Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]([C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:26])=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:27]([N:25]([CH3:26])[C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:35])=[O:5])[S:12][CH:13]=2)=[CH:24][CH:23]=1)(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN(C(=O)c1ccccc1)c1ccc(OCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1ccccc1)c1ccc(OCCc2csc(SC(C)(C)C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.8 %

Procedure:
2-{[4-(2-{4-[Benzoyl(methyl)amino]phenoxy}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (290 mg) obtained in Example 55-1 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (170 mg) as a colorless oil.
Reaction SMILES: CO[N:3]=[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:29][C:28]([CH3:31])([CH3:30])[NH:27][C:26]([CH3:33])([CH3:32])[CH2:25]4)[N:18]=3)=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])([O-])(=O)=O.[Na+].[Na+].CCOC(C)=O>C1COCC1>[NH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:29][C:28]([CH3:31])([CH3:30])[NH:27][C:26]([CH3:32])([CH3:33])[CH2:25]4)[N:18]=3)=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)[CH3:5]
Reactant: CON=C(C)c1ccc(-c2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)s2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(N)c1ccc(-c2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)s2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Compound of Example 51 (366 mg, 0.79 mmol) was dissolved in 20 ml THF and 0.35 ml of LAH (˜2.3 M suspension in THF) added dropwise at room temperature. Afterwards this mixture was stirred for 2 hours at 60° C. After cooling to room temperature 40 ml of saturated sodium sulfate solution was added and stirred for 15 minutes. The title compound was isolated by extraction with EtOAc and purified by chromatography on silicagel (DCM/MeOH/ammonia:95/5/0.5). Yield: 160 mg (47%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][N:12]([CH:14](OC)OC)[CH3:13]>>[CH3:11][N:12]([CH3:14])/[CH:13]=[CH:9]/[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:10]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc(F)c1
Product: CN(C)/C=C/C(=O)c1cccc(F)c1
Yield: 92 %

Procedure:
The title compound was prepared in 92% yield from 1-(3-fluorophenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.93 (3H, s), 3.15 (3H, s), 5.65 (1H, d, J=12.4 Hz), 7.11-7.16 (1H, m), 7.34-7.39 (1H, m), 7.57-7.67 (2H, m), 7.81 (1H, d, J=12.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[NH:6][C:7]([C:9]3[C:13]4[CH2:14][NH:15][CH2:16][CH2:17][C:12]=4[NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22]>>[CH:21]([NH:24][C:25]([N:15]1[CH2:16][CH2:17][C:12]2[NH:11][N:10]=[C:9]([C:7]3[NH:6][C:5]4[CH:18]=[C:19]([CH3:20])[C:2]([CH3:1])=[CH:3][C:4]=4[N:8]=3)[C:13]=2[CH2:14]1)=[O:26])([CH3:23])[CH3:22]
Reactant: CC(C)N=C=O
Reactant: Cc1cc2nc(-c3n[nH]c4c3CNCC4)[nH]c2cc1C
Product: Cc1cc2nc(-c3n[nH]c4c3CN(C(=O)NC(C)C)CC4)[nH]c2cc1C

Procedure:
By proceeding in a manner similar to Example 255(a) above but using 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine [Example 251(a)] and isopropylisocyanate, and subjecting the reaction product to flash column chromatography eluting with ethyl acetate/methanol (19:1, v/v), there was prepared 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide (93.3 mg) as an off-white solid. LC-MS (METHOD M): RT=10.15 minutes, 353 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C@@H:9]1(N2C3N=CN=C(O)C=3N=C2)[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].P([O-])(O)(O)=O.[K+]>>[CH:5]1[N:1]([C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1
Reactant: NC(=O)c1nc[nH]n1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: O=P([O-])(O)O
Agent: [K+]
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 24 h

Procedure:
Each 10 ml of the above suspensions of the treated microbial cells and 10 ml of a suspension of untreated microbial cells obtained similarly as in Example 1 was admixed with each 10 ml of a reaction substrate solution (pH 7.0) containing 20 mM 1,2,4-triazole-3-carboxamide, 20 mM inosine and 25 mM monopotassium dihydrogen phosphate, and the reaction was carried out at 60° C. for 24 hours. Analysis of ribavirin yields gave the results as shown in Table 4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[H-].[Na+].[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:8])=[O:16]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1cccnc1

