Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:3][CH:4]([CH2:12]O)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>C(Cl)Cl>[S:30]([O:1][CH:2]([CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:3][C:4](=[CH2:12])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])([CH3:33])(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)C(CO)CC(O)CCOC1CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(CC(CCOC1CCCCO1)OS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxy-2-hydroxymethyl-6-tetrahydropyranyloxyhexanoate (0.28 g) and triethylamine (0.56 g) in methylene chloride (20 ml), mesylchloride (0.56 g) dissolved in methylene chloride (10 ml) was added dropwise under nitrogen atmosphere and ice-cooling. The mixture was stirred for 2 hours at room temperature and concentrated in vacuo. Saturated aqueous sodium bicarbonate solution was added to the oily residue and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was dissolved in benzene (20 ml), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 g) was added to the solution. The mixture was stirred for 3 hours. Aqueous citric acid solution was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 0.22 g (31%) of tert-butyl 4-mesyloxy-2-methylene-6-tetrahydropyranyloxyhexanoate.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:13])[CH:3]=1.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.N>C(O)C>[CH3:13][C:4]1[CH:3]=[C:2]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([C:15]([F:14])([F:23])[F:24])=[CH:17][CH:18]=2)[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CSc1nc2nc(C)cc(Cl)n2n1
Agent: N
Solvent: CCO
Product: CSc1nc2nc(C)cc(Nc3ccc(C(F)(F)F)cc3)n2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 7-chloro-5-methyl-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine (Intermediate 8 (0.2 g, 0.932 mmol) in ethanol (5 mL), 4-(trifluoromethyl)aniline (ALDRICH, 0.117 mL, 0.932 mmol) was added and the mixture was stirred at room temperature for 3 h. Anhydrous ammonia (0.133 mL, 0.932 mmol) was added and solvent was removed in vacuo. The residue was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures form 95:5 to 40:60%) to yield the title compound as a white solid.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[OH-].[K+].O>CN1CCCC1=O>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([NH:37][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[N:23][CH:22]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: NC1CCCCC1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1cnc2[nH]cc(Cc3cnc(NC4CCCCC4)nc3)c2c1
Temperature: 155 °C
Yield: 25.7 %

Procedure:
In a microwave vial, to 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (37, 60 mg, 0.13 mmol) in 1.0 mL of N-methylpyrrolidinone, cyclohexanamine (62, 0.20 g, 2.0 mmol) is added. The reaction is heated at 155° C. for 25 minutes in a microwave, then potassium hydroxide (1.0 mL, 1.00 M in water, 1.0 mmol) is added and the reaction heated at 95° C. for 15 minutes in a microwave. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are collected and concentrated under vacuum to provide the desired compound (P-3001, 11.4 mg). MS (ESI) [M+H+]+=341.9.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[NH:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[NH:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(Nc1cc(-c2cnccn2)ccc1[N+](=O)[O-])N1CCCC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(-c2cnccn2)cc1NC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 1 N-(2-nitro-5-(pyrazin-2-yl)phenyl)pyrrolidine-1-carboxamide (0.11 g, 0.35 mmol) in methanol (6 mL) and THF (6 mL) was added Pd/C (0.04 g, 0.94 mmol, 0.33 equiv.). The reaction mixture was degassed then stirred at room temperature under H2 atmosphere for 1h. The reaction was filtered through celite and concentrated. The crude solid was washed with ether, and dried under reduced pressure to obtain of pure N-(2-amino-5-(pyrazin-2-yl)phenyl)pyrrolidine-1-carboxamide (0.07 g, 70% yield). ESI+ MS: m/z 284 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 9.30 (s, 1H), 8.55 (s, 1H), 8.40-8.39 (m, 1H), 7.88 (s, 1H), 7.71-7.69 (m, 1H), 7.53 (s, 1H), 6.81 (d, J=8.5 Hz, 1H), 5.31 (s, 2H), 3.40-3.37 (m, 4H), 1.86 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=3[CH:22]=2)=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:22]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(F)cc3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(-c3ccc(F)cc3)ccc2OCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 85.5 %

Procedure:
To methyl 7-(4-fluorophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (0.27 g) were added THF (5.0 ml), ethanol (10.0 ml) and 2N sodium hydroxide solution (1.0 ml), and the mixture was stirred at room temperature for 19 hours. Under reduced pressure, the solvent was removed, and the residue was diluted with water (100 ml). The aqueous layer was made acidic with hydrochloric acid, and the mixture was extracted with ethyl acetate (100 ml). The organic layer was dried with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized and washed with hexane to give 7-(4-fluorophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.22 g, 86%) as white crystals.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[F:9][C:10]([F:46])([F:45])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:14][N:15]([C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1)[C@H:16]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]2[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]1=2.N1C=CC=CC=1>C(Cl)Cl>[F:45][C:10]([F:9])([F:46])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=1)[CH2:14][N:15]([C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1)[C@H:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:4](=[O:5])[CH:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[C:18]2[CH:23]=[C:24]([C:28]([F:29])([F:30])[F:31])[C:25]([CH3:27])=[CH:26][C:17]1=2
Reactant: CCC(CC)C(=O)Cl
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(CC)C(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)cc21
Reaction time: 1 h
Yield: 106.7 %

