Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[NH:31][CH:32]=[N:33][CH:34]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[NH:31][CH:32]=[N:33][CH:34]=2)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1cnc[nH]1
Product: CCN(Cc1cnc[nH]1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(3H-imidazol-4-ylmethyl)-amine
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=CN(C)C)=[CH:7][N:6]=1)=[O:4].I([O-])(=O)(=O)=[O:17].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=[O:17])=[CH:7][N:6]=1)=[O:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1cnc(C=CN(C)C)cn1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(C=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
A solution of the 5-(2-dimethylamino-vinyl)-pyrazine-2-carboxylic acid methyl ester (415 mg, 2.0 mmol) in tetrahydrofuran and water (10 mL, 1:1) was treated with powdered sodium periodate (1.3 g, 6.07 mmol). The mixture was stirred at 25° C. for 30 min, at which time, thin layer chromatography suggested complete conversion to a product less polar than starting material. The reaction mixture was concentrated in vacuo nearly to dryness, and the residue was partitioned with ethyl acetate (50 mL) and a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous phase was extracted with ethyl acetate (2×50 mL). Each of the organic extracts was washed with a saturated aqueous sodium chloride solution (25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude aldehyde, 5-formyl-pyrazine-2-carboxylic acid methyl ester (180 mg), as an orange oil which was used without further characterization or purification.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][CH2:12][C:13]1[N:18]=[C:17]2[S:19][C:20]3[CH2:21][N:22]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:24][C:25]=3[C:16]2=[C:15]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[C:14]=1[Cl:43].O>N1C=CC=CC=1>[CH2:26]([N:22]1[CH2:23][CH2:24][C:25]2[C:16]3[C:17]([S:19][C:20]=2[CH2:21]1)=[N:18][C:13]([CH2:12][NH:11][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)=[C:14]([Cl:43])[C:15]=3[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CNC(=O)c3cccnc3)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
Nicotinoyl chloride hydrochloride (0.18 g) was added to a solution of the compound (0.29 g) obtained in Example 18B in pyridine (4 ml), the mixture was stirred at room temperature for 1 hour, poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate to yield 7-benzyl-3-chloro-4-(3,4-dimethoxyphenyl)-2-(nicotinoylaminomethyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine (0.2 g, 51%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 124 to 125° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=O)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[NH:22][C:20](=[O:21])[C:3]3[CH:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:26][CH:25]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Product: CC(O)C(CCCc1ccccc1)n1ncc2c(=O)[nH]c(Cc3ccc(Cl)cc3)nc21

Procedure:
Starting from 400 mg (1.32 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazole-4-carboxamide and 626 mg (3.77 mmol) of 4-chlorophenylacetyl chloride, the title compounds are prepared analogously to the protocol of Example 13. This gives 150 mg (26%) of the diastereomer which elutes more rapidly, M.p.: 125° C., and 90 mg (16%) of the diastereomer which elutes more slowly, M.p.: 101° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1(O)[C:12]([CH3:14])([CH3:13])[CH2:11][C:10]([CH3:16])([CH3:15])[CH2:9][CH:8]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=1)([CH3:4])[CH3:3].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C(#N)C.O>[CH3:3][Si:2]([C:5]#[C:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][C:10]([CH3:16])([CH3:15])[CH2:9][C:8]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=1)([CH3:1])[CH3:4]
Reactant: Cc1cc(C2CC(C)(C)CC(C)(C)C2(O)C#C[Si](C)(C)C)ccc1F
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CC#N
Solvent: O
Product: Cc1cc(C2=C(C#C[Si](C)(C)C)C(C)(C)CC(C)(C)C2)ccc1F
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of the hydroxy acetylene from Example 1, Step C above (20 g, 55.5 mmol) in acetonitrile (250 ml) is added 20 g (83 mmol) of Burgess reagent. The reaction mixture is heated at reflux for 14 hours, cooled to room temperature and diluted with H2O (1 L). The aqueous solution is extracted with ether and the combined ether layers are washed with H2O. The ether fraction is dried over MgSO4 and the solvent is removed under reduced pressure. Purification by silica gel chromatography (100% hexane) provides 12.7 g (67%) of 1-((trimethylsilyl)ethynyl)-2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohexene as an oil: 1H NMR δ=0.0 (s,9), 0.95 (s,6), 1.15 (s,6), 1.4 ((s,2), 2.1 (s,2), 2.2 (s,3), 6.85 (t,1), 7.25 (m,2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1.N1CCCC1.CO>C(OCC)(=O)C>[O:10]=[C:8]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:1][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(=O)c1ccccc1O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Temperature: 80 °C
Yield: 80.8 %

