Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>>[C:1]1([S:7]([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][CH:26]4[CH2:27][O:28]4)[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCC1CO1
Reactant: O=S(=O)(c1ccccc1)n1c2ccccc2c2c(O)cccc21
Product: O=S(=O)(c1ccccc1)n1c2ccccc2c2c(OCC3CO3)cccc21

Procedure:
reaction of 9-benzenesulfonyl-9H-carbazol-4-ol with epichlorohydrin under basic conditions to give 9-benzenesulfonyl-4-oxiranylmethoxy-9H-carbazole;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:37])([CH3:36])[CH2:23][CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:38][C:39]1[NH:40][CH:41]=[C:42]([N+:44]([O-:46])=[O:45])[N:43]=1.C(=O)([O-])O.[Na+].CN(C)C=O>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:37])([CH3:36])[CH2:23][CH2:24][N:40]3[CH:41]=[C:42]([N+:44]([O-:46])=[O:45])[N:43]=[C:39]3[Cl:38])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(O)COc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
4-{4-[2-Hydroxy-2-methyl-4-(toluene-4-sulfonyloxy)butoxy]phenyl}piperazine-1-carboxylic acid tert-butyl ester (4.69 g, 8.77 mmol), 2-chloro-4-nitro-1H-imidazole (1.55 g, 10.52 mmol), sodium hydrogen carbonate (0.88 g) and dimethylformamide (47 ml) were mixed, and the mixture was stirred at 90 to 100° C. overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. After filtering under reduced pressure, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→3:7) to afford the title compound as a yellow amorphous solid (2.12 g).
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[C:6](=[O:12])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][CH:27]=[C:26]2[N:35]([CH3:43])[C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][CH:27]=[C:26]2[N:35]([CH3:43])[C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:9]([C:7]2[C:6](=[O:12])[N:5]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:4](=[O:20])[N:3]([CH2:1][CH3:2])[CH:8]=2)=[O:11])=[CH:38][CH:37]=1
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(N(C)c3ccc(N)cc3)c2cc1OC
Product: CCn1cc(C(=O)Nc2ccc(N(C)c3ccnc4cc(OC)c(OC)cc34)cc2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and N-(6,7-dimethoxyquinolin-4-yl)-N-methyl-benzene-1,4-diamine by the method described for example 134. mp=199-202° C.; LCMS m/z=570 (M+1); 1H NMR (CDCl3) δ: 10.62 (s, 1H), 8.64 (d, 1H, J=5.0 Hz), 8.60 (s, 1H), 7.50 (d, 2H, J=9.0 Hz), 7.38 (s, 1H), 7.31 (s, 1H), 7.00 (d, 1H, J=5.3 Hz), 6.90 (s, 1H), 6.86 (d, 2H J=8.9 Hz), 4.01 (s, 1H), 4.00 (s, 3H), 3.63 (s, 3H), 3.44 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:32][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[N:16]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]4=[O:31])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1.S(Cl)([Cl:35])=O>C(Cl)Cl>[Cl:35][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:32][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[N:16]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]4=[O:31])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc4ccc(CO)nc4cc3C2)c2cccnc21
Solvent: ClCCl
Product: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc4ccc(CCl)nc4cc3C2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (s)-2-(hydroxymethyl)-1′-{[2-(trimethylsilyl)ethoxy]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (1.44 g, 3.22 mmol) in CH2Cl2 (10 mL) was added thionyl chloride (7.66 g, 64.3 mmol) and the resulting mixture was stirred at ambient temperature for 30 min, then concentrated in vacuo. The residue was concentrated in vacuo from toluene (2×10 mL) to give the title compound in sufficient purity for use in the next step.
Reaction SMILES: [CH3:1][CH:2]([O:4][CH2:5][CH2:6][O:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([O:24]C)[N:14]2[CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:10]([NH2:26])[N:9]=1)[CH3:3].Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:26][C:10]1[N:9]=[C:8]([O:7][CH2:6][CH2:5][O:4][CH:2]([CH3:3])[CH3:1])[N:16]=[C:15]2[C:11]=1[NH:12][C:13](=[O:24])[N:14]2[CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: COc1nc2c(N)nc(OCCOC(C)C)nc2n1CC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)OCCOc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
To a solution of 2-({2-[(1-methylethyl)oxy]ethyl}oxy)-8-(methoxy)-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (165 mg) in dry methanol (17 ml) was added 4.0M hydrogen chloride in 1,4-dioxane (2.95 ml) in one go. The reaction was left to stir at room temperature for 5 hours. The reaction was neutralised by the addition of 2.0M sodium hydroxide solution and concentrated in vacuo to give an off-white solid. The solid was triturated in water, and filtered under vacuum, washing with more water, to give an off-white solid (120 mg).
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29])=[O:22].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1[C:10]2[C@H:11]3[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH2:29])=[O:22])[CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Reactant: Nc1ccccc1C(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ccccc1C(=O)CCCN1CC[C@@H]2[C@H](C1)c1cccc3c1N2CCC3
Yield: 42.6 %