Procedure:
Add 2-ethyl-butyryl chloride (0.014 g, 0.108 mmol) dropwise under an atmosphere of nitrogen to a 0° C. cooled solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.060 g, 0.108 mmol) and pyridine (0.010 g, 0.108 mmol) in methylene chloride (5 mL). After stirring for 1 h, wash the reaction with saturated aqueous sodium bicarbonate solution (10 mL), 2N aqueous hydrogen chloride solution (10 mL), and brine (10 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to afford the title compound as a colorless gum (0.075 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 0.71-2.16 (m, 16H), 2.34-2.43 (m, 1H), 2.43 (s, 3H), 2.50-2.41 (m, 1H), 4.14 (s, 3H), 4.25-4.67 (m, 2H), 6.89 (bs, 1H), 7.43 (s, 1H), 7.75 (s, 2H), 7.85 (s, 1H); ESI MS m/z 651 [C29H31F9N6O+H]+.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][O:17][CH:18]1[CH2:21][N:20]([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N:30]=2)[CH2:19]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH3:16][O:17][CH:18]1[CH2:21][N:20]([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N+:30]=2[O-:4])[CH2:19]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC1CN(CCCc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1CN(CCCc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
H2O2 (70%, 2.0 mL, 39 mmol) was added dropwise to a stirred solution of TFAA (5.4 mL, 39 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 82 (0.93 g, 3.0 mmol) and TFA (1.5 mL, 19.5 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (30 mL) and extracted with DCM (3×150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 83 (0.60 g, 60%) as a red gum: 1H NMR δ 8.31 (s, 1H, H-9), 8.28 (s, 1H, H-5), 4.60-4.70 (m, 2H, CH2N), 4.33-4.40 (m, 1H, CHO), 3.60-3.75 (m, 2H, CH2N), 3.33 (s, 3H, CH3O), 3.25-3.32 (m, 2H, CH2N), 3.12-3.25 (m, 6H, H-6, H-8, CH2), 2.27-2.33 (m, 4H, H-7, CH2); 13C NMR δ 155.5, 152.3, 151.2, 139.1, 134.1, 115.9, 113.9, 67.8, 61.0, 58.9, 56.9, 55.6, 32.9, 32.4, 26.9, 25.6, 22.9; HRMS (FAB+) calcd for C17H23N4O3 (MH+) m/z 331.1770, found 331.1771.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]12[C:14](=[O:15])[O:13][C:11](=[O:12])[CH:9]1[CH2:10]2.[Cl-].[Al+3].[Cl-].[Cl-].CN(C)C=O>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]([C@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[O:15])=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: O=C1OC(=O)C2CC12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)[C@H]1C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.5 g (0.040 mol) of chlorobenzene and 5.0 g (0.0446 mol) of 1,2-cyclopropanedicarboxylic acid anhydride were successively added dropwise to a mixture of 60.0 g (0.45 mol) of anhydrous aluminium chloride and 9 mL (0.115 mol) of anhydrous dimethylformamide while maintaining a reaction temperature of 60° C. to 70° C. and the mixture was then kept at 70° C. for 1 hour. After cooling, the reaction mixture was stirred into a mixture of 500 g of crushed ice and 60 mL of concentrated hydrochloric acid, the precipitate was suction filtered, washed thoroughly with water and dried over Siccapent in a vacuum drying chamber at a temperature of 50° C. 7.8 g (87% of theoretical) of colorless crystals were obtained, m.p. 150° C.-153° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:11]1[C:12]([C:18]([OH:20])=[O:19])=[N:13][C:14](Cl)=[CH:15][CH:16]=1.Cl>CS(C)=O.O>[CH2:3]([S:9][C:11]1[C:12]([C:18]([OH:20])=[O:19])=[N:13][C:14]([S:9][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCS
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCSc1ccc(SCCCCCC)c(C(=O)O)n1
Temperature: 135 °C
Yield: 75.4 %

