Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:14][CH2:15]O>>[Br:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH2:14][CH3:15])=[O:5]
Reactant: CCO
Reactant: CC(C)(CBr)C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)(C)CBr

Procedure:
3-Bromo-2,2-dimethylpropanoic acid (200 mg) was dissolved in EtOH (5 ml) and treated with concentrated H2SO4 (0.4 ml). This mixture was heated at reflux overnight then evaporated. The residue was extracted from H2O with EtOAc (×2) and the combined organic solutions dried and evaporated to give the title compound (316 mg) as a clear oil. δH (CDCl3, 400 MHz) 1.20 (3H, t), 1.32 (6H, s), 3.51 (2H, s), 4.18 (2H, q).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][S:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:27])=[O:26])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=c1[nH]c2nccc(Oc3cccc(NS(=O)(=O)c4ccccc4)c3)c2[nH]1
Yield: 50 %

Procedure:
Method K was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and benzenesulfonyl chloride to afford the title compound as a brown solid (25 mg, 50%). 1H-NMR (δ, ppm, DMSO-d6): ): 6.21 (s, 1H, HPy,5), 6.77 (s, 2H, Harom), 6.95 (s, 1H, Harom), 7.29 (s, 1H, Harom), 7.53-7.86 (m, 6H, Harom), 10.44 (s, 1H, NHSO2), 11.12 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 106.39, 110.14, 113.74, 114.64, 115.83, 126.61, 129.33, 130.82, 133.09, 139.13, 139.36, 141.25, 144.12, 147.16, 154.15, 154.97. HRMS (EI): m/z [M+H] calcd for C18H15N4O4S: 383.0814; found: 383.0815.
Reaction SMILES: [F:1][CH:2]([F:49])[S:3][CH2:4][C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]2[C@H:17]([CH3:18])[C@H:16]3[N:13]([C:14](=[O:22])[C@@H:15]3[C@H:19]([OH:21])[CH3:20])[C:12]=2[C:23]([O:25]CC2C=CC([N+]([O-])=O)=CC=2)=[O:24])[CH2:7][N:6]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O.P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[F:49][CH:2]([F:1])[S:3][CH2:4][C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]2[C@H:17]([CH3:18])[C@H:16]3[N:13]([C:14](=[O:22])[C@@H:15]3[C@H:19]([OH:21])[CH3:20])[C:12]=2[C:23]([OH:25])=[O:24])[CH2:7][NH:6]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CSC(F)F)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CSC(F)F)C3)[C@H](C)[C@H]12
Yield: 58 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(difluoromethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.58 g), 20% palladium hydroxide on carbon (0.5 g), 0.05M phosphate buffer (pH 6.3, 18 ml) and tetrahydrofuran (18 ml) was stirred at ambient temperature for 4 hours under atmospheric pressure of hydrogen. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to remove the organic solvent. The resulting aqueous residue was washed with ethyl acetate (10 ml×2) and the aqueous layer was concentrated under reduced pressure to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (20 ml) eluting in turn with water (80 ml) and 6% aqueous acetone (80 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(difluoromethyl)thiomethylpyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.19 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8](OS(C)(=O)=O)[C@@H:7]([NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:6]1)=[O:4].[C:24](#[N:26])C>[C-]#N.C([N+](CC)(CC)CC)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([C:24]#[N:26])[CH:7]([NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@H](OS(C)(=O)=O)C1
Reactant: CC#N
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Product: COC(=O)C1CC(C#N)C(NC(=O)c2ccc(Cl)s2)C1