Procedure:
N-[(tert-Butoxy)carbonyl]pyridine-3-sulfonamido 2,2-dimethylpropanoate (77) is synthesised from 3-pyridine sulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme 2. (0.99 g, 58%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.16-9.26 (1H, m), 8.89 (1H, d, 4.4 Hz), 8.36 (1H, d, 8.2 Hz), 7.54 (1H, dd, 8.2, 4.9 Hz), 1.42 (9H, s), 1.37 (9H, s)
Reaction SMILES: [F:1][C:2]1[C:11]([B:12]2[O:16]C(C)(C)C(C)(C)[O:13]2)=[C:10]([CH3:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].BrN1C(=O)CCC1=O.N(/C1(C#N)CCCCC1)=N\C1(C#N)CCCCC1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:11]2[B:12]([OH:13])[O:16][CH2:21][C:10]=2[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1F
Agent: N#CC1(/N=N/C2(C#N)CCCCC2)CCCCC1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc2c(c1F)B(O)OC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution or methyl 2-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.6 g, 2.040 mmol) in 40 ml CCl4 was added N-Bromosuccinimide (0.363 g, 2.040 mmol) and (E)-1,1′-(diazene-1,2-diyl)dicyclohexanecarbonitrile (0.050 g, 0.204 mmol). The mixture was stirred at 80° C. overnight. The reaction mixture was extracted with 5% KOH in water (3×20 ml). The water phase stirred for 1 hour and then the solution was cooled to 0° C. and slowly acidified to pH<1 with 1N HCl. The precipitant that formed was filtered onto fritted filter and dried in vacuum for overnight to give 0.137 g of IXS-5-49-1, 1H NMR in DMSO-d6 is consistent with desired product. MS [MH+]=196.
Reaction SMILES: [OH:1][CH:2]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:3]1[NH:12][C:13]([CH3:15])=[O:14].[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[O:18]>>[OH:1][CH:2]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:3]1[NH:12][C:13]([CH3:15])=[O:14].[OH:20][C:16]([C:17]1([O:5][C@@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[C@H:3]([NH:12][C:13]([CH3:15])=[O:14])[C@@H:2]([OH:1])[CH2:19]1)[OH:18])=[O:21]
Reactant: CC(=O)C(=O)[O-]
Agent: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O

