Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[CH3:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Product: Cc1cccc(CC(=O)Nn2nc(S(=O)(=O)c3ccccc3)c3ccccc3c2=O)c1

Procedure:
The product from Example 68B and 2-(3-methylphenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (s, 1H), 8.54-8.57 (m, 1H), 8.37-8.40 (m, 1H), 8.08-8.13 (m, 1H), 7.98-8.03 (m, 3H), 7.78-7.83 (m, 1H), 7.66-7.70 (m, 2H), 7.23 (t, J=7.5
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[I:10]I.[OH-].[K+]>CN(C=O)C>[I:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][N:2]=1
Reactant: c1cnc2[nH]ncc2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 1H-pyrazolo[3,4-b]pyridine (500.0 mg, 4.2 mmol, 1 equiv) in DMF (10 mL) at 0° C., was added iodine (2.13 g, 8.4 mmol, 2 equiv) and potassium hydroxide (943 mg, 16.8 mmol, 4 equiv). The resultant mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction solution was slowly quenched with saturated sodium thiosulfate (Na2S2O5) solution (10 mL), and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (3×50 mL), brined (50 mL), dried over sodium sulfate and concentrated in vacuo to give 3-Iodo-1H-pyrazolo[3,4-b]pyridine (1.02 g) as a yellow powder which was used without further purification: LCMS (ES) M+H 246.2, Rf 2.17 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid /5% acetonitrile /94.9% water, B=0.1% formic acid /5% water/94.9% acetonitrile).
Reaction SMILES: C([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].N(CCO)(CCO)CCO.C(OCC)(=O)C>C(O)C>[OH:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C=CC(C)=CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCN(CCO)CCO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C=CC(C)=CCO
Yield: 71.2 %

Procedure:
27.5 g of ethyl 6-acetoxy-4-methyl-2,4-hexadienoate, 20 g of sodium carbonate and 2 ml of triethanolamine were heated to reflux for 3 hours in 250 ml of ethanol. After the addition of ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Distillation at 110° C./0.4 mmHg gave 15.7 g (71%) of ethyl 6-hydroxy-4-methyl-2,4-hexadienoate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]([F:16])([F:15])[C:12](O)=O>C(Cl)Cl>[Br:8][C:7]1[C:2]2[N:1]=[C:12]([C:11]([F:16])([F:15])[F:10])[O:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1c(O)cccc1Br
Solvent: ClCCl
Product: FC(F)(F)c1nc2c(Br)cccc2o1
Temperature: 120 °C
Yield: 15.9 %

Procedure:
A solution of 2-amino-3-bromophenol (480 mg, 2.6 mmol), polyphosphoric ester (PPE, 3.4 g) and trifluoroacetic acid (0.88 mL, 11.5 mmol) was heated to 100° C. under a nitrogen atmosphere overnight. A reflux condenser was added as was fresh PPE and the reaction heated to 120° C. for 8 hr. The reaction was cooled and diluted with methylene chloride. The solvent was removed by rotoevaporation. The residue was dissolved in fresh methylene chloride and successively washed with 2N sodium hydroxide solution and saturated salt solution. After drying over anhydrous magnesium sulfate and filtering, the solvent was removed by rotoevaporation. The residue was purified by flash column chromatography in silica gel eluted with 15% acetone in hexanes to yield the title compound (110 mg, 16% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[N:7]([CH2:11][C@H:12]1[C@@H:16]([CH2:17][N:18]([CH:31]([CH3:33])[CH3:32])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:15][N:14]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:13]1)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].SCCO.C1CCN2C(=NCCC2)CC1>CC#N>[C:1]([O:5][C:6](=[O:41])[N:7]([CH2:11][C@H:12]1[C@@H:16]([CH2:17][NH:18][CH:31]([CH3:33])[CH3:32])[CH2:15][N:14]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:13]1)[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)N(C[C@@H]1CN(Cc2ccccc2)C[C@@H]1CN(C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: OCCS
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)NC[C@H]1CN(Cc2ccccc2)C[C@H]1CN(C(=O)OC(C)(C)C)C(C)C

