Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-]#N.[Na+].[C:17](#[N:20])[CH:18]=[CH2:19]>O>[C:6]([CH2:19][CH2:18][C:17]#[N:20])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: C=CC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCC(=O)c1ccccc1
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
320 ml of absolute dimethylformamide, 42.5 g (0.4 mol) of freshly distilled benzaldehyde and 9.8 g (0.2 mol) of sodium cyanide are introduced into a 500 ml 4-necked flask equipped with dropping funnel, stirrer, KOH drying tube and internal thermometer. A week exothermic reaction takes place after the addition of sodium cyanide to the reaction mixture and the temperature rises from 30° to 34° C. The reaction mixture is stirred for 15 minutes at a reaction temperature of 30° C and a solution of 15.9 g (0.3 mol) of freshly distilled acrylonitrile and 80 ml of absolute dimethylformamide is introduced dropwise into the reaction mixture in the course of one hour at the same temperature. Stirring is then continued for 1/4 hours at the same temperature. The reaction mixture, which is now very creamy, is poured on to 800 ml of water and vigorously shaken. The aqueous solution is extracted twice with 200 ml of chloroform and twice with 100 ml of chloroform. The combined chloroform solutions are vigorously washed with water and dried over MgSO4 and the chloroform is distilled off. Inoculating crystals are added to the residue. β-Benzoyl-propionitrile then crystallises at once. It is suction filtered and washed with ethanol. 26.6 g of β-benzoylpropionitrile are obtained. M.p.: 69° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH:14]=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:21]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]12([C:11]3[CH:12]=[C:13]([C:14]#[CH:21])[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: COc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(OC)c(C23CC4CC(CC(C4)C2)C3)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A mixture of 3-(1-admantanyl)-4-methoxybenzaldehyde (0.12 g, 0.42 mmol), dimethyl(1-diazo-2-oxopropyl)phosphonate (0.097 g, 0.51 mmol) and K2CO3 (0.069 g, 0.5 mmol) in anhydrous MeOH (5 ml) was stirred overnight at 80° C. The solvent was evaporated and the residue was diluted to 50 ml with EtOAc, washed with H2O, dried over MgSO4 and filtered. The filtrate was passed through SiO2 bead and the filtrate was evaporated to dryness to give the title product (0.05 g; 42%), which was used for the next step without purification. 1H-NMR (CDCl3) 1.75 (s, 3H); 2.05 (broad s, 9H); 2.96 (s, 1H); 3.82 (s, 3H); 6.77 (d, 1H, J=8.31 Hz); 7.29-7.34 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:31]([C:27]5[N:26]([CH3:25])[CH:30]=[CH:29][CH:28]=5)=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cn1cccc1C(=O)Cl
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Solvent: CC(=O)N(C)C
Product: Cn1cccc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 61.7 %

Procedure:
Using N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (327 mg, 1.0 mmol), 1-methyl-1H-pyrrole-2-carbonyl chloride (151 mg, 1.05 mmol) and N,N-dimethylacetamide (6.0 mL), and by a reaction in the same manner as in Example 148, the title compound (268 mg, 62%) was obtained as colorless crystals.
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=1[O:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH:33]=[O:34])=[CH:25][CH:24]=1.O>O1CCCC1.C(O)(=O)C>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:23]=[CH:24][CH:25]=2)[OH:34])=[CH:16][C:15]=1[O:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc(Br)ccc1OCc1ccccc1
Reactant: O=Cc1ccnc2ccccc12
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(C(O)c2ccnc3ccccc23)ccc1OCc1ccccc1
Reaction time: 1 h

