Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[N:35]1C=CC=CC=1CO>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH2:20][C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][N:35]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCc1ccccn1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccn1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed 2-pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give 2-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (11 mg, 0.023 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0N HCl in ether (0.1 mL) was added slowly. The precipitate was collected through filtration under nitrogen to give 2-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate hydrochloride (12 mg, 0.023 mmol). 1H NMR (DMSO-d6) δ 1.92(m, 2H), 2.16(m, 2H), 3.55(m, 2H), 3.89(s, 3H), 4.02(m, 2H), 4.91 (m, 1H), 5.23(s, 2H), 7.05(d, J=8.2 Hz, 1H), 7.14 (s, 1H), 7.37(m, 1H), 7.53(d, J=7.8 Hz, 1H), 7.87(m, 3H), 8.42(s, 1H), 8.57(d, J=4.2 Hz, 1H), 8.85(s, 1H). LC/MS MH30 =475.
Reaction SMILES: [F:1][CH2:2][CH:3]([N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17])[CH:4]=[CH:5][CH3:6].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][CH2:2][CH:3]([N:7]1[C:8](=[O:17])[C:9]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:10]2[C:11]1=[O:12])[CH:4]=[CH:5][CH2:6][Br:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC=CC(CF)N1C(=O)c2ccccc2C1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1C(C=CCBr)CF

Procedure:
A mixture of 1-fluoro-2-phthalimido-3-pentene (800 mg, 3.4 mmoles) prepared as in Step C above, N-bromosuccinimide (612 mg. 3.4 mmoles), carbon tetrachloride (30 mL) and a few mg of benzoyl peroxide is heated under strong reflux during irradiation with a lamp (325 W) during one hour. After washing with water the organic phase is dried over magnesium sulfate and then concentrated under reduced pressure to yield 1-fluoro-2-phthalimido-5-bromo-3-pentene as a slightly yellow oil (1.06 g, quantitative yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[CH2:7][OH:8]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Solvent: C1CCOC1
Product: OCc1cc(Br)ccc1Cl
Temperature: 25 °C

Procedure:
To a solution 5-bromo-2-chlorobenzoic acid (compound 3, 100 g, 425 mmol) in tetrahydrofuran (500 mL) at 0° C. was added borane dimethyl sulfide complex (170 mL, 170 mmol). The resulting mixture was stirred with gradual warming to ambient temperature over 15 h, re-cooled to 0° C., and quenched with methanol. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound as a white solid, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.Br[CH2:10][C:11]([CH:13]1[CH2:15][CH2:14]1)=O.C(=O)([O-])O.[Na+]>COCCOC.C1COCC1>[CH:13]1([C:11]2[N:8]=[C:3]3[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]3[CH:10]=2)[CH2:15][CH2:14]1
Reactant: Cc1nccnc1N
Reactant: O=C(CBr)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Cc1nccn2cc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 70 h
Yield: 43 %

Procedure:
[step 1] 3-Methylpyrazin-2-amine (16 g, 147 mmol) was dissolved in 1,2-dimethoxyethane (122 mL) and THF (61 mL), 2-bromo-1-cyclopropylethanone (36 g, 220 mmol) was added, and the mixture was stirred at room temperature for 70 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 v/v-85/15 v/v) to give 2-cyclopropyl-8-methylimidazo[1,2-a]pyrazine (11g, 43%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1-c1ccc(C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reaction time: 2.5 h
Yield: 100 %

