Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C@@H:10]([C:16](O)=O)[CH2:11][CH2:12][C:13](O)=O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]C.[CH2:19](N(CC)CC)C.C(Br)C1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH:10]1([NH:9][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:11][CH2:12][CH2:13][CH2:19][CH2:16]1
Reactant: CCN(CC)CC
Reactant: CCCCCCC(=O)N[C@H](CCC(=O)O)C(=O)O
Agent: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C1CCC(NC2CCCCC2)CC1
Reaction time: 60 h
Yield: 64.5 %

Procedure:
A solution of 108.8 g (420 mmol) of N-heptanoyl-D-glutamic acid and 50.6 g (500 mmol) of triethylamine in 135 ml of dimethylformamide was treated with 85.7 g (500 mmol) of benzyl bromide and stirred under nitrogen atmosphere for 60 hours. The reaction was poured onto one liter of ethyl acetate and washed successively with two 500 ml portions each of dilute hydrochloric acid and water. The ethyl acetate was then washed with 500 ml of 1N sodium hydroxide. The basic aqueous layer was acidified with dilute acid and extracted with four 500 ml portions of ethyl acetate. The combined ethyl acetate extracts were treated with excess dicyclohexylamine and stirred 18 hours. The suspension was filtered, slurried in fresh ethyl acetate (400 ml) for two hours, refiltered and dried under vacuum to give 49.1 g of dicyclohexylamine salt. The resulting salt (14.0 g) was stirred in dilute hydrochloric acid, filtered and washed with ethyl acetate. The aqueous filtrate was extracted twice with ethyl acetate, and the organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting oil was triturated with hexane to give 7.9 g (86% from salt) of the title ester: mp 76°-79° C. IR (Nujol) 3300, 2700-3100, 1730, 1700, 1645 cm-1 ; NMR (CDCl3) delta 7.35 (s, 5H), 5.20 (s, 2H), 4.70 (m, 1H), 1.85-2.50 (m, 6H), 1.55-1.70 (m, 2H), 1.10-1.40 (m, 6H), 0.75 (t, 3H); [alpha]D =+27.6 (C=0.6, MeOH).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[N:15]1[C:20](=[O:21])[NH:19][C:18](=[O:22])[CH:17]=[N:16]1.I[CH3:24]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[N:15]1[C:20](=[O:21])[N:19]([CH3:24])[C:18](=[O:22])[CH:17]=[N:16]1
Reactant: CI
Reactant: CC(C)Oc1cc(-n2ncc(=O)[nH]c2=O)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(-n2ncc(=O)n(C)c2=O)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 0.6 g (0.025 mole) of sodium hydride in 15 mL of N,N-dimethylformamide was added a solution of 7.5 g (0.024 mole) of 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-1,2,4-triazine-3,5(2H,4H)-dione in 30 mL of N,N-dimethylformamide with external cooling to maintain the reaction temperature below 40° C. After complete addition, the mixture was allowed to come to room temperature and was stirred for one hour. A solution of 3.5 g (0.025 mole) of iodomethane in 10 mL of N,N-dimethylformamide was added to the reaction mixture, and stirring was continued for an additional hour at room temperature. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to produce 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione as an oil, Compound 12 in the tables.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:12])=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH2:30])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[ClH:12].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH:30][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(CCNCCN)cc1OC
Product: COc1ccc(CCNCCNC(=O)c2ccc(NS(C)(=O)=O)cc2)cc1OC
Product: Cl

Procedure:
In a manner similar to Example XVII, react 4-[(methylsulfonyl)amino]benzoyl chloride with N-[2-(3,4-dimethoxyphenyl)ethyl]-1,2-ethanediamine to obtain the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:5]([CH3:17])[N:4]=1>ClCCl.[O-2].[Mn+4].[O-2]>[CH:2]([C:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:5]([CH3:17])[N:4]=1)=[O:1]
Reactant: CCOC(=O)c1c(C(F)(F)F)c(CO)nn1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)c1c(C(F)(F)F)c(C=O)nn1C

Procedure:
A solution of 1.50 g (5.95 mmol) of ethyl 3-(hydroxymethyl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate in 100 ml of dichloromethane is admixed with 4.14 g (47.6 mmol) of manganese(IV) oxide and heated under reflux for four hours. The cooled reaction mixture is filtered over Celite and concentrated by evaporation on a rotary evaporator. This gives 1.36 g of ethyl 3-formyl-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (91%).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][N:14]3[CH:19]=2)=[C:7]([O:20][CH3:21])[CH:6]=1)C(C)=O>Cl>[NH2:1][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][N:14]3[CH:19]=2)=[C:7]([O:20][CH3:21])[CH:6]=1
Reactant: COc1cc(NC(C)=O)ccc1-c1cn2ncccc2n1
Agent: Cl
Product: COc1cc(N)ccc1-c1cn2ncccc2n1