Procedure:
25 ml of tert.-butyllithium solution (1.4M in hexane) are added dropwise at -70° within 10 minutes to 10 g of 4-(benzyloxy)-3-methoxy-bromobenzene dissolved in 100 ml of tetrahydrofuran. After stirring at -70° for 1 hour, 5 g of quinoline-4-carbaldehyde dissolved in 50 ml of tetrahydrofuran are added dropwise within 30 minutes. The reaction mixture is stirred at -40° for 1 hour and at -5° for 1 hour, poured into 200 ml of water and adjusted to pH 4 with glacial acetic acid. The mixture is extracted three times with 50 ml of ether each time. The combined ether phases are washed with water, dried over sodium sulfate and evaporated. There is obtained α-[4-(benzyloxy)-3-methoxyphenyl]-4-quinolinemethanol as an amorphous solid.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=O)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.C(Cl)(=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH3:34][O:33][C:31](=[O:32])[NH:30][CH:26]([C:25]([N:10]1[CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[CH2:12][N:8]([C:6](=[O:5])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:9]1)=[O:35])[CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CN(C(=O)c2ccccc2)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(4-Bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-1′-carboxylic acid tert-butyl ester (55.6 mg, 0.101 mmol) was dissolved in dichloromethane (0.5 mL) and HCl (4M dioxane, 0.5 mL) was added. The resultant suspension was stirred at room temperature for 20 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in THF (1 mL) and diisopropyl ethylamine (26.0 mg, 0.202 mmol) was added, followed by benzoyl chloride (15.6 mg, 0.11 mmol). The reaction was stirred at room temperature. After 10 minutes, all starting material was consumed. All volatiles were removed in vacuo and the crude brown solid {1-[1′-Benzoyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester was used in the coupling reaction without further analysis or purification: LCMS-ESI+: calc'd for C26H28BrN5O4: 554.4 (M+). Found: 554.3/556.4 (M+H+).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][CH:16]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH2:19][CH2:18][NH:17]2)=[CH:13][CH:12]=1.C(Cl)Cl.[CH:31]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32]1>O>[CH:31]1([C:35]([N:17]2[CH2:18][CH2:19][C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=3[CH:16]2[CH2:15][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:27][CH:26]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CCC1
Reactant: COc1ccc(CC2NCCC3=C2CCCC3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CC2C3=C(CCCC3)CCN2C(=O)C2CCC2)cc1

Procedure:
Triethylamine (22.2 g., 0.22 mole) is slowly added to 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline hydrochloride Ia (29.4 g., 0.1 mole) dissolved in 200 ml. of methylene chloride with stirring and ice-bath cooling. Cyclobutylcarbonyl chloride (13 g., 0.107 mole) in 30 ml. of methylene chloride is then added dropwise with stirring to the mixture while maintaining a temperature of 0° to 5° C. After stirring the reaction mixture for 1 hr. at room temperature, 100 ml. of water is added, the mixture acidified by adding 50 ml. of 10% sulfuric acid, and the methylene chloride layer separated. If desired, the methylene chloride solution containing IIa can be used for the next step directly or concentrated to give an oil which solidifies upon standing. Recrystallization of a sample of the solidified material from acetone provides crystalline product IIa, m.p. 89°-91°.
Reaction SMILES: [P:1]([O-:38])([O:34][CH2:35][CH2:36]Br)([O:3][CH2:4][CH:5]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[CH3:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[P:1]([O-:38])([O:34][CH2:35][CH2:36][N+:40]1([CH3:39])[CH2:44][CH2:43][CH2:42][CH2:41]1)([O:3][CH2:4][CH:5]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCBr)OCc1ccccc1
Reactant: CN1CCCC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCC[N+]1(C)CCCC1)OCc1ccccc1
Reaction time: 8 h
Yield: 46.6 %

Procedure:
In 30 ml of toluene were dissolved 7.5 g (12 mmole) of 2-benzyloxy-3-(octadecyloxy)propyl 2-bromoethyl phosphate and 10.2 g (120 mmole) of N-methylpyrrolidine, and the solution was allowed to stand at room temperature for 8 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 60 ml of methanol. 3.3 g (12 mmole) of silver carbonate was added to the solution, followed by heating under reflux for 1 hour. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:water=65:25:4) to give 3.5 g (47 %) of 2-benzyloxy-3-(octadecyloxy)-propyl 2-(N-methylpyrrolidinio)ethyl phosphate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18](F)=[C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:32]#[N:33].[CH3:34][O:35][CH2:36][CH2:37][OH:38]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:38][CH2:37][CH2:36][O:35][CH3:34])=[C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:32]#[N:33]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(F)c(OCCN4CCOCC4)cc23)c(Cl)cc1Cl
Reactant: COCCO
Product: COCCOc1cc2ncc(C#N)c(Nc3cc(OC)c(Cl)cc3Cl)c2cc1OCCN1CCOCC1