Procedure:
A solution of ((3S*,4R*)-1-benzyl-4-{[isopropyl-(2-nitro-benzenesulfonyl)-amino]-methyl}-pyrrolidin-3-ylmethyl)-isopropyl-carbamic acid tert-butyl ester (8.9 g, 23.02 mmol), 2-mercaptoethanol (0.81 mL, 11.60 mmol), and DBU (0.79 mL, 5.27 mmol) in CH3CN (10 mL) is stirred for 2 h at room temperature. The mixture is concentrated and then diluted with Et2O and H2O. The organic layer is separated, and the aqueous phase is extracted 3 times with Et2O. The combined organic extracts are dried (MgSO4), and the solvent is concentrated to give the title compound which is used without further purification in the next step. TLC, Rf (AcOEt)=0.61. MS (LC-MS): 404.3 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.45 min.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[S:40][C:39]([C:41]([O:43]CC)=[O:42])=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[S:40][C:39]([C:41]([OH:43])=[O:42])=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C(=O)O)s3)oc2C)c(OC)c1)OCC
Yield: 25.8 %

Procedure:
To a mixture of ethyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]thiophene-2-carboxylate (1.05 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was heated under reflux for 30 min. To the reaction mixture were added 1N hydrochloric acid (5 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]thiophene-2-carboxylic acid as colorless crystals (0.26 g, yield 25%) from a fraction eluted with ethyl acetate-methanol (6:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point: 165-166° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH2:13][CH:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1.C(N(CC)CC)C.CS(C)=O>O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:13][CH:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(NC2CN(C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Temperature: 95 °C
Yield: 116.6 %

Procedure:
Into a 100 mL 3-Neck round-bottomed flask equipped with reflux condenser were charged 4-fluoro-2-methoxy-1-nitrobenzene (4.086 g) and tert-butyl 3-aminoazetidine-1-carboxylate (4.4 g), triethylamine (9.6 mL), and dimethyl sulfoxide (20 mL). The reaction mixture was heated at 95° C. for 8 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine (50 mL×2), dried over sodium sulfate, and concentrated completely under reduced pressure at 40° C. to give the title compound (9 g) which was used without further purification.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=O)([O:41][CH3:42])=[O:40].O>O1CCCC1>[CH3:42][O:41][C:39](=[O:40])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:28][CH:27]=1
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)CCCCCCCC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCCCCCC=Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 12.8 %