Procedure:
22.3 g of methyl 4'-methyl-(1,1'biphenyl)-2-carboxylate were dissolved in 900 ml of tetrachloromethane under a nitrogen flow. Then there were added 17.8 g of 1-bromo-2,5-pyrrolidinedione and a catalytic amount of dibenzoyl peroxide. After stirring for 2.5 hours at reflux temperature under a nitrogen atmosphere, the reaction mixture was cooled and filtered. The filtrate was evaporated, yielding >30 g (100% ) of methyl 4'-(bromomethyl)[1,1'-biphenyl]-2-carboxylate as a crude residue (interm. 44).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:20][C:21]([O:23]CC)=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([F:19])([F:18])[CH:15]([F:17])[F:16])=[CH:8][CH:7]=1)=[O:4].[NH3:26].C(O)C>>[F:18][C:14]([F:19])([CH:15]([F:17])[F:16])[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]2[CH2:20][C:21](=[O:23])[NH:26][CH2:2][C:3]2=[O:4])=[CH:7][CH:8]=1
Reactant: N
Reactant: CCOC(=O)CN(C(=O)CCl)c1ccc(OCC(F)(F)C(F)F)cc1
Solvent: CCO
Product: O=C1CN(c2ccc(OCC(F)(F)C(F)F)cc2)C(=O)CN1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
The resulting N-chloroacetyl-N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (1.9 g) was dissolved in 20 ml of 10.5% ammonia-ethanol and the solution was stirred at 60° C. for four hours. After cooling, the crystals separated rated out therefrom were collected by filtration and washed with cold ethanol to give 1.5 g of 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,5-piperazinedione as colorless crystals.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([CH:16]([C:19]2[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([OH:29])=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=2)CCl)C=C(C(C)(C)C)C=1O)(C)(C)C.[C:34]([O-:37])(=O)[CH3:35].[Na+]>C(O)(=O)C>[C:30]([C:21]1[CH:20]=[C:19]([CH:16]=[CH:7][C:6]2[CH:5]=[C:35]([C:23]([CH3:25])([CH3:24])[CH3:22])[C:34]([OH:37])=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=2)[CH:24]=[C:23]([C:25]([CH3:27])([CH3:26])[CH3:28])[C:22]=1[OH:29])([CH3:32])([CH3:31])[CH3:33]
Reactant: CC(C)(C)c1cc(C(CCl)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Yield: 162.4 %

Procedure:
To a 100 milliliter round-bottomed flask equipped with a magnetic stirrer and a reflux condenser capped with a paraffin-sealed gas bubbler was added 9.45 grams (0.022 mole) of 1,1-bis(3,5-di-t-butyl-4-hydroxyphenyl)-2-chloroethane (from EXAMPLE 10 above), 20 milliliters of glacial acetic acid, and 2.0 grams (0.024 mole) of anhydrous sodium acetate. The mixture was stirred and heated to reflux for 4 hours. The resulting homogeneous solution was cooled to ambient temperatures to induce crystallization of the product. The precipitated solid material was collected by suction filtration, washed successively with acetic acid and water, and dried to yield 7.8 grams (90 percent) of 3,5,3',5'-tetra-t-butyl-4,4'-dihydroxystilbene, which identity was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]=4[N+:31]([O-])=O)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2>[C].[Pd].C(O)C>[NH2:31][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:20]=1[O:19][CH2:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][N:10]([C:6]2[C:3]3[CH:4]=[CH:5][S:1][C:2]=3[CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14]1)[C:24]([NH:26][CH2:27][CH3:28])=[O:25]
Reactant: CCNC(=O)c1ccc(OCCCN2CCN(c3cccc4sccc34)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCNC(=O)c1ccc(OCCCN2CCN(c3cccc4sccc34)CC2)c(N)c1
Yield: 84.7 %

