Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]=[C:26]3[CH3:50])[CH:23]=2)[O:18][C:17]([CH3:52])([CH3:51])[CH2:16]1>C(OCC)(=O)C>[CH3:13][O:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]5[NH:3][C:4](=[O:7])[O:5][N:46]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]=[C:26]3[CH3:50])[CH:23]=2)[O:18][C:17]([CH3:51])([CH3:52])[CH2:16]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(OC)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(OC)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.53 g), sodium hydrogen carbonate (0.77 g) and dimethyl sulfoxide (4 mL) was stirred at 50° C. for 30 min, 4′-{[1-(4-methoxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.41 g) was added, and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (4 mL), N,N′-carbonyldiimidazole (0.19 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.35 g, 77%) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][NH2:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[N:3]=1.[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1C=O.[CH2:35](O)C>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:4]2[N:5]=[C:6]([NH:8][N:9]=[CH:35][C:30]3[CH:29]=[CH:26][C:25]([O:24][C:23]([F:22])([F:33])[F:34])=[CH:32][CH:31]=3)[N:7]=[CH:2][N:3]=2)=[CH:12][C:13]=1[C:18]([F:21])([F:20])[F:19]
Reactant: O=Cc1ccccc1OC(F)(F)F
Reactant: CCO
Reactant: NNc1nc(Cl)nc(Nc2ccc(F)c(C(F)(F)F)c2)n1
Product: Fc1ccc(Nc2ncnc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of (4-Chloro-6-hydrazino-[1,3,5]triazin-2-yl)-(4-fluoro-3-trifluoromethylphenyl)-amine (XXIII) (264 mg, 1.38 mmol) in ethanol (8 mL) was added trifluoromethoxybenzaldehyde (200 mg, 0.694 mmol). The mixture was stirred overnight and filtered to give a white precipitate. The mother liquor was concentrated in vacuo and the residue recrystallized from ethyl acetate. The solids were combined and dried in vacuo to afford the titled compound 3 as white solid (123 mg, 38% yield): m.p. 185-186° C.; ESI/MS 461 (M+H), 459(M−H); 1H NMR (CDCl3): δ 8.5 (bs, 1H), 7.95 (s, 1H), 7.80 (m, 2H), 7.65 (m, 1H), 7.2-7.4, m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2([OH:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]2[CH2:32][C@@H:31]([CH2:33][C:34](O)=[O:35])[C:30](=[O:37])[N:29]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:28][C:22]2=[C:23]2[C:27]=1[NH:26][CH:25]=[CH:24]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[CH2:32][C@@H:31]([CH2:33][C:34]([N:14]3[CH2:13][CH2:12][C:11]([C:4]4[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]5[NH:8][CH:9]=[CH:10][C:5]=45)([OH:17])[CH2:16][CH2:15]3)=[O:35])[C:30](=[O:37])[N:29]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:28][C:22]2=[C:23]2[C:27]=1[NH:26][CH:25]=[CH:24]2
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ccc23)C[C@@H](CC(=O)O)C1=O
Reactant: OC1(c2cc(Cl)nc3[nH]ccc23)CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ccc23)C[C@@H](CC(=O)N2CCC(O)(c3cc(Cl)nc4[nH]ccc34)CC2)C1=O
Temperature: 25 °C
Yield: 76.5 %

Procedure:
To 4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-ol (69 mg, 0.304 mmol) in DMF (2 mL) was added (S)-2-(7-chloro-2-neopentyl-3-oxo-1,2,3,4,5,8-hexahydroazepino[3,4-e]indol-4-yl)acetic acid (100 mg, 0.276 mmol), EDC (58.3 mg, 0.304 mmol), HOBT (41.0 mg, 0.304 mmol), at rt, followed by diisopropylethylamine (0.192 ml, 1.10 mmol). The mixture was stirred at rt over night, partial of the solvent was removed under N2, the residue was purified on reverse phase PrepHPLC to afford the expected product, (S)-7-chloro-4-(2-(4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-hydroxypiperidin-1-yl)-2-oxoethyl)-2-neopentyl-1,2,4,5-tetrahydroazepino[3,4-e]indol-3(8H)-one (126 mg, 57%) as a tan solid. 