Procedure:
To a solution of 18.2 g (43 mmol) of 4-chlorobenzyltriphenylphosphonium chloride in 200 mL of dry tetrahydrofuran at -78° C. is added dropwise, 30.7 mL (43 mmol) of a 1.4M solution of potassium hexamethyldisilazide in tetrahydrofuran. This is allowed to stir for 1 hour when 8.0 g (43 mmol) of 8-carbomethoxyoctanal is added dropwise. The solution is stirred at -78° C. for 2 hours, allowed to warm to room temperature, and stirred for 2 days. The reaction is worked up by adding water and extracting three times with diethyl ether. The ether extracts are combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow solid. Pad filtration through flash silica gel eluting with 10% ethyl acetate/hexane, gives a yellow oil after concentration in vacuo. Flash chromatography on a 60 mm×150 mm silica column eluting with 5% ethyl acetate/hexane gives 1.62 g (13%) of 10-(4-chlorophenyl)-dec-9-enoic acid methyl ester as a mixture of E and Z isomers.
Reaction SMILES: C(OC[Li])C.C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C.[CH2:26]([O:28][CH2:29]Cl)[CH3:27].[Br:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[C:40]([CH:49]=[O:50])=[CH:41][C:42]3[NH:46][CH:45]=[N:44][C:43]=3[C:47]=2[F:48])=[C:34]([Cl:51])[CH:33]=1>C1COCC1>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[C:40]([CH:49]([OH:50])[CH2:29][O:28][CH2:26][CH3:27])=[CH:41][C:42]3[NH:46][CH:45]=[N:44][C:43]=3[C:47]=2[F:48])=[C:34]([Cl:51])[CH:33]=1
Reactant: CCOCCl
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: [Li]COCC
Solvent: C1CCOC1
Product: CCOCC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a solution of lithiomethyl ethyl ether in THF (6 mL) (prepared from 4,4′-di-tert-butylbiphenyl (585 mg, 2.20 mmol), Li (18 mg, 2.59 mmol), and EtOCH2Cl (0.20 mL, 2.05 mmol) by the procedure reported in Tetrahedron 1996, 52, 1643) is added a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f (29 mg, 0.080 mmol) in THF (1 mL) at −78° C. The resulting solution is stirred for 1 hour and then quenched with saturated aqueous NH4Cl at −78° C., warmed to room temperature, and extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (100% CH2Cl2 to 3% to 5% MeOH in CH2Cl2) to give the desired product (15 mg, 44%): MS APCI (+) m/z 428, 430 (M+, Br pattern) detected.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:10]2[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=O)=O.[C:39](#[N:45])[CH2:40][CH2:41][CH2:42][C:43]#[CH:44].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C.[Cu](I)I>[C:39]([CH2:40][CH2:41][CH2:42][C:43]#[C:44][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:11]([CH2:21][NH:22][C:23](=[O:24])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[C:10]2[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)#[N:45]
Reactant: C#CCCCC#N
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OS(=O)(=O)C(F)(F)F)cc23)cc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(C#CCCCC#N)cc23)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
To a solution of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl trifluoromethanesulfonate (3.03 g, 6.13 mmol), copper iodide (176 mg, 0.920 mmol) and hex-5-ynenitrile (2.86 g, 30.7 mmol) in tetrahydrofuran (30 ml)-triethylamine (10 ml) was added dichlorobistriphenylphosphinepalladium (431 mg, 0.613 mmol), and the mixture was stirred under an argon atmosphere at 80° C. for 10 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give black crystals. The crystals were recrystallized from ethyl acetate-n-hexane to give tert-butyl {[6-(5-cyanopent-1-yn-1-yl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.56 g, yield 84%) as white crystals. Subsequently, tert-butyl {[6-(5-cyanopent-1-yn-1-yl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.56 g, 5.17 mmol) and 10% palladium-carbon (550 mg) were suspended in a mixed solvent of ethanol (200 ml)-tetrahydrofuran (35 ml) and the mixture was stirred under a hydrogen atmosphere at room temperature for 3.5 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl {[6-(5-cyanopentyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.37 g, yield 92%) as white crystals.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S([O-])(=O)=O)=[CH:3][CH:2]=1.[NH2:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15].C[Si](C)(C)N[Si](C)(C)C.C(N(C(C)C)CC)(C)C.[Br-:38]>C(Cl)Cl>[Br:38][C:4]1[CH:5]=[CH:6][C:1]([CH2:11][NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=[CH:2][CH:3]=1
Reactant: [Br-]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NCc1ccc(Br)cc1)C(=O)O
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a suspension of 10 g (34.6 mmol) of p-toluenesulphonate of L-valine in 100 mL of CH2Cl2 is added at 20-25° C. and under nitrogen atmosphere 8.0 mL (38 mmol) of 1,1,1,3,3,3-hexamethyldisilazane. After shaking the mixture at 20-25° C. for one hour, 13.2 mL (76 mmol) of diisopropylethylamine and 8.64 g (34.6 mmol) of 4-bromobenzylo bromide are added and heated at reflux. When all the 4-bromobenzylo bromide has been consumed, the solvent is evaporated off at low pressure, 100 mL of water is added and after 1 h at 0° C. the solid is filtered and dried in an air oven at 40° C. to provide 8.8 g (89%) of N-(4-bromobenzyl)-L-valine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH2:47][CH3:48])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH2:47][CH3:48])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K23) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (422 mg, 90%).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].ON1C2C=CC=CC=2N=N1.[CH3:17][N:18]([CH2:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]3[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=3[C:44](O)=[O:45])=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1)[C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl>ClCCl.C(OCC)(=O)C>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=1[NH:41][C:38]1[CH:37]=[CH:36][C:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][N:18]([CH3:17])[C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:30]=2)=[CH:40][CH:39]=1
Reactant: CC(C)CCN
Reactant: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(Nc3ccccc3C(=O)O)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(Nc3ccccc3C(=O)NCCC(C)C)cc2)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 91.3 %