Procedure:
5% palladium carbon (0.8 g) was added to an ethanol solution (30 ml) of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-N-ethyl-3-nitrobenzamide (1.0 g, 2.1 mmol) and the mixture was subjected to catalytic reduction at room temperature under normal pressure. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. Water was added to the residue and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and thereafter concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1→20:1). The purified product was concentrated under reduced pressure to obtain 3-amino-4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-N-ethyl-benzamide (0.78 g, 83% yield) as yellow amorphous solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[CH2:26][NH2:27])[C:6]([NH:8][C@H:9]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:12]=2[O:11][B:10]1[OH:22])=[O:7].CC(O)=O.[CH3:32][C:33]([CH3:35])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[NH2:27][CH2:26][C:25]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:12]=3[O:11][B:10]2[OH:22])=[O:7])=[CH:4][C:3]=1[CH2:2][NH:1][CH:33]([CH3:35])[CH3:32]
Reactant: NCc1ccc(C(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)cc1CN
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NCc1cc(C(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)ccc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(3,4-bis(aminomethyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 14 (44.1 mg) in methanol (2 mL) was added TEA (0.042 mL), AcOH (0.050 mL), acetone (0.030 mL), and sodium triacetoxyborohydride (70 mg). The resulting reaction mixture was stirred at room temperature for overnight. After removal of the solvents, the product was then purified by reverse phase HPLC and dried using lyophilization. ESI-MS m/z 412 (MH)+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:25](Br)[CH:26]([CH3:28])[CH3:27]>O>[CH3:25][CH:26]([CH3:28])[CH2:27][C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(C)CBr
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(CC(C)C)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium hydride (21 gram, 0.482 mole) was added to 200 ml dimethylformamide at 20° C. under nitrogen atmosphere. Then 80 grams (0.325 mole) of triethyl ethane-1,1,2-tricarboxylate (compound [3] made in example I) was added to the solution at a temperature of below 30° C. The reaction mixture was maintained at room temperature for 4 hours and 52 ml (0.482 mole) of isobutyl bromide (R2-X) was added drop wise after which the reaction mixture was stirred for another 20 hours at room temperature. When the reaction was complete 1 liter of cold water was added and the organic materials were extracted with dichloromethane (500 ml). The organic extracts were dried over sodium sulfate filtered and evaporated to give an oily substance, which was vacuum distilled to give 88 gram (89% of the theoretical maximum yield) triethyl 4-methylpentane-1,2,2-tricarboxylate, compound [4].
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2].[H][H]>[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][CH2:53][C:54]3[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(F)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: [H][H]
Agent: [Rh]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCCc4ccc(F)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 34 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-p-fluorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (22 mg in 2 ml ethanol) was added 6 mg of 5% rhodium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 45 minutes, the mixture was filtered over Celite, concentrated and purified by preparative TLC on silica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (7.5 mg).
Reaction SMILES: [ClH:1].C([N:5]1[CH2:9][CH2:8][C@H:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]3[O:20][C:21]4[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[NH:29])=[CH:24][C:22]=4[CH:23]=3)=[CH:13][C:12]=2[OH:31])[CH2:6]1)(=O)C>Cl>[ClH:1].[ClH:1].[OH:31][C:12]1[CH:13]=[C:14]([CH2:17][CH2:18][C:19]2[O:20][C:21]3[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[NH:29])=[CH:24][C:22]=3[CH:23]=2)[CH:15]=[CH:16][C:11]=1[O:10][C@H:7]1[CH2:8][CH2:9][NH:5][CH2:6]1
Reactant: CC(=O)N1CC[C@H](Oc2ccc(CCc3cc4cc(C(=N)N)ccc4o3)cc2O)C1
Agent: Cl
Product: N=C(N)c1ccc2oc(CCc3ccc(O[C@H]4CCNC4)c(O)c3)cc2c1
Yield: 64.8 %

Procedure:
1.0 g of 2-[2-[4-[((3S)-1-acetyl-3-pyrrolidinyl)oxy]-3-hydroxyphenyl]ethyl]-5-benzofurancarboxamidine hydrochloride was dissolved in 30 ml of 6 N hydrochloric acid, and the solution was refluxed under heating for 4 hours. After distilling off the solvent, the resulting residue was subjected to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/acetonitrile mixture as an elution solvent. In this way, 320 mg of the title compound was obtained in a solid form.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[C:14](OC)=[O:15])[CH3:9]>C1COCC1.CCOCC>[CH3:9][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([CH2:14][OH:15])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=1)[CH3:7]
Reactant: COC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)c(CN(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 45.8 %