1H-NMR (400 MHz, MeOD) δ ppm 0.78-0.84 (m, 11H) 1.73 (s, 1H) 1.76-1.83 (m, 1H) 2.25-2.36 (m, 2H) 2.66-2.76 (m, 1H) 3.03 (d, J=13.35 Hz, 1H) 3.09-3.20 (m, 4H) 3.62-3.73 (m, 2H) 4.08 (d, J=12.84 Hz, 2H) 4.51 (d, J=10.83 Hz, 1H) 4.65 (d, J=17.12 Hz, 1H) 5.51 (d, J=17.12 Hz, 1H) 6.99 (d, J=3.53 Hz, 1H) 7.20-7.24 (m, 2H) 7.26-7.29 (m, 2H) 8.24 (s, 1H); Mass spec. 596.47 (MH+) calc. for C31H35Cl2N5O3 595.21.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:18][N:17]([C:19](=[O:21])[CH3:20])[C:16]4[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=4[CH2:14][CH2:13][C:12]=3[CH:26]=2)[CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(O[Na])(C)(C)C.[NH2:79][CH2:80][CH2:81][N:82]1[CH2:86][CH2:85][CH2:84][CH2:83]1>C1(C)C=CC=CC=1>[C:19]([N:17]1[CH2:18][C:11]2[CH:10]=[CH:9][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:79][CH2:80][CH2:81][N:82]4[CH2:86][CH2:85][CH2:84][CH2:83]4)[N:7]=3)=[CH:26][C:12]=2[CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]1=2)(=[O:21])[CH3:20]
Reactant: NCCN1CCCC1
Reactant: CC(=O)N1Cc2ccc(-c3cccc(Br)n3)cc2CCc2ccccc21
Agent: CC(C)(C)O[Na]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)N1Cc2ccc(-c3cccc(NCCN4CCCC4)n3)cc2CCc2ccccc21
Temperature: 95 °C
Yield: 32.9 %

Procedure:
A mixture of 1-[9-(6-Bromo-pyridin-2-yl)-11,12-dihydro-6H-dibenzo[b,f]azocin-5-yl]-ethanone (prepared according to Example 14 and Example 195 starting from Example 2) (17 mg, 0.04 mmol), BINAP (5 mg, 0.008 mmol), t-BuONa (10 mg, 0.1 mmol) and N-(2-aminoethyl)pyrrolidine (6 μl, 0.05 mmol) in toluene (2 mL) was purged with argon, then heated at 95° C. for 1 h. The reaction mixture was cooled to room temperature, concentrated and purified by preparative reversed-phased HPLC to give the title compound (5.8 mg, 33%). HPLC Rt=1.52(b) min. m/z=441 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:25](=O)[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>O1CCCC1>[NH3:9].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCC(=O)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: C1CCOC1
Product: COC(=O)CCCN1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Product: N
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To a solution of methyl 4-{(3S)-3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)methyl]piperidin-1-yl}-4-oxobutanoate (240 mg) in tetrahydrofuran (5 mL) at room temperature under argon was added a 1M solution of BH3 in THF (1 mL). The solution was heated to reflux temperature for 1 hour and then cooled to ambient temperature. The reaction was quenched with methanol and then concentrated at reduced pressure. To the residue was added saturated HCl in methanol (10 mL) and the mixture was heated to reflux temperature for 1 hour and then cooled to ambient temperature. The mixture was stirred at ambient temperature overnight and then concentrated at reduced pressure. The residue was purified using reverse phase HPLC eluting with a mixture of 5-95% acetonitrile in water and then SCX-2 column eluting with methanol then 7M NH3 in methanol to give methyl 4-{(3R)-3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)methyl]piperidin-1-yl}butanoate (80 mg, 34%).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=[O:7])[CH2:4][NH:5][CH3:6].C(OCC)(=O)C.C(=O)([O-])O.[Na+].[CH2:20]([O:27][CH2:28][C:29](Cl)=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:20]([O:27][CH2:28][C:29]([N:5]([CH3:6])[CH2:4][C:3](=[O:7])[CH:2]([CH3:8])[CH3:1])=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CNCC(=O)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)CN(C)C(=O)COCc1ccccc1
Temperature: 0 °C
Yield: 41.6 %

Procedure:
A mixture of 6.1 g (52.9 mmol) of 3-methyl-1-methylamino-2-butanone, 70.0 ml of ethyl acetate and 41.0 ml of water was stirred at 0° C. Added was 7.1 g (84.6 mmol) of sodium hydrogen carbonate, and the mixture was stirred for 10 minutes. There was added 8.5 ml (54.0 mmol) of benzyloxyacetylchloride over 30 minutes. After stirring at room temperature for 10 hours, the ethyl acetate layer was seperated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (hexane/ethyl acetate 1:1) to give 5.8 g of 2-benzyloxy-N-methyl-N-(3-methyl-2-oxobutyl)-acetamide (18a') (yield 42%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21].COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:26]3[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
For example, N-BOC-piperazine and methanesulfonyl chloride were reacted together in dichloromethane and triethylamine to yield 4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester. Cleavage of the BOC protecting group using HCl (2M) in dichloromethane yielded 1-methanesulfonyl-piperazine. HCl salt. A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (1.00 g), 1-methanesulfonyl-piperazine (750 mg) and trimethylorthoformate (3.80 mL) was stirred in 1,2-dichloroethane (30 mL) for 6 hrs at room temperature. To this was added sodium triacetoxyborohydride (900 mg) and the reaction mixture was stirred for 24 hours at room temperature. The mixture was then quenched with brine, extracted with dichloromethane, dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with hot ethyl acetate to yield 2-chloro-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine as a white solid (1.01 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:17](=[O:18])[NH:16][CH2:15][CH2:14][C:13]=1[C:12]=23)=[O:4].IC1N[C:22]2[CH:23]=[CH:24]C=C3C(=O)N[CH2:30][CH2:29][C:28]=1[C:27]=23.C(N(CC)CC)C.C(O)CCCCCCC>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].CN(C=O)C>[CH2:1]([O:2][C:3]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:17](=[O:18])[NH:16][CH2:15][CH2:14][C:13]=1[C:12]=23)=[O:4])[CH2:24][CH2:23][CH2:22][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: COC(=O)c1[nH]c2cccc3c2c1CCNC3=O
Reactant: O=C1NCCc2c(I)[nH]c3cccc1c23
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCCCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCOC(=O)c1[nH]c2cccc3c2c1CCNC3=O

Procedure:
Following a procedure similar to that described for Example MM (Compound 42), 2-iodo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (330 mg, 1.06 mmol), triethylamine (342 mg, 3.38 mmol), and palladium tetrakis(triphenylphosphine) (61 mg, 0.05 mmol) were reacted in 20 mL 1:1 n-octanol:DMF in a sealed tube under a carbon monoxide atmosphere to yield 6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid octyl ester, 250 mg (58%), as a white solid: m.p. 170-171° C.; 1H NMR (300 MHz, d6-DMSO) δ0.85 (t, J=7.2 Hz, 3H), 1.27 (m, 8H), 1.42 (m, 2H), 1.73 (m, 2H), 3.25 (m, 2H), 3.42 (m, 2H), 4.30 (t, J=6.6 Hz, 3H), 7.38 (app t, J=7.5 Hz, 1H), 7.62 (dd, J=8.1, 0.9Hz, 1H), 7.74 (dd, J=7.5, 0.9Hz, 1H), 8.17 (br t, 1H), 11.86 (br s, 1H). MS (FAB, MH+) 343. Anal. (C20H26N2O3) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+]=[N-])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:14][N:15]1[CH:20]=[CH:19][CH2:18][CH:17]=[CH:16]1>CCOCC>[CH3:14][N:15]1[CH:16]=[CH:17][CH2:18][CH:19]2[CH:20]1[N:11]2[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN1C=CCC=C1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(N)cc1
Solvent: CCOCC