Procedure:
Following the procedure used to prepare Example 15, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-(2-morpholin-4-ylethoxy)-3-quinolinecarbonitrile (102 mg, 0.21 mmol) and 2-methoxyethanol provides 86 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(2-methoxyethoxy)-6-(2-morpholin-4-ylethoxy)3-quinolinecarbonitrile, mp 158-159° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]([C:15]#[N:16])[C:7](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:8]#[N:9])[CH3:2]>C(OCC)(=O)C.C(O)C.CO.[Pt]=O>[CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]2[C:7](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH2:8][N:9]=[C:15]2[NH2:16])[CH3:2]
Reactant: CCOc1cc(C#N)c(C#N)c(F)c1OCC
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: CCOc1cc2c(c(F)c1OCC)C(N)=NC2
Temperature: 25 °C
Reaction time: 96 h
Yield: 20 %

Procedure:
After dissolving 4,5-diethoxy-3-fluorophthalonitrile (103 g) in ethyl acetate-ethanol-methanol (600 ml-600 ml-300 ml), platinum oxide (8 g) was added and the mixture was stirred at room temperature for 4 days under a hydrogen stream. The reaction mixture was filtered through celite, the organic layer was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (21 g) as yellow crystals.
Reaction SMILES: [C:1]([C@:3]1([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:11][CH:6](OC(=O)C)[C@H:5]([O:12][C:13](=[O:15])[CH3:14])[C@@H:4]1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[CH:2].[NH:33]1[CH:40]=[CH:39][C:37](=[O:38])[NH:36][C:34]1=[O:35].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)([O-])O.[Na+]>ClCCCl>[C:1]([C@:3]1([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:11][C@@H:6]([N:33]2[CH:40]=[CH:39][C:37](=[O:38])[NH:36][C:34]2=[O:35])[C@H:5]([O:12][C:13](=[O:15])[CH3:14])[C@@H:4]1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)#[CH:2]
Reactant: C#C[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCCl
Product: C#C[C@]1(COCc2ccccc2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 14 (2.5 g, 5.70 mmol) was dissolved in 1,2-dichloroethane (80.0 ml), and uracil (1.60 g, 14.27 mmol) and N,O-bis(trimethylsilyl)acetamide (9.86 ml, 39.74 mmol) were added to the solution, followed by refluxing for one hour. After the reaction mixture was allowed to cool to room temperature, trimethylsilyl trifluoromethanesulfonate (2.06 ml, 11.40 mmol) was added thereto, followed by stirring overnight at 50° C. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and after stirring, precipitate was filtered. The organic layer was dried over anhydrous magnesium sulfate and concentrated through distillation under reduced pressure. The residue was purified by means of silica gel column chromatography (silica gel 300 ml, eluent; n-hexane:ethyl acetate=2:3), to thereby yield a colorless viscous compound (Compound 15; 2.44 g, 4.97 mmol, 87.2%).
Reaction SMILES: C[C:2](C)([C:6]([O-:8])=O)[C:3]([O-:5])=O.[CH3:10][O:11][C:12]([NH2:14])=[NH:13].Cl.C[O-].[Na+]>>[CH3:10][O:11][C:12]1[N:14]=[C:3]([OH:5])[CH:2]=[C:6]([OH:8])[N:13]=1
Reactant: COC(=N)N
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1nc(O)cc(O)n1