Procedure:
0.3 g (1 mmol) of 2-(4-Acetamino-2-methoxyphenyl)-imidazo[1,2-b]pyridazine are heated for 11/2 hours in 20 ml of 6N hydrochloric acid over a steam bath. After cooling and filtration, the residue is made alkaline with conc. ammonia. The product precipitated is suction filtered, washed with water and dried at 100° C. over potassium hydroxide in a drying gun.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([C:4](O)=[O:5])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:2]([CH3:1])([CH3:3])[CH2:4][OH:5])=[CH:9][CH:10]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(CO)Oc1ccc(Cl)cc1

Procedure:
The title compound was prepared by the procedure of Preparation 2 in quantitative yield from clofibric acid (Aldrich Chem. Co.) and lithium aluminum hydride.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([N:28]4[CH2:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][N:10](C2CCCCO2)[CH:11]=1)=[O:5])[CH3:2].Cl>O1CCOCC1.C(OC(C)C)(C)C>[CH2:35]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([N:28]4[CH2:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][NH:10][CH:11]=1)=[O:5])[CH3:36]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCCOCC3)cc2[nH]1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(N3CCCOCC3)cc2[nH]1
Temperature: 22 °C
Yield: 72.8 %

Procedure:
A solution of 380 mg of 1,1-diethyl-3-[3-(5-fluoro-6-perhydro-1,4-oxazepin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]urea in solution in 5 mL of a 4N solution of hydrochloric acid in dioxane is stirred at 22° C. for 2 hours. The reaction medium is concentrated under vacuum in a rotary evaporator, and then again reacted at 22° C. for 16 hours with 5 mL of a 4N solution of hydrochloric acid in dioxane is stirred at 22° C. The reaction medium is concentrated under vacuum in a rotary evaporator. The product is diluted in ethyl acetate, and washed with 2 times 20 mL of a 2N aqueous solution of sodium hydroxide. The aqueous phases are extracted with 3 times 20 mL of ethyl acetate. The organic phases are dried over MgSO4, filtered and concentrated under vacuum in a rotary evaporator. The yellow foam obtained is made into a paste in isopropyl ether, triturated, filtered and dried under vacuum at 40° C. 230 mg of 1,1-diethyl-3-[3-(5-fluoro-6-perhydro-1,4-oxazepin-4-yl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]urea are obtained in the form of a pale yellow solid. 1H NMR (500 MHz, DMSO-d6, δ in ppm): 1.23 (t, J=7.0 Hz, 6H); 1.96 (m, 2H); 3.35 (m masked, 4H); 3.39 (q partially masked, J=7.0 Hz, 4H); 3.79 (m, 4H); from 6.98 to 7.39 (broad m, 2H); 7.98 (s, 1H); 9.87 (broad s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]2)=[C:4]([CH:10]([OH:14])[C:11]([O-:13])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:22])[F:23])[CH2:17][CH2:16]2)=[C:4]([C@H:10]([O:14][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:7]([CH3:8])[CH3:2])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c(C(O)C(=O)[O-])c(N2CCC(C(F)(F)F)CC2)c1Br
Solvent: ClCCl
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C(F)(F)F)CC2)c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 178 %

Procedure:
The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate (1.9 g, 4.19 mmol) and 0.4 mL of 70% HClO4 in DCM (20 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, after which it was recooled, and an additional 0.4 mL of 70% HClO4 was added, and the reaction stirred for 24 h at rt. The reaction was then diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (5-12% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate 1.9 g (90%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO) δ 6.11 (br. s, 1H), 4.93-4.91 (m, 1H), 3.84 (br. s, 1H), 3.209 (br. s, 1H), 3.08 (br. s, 1H), 2.89 (br. s, 1H), 2.53 (s, 3H), 2.44 (br. s, 3H), 1.96 (br. s, 1H), 1.86 (br. s, 2H), 1.64-1.53 (m, 2H), 1.16 (d, J=6.3 Hz, 3H), 1.14 (s, 9H), 1.07 (d, J=6.3 Hz, 3H). UPLC (M+H)=511.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:37])[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:28]2[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][C:23]1=2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:26]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:37])([CH3:21])[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:28]=4[CH:27]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 6′-chloro-2,3,5,6-tetrahydro-1,2′-bipyrazinyl-4-carboxylic acid tert-butyl ester (preparation analogous to US 2005/176722) and 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylboronic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.NN>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NCCCCOc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NCCCCOc2ccc(N)cc2)cc1
Temperature: 25 °C