Procedure:
The title compound (0.080 g, 42%) was prepared by the general method of Example 402 from (7aR,11aS)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.11 g, 0.50 mmol), 4-chloro-2′-aminobutyrophenone (0.20 g, 1.0 mmol), KI (catalytic) and K2CO3 (0.14 g, 1.0 mmol) after chromatographic purification as a white amorphous solid. The 1H NMR was identical to that of Example 404, 4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-aminophenyl)-1-butanone
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([CH2:34][N:35]3[CH2:41][CH2:40][CH2:39][CH2:38]CC3)[S:32][CH:33]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:19]=[S:16]1(=[O:20])[CH2:17][CH2:18][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:29]4[CH:30]=[C:31]([CH2:34][N:35]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[S:32][CH:33]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Reactant: CC1(C)OB(c2csc(CN3CCCCCC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2csc(CN3CCCC3)c2)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 12 %

Procedure:
5-bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxamide (0.035 g, 0.098 mmol) and 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]methyl}hexahydro-1H-azepine (0.038 g, 0.130 mmol, 1.3 eq) was dissolved in a 6:1 solution of 1,4 dioxane/water in a 20 mL microwave reaction vessel. Potassium carbonate (0.068, 0.490 mmol, 5 eq) was added and the solution was degassed with Argon. PdCl2(dppf) (0.012 g, 0.017 mmol, 0.17 eq) was added and the reaction was heated in a microwave at 100° C. for 20 min. The solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/Water with 0.1% TFA. The desired fractions were concentrated, giving 0.0052 g (12%) of the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH2:19][N:6]2[CH:7]=[CH:8][C:9]3[C:10]([CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=3)=[C:5]2[N:4]=1.O=S(Cl)[Cl:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:22][CH2:2][C:3]1[CH2:19][N:6]2[CH:7]=[CH:8][C:9]3[C:10]([CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=3)=[C:5]2[N:4]=1
Reactant: CCOC(=O)c1cc2c3n(ccc-2n1)CC(CO)=N3
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c3n(ccc-2n1)CC(CCl)=N3
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 52 %

