 (s, 2H), 3.77-3.65 (m, 1H), 3.27-3.23 (m, 1H), 3.09-2.99 (m, 2H), 2.55 (s, 3H), 2.43 and 2.33 (2 singlets, amide rotamers, ArCH3, 3H), 2.05-2.00 (m, 1H), 1.83-1.76 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[C:6]([F:15])[C:3]=1[CH2:4][OH:5].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[C@H:25]([CH2:32][CH3:33])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[C:6]([F:15])[C:3]=1[CH2:4][O:5][C:29]([N:26]1[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][C@H:25]1[CH2:32][CH3:33])=[O:30]
Reactant: COCCOc1cc(F)c(CO)c(Cl)c1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)cc(OCCOC)cc1Cl
Yield: 89 %

Procedure:
This compound was prepared from 2-chloro-6-fluoro-4-(2-methoxy-ethoxy)-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (370 mg; 89%); MS (ISP): 492.3 (M+NH4)+.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:21][CH:20]=1)[CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][C:8]=1[CH3:9].[H][H]>O1CCOCC1.[Pd]>[CH3:1][N:2]([CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:23][CH:24]=1)[CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:7][C:8]=1[CH3:9]
Reactant: Cc1oc(-c2ccccc2)nc1CN(C)CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccccc2)nc1CN(C)CCOc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 99.6 %

Procedure:
5-[4-[2-[N-methyl-N-(5-methyl-2-phenyl-4-oxazolyl)methylamino]ethoxy]phenyl methylene]thiazolidine-2,4-dione (2.5 g) obtained in example 18, was dissolved in dry 1,4-dioxane (100 ml) and was reduced with hydrogen (50 psig) in the presence of 10% palladium on charcoal (2.5 g) at ambient temperature until hydrogen uptake ceased. The solution was filtered through a bed of celite, the filter pad was washed exhaustively with dioxane and the combined filtrate was evaporated to dryness under reduced pressure to afford 2.5 g of the title compound after crystallisation from a mixture of benzene and petroleum ether.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[CH3:13][O:11][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc2[nH]ccc2c1
Reaction time: 0.75 h

Procedure:
To a solution of 1H-indole-5-carboxylic acid (5 g, 31.0 mmol) in 70% methanol/methylene chloride (105 mL) at 0° C. was added 1M trimethylsilyldiazomethane in hexanes (46 mL, 46 mmol). After 45 min., the reaction mixture was concentrated to afford 1H-indole-5-carboxylic acid methyl ester (5.2 g).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([N:12]=[N:13][C:14](Cl)([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])([CH3:11])([CH3:10])[CH3:9]>CCOCC>[C:8]([N:12]=[N:13][C:14]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)CC(C)(Cl)N=NC(C)(C)C
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Product: CC(C)CC(C)(N=NC(C)(C)C)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a clean, dry 250 ml. round bottom 4 neck flask equipped with a magnetic stirrer, thermometer, condenser and addition funnel,, which was being purged with nitrogen was added an ether solution containing 0.06 moles of phenyllithium. The solution was cooled to 5° C and a solution of 10.25 g. (0.05 moles) of 2-t-butylazo-2-chloro-4-methylpentane in 50 ml. ether was added dropwise over 1/2 hour. After the addition was complete, the reaction was warmed to 20° C. and stirred for 1/2 hour. The excess phenyllithium was destroyed with wet ether and the reaction mixture poured into 200 ml. water. The ether layer was separated, dried over anhydrous sodium sulfate, filtered and the ether removed on a rotating evaporator leaving 11.9 g. (96%) of a liquid. The infrared spectrum was in agreement with the structure of the title compound.