Procedure:
5.0 g of 4-methyl-N-[4-(4-nitrophenoxy)-butyl]benzenesulfonamide (Example 35) is dissolved in 500 ml of ethanol, 1.5 ml of anhydrous hydrazine and 500 mg of 10% palladium on carbon are added, and the mixture is then stirred under reflux for four hours. The reaction mixture is filtered hot. Cooling the filtrate to room temperature produces a precipitate, which is collected. The filtrate is reheated to boiling and utilized to re-extract the palladium-carbon residue, and after filtration, cooled to room temperature, the precipitate being collected. The process is repeated until no further precipitate is formed on cooling to room temperature. After drying at 60° in vacuo, the combined precipitates weigh 3.3 g; m.p. 176°-178° C.
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:21]=[C:20]2[C:11]([O:12][CH2:13][CH2:14][N:15]3[C:19]2=[N:18][C:17]([C:22]2[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][N:23]=2)=[CH:16]3)=[CH:10][CH:9]=1)[CH3:7])(=O)=O.[C:30]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:33])([CH3:32])[CH3:31]>O1CCOCC1>[C:30]([N:34]1[CH2:39][CH2:38][N:37]([CH:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:14][N:15]4[CH:16]=[C:17]([C:22]5[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][N:23]=5)[N:18]=[C:19]4[C:20]=3[CH:21]=2)[CH3:7])[CH2:36][CH2:35]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(OS(C)(=O)=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Reactant: CC(C)(C)N1CCNCC1
Solvent: C1COCCO1
Product: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CCN(C(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate from Example 146 (140 mg, 0.340 mmol) and 1-tert-butylpiperazine (238 mg, 1.70 mmol) in 1,4-dioxane (4 mL) was stirred at 90° C. for 16 h under nitrogen atmosphere. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give racemic 10-(1-(4-tert-butylpiperazin-1-yl)ethyl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. Further purification and separation of enantiomers was conducted by chiral HPLC (OD-H column, 2% EtOH (0.1% DEA) in n-hexane isocratic) to give a first eluting peak, 26 mg of 149 and a second eluting peak, 27 mg of 150 (34% total yield)
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[CH:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:26]=[CH:27][C:28]=1[NH2:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:26]=[CH:27][C:28]=1[NH:29][C:13]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:15]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: CC(C)n1cc(C(=O)O)c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)c2cn(C(C)C)c3ccccc23)c(Cl)c1
Temperature: -15 °C
Yield: 91.1 %

Procedure:
To a solution of 1-isopropylindole-3-carboxylic acid (159.6 mg, 0.785 mmol) in methylene chloride (3.5 ml) was added oxalyl chloride (101.0 μl, 1.178 mmol) under stirring at −15° C. The reaction mixture was stirred for 2.5 hours at room temperature and then distilled under reduced pressure to remove the solvent. The residue was dissolved in methylene chloride (3.5 ml), followed by the addition of a solution of methyl 3-chloro-4-aminophenylacetate (164.6 mg, 0.824 mmol) in methylene chloride (3.5 ml) and triethylamine (0.35 ml, 2.474 mmol) under stirring at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then distilled under reduced pressure to remove the solvent. The residue was dissolved in chloroform. The resulting solution was washed successively with 1N HCl and saturated saline, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby methyl 3-chloro-4-((1-isopropyl-3-indolylcarbonyl)amino)phenylacetate (275.3 mg, 91%) was obtained as a brown solid. The resulting compound was provided for the subsequent reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:6]([O:12][S:13](=[O:34])(=[O:33])[NH:14][C:15](=[O:32])[CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=2[CH:29]([CH3:31])[CH3:30])=[C:5]([CH:35]([CH3:37])[CH3:36])[CH:4]=1)#[N:2].[H][H].Cl>N.C(OCC)C.[Ni]>[NH2:2][CH:1]=[C:3]1[CH:4]=[C:5]([CH:35]([CH3:36])[CH3:37])[C:6]([O:12][S:13](=[O:33])(=[O:34])[NH:14][C:15](=[O:32])[CH2:16][C:17]2[C:18]([CH:29]([CH3:30])[CH3:31])=[CH:19][C:20]([CH:26]([CH3:27])[CH3:28])=[CH:21][C:22]=2[CH:23]([CH3:25])[CH3:24])=[C:7]([CH:9]([CH3:11])[CH3:10])[CH2:8]1
Reactant: [H][H]
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(C#N)cc2C(C)C)c(C(C)C)c1
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CCOCC
Product: CC(C)C1=CC(=CN)CC(C(C)C)=C1OS(=O)(=O)NC(=O)Cc1c(C(C)C)cc(C(C)C)cc1C(C)C