Procedure:
A mixture of 1-(2-hydroxyphenyl)ethanone (50 g, 0.37 mol), benzyl 4-oxopiperidine-1-carboxylate (94 g, 0.40 mol), pyrrolidine (61 mL, 0.73 mol) and methanol (24 mL) was heated at 80° C. for 20 hours. After cooling to 25° C., the reaction mixture was diluted with ethyl acetate (1000 mL) and partitioned with 1M aqueous HCl (500 mL). The organic phase was washed with 1M aqueous HCl (2×500 mL), water (500 mL), saturated sodium chloride solution (500 mL), dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0-30% ethyl acetate in hexane) afforded benzyl 4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (105 g, 81% yield) as a yellow oil. ESI-MS m/z calc. 351.2. found 352.2 (M+1)+; Retention time: 2.30 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=7.8 Hz, 1H), 7.54-7.47 (m, 1H), 7.44-7.29 (m, 5H), 7.02 (dd, J=14.8, 7.8 Hz, 2H), 5.16 (s, 2H), 4.10-3.90 (m, 2H), 3.36-3.24 (m, 2H), 2.73 (s, 2H), 2.12-2.00 (m, 2H), 1.71-1.58 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]=O)=[CH:10][C:5]=2[CH2:4][O:3]1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[N:24]3[CH2:23][CH2:22][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:26][CH2:25]3)=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(/C=C/c2ccc3c(c2)COC3=O)CC1
Temperature: 25 °C

Procedure:
A mixture of (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (3.5 g, 20 mmol), Boc-piperazine (3.5 g, 20 mmol) and anhydrous MgSO4(20 g, 166 mmol) in 100 mL of anhydrous DCM were stirred at room temperature over night. The solid was filtered and the solvent was evaporated at reduced pressured to get the crude product. The crude product was purified via column chromatograph to afford tert-butyl 4-[(E)-2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethenyl]piperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3) δ ppm 7.74 (d, J=8.2 Hz, 1H), 7.29˜7.34 (m, 2H), 6.88 (d, J=13 Hz, 1H), 5.55 (d, J=14 Hz, 1H), 5.25 (s, 2H), 3.49˜3.58 (m, 4H), 3.12˜3.17 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.Cl.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]2[N:23]1[C:31]2[C:26](=[CH:27][C:28]([NH2:32])=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>C(O)=O>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]2[N:23]1[C:31]2[C:26](=[CH:27][C:28]([NH:32][CH:1]=[O:3])=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: COc1cc2ncnc(N3CCc4cc(N)ccc43)c2cc1OC
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O=CO
Product: COc1cc2ncnc(N3CCc4cc(NC=O)ccc43)c2cc1OC
Temperature: 5 °C

Procedure:
Formic acid (42 μL) was added to acetic anhydride (88 μL) while stirring at 5° C. and the mixture was allowed to stir at 20° C. for 1 hour before adding 1-(6,7-dimethoxy-quinazolin-4-yl)-2,3-dihydro-1H-indol-5-ylamine (102 mg, 0.316 mmol; freebase from Example 83). The mixture was stirred at 20° C. for 1.5 hours, quenched with H2O (5 mL), stirred 30 min. and diluted with CHCl3 (15 mL). The organic phase was separated and washed with saturated aqueous NaHCO3, dried over Na2 SO4(s), filtered and concentrated in vacuo. Flash chromatography on silica (4% MeOH/CH2Cl2) afforded 66 mg of product. (M.P. 239°-244° C. (dec); LC-MS: 351 (MH+); anal. RP18-HPLC RT: 2.92 min.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C(O)C.[C].[Pd].[C].[Rh].[Pt](=O)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16]3=[N:17][S:18](=[O:21])(=[O:22])[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Agent: [Pd]
Agent: [Rh]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture of 10% palladium-carbon (50% wet, 15 mg) and 9-(4-tert-butylphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) in THF (25 mL) and ethanol (25 mL) was stirred under a hydrogen atmosphere at room temperature, and stirred under a hydrogen atmosphere (3.5 atm) for 1 hr. To the reaction mixture was added 5% rhodium-carbon (50% wet, 15 mg), and the mixture was stirred under a hydrogen atmosphere (3.5 atm) for 4 hr. To the reaction mixture was added platinum dioxide (15 mg) and the mixture was stirred under a hydrogen atmosphere for 2 hr. The reaction mixture was filtered, the filtrate was concentrated, and the residue was crystallized from THF and diisopropyl ether to give the title compound (35 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:14]=[C:13]([Cl:12])[CH:19]=[C:18]([Cl:20])[CH:17]=1)=[O:9]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc(Br)ccc1O
Yield: 61.6 %