Procedure:
A solution of lithium aluminium hydride in THF (1 M, 7 mL, 7 mmol) was added dropwise to a stirring solution of the ester compound of Example 151 (1.66 g, 4.7 mmol) in THF (25 mL) at room temperature under nitrogen. The mixture was stirred for 3 h before being diluted with ether (100 mL) and quenched by the cautious addition of sodium hydroxide (2 M) (approximately 1 mL). The mixture was stirred for 10 min before being dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography {SiO2; [(MeOH/ 880 NH3) 9:1] in DCM (2% →4%)] gave the desired alcohol compound (0.7 g, 48%); Example 90: δH(CDCI3, 400 MHz) 2.13 (6 H, s), 3.39 (2 H, s), 4.70 (2 H, s), 6.93-6.98 (3 H, m), 7.30 (1 H, d), 7.52-7.56 (3 H, m); MS m/z (TS+) 326 (MH+).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20]Br.[CH3:22][Si:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][C:26]#[C:27][CH2:28]O>C(Cl)Cl.CCCCC>[Br:20][CH2:28][C:27]#[C:26][CH2:25][CH2:24][Si:23]([CH3:31])([CH3:30])[CH3:22]
Reactant: C[Si](C)(C)CCC#CCO
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Product: C[Si](C)(C)CCC#CCBr
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a flame dried flask was added PPh3 (1.76 g, 6.73 mmol) followed by dry CH2Cl2 (60 mL). The mixture was placed in an ice bath and bromine (0.34 mL, 6.41 mmol) was added dropwise. A small amount of PPh3 was added until the reaction went from yellow to clear in color. After 0.5 h at 0° C., 5-trimethylsilanylpent-2-yn-1-ol (1.0 g, 6.41 mmol) was dissolved in CH2Cl2 (5 mL) and added dropwise. After 4 h at 0° C., the reaction mixture was poured into a separatory funnel, diluted with pentane (250 mL) and extracted with H2O (100 mL) and sat. NaHCO3 (100 mL). The organic layer was dried (MgSO4), filtered and reduced in volume to 50 mL. The crude solution was chromatographed on a pad of silica gel with pentane (500 mL). After evaporation of the pentane, (5-bromopent-3-ynyl)trimethylsilane (1.2 g 87%) was obtained as a clear oil: IR (neat, cm-1) 2953, 2922, 2899, 2230, 1431, 1317, 1248, 1208, 852; 1H NMR (300 MHz, CDCl3) δ0.03 (s, 9H), 0.79 (t, J=8 Hz, 2H), 2.28 (tt, J1 =8 Hz, J2 =2 Hz, 2H), 3.92 (t, J=2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ1.7, 13.6, 15.7, 15.8, 74.6, 90.2; HRMS (EI) m/z calcd for C7H12BrSi (M-CH3) 202.9892, found 202.9889 LRMS (EI) m/z 203 (M-CH3), 137, 73, 66.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:30]([OH:32])=[O:31])=[C:19]([C:20]3[NH:21][C:22](=[O:29])[C:23]([CH:26]([CH3:28])[CH3:27])([CH3:25])[N:24]=3)[C:14]=2[N:13]=[C:12]1[CH3:33])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.CO>[CH2:4]([N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:30]([O:32][CH3:3])=[O:31])=[C:19]([C:20]3[NH:21][C:22](=[O:29])[C:23]([CH:26]([CH3:28])[CH3:27])([CH3:25])[N:24]=3)[C:14]=2[N:13]=[C:12]1[CH3:33])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: Cc1nc2c(C3=NC(C)(C(C)C)C(=O)N3)c(C(=O)O)ccc2n1Cc1ccccc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ccc2c(nc(C)n2Cc2ccccc2)c1C1=NC(C)(C(C)C)C(=O)N1
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
A solution of diazomethane in ether is added to a suspension of 1-benzyl-4-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-2-methyl-5-benzimidazolecarboxylic acid (1.15 g, 2.84 mmol) in methanol until the yellow color persists The reaction is stirred for 5 minutes, quenched with 2 drops of acetic acid and concentrated in vacuo. The resultant residue is purified by HPLC (silica gel, ethyl acetate eluent) to give the title product as a white powder (0.480 g, 40.3%), mp 194°-196° C.
Reaction SMILES: [CH:1]([C:3]1(O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].[C:10](OC)([O:14]C)([O:12][CH3:13])[CH3:11]>C(O)(=O)CC>[C:3]1(=[CH:1][CH2:2][CH2:11][C:10]([O:12][CH3:13])=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C=CC1(O)CCCCC1
Reactant: COC(C)(OC)OC
Solvent: CCC(=O)O
Product: COC(=O)CCC=C1CCCCC1
Temperature: 115 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
A distillation column-provided four-necked flask having a volume of one liter, which was equipped with a dropping funnel, a thermometer, a stirring device and a reflux ratio regulator, was charged with 250 g (1.922 moles) of 1-vinyl-1-cyclohexanol, 415.6 g (3.843 moles) of trimethyl orthoacetate and 1.4 g (0.019 moles) of propionic acid, and the internal temperature was raised to 115° C. Heating was continued for 12 hours while removing a fraction of not higher than 65° C. from a column top of the distillation column. After confirming the disappearance of 1-vinyl-1-cyclohexanol by a gas chromatographic analysis of the reaction solution, the reaction solution was distilled in vacuo. Fractions of from 120 to 130° C./1.2 kPa were collected to obtain 301.2 g (1.653 moles) of methyl 4-cyclohexylidenebutanoate. The yield was 86.0%.
Reaction SMILES: C([O-])(=[O:3])C.[K+].Cl[C:7]1[N:12]=[N:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:32])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[C:33]([C:35]1[CH:45]=[C:44]([CH3:46])[C:38]2[N:39]([CH3:43])[C:40](=[O:42])[O:41][C:37]=2[CH:36]=1)=[O:34]>C(O)(=O)C>[CH3:43][N:39]1[C:38]2[C:44]([CH3:46])=[CH:45][C:35]([C:33]([C:8]3[C:7](=[O:3])[NH:12][N:11]=[C:10]([N:13]4[CH2:14][CH2:15][CH:16]([N:19]5[CH2:25][CH2:24][C:23]6[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:22]=6[NH:21][C:20]5=[O:32])[CH2:17][CH2:18]4)[CH:9]=3)=[O:34])=[CH:36][C:37]=2[O:41][C:40]1=[O:42]
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)c(Cl)nn3)CC1)C(=O)N2
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)c(=O)[nH]n3)CC1)C(=O)N2
Reaction time: 16 h