Procedure:
95 mg (1.1 mmol) of 3-methylbutylamine and 160 mg (1.2 mmol) of 1-hydroxybenzotriazole are successively added to a solution of 500 mg (1.1 mmol) of 2-{3′-[(methyloctanoylamino)methyl]biphenyl-4-ylamino}benzoic acid (Example 6) in 15 ml of dichloromethane. The reaction medium is cooled to 0° C. and 230 mg (1.2 mmol) of EDCl are added portionwise. The reaction medium is stirred from 0° C. to room temperature over 6 hours, diluted with ethyl acetate, washed with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 530 mg of N-(3-methylbutyl)-2-{3′-[(methyloctanoylamino)methyl]biphenyl-4-ylamino}benzamide are obtained in the form of a yellow oil, in a yield of 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[N:7]([CH2:16][CH2:17][CH2:18][O:19]S(C)(=O)=O)[C:6]=2[CH:24]=1.[O:25]=[C:26]1[C:34]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH:28]2[NH:27]1.C(=O)([O-])[O-].[K+].[K+].[ClH:46]>C(O)C.CO.O>[OH2:19].[ClH:1].[ClH:46].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[N:7]([CH2:16][CH2:17][CH2:18][N:37]3[CH2:38][CH2:39][C:34]4([N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][CH:28]5[NH:27][C:26]4=[O:25])[CH2:35][CH2:36]3)[C:6]=2[CH:24]=1
Reactant: O=C1NC2CCCCN2C12CCNCC2
Reactant: CS(=O)(=O)OCCCN1c2ccccc2CCc2ccc(Cl)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: O=C1NC2CCCCN2C12CCN(CCCN1c3ccccc3CCc3ccc(Cl)cc31)CC2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 5 g of 3-chloro-5-(3-methylsulfonyloxypropyl)-10,11-dihydro-5H-dibenz[b,f]azepine, 4 g of 1,2,3,5,6,7,8,8a-octahydro-2-oxoimidazo[1,2-a]pyridine-3-spiro-4'-piperidine, 4 g of potassium carbonate and 4 g of water in 40 ml of ethanol is stirred at 60° C. for 4 hours. The upper layer is separated and concentrated, and the residue is dissolved in 100 ml of toluene. The toluene solution is washed with water, dried, concentrated to about 15 ml and allowed to stand. The precipitated crystals are collected by filtration and recrystallized from ethanol. The crystals thus obtained are dissolved in methanol, and methanolic hydrochloric acid is added to give 1'-[3-(3-chloro-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-propyl]-1,2,3,5,6,7,8,8a-octahydro-2-oxo-imidazo[1,2-a]pyridine-3-spiro-4'-piperidine dihydrochloride monohydrate, m.p. 261° C. This product is dried at 120° C. under reduced pressure for 4 hours to give the anhydrous product as white crystals, m.p. 271° C., 4.3 g.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10](=[O:21])[CH2:9]3.[CH3:24][CH:25](Cl)[CH2:26][N:27]([CH3:29])[CH3:28].C([O-])(=O)/C=C/C([O-])=O>>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:25]([CH3:24])[CH2:26][N:27]([CH3:29])[CH3:28])=[CH:16][CH:15]=1)[C:10](=[O:21])[CH2:9]3
Reactant: O=C1CC2CCc3ccc(F)cc3C2=NN1c1ccc(O)cc1
Reactant: CC(Cl)CN(C)C
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: CC(CN(C)C)Oc1ccc(N2N=C3c4cc(F)ccc4CCC3CC2=O)cc1

Procedure:
By conducting reactions and treatments in the same manner as in Example 1 using 9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one and 1-methyl-2-dimethylaminoethyl chloride, there are obtained crude crystals, which are subjected to silica gel column chromatography. The crystals obtained from fractions at earlier stage are converted into fumarate, followed by recrystallization from ethanol to give 9-fluoro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.fumarate.1/2 hydrate [referred to as compound of Example 11a], m.p. 176°-179° C. (decomposition). The crystals obtained from fractions at later stage are converted into fumarate, which is recrystallized from water to give 9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.fumarate [referred to as compound of Example 11b], m.p. 194°-195° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([S:13](Cl)(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:19]([C:22]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[C:25]([CH:32]([CH3:34])[CH3:33])[C:23]=1[NH2:24])([CH3:21])[CH3:20]>N1C=CC=CC=1>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([S:13]([NH:24][C:23]2[C:25]([CH:32]([CH3:33])[CH3:34])=[CH:26][C:27]([CH:29]([CH3:31])[CH3:30])=[CH:28][C:22]=2[CH:19]([CH3:21])[CH3:20])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)c1cc(C(C)C)c(N)c(C(C)C)c1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CC(C)c1cc(C(C)C)c(NS(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.4 %

Procedure:
3,5-Bis(trifluoromethyl)benzenesulfonyl chloride (0.037 g, 0.12 mmol) was added to a solution of 2,4,6-triisopropylaniline (0.025 g, 0.11 mmol) in dry pyridine (1 mL). After stirring at room temperature for 1 day, the reaction was concentrated under vacuum. To this was added ethyl acetate (30 mL), and the mixture was washed with 0.1 N HCl (2×20 mL) followed by saturated NaHCO3 (2×20 mL) then saturated NaCl (2×20 mL). After drying the organic layer over MgSO4, the mixture was concentrated under vacuum. The crude compound was purified by silica gel chromatography using hexanes/ethyl acetate (4:1) to afford the title compound (0.040 g. 71% yield). ES-MS negative Q1 (m/z) 494.6. 1H NMR (CDCl3) 8.14 (s, 2H), 8.05 (s, 1H), 6.96 (s, 2H), 6.05 (s, 1H), 2.97 (m, 2H), 2.88 (m, 1H), 1.23 (d, 6H), 0.98 (d, 12H).