Procedure:
Using 5-bromosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([NH:33][CH3:34])=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([NH:33][CH3:34])=[O:32])=[CH:4][CH:3]=1
Reactant: CNC(=O)CCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2C(F)(F)F)CC1
Product: CNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-N-methyl-acetamide gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH2:30]([N:33]=[C:34]=[S:35])[CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:34]([NH:33][CH2:30][CH2:31][CH3:32])=[S:35])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: CCCN=C=S
Reactant: COc1ccc(Cl)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Product: CCCNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(Cl)ccc1OC

Procedure:
4-(5-Chloro-2-methoxybenzamidomethyl)-6-(n-propylaminothiocarbonylaminosulfonyl)-7-methoxychroman ##STR36## 4-(5-Chloro-2-methoxybenzamidomethyl)-6-(n-propylaminothiocarbonylaminosulfonyl)-7-methoxychroman is prepare from 4-(5-chloro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-methoxychroman and n-propyl isothiocyanate. Melting point: 183°-184° C.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:61])([F:60])[C:4]1[CH:5]=[C:6]([CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:55]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([N:18]2[CH2:23][CH2:22][N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:20][CH2:19]2)=[O:17])[CH2:11][C@H:10]1[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)=[O:8].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[ClH:1].[ClH:1].[F:60][C:3]([F:2])([F:61])[C:4]1[CH:5]=[C:6]([CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:55]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:17])[CH2:11][C@H:10]1[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)=[O:8]
Reactant: O=C(CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)N1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)N1CCNCC1
Reaction time: 1 h

Procedure:
A solution of 4N hydrogen chloride in ethyl acetate solution (1.5 ml) was added dropwise to a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)-4-[(4-trityl-1-piperazinyl)carbonylmethyl]piperazine (480 mg) in ethyl acetate (5 ml) at 0° C. The resulting mixture was stirred at the same temperature for 1 hour and then allowed to stand overnight. Aqueous saturated sodium bicarbonate solution (20 ml) was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic phase was washed with brine and dried. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on a silica gel eluting with a mixture of dichloromethane and methanol (5:1) and treated with 4N hydrogen chloride in dioxane solution to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)-4-[(1-piperazinyl)carbonylmethyl]piperazine dihydrochloride (250 mg).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]1([CH2:13][CH2:14][NH2:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1>C(Cl)Cl>[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]=1[CH2:13][CH2:14][NH:15][CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CBr
Reactant: NCCC1=CCCCC1
Solvent: ClCCl
Product: COC(=O)CNCCC1=CCCCC1
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a solution of methyl bromoacetate (5 g, 32.7 mmol) in DCM (150 mL) was added 2-(1-cyclohexenyl)ethylamine (11.4 ml, 81.71 mmol) over 5 min. After 2 h, the solvent was removed and the residue purified on silica gel (Merck 60; (1:9) ethyl acetate/hexane) to afford methyl 2-[N-(2-cyclohex-1-enyl)ethylamino]acetate (5.0 g, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH3:15])[C:7]([NH2:9])=[O:8])([O-])=O.[C:16](OC(=O)C)(=O)[CH3:17]>[Ni].C(O)(=O)C>[CH2:14]([N:13]1[C:12]2[CH:11]=[CH:10][C:6]([C:7](=[O:8])[NH2:9])=[CH:5][C:4]=2[N:1]=[C:16]1[CH3:17])[CH3:15]
Reactant: CCNc1ccc(C(N)=O)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Solvent: CC(=O)O
Product: CCn1c(C)nc2cc(C(N)=O)ccc21

Procedure:
A mixture of III (125 g - 0.6 mole), acetic anhydride (214 g - 2.1 moles), Raney Nickel (1.2 ml) and acetic acid (36 g - 0.6 mole) was hydrogenated at 80° C and a pressure of 100 to 30 atm. Reaction time: 5 hours. After cooling, the catalyst was filtered, the filtrate was concentrated by normal pressure until 135 ml of distillate were collected. 150 ml of H2SO4 6N were added to the residue. The reaction was very exothermic. The solution was refluxed with active carbon for 15 min. and filtered. The filtrate was mixed with 1.2 kg of ice and exactly neutralized with 2N NaOH. The precipitate was washed with water and dried at 100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[CH2:7][C:6]=2[CH:16]=1.[CH:17]1([CH2:21]Br)[CH2:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:21][CH:17]3[CH2:20][CH2:19][CH2:18]3)[C:10](=[O:12])[CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[CH2:7][C:6]=2[CH:16]=1
Reactant: O=C1Nc2ccc(Cl)cc2CN2CCCC12
Reactant: BrCC1CCC1
Product: O=C1C2CCCN2Cc2cc(Cl)ccc2N1CC1CCC1