Procedure:
Under a nitrogen atmosphere 3.10 mL (27.0 mmol) dimethylmalonate, 3.00 g (27.1 mmol) o-methylisourea hydrochloride and 15.0 mL (80.8 mmol) sodium methoxide solution (30%) were refluxed for 1.25 h with stirring. The reaction mixture was cooled. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OC)=O.[NH2:28][CH:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=[O:40])[N:32]([CH:41]([CH3:43])[CH3:42])[N:31]([CH3:44])[C:30]1=[O:45]>ClCCl>[CH3:44][N:31]1[C:30](=[O:45])[CH:29]([NH:28][C:13](=[O:15])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:10]([CH3:11])[CH3:12])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=[O:40])[N:32]1[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)N1C(=O)c2ccccc2C(N)C(=O)N1C
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NC1C(=O)N(C)N(C(C)C)C(=O)c2ccccc21
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of N-boc-(L)-valine (IV, 1.04 g, 4.8 mmol) in dichloromethane (100 mL) was added the N-methyl morpholine (0.56 g, 5.6 mmol) and methyl chloroformate (0.37 mL, 4.8 mmol) at 0° C. The resulting solution was stirred for 10 minutes before the addition of a solution of 5(R,S)-amino-2,3,4,5-tetrahydro-3-methyl-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione (IIIA, 1.0 g, 4.04 mmol) in dichloromethane (5 mL) and it was further stirred for another 1 h. The resulting mixture was washed with 1N hydrochloric acid (50 mL), sodium bicarbonate (50 mL), brine (50 mL) and dried over MgSO4, filtered and concentrated to afford the crude product. This product was purified further on flash (silica gel) chromatography (hexane/ethyl acetate, 3/2) to afford 2,3,4,5-tetrahydro-3-methyl-5(R,S)-[[(2S)-2-[(1,1-dimethylethoxycarbonyl)amino]-3-methyl-1-oxobutyl]amino]-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione(1.5 g, 83%).
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[N:10]=1)C1C=CC=CC=1.[CH2:30]([O:37][C:38]1[C:46]([F:47])=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][C:39]=1[F:48])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38]1[C:39]([F:48])=[CH:40][C:41]([C:42]([NH:15][C:14]2[C:9]([OH:8])=[N:10][C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:21])=[N:12][CH:13]=2)=[O:43])=[CH:45][C:46]=1[F:47])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[C@@H](COc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(F)c(OCc2ccccc2)c(F)c1
Product: C[C@@H](COc1ncc(NC(=O)c2cc(F)c(OCc3ccccc3)c(F)c2)c(O)n1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((4-(benzyloxy)-5-nitropyrimidin-2-yl)oxy)propan-2-yl)carbamate and 4-(benzyloxy)-3,5-difluorobenzoic acid, and in the same manner as in Step A of Example 4, Step D of Example 83 and Step B of Example 123, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[CH:22]=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].C(N(CC)CC)C.[Cl:39][C:40]([Cl:45])([Cl:44])[C:41](Cl)=[O:42]>ClCCl>[Cl:39][C:40]([Cl:45])([Cl:44])[C:41]([C:22]1[N:14]2[C:13]([CH2:12][N:11]([C:9]([C:7]3[CH:6]=[CH:5][C:4]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])=[C:3]([O:2][CH3:1])[CH:8]=3)=[O:10])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15]2)=[CH:24][CH:23]=1)=[O:42]
Reactant: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.7 %

Procedure:
A solution of 10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step E (21 mmol) and triethylamine (43 mmol) in anhydrous dichloromethane (45 mL) was cooled in an ice bath. To the stirred solution was added, dropwise, trichloroacetyl chloride (65 mmol). The mixture was allowed to stir at ambient temperature for 72 hours. The solution was washed with 0.1 N hydrochloric acid and brine and dried over anhydrous sodium sulfate. Evaporation gave a green foam. This was crystallized by heating in ethyl acetate and chloroform to give 10.2 g of the title compound as a white powder (85%), m.p. 221-222° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].N=C=N.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=2)=[O:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2]
Reactant: CCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: Nc1ccc(F)cc1
Agent: N=C=N
Solvent: ClCCl
Product: CCN(CC(=O)Nc1ccc(F)cc1)c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 11 %