Procedure:
A solution of (1R,3S,4R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methanesulfonyloxy-cyclopentanecarboxylic acid methyl ester (150 mg) in acetonitrile (5 ml) was treated with tetraethylammonium cyanide (74 mg) and heated to reflux for 4 hrs. The reaction mixture was concentrated. The crude product was isolated by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 95:5) to give 3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-cyano-cyclopentanecarboxylic acid methyl ester (100 mg) as light brown oil.
Reaction SMILES: [CH2:1]([NH:4][C:5]([N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3].[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][C:29]([NH:21][S:18]([C:16]2[CH:15]=[CH:14][C:11]3[CH2:12][CH2:13][N:7]([C:5](=[O:6])[NH:4][CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9][C:10]=3[CH:17]=2)(=[O:20])=[O:19])=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCCNC(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Reactant: O=C=NC1CCCCC1
Product: CCCNC(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
By the reaction of 3-propylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-[(3-propylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepin-7-sulfonamide with propylisocyanate in a manner analogous to that described in Example 8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>COCCOC.CCO.O.[Cl-].[Na+].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>[Cl:27][C:21]1[CH:20]=[C:19]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:32]4[CH:33]=[N:28][CH:29]=[N:30][CH:31]=4)[CH:3]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: OB(O)c1cncnc1
Reactant: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1Cl
Yield: 37.2 %

Procedure:
1-(3-Bromophenyl)-1-(3-chloro-4-methoxyphenyl)-4-fluoro-1H-isoindol-3-amine (570 mg, 1.28 mmol), pyrimidin-5-ylboronic acid (190 mg, 1.53 mmol), cesium carbonate (1250 mg, 3.84 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (104 mg, 0.13 mmol) were dissolved in DME:EtOH:Water (6:3:1) (5 mL) and irradiated in a microwave oven for 20 min at 150° C. EtOAc, water and brine were added. The organic phase was collected, dried, filtered and then the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give 212 mg (37%) of the title product. MS (ES+) m/z 445 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9](OC)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.[NH3:17]>>[NH2:17][C:9]1[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:11](=[O:12])[CH:10]=1
Reactant: COc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: N
Product: Nc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: -78 °C

Procedure:
8-Chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.4 g) was treated with 80 mL of liquid anhydrous ammonia chilled to -78° C. The mixture was sealed in a pressure vessel and warmed to 26° C. for 22.5 hours. The excess ammonia was evaporated to give a solid. The solid was recrystallized from 5 mL hot dimethylformamide and water; crystallization was initiated by cooling the solution in an ice bath. The solid was filtered, washed (water) and vacuum dried (100° C., 15 Pa) to give the title compound (0.274 g); mp 344.5°-346.4° C. (dec); NMR: 11.47 (s,1), 8.10 (d,1, J=8.7), 7.53 (d,1, J=2.0), 7.27 (dd,1, J=8.7, 2.0), 7.1 (broad s,2, NH2), 6.23 (s,1).
Reaction SMILES: COC(=O)CC1C2C(=CC=CC=2)C(Br)=CC=1.C([N-]C(C)C)(C)C.[Li+].BrCCBr.C[O:30][C:31](=[O:47])[CH:32]([C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([Br:46])=[CH:38][CH:37]=1)[CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.CN(C)P(N(C)C)(N(C)C)=O>[Br:46][C:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]([C:32]2([C:31]([OH:30])=[O:47])[CH2:34][CH2:33]2)=[CH:37][CH:38]=1
Reactant: COC(=O)C(CCBr)c1ccc(Br)c2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: COC(=O)Cc1ccc(Br)c2ccccc12
Agent: O=C([O-])[O-]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)C1(c2ccc(Br)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a solution of (4-Bromo-naphthalen-1-yl)-acetic acid methyl ester (Example 472a), 687 mg) in tetrahydrofuran (13 mL) and Hexamethylphosphoramide (1.3 mL) was added at −78° C. a solution of lithiumdiisopropylamide (2M, 2.71 mL) in tetrahydrofuran/heptane/ethylbenzene within 5 min. 1,2-dibromoethane (695 mg) was added rapidly and the reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under vacuo and the residue partitioned between ethylacetate and a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a crude mixture containing 4-Bromo-2-(4-bromo-naphthalen-1-yl)-butyric acid methyl ester. This crude material was dissolved in tetrahydrofuran (13 mL) at room temperature and potassium carbonate (692 mg) was added. The mixture was stirred at room temperature for 36 hr, concentrated under vacuo, partitioned between ethyl acetate and a hydrochloric acid (0.1N). The aqueous layer was extracted with ethyl acetate and the combined organic layers were concentrated in vacuo. The crude mixture was concentrated to dryness and purified by chromatography on silica gel to yield the title compound as a colorless oil (215 mg; 30%). MS (ESI): m/z=290 [M−H]−.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[NH2:15][CH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1>ClCCl>[C:8]([NH:15][CH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.76 ml, 5.45 mmol) and acetic anhydride (0.43 ml, 4.56 mmol) were added to an ice-cooled solution of tert-butyl 3-(aminomethyl)-1-azetidinecarboxylate (J. Med. Chem. 2001; 44(1); 94) (850 mg, 4.56 mmol) in dichloromethane (50 ml), and the reaction stirred for 30 minutes. The solution was washed with water (50 ml), brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate as eluant to afford the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[O:13]C(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.ClCCl.C(OCC)(=O)C>[OH:13][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:12])[CH2:11][C:2]1([CH3:17])[CH3:1]
Reactant: CC(=O)OC1c2ccccc2C(=O)CC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)c2ccccc2C1O
Reaction time: 8 h