Procedure:
To a solution of 11 (47 mg, 0.18 mmol) in dry methylene chloride (10 mL), under argon, were added SOCl2 (15 μl, 0.21 mmol) and triethylamine (29 μl, 0.21 mmol). The solution was stirred at room temperature for 45 min then the solvent was removed in vacuo. The crude product was purified by chromatography using CH2Cl2/EtOH (97/3, v/v) as eluent to give compound 12 (26 mg, 52%); mp 270-272° C.; IR (KBr) 1701, 1248, 1189 cm−1; 1H NMR (400 MHz, (acetone-d6) δ 1.41 (t, 3H, J=7 Hz), 4.41 (q, 2H, J=7 Hz), 4.86 (s, 2H), 7.20 (d, 1H, J=7 Hz), 7.52 (s, 1H), 7.90 (s, 1H), 8.28 (d, 1H, J=7 Hz), 11.63 (brs, 1H); 13C NMR (100 MHz, (acetone-d6) δ 14.7, 40.6, 61.3, 102.9, 107.9, 113.1, 114.7, 125.0, 127.5, 134.3, 140.9, 142.3, 161.5; MS m/z 279 (M++2, 9), 277 (M+, 20), 196 (43), 149 (33), 85 (63), 71 (72), 57 (100). Anal. Calcd for C13H12ClN3O2: C, 56.22; H, 4.36; N, 15.13. Found: C, 56.07; H, 4.43; N, 15.10.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([O:20][CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(OC(C)C)(C)C.[OH-].[Na+]>C(OCC)(=O)C>[CH3:21][O:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: COC1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
To a solution of 4-methoxy-4-phenylpiperidine-1-carboxylic acid tert-butyl ester (6.5 g) in ethyl acetate (65 ml) was added dropwise 4N-HCl/ethyl acetate (56 ml) at ambient temperature. The reaction mixture was stirred for 1.5 hours at ambient temperature. To the reaction mixture was added diisopropyl ether. The precipitate was collected by filtration to give powder. The powder was adjusted to pH 11 with 1N-NaOH, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-methoxy-4-phenylpiperidine (3.47 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[NH:29][C:28](=[O:30])[S:27][N:26]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:37]>O1CCCC1.C(OCC)(=O)C>[ClH:37].[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[NH:29][C:28](=[O:30])[S:27][N:26]=1)=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nsc(=O)[nH]3)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(-c3nsc(=O)[nH]3)ccc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
Tert-butyl[2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.050 g, 0.10 mmol) was dissolved in tetrahydrofuran (3 ml) and a solution (2 ml) of 4N hydrogen chloride in ethyl acetate was added. The mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and diisopropyl ether-ethyl acetate (2:1) was added to the residue to give 3-(aminomethyl)-2-isobutyl-6-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)-4-phenyl-1(2H)-isoquinolinone hydrochloride (0.041 g, 94%) as a pale-yellow powder.
Reaction SMILES: [O:1]=[C:2]([C:25]1[O:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:28][N:29]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C(=O)OC(C)(C)C)=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]([C:25]1[O:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:28][N:29]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N(c1ccccc1)c1ccc(CCC(=O)c2ncc(-c3ccccn3)o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1ccc(Nc2ccccc2)cc1)c1ncc(-c2ccccn2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A solution of tert-butyl 4-(3-oxo-3-(5-(pyridin-2-yl)oxazol-2-yl)propyl)phenyl-(phenyl)carbamate (S36, 26 mg, 0.055 mmol) in anhydrous CH2Cl2 (0.8 mL) was treated with TFA (0.2 mL) and was stirred for 1 h at 0° C. The reaction mixture was allowed to warm at 25° C. and was stirred for 2 h. The reaction mixture was concentrated, diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. Column chromatography (SiO2, 1×3 cm, pretreated with 1% Et3N-hexanes, 10-25% EtOAc-hexanes gradient) afforded 11g (14 mg, 0.038 mmol, 70%) as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) 8.67 (app d, 1H, J=4.0 Hz), 7.89-7.86 (m, 2H), 7.81 (td, 1H, J=7.7, 1.8 Hz), 7.33-7.31 (m, 1H), 7.25 (dd, 2H, J=8.4, 7.3 Hz), 7.18 (d, 2H, J=8.4 Hz), 7.04-7.01 (m, 4H), 6.90 (t, 1H, J=7.3 Hz), 5.68 (br s, 1H), 3.45 (t, 2H, J=7.7 Hz), 3.07 (t, 2H, J=7.7 Hz); 13C NMR (CDCl3, 150 MHz) 187.5, 157.3, 153.3, 150.1, 146.3, 143.5, 141.3, 137.1, 133.1, 129.3 (2C), 126.9, 124.1, 120.6, 120.4, 118.4, 117.3, 40.9, 29.1, 28.2; IR (film) νmax 3389, 3053, 2925, 1698, 1598, 1519, 1495, 1469, 1425, 1380, 1311, 1176, 1152, 1118, 1064, 991, 911, 784, 738, 694 cm−1; ESI-TOF m/z 369.1475 (C23H19N3O2+ requires 369.1477).
Reaction SMILES: [CH2:1]1[O:21][C:20]2[C:3](=[CH:4][C:5]3[C:11](=[O:12])[C:10]4[CH:13]=C(C#N)[CH:15]=[CH:16][C:9]=4[CH2:8][O:7][C:6]=3[CH:19]=2)[O:2]1.Cl.[C:23]([OH:26])(=[O:25])[CH3:24]>>[CH2:1]1[O:21][C:20]2[C:3](=[CH:4][C:5]3[C:11](=[O:12])[C:10]4[CH:13]=[C:24]([C:23]([OH:26])=[O:25])[CH:15]=[CH:16][C:9]=4[CH2:8][O:7][C:6]=3[CH:19]=2)[O:2]1
Reactant: N#Cc1ccc2c(c1)C(=O)c1cc3c(cc1OC2)OCO3
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)c1ccc2c(c1)C(=O)c1cc3c(cc1OC2)OCO3