Procedure:
A mixture of N-[4-cyano-3-(trifluoromethyl)phenyl]-N-ethyl glycine, Example 91B (0.074 g, 0.25 mmol), and resin bounded carbodiimide (0.50 g, 1.26 mmol/g) was shaken in CH2Cl2 (15 mL) for 30 min, then 4-fluoroaniline (0.044 g, 0.4 mmol) was added, and the mixture was shaken for another 12 h. The resin was filtered and washed with CH2Cl2 (2×10 mL). The resulting filtrate was concentrated under vacuum. The residue was triturated with Et2O to obtain 0.018 g (11%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.42-7.39 (m, 2H), 7.06-6.99 (m, 4H), 6.85 (dd, J=9.0, 2.7 Hz, 1H), 4.10 (s, 2H), 3.64 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H); MS (APCI) m/z 366 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20](=[O:25])C(F)(F)F)=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].[OH2:28]>CN(C=O)C.COC(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]([OH:25])=[O:28])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1cn(Cc2cc(F)cc(F)c2)c2cc(Cl)ccc12)C(F)(F)F
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: O=C(O)c1cn(Cc2cc(F)cc(F)c2)c2cc(Cl)ccc12
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
To a solution of 2.2 g (6.5 mmol) 1-[6-chloro-1-(3,5-difluoro-benzyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone in 65 ml DMF were added 1.7 g (36 mmol) sodium hydride (50% in oil) at room temperature. After stirring for 5 min. 0.59 ml (33 mmol) water were added dropwise. Stirring was continued at room temperature for 45 min. The reaction mixture was diluted with 150 ml of tert-butyl methyl ether and extracted with two 150-ml portions of a 1 M aqueous solution of sodium hydroxide. The combined aqueous layers were acidified to pH 1 with concentrated hydrochloric acid solution and extracted with three 150-ml portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dried in high vacuo at 80° C. to give 2.0 g (95%) of the crude title compound as a brown solid.
Reaction SMILES: [F-:1].[K+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11]>O1CCOCC1>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([F:1])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=S(=O)(F)c1ccccc1F
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Potassium fluoride (99%) (12 g, 216 mmol) was added to a solution of 2-fluoro-benzenesulfonyl chloride (10 g, 51 mmol) in 1, 4 dioxane (35 mL). The reaction mixture was refluxed for 24 hours, then cooled to room temperature and poured into ice water (200 mL). The ice water was extracted with chloroform (3×50 mL). The combined chloroform layers were dried (MgSO4), filtered, and concentrated to afford 2-fluoro-benzenesulfonyl fluoride (2a) as a colorless oil 6.7 g (74%). (M+H)+=177
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4]1[C:12]([C:13](OC3C=CC=CC=3)=[O:14])=[CH:11][C:10]([OH:22])=[CH:9][C:5]=12.[C:23]([C:28]1[CH:38]=[C:37]([C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])[CH:36]=[CH:35][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][NH2:34])([CH2:26][CH3:27])([CH3:25])[CH3:24]>>[OH:1][CH:2]1[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4]1[C:12]([C:13](=[O:14])[NH:34][CH2:33][CH2:32][CH2:31][O:30][C:29]3[CH:35]=[CH:36][C:37]([C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])=[CH:38][C:28]=3[C:23]([CH2:26][CH3:27])([CH3:24])[CH3:25])=[CH:11][C:10]([OH:22])=[CH:9][C:5]=12
Reactant: O=C(Oc1ccccc1)c1cc(O)cc2c1C1CCC2C1O
Reactant: CCC(C)(C)c1ccc(OCCCN)c(C(C)(C)CC)c1
Product: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(O)cc3c2C2CCC3C2O)c(C(C)(C)CC)c1

Procedure:
The phenyl ester (14.8 g) synthesized in (2) above was mixed with 3-(2,4-di-t-pentylphenoxy)propylamine (14.6 g), and the mixture was reacted at 140° C. under a reduced pressure of 20 mmHg for 4 hours. After cooling, the reaction product was crystallized from n-hexane to obtain 3,6-dihydroxy-4-[3-(2,4-di-t-pentylphenoxy)propylcarbamoyl]benzonorbornene. (Yield: 15.1 g (61.2 %), m.p.: 142° C.)