Procedure:
To a solution of acetic acid 2,2-dimethyl-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl ester (4.03 g, 16.7 mmol) in methanol (50 mL) and dichloromethane (10 mL) is added potassium carbonate (2.33 g, 16.66 mmol). The reaction is permitted to stir for 8 hours at which time it is diluted with ethyl acetate and the resulting solution is washed successively with water and brine. The aqueous phases are then back-extracted with dichloromethane and the organic phases are then combined, dried over magnesium sulfate, filtered, and concentrated to furnish 4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-naphthalen-1-one; 1H NMR (400 MHz, CDCl3) δ ppm 1.04 (s, 3 H), 1.11 (s, 3 H), 2.07 (d, J=6.1 Hz, 1 H), 2.46 (d, J=16. 7 Hz, 1 H), 2.78 (d, J=16.7 Hz, 1 H), 4.64 (d, J=5.8 Hz, 1 H), 7.38-7.46 (m, 1 H), 7.59-7.63 (m, 2 H), 8.02 (d, J=7.8 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:11]C(=O)C.C(O)C.Cl>O>[Cl:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11]
Reactant: CC(=O)Nc1ccc2[nH]cnc2c1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2[nH]cnc2c1Cl
Temperature: 85 °C

Procedure:
58 mg (0.277 mmol) of N-(4-chloro-1H-benzimidazol-5-yl)acetamide (24-1) was suspended in a mixture of water, ethanol and concentrated HCl (0.06:1:0.4) for a total of 1 mL. The suspension was stirred and heated at 85° C. under nitrogen for 1 hour and after this time everything was soluble. The heat was turned off the solution was stirred overnight. The reaction was quenched with saturated NaHCO3. The pH was adjusted to 8 by adding solid NaHCO3 and Na2CO3. Extracted the reaction with ethyl acetate, dried, filtered and evaporated to recover the desired product 24-2. MS (M+1): measured 168.2; theoretical 167.0. 1H NMR (CD3OD): 6.75 (dd, 1H), 7.37 (d, 1H), 7.93 (s, 1H).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][CH:11]1[C:39](=[O:40])[N:13]2[CH:14]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:15]([CH2:19][O:20]C=O)=[C:16]([CH3:18])[S:17][C@H:12]12)=[O:9].CCOC(C)=O.O>CN(C=O)C>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][CH:11]1[C:39](=[O:40])[N:13]2[CH:14]([C:23]([O:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:24])[C:15]([CH2:19][OH:20])=[C:16]([CH3:18])[S:17][C@H:12]12)=[O:9]
Reactant: CC1=C(COC=O)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1=C(CO)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.2 %