Procedure:
Heat a mixture of 4.98 gm. (0.0178 mole) of 6,11-dihydro-2,3-methylenedioxy-11-oxodibenz[b,e]-oxepin-9-carbonitrile, 90 ml. of acetic acid, 9 ml. of concentrated hydrochloric acid under reflux of 74 hours. Cool the reaction mixture and separate the solids by filtration and dry (yield 3.45 gm.). Suspend the solids in water and treat with N-methylpiperazine. Remove base insolubles by filtration and acidify the filtrate with concentrated hydrochloric acid to the Congo Red end point. Separate the solids by filtration and dry. Purify by recrystallization from acetic acid to obtain the title product (m.p. 320°-321° C.)
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O-:21])=[O:20])(=[O:3])[CH3:2].[Na+:22].[Na].C(N(CC)CC)C.[Br:31]Br>O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl.C(Cl)(Cl)(Cl)Cl>[C:1]([NH:4][CH:5]=[C:6]([Br:31])[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O-:21])=[O:20])(=[O:3])[CH3:2].[Na+:22]
Reactant: BrBr
Reactant: CC(=O)N/C=C/SC1=C(C(=O)[O-])N2C(=O)[C@@H]([C@H](C)O)[C@H]2C1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)NC=C(Br)SC1=C(C(=O)[O-])N2C(=O)[C@@H]([C@H](C)O)[C@H]2C1
Temperature: 25 °C

Procedure:
Sodium (5R,6R)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (200 mg; 85% pure) in water (10 ml) was treated with dichloromethane (10 ml) containing Aliquat 336 (600 mg). After shaking and separating the aqueous layer was again treated with dichloromethane (10 ml) containing Aliquat 336 (600 mg). The two dichloromethane extracts were dried (MgSO4) and evaporated to leave a mixture of Aliquat 336 and the quaternary ammonium salt corresponding to the starting sodium salt. This mixture was taken up in dry dichloromethane (10 ml), cooled to -70° and treated with triethylamine in dichloromethane (0.55 ml; 100 mg/ml), followed by bromine in carbon tetrachloride (0.82 ml; 100 mg/ml). After stirring in the cold for 25 minutes the mixture was warmed to room temperature, washed with water (3.5 ml) and extracted with saturated aqueous NaCl (2×5 ml). The NaCl extracts were combined and loaded onto a column of DIAION HP20 (18×1 cm). The column was eluted with saturated aqueous NaCl (25 ml) and then with deionised water. Some fractions containing the title compound (λmax ca 299 and 248 nm) were obtained. The column was then eluted with water containing 10% ethanol to give further fractions containing the title compound. Fractions containing the title compound were combined and evaporated in vacuo to low volume, ethanol was added and evaporated to low volume (4×), and toluene added and evaporated to dryness (3×) to give the title compound (29 mg) of estimated purity of ca 40%:λmax (H2O) 300(6,100), 246 (9,000) nm; λmax(KBr) 1750, 1690, 1620 cm-1.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([CH3:27])[C:21]3=[C:20]([Br:28])[N:19]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1.C(O)(=O)C>Br>[BrH:28].[Br:28][C:20]1[N:19]=[C:18]([C@H:15]2[CH2:16][CH2:17][C@H:12]([CH2:11][NH2:10])[CH2:13][CH2:14]2)[N:22]2[CH:23]=[CH:24][N:25]=[C:26]([CH3:27])[C:21]=12
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C

Procedure:
Benzyl((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methylcarbamate (1.5 g, 3.28 mmol) was dissolved in hydrobromic acid 33% in acetic acid (15 mL, 3.28 mmol) and the resulting mixture was stirred at room temperature. After eight hours the reaction mixture was concentrated in vacuo and dried in a vacuum oven (40° C.) for three days to yield ((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methanamine hydrobromide (1.77 g).
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24].N(OC(C)(C)C)=O>O1CCCC1>[C:19]([C:4]1[C:3]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:2][N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N

Procedure:
To a stirred solution of 5-aniino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trimethylsilylethynylpyrazole (30 mg, the compound of Example C1) in tetrahydrofuran (10 ml) was added dropwise over five minutes t-butyl nitrite (0.025 ml). The nixture was heated under reflux for 30 minutes, then cooled and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with dichloromethane: hexane (1:4) to provide the title compound as a white solid m.p. 128-9° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH:9]=[CH2:10])[CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: [H][H]
Reactant: C=Cc1cc(Br)ccc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(Br)ccc1F
Yield: 61.1 %