Procedure:
To 300 ml of DMSO was added 84.5 g of powdered NaOH with vigorous stirring followed by the addition of 150 g of n-hexyl mercaptan. The anion of the mercaptan was allowed to form and then 111 g of 3,6-dichloro-2-pyridinecarboxylic acid in 110 ml of DMSO was added through a dropping funnel. The temperature was increased during addition to 135° C. and maintained at that temperature for 21/2 hours. Upon cooling the brown solution was poured into three volumes of water. The resulting solution was acidified with HCl and extracted with 1,1,1-trichloroethane. The organic layer was dried over MgSO4 and the solvent removed on a rotary evaporator. The reaction yielded 155 g (68% yield) of 3,6-bis(n-hexylthio)-2-pyridinecarboxylic acid as a dark oil which solidified on standing; m.p. 40°-42° C.
Reaction SMILES: [Br:1][CH:2]([CH:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]C)=[O:4].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(Br)C(Br)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)C(Br)=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 50 g of methyl 2,3-dibromo-3-phenylpropanoate 1B, 100 ml of triethylamine and 500 ml of toluene is heated to boiling for 1 h, then cooled to room temperature and filtered. The filtrate is evaporated in vacuo and the α-bromocinnamic acid 1C thus obtained is reused without purification. 0.2 mol of imidazopyridine, dissolved in 150 ml of anhydrous DMF, is added dropwise with stirring to a suspension of 4.7 g of NaH (80% strength in mineral oil) in 100 ml of anhydrous DMF. During this process, the temperature of the mixture is kept below 35° C. by cooling with ice. After addition is complete, the mixture is stirred at room temperature for 1 h. The α-bromocinnamic acid previously prepared is dissolved in 200 ml of anhydrous DMF and the solution of the azole sodium salt is added dropwise with stirring while cooling with ice. After stirring at room temperature for 2 hours, 10.8 ml of glacial acetic acid are added, the mixture is stirred into 1.5 l of ice water and extracted several times with ethyl acetate, and the organic phases are washed with water. The organic phases are dried and evaporated in vacuo, and the residue is crystallized from ethyl acetate. 37.0 g of 1D are obtained as pale yellow crystals.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:31])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37]Cl>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=5)=[CH:18]4)=[CH:13][C:12]=3[O:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Reactant: COCCOCCl
Product: COCCOCOc1cc2ccc(-c3ccc(C(=O)OC)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 54.1 %

Procedure:
Following the basic procedure of Example 12, by reacting 980 mg (2.4 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 330 μl (28.6 mmol) of methoxyethoxymethyl chloride, 650 mg (55%) of the expected compound were obtained in the form of an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][C:9]2=[C:10]3[C:14](=[CH:15][CH:16]=[C:8]2[O:7][CH2:6][CH2:5]1)[NH:13][CH:12]=[CH:11]3.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])#[N:19].O>CN(C=O)C>[CH3:3][N:4]1[CH2:17][C:9]2=[C:10]3[C:14](=[CH:15][CH:16]=[C:8]2[O:7][CH2:6][CH2:5]1)[N:13]([S:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]#[N:19])(=[O:28])=[O:27])[CH:12]=[CH:11]3
Reactant: CN1CCOc2ccc3[nH]ccc3c2C1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3C#N)c2C1
Reaction time: 1 h
Yield: 35.4 %

Procedure:
NaH (60% in mineral oil, 0.040 g, 1.0 mmol) was charged into a pyrex tube under nitrogen gas and 2-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Intermediate 6, 100 mg, 0.492 mmol) in dry DMF (1 mL) was added. The reaction mixture was stirred at room temperature for 20 minutes before 2-cyanobenzenesulfonyl chloride (0.11 g, 0.50 mmol) was added and the reaction mixture was stirred for 1 hour. Water (2 mL) was added and the solution was extracted with DCM. The combined organics were evaporated and the solid residue was washed with diethyl ether to give 64 mg of the title compound. MS m/z 368 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C:12]([O:14][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC(CNC(=O)OC(C)(C)C)CC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CC(CNC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 108.2 %