Procedure:
[(2,4,6-Triisopropyl-phenyl)-acetyl]-sulfamic acid 4-cyano-2,6-diisopropyl-phenyl ester (5.15 g, 9.8 mmol) was dissolved in 100 mL of methanolic ammonia and 2.0 g of Raney-nickel was added. The resulting mixture was stirred under 50 psi of hydrogen at room temperature for 20 hours. Filtered and concentrated the residue to give a dark solid. Suspended in diethyl ether and acidified with HCl gas. Concentrated in vacuo and neutralized the residue with saturated aqueous sodium bicarbonate. The resulting white suspension was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([C:25](=[O:48])[C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:47])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)=[CH:28][CH:27]=2)[CH2:17][CH2:16][C:15]1=[O:49].C(N(CC)CC)C>ClCCl>[CH:12]([CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([C:25](=[O:48])[C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:47])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)=[CH:30][CH:31]=2)[CH2:17][CH2:16][C:15]1=[O:49])=[O:11]
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CCO)c4ccccc43)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CC=O)c4ccccc43)cc2)cc1
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
To a solution of oxalyl chloride (0.134 ml) in dichloromethane (10 ml) was added dimethyl sulfoxide (0.109 ml) at -78° C. and the mixture was stirred at the same temperature. After 10 minutes, 1-(2-hydroxyethyl) -5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (400 mg) in dichloromethane (10 ml) was added dropwise at -78° C. and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added triethylamine (0.537 ml) and the mixture was allowed to ambient temperature. The solution was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 1-formylmethyl-5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (301 mg) as an unstable oil. The oil was used for next step without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([OH:11])=O.S(Cl)(Cl)=O.C[N:19]([CH3:22])C=O.[CH:23]1C=CC=C[CH:24]=1>>[CH2:22]([NH:19][C:9]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:13])[F:12])=[O:11])[CH:23]=[CH2:24]
Reactant: c1ccccc1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: C=CCNC(=O)c1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 0.26 g of 4-trifluoromethyl-3-pyridine carboxylic acid and 0.24 g of thionyl chloride in 10 ml of benzene was refluxed under heating for 30 minutes in the presence of a catalytic amount of dimethylformamide. Excess thionyl chloride and benzene were distilled off under reduced pressure. Then, the residue was dissolved in 15 ml of tetrahydrofuran. Then, 0.21 g of triethylamine and 0.12 g of allylamine were added thereto, and the mixture was stirred at room temperature for 20 hours. Then, the mixture was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.21 g of the desired product (Compound No. 22) having a melting point of from 75.5° to 77° C.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:41]=[CH:40][C:34]2[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=2[C:32]=1[CH2:42][CH2:43][CH3:44])C>CCCCCC.C(OCC)(=O)C>[C:19]([CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:7]([CH2:6][CH2:5][C:4]([OH:45])=[O:3])=[C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:41]=[CH:40][C:34]3[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=3[C:32]=1[CH2:42][CH2:43][CH3:44])[CH:9]=[CH:10]2)([OH:21])=[O:20]
Reactant: CCCc1c(OCCCCCOc2ccc3cc(OCC(=O)OCC)ccc3c2CCC(=O)OCC)ccc2c1OCCC2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCOc2ccc3cc(OCC(=O)O)ccc3c2CCC(=O)O)ccc2c1OCCC2=O
Yield: 52.4 %

Procedure:
Starting with 0.736 g (1.19 mmol) of 2-[[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyl]oxy]-6-(2-ethoxy-2-oxoethoxy)-1-naphthalenepropanoic acid ethyl ester from the preceding example, the title compound (0.352 g; 52.6%) was obtained as a white solid, mp 160.5°-163° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 226.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[Br:19]C1C=CC(C(C)(C)C)=C(O)C=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1C=CCCC1>ClCCl>[Br:19][C:7]1[CH:2]=[CH:3][C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])=[C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=1
Reactant: CC(C)(C)c1ccc(Br)cc1O
Reactant: CC(C)(C)c1cc(Br)ccc1OC1CCCCO1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(Br)cc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Using the same procedure as for the preparation of 4-bromo-2-t-butyl-1-(2-tetrahydropyranoxy)benzene (Compound H), but instead using 8.18 g (35.7 mmol) of 5-bromo-2-t-butylphenol (Compound D), 0.90 g, 3.6 mmol) of pyridinium p-toluenesulfonate and 4.50 g (4.9 ml, 53.6 mmol) of 3,4-dihydro-2H-pyran and 50 ml of dichloromethane stirred at room temperature for 21 hours produced a dark yellow solution. At this time an additional 1.80 g (7.2 mmol) of pyridinium p-toluenesulfonate was added to the solution and it was allowed to stir at room temperature for 19 hours. After aqueous workup a clear, yellow oil was isolated. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) yielded the title compound as a clear, slightly yellow oil. PMR (CDCl3): d 1.38 (9H, s), 1.6-2.1 (6H, m), 3.65-3.75 (1H, m), 3.8-3.95 (1H, m), 5.45 (1H, t, J=2.5 Hz), 7.03 (1H, dd, J=8.4, 2.0 Hz), 7.13 (1H, d, J=8.4 Hz), 7.33 (1H, d, J=2.0 Hz).