Procedure:
4-Bromo-1-fluoro-2-vinylbenzene (470 mg) was hydrogenated in EtOAc with 10% Pd/C (100 mg) with a hydrogen balloon for 2.0 h. The Pd/C was removed by filtration. The filtrate was condensed to give 95A (290 mg, 62% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (t, J=6.81 Hz, 3H) 2.63 (d, J=7.03 Hz, 2H) 6.88 (t, J=8.57 Hz, 1H) 7.25 (s, 1H) 7.32 (d, J=4.39 Hz, 1H).
Reaction SMILES: [CH2:1]([O:48][CH:49]1[C@H:53]2[C@H:54](O[Si](C(C)(C)C)(C)C)[N:55](C(OCC(Cl)(Cl)Cl)=O)[C:56]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH:51]=[C:50]1[C:82]1[CH:83]=[C:84]2[C:89](=[CH:90][CH:91]=1)[N:88]=[CH:87][CH:86]=[CH:85]2)[CH2:2][CH2:3][O:4][CH:5]1[C@H:9]2[C@H:10](O[Si](C(C)(C)C)(C)C)[N:11](C(OCC(Cl)(Cl)Cl)=O)[C:12]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=3[C:14](=[O:15])[N:8]2[CH:7]=[C:6]1[C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2>C1COCC1>[CH2:3]([O:4][CH:5]1[C@@H:9]2[CH:10]=[N:11][C:12]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=3[C:14](=[O:15])[N:8]2[CH:7]=[C:6]1[C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)[CH2:2][CH2:1][O:48][CH:49]1[C@@H:53]2[CH:54]=[N:55][C:56]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH:51]=[C:50]1[C:82]1[CH:83]=[C:84]2[C:89](=[CH:90][CH:91]=1)[N:88]=[CH:87][CH:86]=[CH:85]2
Reactant: COc1ccc2c(c1)C(=O)N1C=C(c3ccc4ncccc4c3)C(OCCCOC3C(c4ccc5ncccc5c4)=CN4C(=O)c5cc(OC)ccc5N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]34)[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)N2C(=O)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)N1C=C(c3ccc4ncccc4c3)C(OCCCOC3C(c4ccc5ncccc5c4)=CN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Yield: 33.1 %

Procedure:
10% Cd/Pb couple (516 mg, 4.21 mmol, 25 eq) was added to a rapidly stirring mixture of 23 (234 mg, 0.17 mmol), THF (5 mL) and 1 N NH4OAc (5 mL). The reaction mixture was allowed to stir for 5 hours when TLC showed complete consumption of the starting material and formation of a small amount of side products. The solids were filtered and rinsed with H2O and a large amount of MeOH. Excess solvent was removed and the residue was diluted with H2O (35 mL) and CHCl3 (35 mL). The aqueous layer was extracted with CHCl3 (3×30 mL) and the organic extracts were combined, washed with brine (100 mL) and dried (MgSO4). Filtration and evaporation of solvent afforded the crude product which was purified by flash column chromatography (99.5:0.5 v/v CHCl3/MeOH then gradient to 96:4 v/v CHCl3/MeOH) to afford 24 as a yellow glass (44 mg, 33%): 1H NMR (400 MHz, CDCl3) 8.85 (dd, 2H, J=1.6, 4.2 Hz, Harom), 8.09 (d, 2H, J=7.6 Hz, Harom), 8.03 (d, 2H, J=9.0 Hz, Harom), 7.88 (d, 2H, J=3.9 Hz, H11), 7.82 (dd, 2H, J=1.8, 8.9 Hz, Harom), 7.24 (s, 2H, H3), 7.59 (s, 2H, Harom), 7.52 (s, 2H, H6), 7.48 (dd, 2H, J=4.3, 8.3 Hz, Harom), 6.88 (s, 2H, H9), 4.48-4.42 (m, 2H, H11a), 4.39-4.28 (m, 4H, OCH2CH2CH2O), 3.94 (s, 6H, OCH3×2), 3.76-3.63 (m, 2H, H1), 3.09-2.98 (m, 2H, H1), 2.46-2.43 (m, 2H, OCH2CH2CH2O).