Procedure:
To a stirred suspension of (37) (1.24 g, 4.78 mmol) and Cs2CO3 (1.56 g, 4.78 mmol) in DMF (20 mL) was added benzyl bromide (0.56 mL, 4.68 mmol). The resulting mixture was stirred at ambient temperature until the reaction was complete (˜2 h, as monitored by LC/MS). The mixture was poured into ice water and extracted with dichloromethane. The combined organic phase was washed with water and brine, then dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (38) (1.77 g, 100%), which was used without further purification in the following example. 1H-NMR (CDCl3, 400 MHz): δ 0.86 (2 d, 6H), 1.13 (m, 2H), 1.42 (s, 9H), 1.62 (m, 1H), 2.31 (m, 2H), 3.00 (m, 1H), 3.18 (m, 1H), 4.75 (br.s, 1H), 5.10 (s, 2H), 7.33 (m, 5H). MS (ESI) m/z 372.30 (M+Na+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[CH:12]=[CH2:13].[CH2:14]([NH2:17])[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([NH:17][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:12]=[CH2:13])[CH:15]=[CH2:16]
Reactant: C=Cc1c(F)ccc([N+](=O)[O-])c1F
Reactant: C=CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCNc1c([N+](=O)[O-])ccc(F)c1C=C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of 1,3-difluoro-4-nitro-2-vinylbenzene (115 mg, 0.621 mmol) in DMF (3 mL) was added allylamine (0.0513 mL, 0.683 mmol) and potassium carbonate (0.173 g, 1.24 mmol). The reaction mixture was stirred at RT for 2 h, and then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 1-5% EtOAc in cyclohexane) affording the title compound as a yellow oil (109.6 mg, 79%). 1H NMR (CDCl3, 300 MHz): 8.08 (1H, dd J=9.4, 5.8 Hz), 7.64 (1H, bs), 6.57 (1H, t, J=9.3 Hz), 6.51 (1H, dd, J=18.0, 11.6 Hz), 5.81 (1H, tdd, J=17.1, 10.2, 5.5 Hz), 5.72 (1H, ddd, J=18.0, 2.5, 1.6 Hz), 5.65 (1H, ddd, J=11.6, 1.5, 0.9 Hz), 5.26 (1H, dq, J=17.1, 1.5 Hz), 5.17 (1H, dq, J=10.2, 1.4 Hz), 3.98 (2H, ddt, J=6.3, 5.5, 1.6 Hz)
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:9][C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[C:3]([O:18][CH3:19])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH:13]4[CH2:14][CH2:15]4)[CH2:9][C:8](=[O:16])[NH:7][C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)NC(=O)CN(CC1CC1)C2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)NC(=O)CN(CC1CC1)C2
Yield: 23.9 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-cyclopropylmethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (150 mg, 0.57 mmol) and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (143 mg, 0.48 mmol) were coupled to afford (1S,2S,3R,4R)-3-[5-chloro-2-(4-cyclopropylmethyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (60 mg, 24%) as a mustard yellow solid following preparative tlc on silica gel (10% MeOH-DCM); 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 2H), 7.90 (s, 1H), 7.52 (s, 1H), 7.16 (d, J=8 Hz, 1H), 6.79 (s, 1H), 6.30 (m, 3H), 5.69 (s, 1H), 4.38 (t, J=8 Hz, 1H), 3.93 (s, 3H), 3.78 (m, 2H), 3.43 (m, 2H), 3.06 (s, 1H), 2.87 (s, 1H), 2.57 (m, 3H), 2.24 (d, J=9 Hz, 1H), 1.60 (d, J=9 Hz, 1H), 0.92 (m, 1H), 0.59 (m, 2H), 0.22 (m, 2H); MS (m/e) 524 (M+1); mp 152° C.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH:6]=[CH:7][C:8]([CH3:22])=[CH:9][CH:10]=[CH:11][CH:12]=[C:13]([CH3:21])[CH:14]=[CH:15][CH:16]=[C:17]([CH3:20])[CH2:18][OH:19])[CH2:3][OH:4]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:20][C:17](=[CH:16][CH:15]=[CH:14][C:13]([CH3:21])=[CH:12][CH:11]=[CH:10][CH:9]=[C:8]([CH3:22])[CH:7]=[CH:6][CH:5]=[C:2]([CH3:1])[CH:3]=[O:4])[CH:18]=[O:19]
Reactant: CC(C=CC=C(C)CO)=CC=CC=C(C)C=CC=C(C)CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C=O)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=O
Yield: 73.2 %

Procedure:
To a suspension of 2,6,11,15-tetramethyl-hexadeca-2,4,6,8,10,12,14-heptaene-1,16-diol (50 g, 0.166 mol) in 3000 mL of DCM was added portionwise manganese dioxide (500 g, 5.75 mol) at room temperature. The mixture 15 was After heated to reflux for 2 h, the solid was filtered via celite and washed with CH2Cl2. The solvent was removed under reduced pressure to give 36 g of pure product (73%). 1H-NMR (300 Hz DMSO-d6) δ 9.42 (s, 2H, CHO), 7.18 (s, 1H, CH), 7.16 (s, 1H, CH), 6.93 (m, 6H, CH), 2.01 (s, 6H, CH3), 1.82 (s, 6H, CH3).
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[ClH:13]>C(Cl)(Cl)Cl>[Cl:13][CH2:3][CH2:2]/[CH:1]=[CH:4]/[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: OC(c1ccc(F)cc1)C1CC1
Reactant: Cl
Solvent: ClC(Cl)Cl
Product: Fc1ccc(/C=C/CCCl)cc1

Procedure:
Dissolve 12.8 g (0.077 mole) of α-cyclopropyl-4-fluorobenzenemethanol in 60 ml of CHCl3, add 20 ml of concentrated HCl and reflux overnight. Separate the two layers, and extract the aqueous layer with methylene chloride. Combine the methylene chloride extracts with the chloroform layer and wash with saturated aqueous sodium bicarbonate, and dry over magnesium sulfate. Evaporate the organic solvents to yield the title compound.