Procedure:
The second reaction was run with the recovered enzyme under the same conditions with exceptions in the amounts of substrates (40 mmol of ManNAc and 400 mmol of pyruvate) and the volume of solution (260 mL). The 10-day operation gave 91% conversion of ManNAc to Neu5Ac. The recovered enzyme retained 50% of its initial activity, and the products in solution were stored at -10° C. until further purified. The excess pyruvate was removed by a three step procedure. Fifty-two mL portions of the solution were passed through a 2.5×40 cm column of Dowex 50W-X8 (hydrogen form) with water elution. The portion of the eluent which contained the product was lyophilized to a paste. The paste was slurried in ethyl acetate and the Neu5Ac product recovered by filtration. The collected white powder was dried under a stream of dry air to yield 2.7 g of Neu5Ac as a mono-hydrate. The 1H-NMR spectrum of the product so obtained was identical to the reported spectrum. Brown, E. B., Brey, W. S., Jr., Weltner, W., Jr. Biochem. Biophys. Acta 399 (1975) 124-30.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1>C(#N)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:1](=[O:2])[N:21]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:27]3)[C:15]=2[CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)N1CCC(Nc2cc(Cl)ccc2N)CC1
Solvent: CC#N
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
1,1′-Carbonyldiimidazole (15.7 g, 97 mmol) was added portionwise over 10 minutes to a stirred solution of D6 (18.0 g, 60 mmol) in acetonitrile (300 mL). The reaction mixture was stirred at room temperature for 6 hours and the resulting precipitate was collected by filtration to give the title compound (12.0 g, 62% yield) as a violet solid that was used without further purification. (Rf: 0.2 (ethyl acetate))
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14](=[O:39])[CH2:15][CH2:16][CH2:17][CH:18](Br)[CH:19]1[O:37][C@H:22]2[CH2:23][C@@H:24]([OH:36])[C@H:25](/[CH:26]=[CH:27]/[C@@H:28]([OH:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34])[C@H:21]2[CH2:20]1.Cl.P([O-])([O-])([O-])=O>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14](=[O:39])[CH2:15][CH2:16][CH2:17]/[CH:18]=[C:19]1/[CH2:20][C@@H:21]2[C@@H:25](/[CH:26]=[CH:27]/[C@@H:28]([OH:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34])[C@H:24]([OH:36])[CH2:23][C@@H:22]2[O:37]/1
Reactant: COC(=O)CCCC(Br)C1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCCCl)[C@H](O)C[C@@H]2O1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)CCC/C=C1/C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCCCl)[C@H](O)C[C@@H]2O1
Temperature: 50 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
Under an atmosphere of nitrogen, 0.1 ml of DBU was added to a solution of 50 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-bromo-6,9-epoxy-11,15-dihydroxy-20-chloroprost-13-enoic acid methyl ester (prepared as described in Example 3) in 0.2 ml of toluene. The mixture was stirred at 50° C. for 1 hour, then at 70° C. for 1.5 hours and then cooled to 0° C. To the reaction mixture were added 0.5 ml of 1 N hydrochloric acid and 0.5 ml of phosphate buffer solution (pH 6.86) with cooling to 0° C. The reaction mixture was extracted quickly with diethyl ether. The extract was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on Florisil using a mixture of ethyl acetate and n-hexane (1:1) containing 0.1% of triethylamine as eluent to give 15 mg of the title compound having the following physical characteristics:
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][O:12][C@@H:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C@@H:11]2[O:12][CH2:13][CH2:14][NH:9][CH2:10]2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(CCc2ccccc2OC[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(CCc2ccccc2OC[C@H]2CNCCO2)c1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
10 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 1.68 g of (R)-4-t-butoxycarbonyl-2-{2-[2-(3-methoxyphenyl)ethyl]phenoxymethyl}morpholine [prepared as described in step (a) above] in 10 ml of dioxane, and the resulting mixture was allowed to stand at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in a small amount of methylene chloride. Ethyl acetate was added to the mixture, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 1.24 g (yield 86%) of the title compound as colorless crystals, melting at 112°-113° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19][CH2:20]Br>C(#N)C>[Br:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCc1ccc(OCCCBr)cc1
Temperature: 70 °C
Yield: 77.3 %

Procedure:
To a solution of 4-hydroxyphenethyl alcohol (4.37 g, 31.0 mmol) and potassium carbonate (6.55 g, 47.0 mmol) in acetonitrile (62.0 mL) was added 1,3 dibromopropane (31.0 mL, 316 mmol). The reaction mixture was heated to 70° C. for 12 hours and then cooled to room temperature, filtered and concentrated under vacuum. The resulting oil was purified by silica gel chromatography using a mixture of 4:1 hexanes and ethyl acetate to give the title compound (6.21 g) as a white solid.
Reaction SMILES: ClCC#N.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.Cl.[O:15]1CCO[CH2:17][CH2:16]1>[Cl-].[Zn+2].[Cl-]>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]2[C:16](=[O:15])[CH2:17][O:13][C:9]=2[CH:8]=1
Reactant: C1COCCO1
Reactant: COc1cccc(O)c1
Agent: Cl
Agent: N#CCCl
Agent: [Cl-]
Product: COc1ccc2c(c1)OCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
Chloroacetonitrile (3.5 ml, 55.2 mmol) was added dropwise to a stirred solution containing 3-methoxyphenol (5 ml, 46 mmol) and zinc chloride (6.9 g, 50.6 mmol) in anhydrous dioxane (30 ml) at room temperature. The resulting solution was saturated with dry hydrogen chloride gas. After stirring at room temperature overnight, the yellow precipitate was filtered and washed with anhydrous ether (100 ml). The collected precipitate was dissolved in water (80 ml) and heated to reflux for 1 hour. The solution was allowed to cool to approximately 40° C., and aqueous sodium hydroxide (20% w/v) (7.5 ml) was added. After stirring at that temperature for 30 minutes a pale yellow precipitate had formed. A heterogeneous system was then taken to pH≈7 by addition of hydrochloric acid (1 M). The precipitate was filtered, washed with water, and recrystallized from acetone to give the desired compound as a light yellow powder (4.14 g, 54.8%). 1H NMR: 8 (ppm): 3.85 (OMe); 4.9 (CH2); 6.50-6.46 (2 H-Phenyl); 7.70-7.66 (1 H-Phenyl).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:15]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([CH:43](O)[CH2:44][C:45]([O:47]C)=[O:46])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N1CCN(C2C=CC(C(=O)CC(OC)=O)=CC=2)CC1)CCCCCCCCCCCCCCC.[BH4-].[Na+].Cl>CO.C(Cl)Cl>[CH2:15]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([CH:43]=[CH:44][C:45]([OH:47])=[O:46])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCN1CCN(c2ccc(C(O)CC(=O)OC)cc2)CC1
Agent: CCCCCCCCCCCCCCCCN1CCN(c2ccc(C(=O)CC(=O)OC)cc2)CC1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCCCCCCCN1CCN(c2ccc(C=CC(=O)O)cc2)CC1