Procedure:
A 22.8 ml portion of 2N HCl was added to a solution of 30 g of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-formyloxymethylceph-2-em-4-carboxylate in 100 ml of DMF, and the mixture was stirred at room temperature for 20 hours. AcOEt and H2O were added to the reaction solution to separate out the AcOEt layer. The AcOEt layer was washed with 5% aqueous NaHCO3 solution and with saturated aqueous NaCl solution, and dried over Na2SO4, followed by distilling off the AcOEt under reduced pressure. The residue was added on a column of silica gel and washed with CH2Cl2.AcOEt (10:1). Then, the fractions eluted with acetone were collected, and the solvent was distilled off under reduced pressure, resulting 14.6 g (62%) of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-hydroxymethylceph-2-em-4-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:24]#[N:25])=[CH:12][N:13]=[C:14]([NH:15][CH:16]4[CH2:21][CH2:20][CH:19]([OH:22])[CH:18]([F:23])[CH2:17]4)[C:5]=3[C:4]=2[CH:3]=1.OO.C(=O)([O-])[O-:29].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:24]([NH2:25])=[O:29])=[CH:12][N:13]=[C:14]([NH:15][CH:16]4[CH2:21][CH2:20][CH:19]([OH:22])[CH:18]([F:23])[CH2:17]4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: N#Cc1cnc(NC2CCC(O)C(F)C2)c2c1[nH]c1ccc(F)cc12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cnc(NC2CCC(O)C(F)C2)c2c1[nH]c1ccc(F)cc12
Temperature: 70 °C

Procedure:
To a stirred solution of 8-fluoro-1-[(3-fluoro-4-hydroxycyclohexyl)amino]-5H-pyrido[4,3-b]indole-4-carbonitrile (72 mg, 0.21 mmol) in DMSO were added hydrogen peroxide (30%, 0.18 mL, 2.10 mmol) and potassium carbonate (157 mg, 1.14 mmol). The reaction mixture was heated to 70° C. for 4 h, cooled to room temperature, filtered, and purified by prep-HPLC to afford the title compound. 1H NMR (500 MHz, CD3OD) δ 8.48 (s, 1H); 7.92 (dd, 1H); 7.57 (dd, 1H); 7.16 (dt, 1H); 4.35-4.52 (m, 2H); 3.71 (m, 1H); 1.46-2.55 (series of m, 6H). LRMS (APCI) calc'd for (C18H18F2N4O2) [M+H]+, 361.1. found 361.0.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]([CH:12]([CH3:14])[CH3:13])=[N:7][C:8]=1[CH:9]([CH3:11])[CH3:10].[O-:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Na+].O>O1CCCC1>[CH:12]([C:6]1[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:3]([CH2:2][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:8]([CH:9]([CH3:10])[CH3:11])[N:7]=1)([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CCl)c1-c1ccc(F)cc1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(COc2ccccc2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
3.22 g (9.1 mmol) of the compound from Example 86 dissolved in 50 ml of absolute tetrahydrofuran are added dropwise at 0° C. to a solution of 2.11 g (18.2 mmol) of sodium phenoxide in 50 ml of absolute tetrahydrofuran and the mixture is heated to reflux for 4 days. After cooling to room temperature, the mixture is diluted using 150 ml of water and extracted several times using ether. The combined organic phases are dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using petroleum ether/ethyl acetate 95.5).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S([O-])([O-])(=O)=O.[CH2:21]([N+:25](CCCC)(CCCC)CCCC)[CH2:22]CC.C([N+](CCCC)(CCCC)CCCC)CCC.BrCC#N.[OH-].[Na+]>C(Cl)Cl.O>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:22][C:21]#[N:25])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1=Cc2ccccc2Nc2ccccc21
Agent: N#CCBr
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CCN1c2ccccc2C=Cc2ccccc21
Reaction time: 120 h
Yield: 51.7 %