Product: CN1C=CCC2C1N2S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A solution of 4-aminobenzenesulfonyl azide (0.63 g, 3.2 mmol) in 75 ml ether was added slowly to a solution of 1-methyl-1,4-dihydropyridine (0.30 g, 3.2 mmol) in 75 ml ether with stirring at 25° C. Evolution of nitrogen gas was immediate. The reaction was allowed to proceed for 2 hours and the solvent was removed in vacuo to give 2-methyl-7-[(4-aminophenyl)sulfonyl]-2,7-diazabicyclo[4.1.0]hept-3-ene (0.82 g, 97%) with mp 188-190° . Hydrogenation of 2-methyl-7-[(4-aminophenyl) sulfonyl]-2,7-diazbicyclo[4.1.0]hept-3-ene (33 mg, 0.117 mmol) in 15 ml ethanol was effected using 10% palladium on charcoal (15 mg) and hydrogen gas at 30 psi for 4 hours. Removal of the catalyst by filtration and evaporation of the solvent in vacuo gave 1-methylpiperidylidene-2-(4-aminophenyl)sulfonamide (31 mg, 93%) with mp 186-188° ; IR (KBr) 3480 and 3380 cm-1 (NH2) and 1590 cm-1 (C=N).
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[O:10]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]3[C:21](=[CH:22][C:11]1=2)[CH2:20][CH2:19][CH2:18][C:17]3=[O:23]>C(Cl)(Cl)Cl>[Br:7][CH:18]1[CH2:19][CH2:20][C:21]2[C:16](=[CH:15][C:12]3[CH2:13][CH2:14][O:10][C:11]=3[CH:22]=2)[C:17]1=[O:23]
Reactant: O=C1CCCc2cc3c(cc21)CCO3
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: O=C1c2cc3c(cc2CCC1Br)OCC3
Reaction time: 8 h
Yield: 103.6 %

Procedure:
55.33 g of pyridinium bromide perbromide are added portionwise at 0° C. to a solution of 27.1 g of 2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan-5-one, the compound of Example 17, in 1.5 l of chloroform. The mixture is left overnight at room temperature. The reaction mixture is then washed with water and the organic phase dried over anhydrous magnesium sulfate. Evaporation of the chloroform yields 39.85 g of a mixture which is then purified on a silica column using a mixture of methylene chloride and cyclohexane (80:20 V/V) as solvent. The product obtained is then recrystallized in ethyl acetate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(/[CH:13]=[CH:14]/B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.I[C:19]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)=[O:29])[C:21](=[O:43])[CH:20]=1.O1CCOCC1.O>C(OCC)(=O)C.[Pd]>[CH3:42][C@@:27]([S:38]([CH3:41])(=[O:39])=[O:40])([CH2:26][CH2:25][N:22]1[CH:23]=[CH:24][C:19](/[CH:14]=[CH:13]/[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:20][C:21]1=[O:43])[C:28]([NH:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)=[O:29]
Reactant: OB(O)/C=C/c1ccccc1
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@](CCn1ccc(/C=C/c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
Pd EnCat™ (133 mg, 0.04 mmol, 0.1 equiv), was added to a mixture of potassium carbonate (166 mg, 1.2 mmol, 3.0 equiv), [(E)-2-phenylvinyl]boronic acid (65 mg, 0.44 mmol, 1.1 equiv), and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (200 mg, 0.40 mmol), which may be synthesized as described Preparation 2B, in 2:1 1,4-dioxane-water (3.6 mL). The reaction was heated to 80° C. and allowed to stir overnight. The reaction was diluted with ethyl acetate (10 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The crude material was purified by flash chromatography ((1:1-0:1 heptane/ethyl acetate) to provide a white residue (90 mg, 47%). MS (LCMS) m/z 473.7 (M−1).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C(N(CC)C(C)C)(C)C.[F:17][C:18]([F:46])([F:45])[C:19]1[CH:20]=[C:21]([CH:42]=[CH:43][CH:44]=1)[CH2:22][NH:23][C:24](=[O:41])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35](F)[CH:34]=[CH:33][C:32]=2[N+:38]([O-:40])=[O:39])[CH:26]=1>CN(C)C=O.O>[F:17][C:18]([F:45])([F:46])[C:19]1[CH:20]=[C:21]([CH:42]=[CH:43][CH:44]=1)[CH2:22][NH:23][C:24](=[O:41])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35]([N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[CH:34]=[CH:33][C:32]=2[N+:38]([O-:40])=[O:39])[CH:26]=1
Reactant: CCCNCCC
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)c1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 8 h

Procedure:
Into a 10-mL vial, was placed a solution of dipropylamine (216.9 mg, 2.15 mmol, 3.00 equiv) in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (277 mg, 2.15 mmol, 3.00 equiv), and a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide 14d (300 mg, 0.72 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL). The resulting solution was stirred for 8 h at 90° C. to 100° C. in an oil bath. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×70 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was obtained as 400 mg of a yellow to green oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[Cl:10].C(N(CC)CC)C.O1CCCC1.[S:23]1[C:27]2[C:28]3[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=[C:24]1[C:37](Cl)=[O:38]>>[Cl:10][C:4]1[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:3]=1[N:2]([CH3:1])[C:37]([C:24]1[S:23][C:27]2[C:28]3[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=1)=[O:38]
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Reactant: CNc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(Cl)cc1Cl

Procedure:
To a solution of N-methyl-2,4-dichloroaniline (0.133 g, 0.755 mmol) and triethylamine (0.105 mL, 0.755 mmol) in tetrahydrofuran (1.5 mL, 18 mmol) was added 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl chloride (0.100 g, 0.378 mmol) portion wise as a solid. Reaction was stirred at room temperature with monitor for formation of desired product. The reaction was stirred overnight. After aqueous workup, the crude was taken into DMF at a concentrated of 100 mg/ml and purified by preparative RP-HPLC to give 108. Yield=30% of theoretical. MS: (ESI+) 405.5
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[NH:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>ClCCl.O>[CH2:34]([O:33][C:31]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[NH:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:4][CH:3]=1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
To a solution of (3aR*,10aS*)-9-(4-aminobenzyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (3.64 g, 12 mmol) in dichloromethane (15 mL) was added a solution of sodium carbonate (1.88 g, 18 mmol) in water (15 mL) at 0° C. To this mixture was added benzyl chloroformate (2.0 mL, 14 mmol) at the same temperature and the mixture was stirred at 0° C. for 15 minutes. Upon phase separation, the aqueous layer was extracted with dichloromethane and the pooled organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to provide 4.18 g (yield 79%) of the title compound. m.p. 161.7°-162.5° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[F:27][C:28]([F:40])([F:39])[CH:29]([CH3:38])[O:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:37]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH:29]([CH3:38])[C:28]([F:27])([F:39])[F:40])=[CH:32][CH:33]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Product: CC(Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1)C(F)(F)F

Procedure:
Light brown crystalline solid. MS (ESI): 517.1. (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH-].[C:6]([OH:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([OH:16])=[O:15])([C:10]([OH:12])=[O:11])[OH:9].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:6]([O-:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([O-:16])=[O:15])([C:10]([O-:12])=[O:11])[OH:9].[CH2:1]([N+:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:2]=[CH2:3].[CH2:1]([N+:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:2]=[CH2:3].[CH2:1]([N+:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: c1ccncc1
Agent: [OH-]
Product: C=CC[n+]1ccccc1
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
Pyridine is reacted with allyl bromide; the halide intermediate is converted to the hydroxide with Rexyn 201, and then reacted with citric acid.