Procedure:
6.81 g. (48 mmole) Phosphorus pentoxide are suspended in 100 ml. methylene chloride, 15.2 g. (32 mmole) methyl 3-{4-[1-(n-hexadecyl)-piperazin-4-yl]-phenyl}-3-hydroxypropionate (colourless oil, prepared by the reduction of methyl 3-{4-[1-(n-hexadecyl)-piperazin-4-yl]-phenyl}-3-oxopropionate with sodium borohydride in methanol) are added thereto and the mixture is heated, with vigorous stirring, for 12 hours at reflux temperature. Subsequently, the smeary polyphosphoric acid is separated by decantation, the liquid phase is evaporated, the evaporation residue is dissolved in ethanol and, after the addition of 50 ml. 2N aqueous potassium hydroxide solution, the mixture is heated for 6 hours to 85° C. Subsequently, the ethanol is distilled off, the aqueous phase is extracted with diethyl ether and thereafter acidified with 6N hydrochloric acid. The precipitated product is filtered off with suction, washed with cold 2N hydrochloric acid and dried to give 8.8 g. (56% of theory) of the hydrochloride of the desired compound; m.p. 251°-253° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)#[N:10]>CC(N(C)C)=O>[Cl:1][C:21]1[C:20]2[C:25](=[CH:26][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:9]#[N:10])[CH:12]=3)=[CH:18][CH:19]=2)[C:24](=[O:27])[NH:23][CH:22]=1
Reactant: N#Cc1cccc(-c2ccc3cc[nH]c(=O)c3c2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)N(C)C
Product: N#Cc1cccc(-c2ccc3c(Cl)c[nH]c(=O)c3c2)c1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A solution of N-chlorosuccinimide (307 g, 2.3 mol) in DMA (1.2 L) was added to a stirred suspension of 7-(3-cyanophenyl)isoquinolinone (0.54 kg, 2.2 mol) in boiling DMA (3.9 L) over a period of 1 hour under N2. The mixture was heated at reflux overnight and cooled to room temperature. The solid was collected by filtration, washed with MeCN (1.0 L) and dried in vacuo at 50° C. to give 4-chloro-7-(3-cyanophenyl)isoquinolinone (0.5 kg, 1.78 mol, 81%) as an off white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[CH:8]3[CH2:19][CH:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([Br:18])=[CH:13][C:12]=4[C:6]2=[N:5][C:4]=1[C:20]([NH2:22])=[O:21])[CH2:9]3.[CH:23]1([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24]1>>[Br:18][C:14]1[C:15]([F:17])=[CH:16][C:11]2[CH:10]3[CH2:9][CH:8]([CH2:19]3)[N:7]3[C:3]([CH2:2][NH:1][C:27]([CH:23]4[CH2:26][CH2:25][CH2:24]4)=[O:28])=[C:4]([C:20]([NH2:22])=[O:21])[N:5]=[C:6]3[C:12]=2[CH:13]=1
Reactant: NCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: O=C(O)C1CCC1
Product: NC(=O)c1nc2n(c1CNC(=O)C1CCC1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
3-(Aminomethyl)-10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with cyclobutanecarboxylic acid similar to as described in example 2 with non-critical modifications to afford crude 10-bromo-3-(cyclobutanecarboxamidomethyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-methyl-3-butyne-ol via General Procedure F to afford 12 mg (29.3%) of 3-[(cyclobutanecarbonylamino)methyl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetra hydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[C:20]3[C:19](=[O:31])[CH2:18][CH2:17][C:16]([CH3:33])([CH3:32])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1.[Cl-].[Li+].[CH2:37]([Sn](CCCC)(CCCC)C=C)[CH2:38]CC>CN1CCCC1=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21]([CH:37]=[CH2:38])[C:20]3[C:19](=[O:31])[CH2:18][CH2:17][C:16]([CH3:32])([CH3:33])[C:15]=3[CH:14]=2)=[CH:9][CH:10]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)Cc1ccc(C#Cc2cc(OS(=O)(=O)C(F)(F)F)c3c(c2)C(C)(C)CCC3=O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=Cc1cc(C#Cc2ccc(CC(=O)OC)cc2)cc2c1C(=O)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
A solution of {4-[8,8-dimethyl-5-oxo-4-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acetic acid methyl ester (Intermediate 69, 0.233 g, 0.47 mmol) in anhydrous 1-methyl 2-pyrrolidinone (3 mL) was sparged with argon, and treated with lithium chloride (0.061 g, 1.45 mmol), tri-2-furylphosphine (0.0071 g, 0.031 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.007 g, 0.015 mmol). After 5 minutes, tributyl(vinyl)tin (0.175 g, 0.55 mmol) was added and the resulting reaction mixture was stirred at ambient temperature for 2.5 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine and water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 10-15% ethyl acetate in hexane as the eluent to afford the title compound (0.15 g, 86%) as a white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([CH3:18])[CH:8]=1.C[O:20][B:21](C)[O:22]C.Cl>CCCCCC.C1COCC1>[CH3:18][C:9]1[CH:8]=[C:7]([B:21]([OH:22])[OH:20])[CH:12]=[CH:11][C:10]=1[O:13][C:14]([F:17])([F:16])[F:15]
Reactant: Cc1cc(Br)ccc1OC(F)(F)F
Reactant: COB(C)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(B(O)O)ccc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
At −78° C., 8.5 ml (1.4 g, 21.1 mmol) of a 2.5M solution of n-butyllithium in hexane were initially charged in 30 ml of THF. 4.9 g (19.2 mmol) of 4-bromo-2-methyl(trifluoromethoxy)benzene were dissolved in 15 ml of THF and slowly added dropwise. 3.0 g (28.8 mmol) of trimethylboronic acid were then added dropwise. The mixture was stirred at −78° C. for 2 h, and 11 ml of 2 N hydrochloric acid were then added. The mixture was allowed to warm to RT, and the organic phase was separated off. The solvent was removed under reduced pressure and the residue was recrystallized from n-heptane. Yield: 3.3 g (78% of theory)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]2[S:16][CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[C:4]=2[O:3]1.[Br:22]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Br:22][C:17]1[S:16][C:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:8][C@H:2]([CH3:1])[O:3][C:4]=2[C:18]=1[CH:19]([CH3:21])[CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1csc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC(C)c1c(Br)sc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Yield: 86.3 %

Procedure:
A solution of tert-butyl (2S)-2-methyl-8-(1-methylethyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (839 mg) obtained in Example 15, step 1, N-bromosuccinimide (503 mg) and acetonitrile (10 mL) was stirred at room temperature for 1.5 hr, 10% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 3→7% ethyl acetate/hexane) to give the title compound (908 mg, 86%) as a solid.