Procedure:
(Z)-5H-dibenzo[b,f]azepine (0.1 g, 0.5 mmol), tetrabutylammonium sulfate (0.35 g, 1.0 mmol), 2-bromoacetonitrile (0.4 mL, 5.0 mmol) and 50% aqueous sodium hydroxide (1 mL) were mixed in DCM (1 mL) and the reaction mixture was stirred for 5 days. The mixture was diluted in water and the aqueous layer was extracted with DCM (2 times). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (0% to 50% ethyl acetate in hexanes) to afford title compound 365 (60 mg, 50%). 1H NMR (CDCl3) δ (ppm): 7.36-7.31 (m, 2H), 7.26-7.23 (m, 2H), 7.17-7.11 (m, 4H), 6.76 (s, 2H), 4.47 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[N:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[S:16][CH:17]=2)=O)=[C:8]([Cl:21])[C:7]([O:22][CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CC([O-])(C)C.[K+].Cl>CC(O)(C)C>[Cl:21][C:8]1[C:7]([O:22][CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([C:13]1[N:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[S:16][CH:17]=1)[CH:2]=[C:1]2[OH:3]
Reactant: COC(COc1ccc(C(C)=O)c(NC(=O)c2csc(C(C)C)n2)c1Cl)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(COc1ccc2c(O)cc(-c3csc(C(C)C)n3)nc2c1Cl)OC
Temperature: 75 °C
Yield: 85.1 %

Procedure:
2-Isopropyl-thiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxy-ethoxy)-phenyl]-amide (5.5 g, 12.91 mmol) and KOtBu (3.04 g, 27.11 mmol) were dissolved in tBuOH (100 mL) under an atmosphere of nitrogen. The reaction was heated to 75° C. for 4 hours. The reaction was cooled to rt and the pH was adjusted to 4 with 2N HCl(aq). The reaction mixture was concentrated and taken up in EtOAc (100 mL). The mixture was washed with ½ sat. brine. The organic layer was dried with Na2SO4, filtered and was concentrated. 8-Chloro-7-(2,2-dimethoxy-ethoxy)-2-(2-isopropyl-thiazol-4-yl)-quinolin-4-ol (4.49 g, 85%) was isolated by silica gel chromatography as a yellow solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.Cl>O1CCCC1>[CH2:1]([S:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1SCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccccc1SCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
To a solution of 2-benzylsulfanyl benzoic acid 3 (50 mg, 0.206 mmol) in THF at 0° C. was added LiAlH4 (0.62 mL of a 1.0 mL solution in THF, 0.62 mmol) and the mixture was stirred at 0° C. for 15 minutes then allowed to warm to room temperature. The solution was stirred for 2 hours. The mixture was cooled at 0° C. then methanol (MeOH) was added slowly followed by HCl (0.5N) and tetrahydrofuran (THF). The mixture was stirred at room temperature for 30 minutes. It was then concentrated to remove THF, extracted with CH2Cl2 (3×), dried over MgSO4, filtered and concentrated to give 30 mg of the product as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][S:15][C:10]=2[CH2:9][C:8]2[N:16]=[CH:17][CH:18]=[CH:19][C:7]1=2)=[O:5].[Cl-]>C(O)C>[Cl:1][C:2]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][S:15][C:10]=2[CH2:9][C:8]2[N:16]=[CH:17][CH:18]=[CH:19][C:7]1=2)=[O:5]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1Cc2ccsc2Cc2ncccc21
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3ccsc3Cc3ncccc32)c(Cl)c1

Procedure:
As described for Reference Example 204 5-(2-chloro-4-nitrobenzoyl)-4,10-dihydro-5H-pyrido[3,2-b]-thieno[2,3-e]azepine is reduced with stannus chloride (SnCl2) in ethanol to give the product as a solid.