Procedure:
If 7-chloro-1,2,3,5,10,11a-hexahydro-11H-pyrrolo- [2,1-c] [1,4]benzodiazepin-11-one is treated with cyclobutylmethylbromide by the procedure of Example 18, the above product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8]([OH:10])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.CS(C)=O>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:8](=[O:10])[C:7]3[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[N:5][CH:6]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1cncc(C(=O)O)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cncc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)c1

Procedure:
From 5-methoxy-nicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+5.8° (c=0.10, DMSO), ES-MS m/e (%): 402 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Cu][C:12]#[N:13].C(#N)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: N#C[Cu]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: N#CC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 169.1 %

Procedure:
43.8 g (0.1 mol) 3-chlorobenzoyl chloride, 29.1 g (0.13 mol) copper (I) cyanide, and 20 mL acetonitrile in 37 mL toluene was refluxed for 3 hours, and then cooled to room temperature. Insoluble material was filtered and the residue was washed with toluene. The solvent in the resulting filtrate was evaporated under reduced pressure, and the residue was distilled to yield 28 g 3-chlorophenyloxoacetonitrile (yield=68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH2:13]O)=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C1COCC1>[Br:35][CH2:13][C:11]1[S:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][CH:10]=1
Reactant: OCc1ccc(-c2ccccc2Cl)s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccccc1-c1ccc(CBr)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
200 mg (0.74 mmol) of the compound from Example 52A and 291 mg (1.11 mmol) of triphenylphosphine were dissolved in 8 ml of THF, and 367 mg (1.11 mmol) of carbon tetrabromide were added at RT. The mixture was then stirred at RT for 16 h. For work-up, the mixture was filtered through 20 g of kieselguhr, the filter residue was rinsed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 5:1). This gave 113 mg of contaminated target product (32% pure, 17% of theory) which were immediately reacted further.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:36]([O:37][CH2:38][CH:39]([F:41])[F:40])=[CH:35][C:14]3[N:15]([CH3:34])[C:16]([NH:18][C:19]4[CH:24]=[C:23]([CH2:25][NH:26][S:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[CH:22]=[CH:21][C:20]=4[Cl:33])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:47]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:36]([O:37][CH2:38][CH:39]([F:41])[F:40])=[CH:35][C:14]3[N:15]([CH3:34])[C:16]([NH:18][C:19]4[CH:24]=[C:23]([CH2:25][NH:26][S:27]([C:29]([CH3:31])([CH3:32])[CH3:30])(=[O:47])=[O:28])[CH:22]=[CH:21][C:20]=4[Cl:33])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1c(Nc2cc(CNS(=O)C(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Solvent: ClCCl
Product: Cn1c(Nc2cc(CNS(=O)(=O)C(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Temperature: 25 °C

Procedure:
A mixture of N-(4-bromo-phenyl)-2-(2-chloro-5-{[(tert-butylsulfinyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide (100 mg; 0.15 mmol), m-chloroperoxybenzoic acid (28 mg; 0.16 mmol) and DCM (20 mL) was stirred over night at rt. The mixture was basicified to pH ˜8-9 and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give the title compound. Yield: 24 mg (23%). 200 MHz 1H-NMR (DMSO-d6, ppm) 10.06-10.02 (1H, m) 7.75-7.62 (4H, m) 7.54-7.44 (4H, m) 7.27-7.17 (2H, m) 6.95-6.84 (1H, m) 6.57-6.49 (1H, m) 4.58-4.42 (2H, m) 4.16-4.09 (2H, m) 3.57-3.51 (3H, m) 1.29 (9H, s). MS m/z: 684, 686, 690 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.C1COCC1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[O:9]
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
A solution of 5-Bromoisatoic anhydride (2.00 g, 8.26 mmol) in THF (53.62 mL, 661.1 mmol) was treated with diethylamine (1.28 mL, 12.40 mmol) and allowed to stir overnight at rt. The mixture was concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→4% MeOH in DCM] to afford 326 mg of the title compound (15%). 1H NMR (400 MHz, CD3OD) δ 7.24 (dd, J=2.27, 8.84 Hz, 1H), 7.13 (d, J=2.27 Hz, 1H), 6.71 (d, J=8.59 Hz, 1H), 3.43 (br. s., 4H), 1.18 (br. s., 6H). MS (ESI): m/z 271.41 [M+H]+. UPLC: tR=1.09 min (UPLC-SQD: analytical—2 min).