Procedure:
0.10 g (1.02 mmol) potassium acetate were added to 0.13 g (0.20 mmol) 3-{1-[6-chloro-5-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one (mixture) in 2 mL acetic acid and the mixture was boiled for 16 h under a nitrogen atmosphere. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.C(N(CC)CC)C.[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl>[Br:18][CH2:19][C:20]([O:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:21]
Reactant: COc1ccc(CO)cc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)CBr)cc1
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
To a -78° C. solution of p-methoxybenzyl alcohol (6.91 g, 50 mmol) and triethylamine (6.95 mL, 50 mmol) in anhydrous CH2Cl2 (50 mL) was added a solution of bromoacetyl bromide (10.1 g, 50 mmol) in CH2Cl2 at -78° C. under nitrogen, over a period of 10 min. The cooling bath was removed, and the reaction mixture was stirred for 2 h. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to provide 12 g (93% yield) of p-methoxybenzyl bromoacetate as a dark colored oil which was used in the next reaction without purification. A portion was purified by column chromatography on silica gel (elution with 20% ethyl acetate/hexanes) to give a clear, colorless oil. 1H NMR (300 MHz, CDCl3) δ3.79 (s, 3H), 3.83 (s, 2H), 5.12 (s, 2H), 6.87 (m, 2H), and 7.30 (m, 2H); IR (film) 1738 cm-1 ; MS (ESI/NH4OAc) M+NH4+ =276.