Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[C:15]([Cl:23])[CH:14]=[CH:13][CH:12]=2)[C:5]([O:7][CH3:8])=[O:6].[CH3:25][O-].[Na+].CI>CO>[CH3:1][O:2][C:3](=[O:24])[C:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[C:15]([Cl:23])[CH:14]=[CH:13][CH:12]=2)([CH3:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[O-]
Reactant: COC(=O)C(C(=O)OC)c1[nH]c2cccc(Cl)c2c1CCN=[N+]=[N-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COC(=O)C(C)(C(=O)OC)c1[nH]c2cccc(Cl)c2c1CCN=[N+]=[N-]
Reaction time: 0.5 h

Procedure:
To a solution of 2-[3-(2-azidoethyl)-4-chloro-1H-indol-2-yl]-propanedioic acid dimethyl ester (19.3 mmol) in dry MeOH (0.1 L) at 0° C. under argon was added a 25% NaOMe in MeOH (4.37 mL, 19.11 mmol). The reaction mixture was stirred for 30 min, and MeI (1.82 mL, 29.2 mmol) was added. The mixture was stirred briefly at rt, and then was refluxed overnight. The reaction mixture was concentrated. The residue was taken up with cold H2O. This mixture was extracted with Et2O. The combined Et2O extracts were washed with H2O, dried, filtered, and concentrated to an oil. This oil was purified by silica chromatography to give the title compound: TLC Rf=0.50 (CH2Cl2), MS (ESI+) 387.0; 1H NMR (300 MHz CDCl3) δ 9.95 (1H), 7.27 (1H), 7.07 (2H), 3.83 (6H), 3.48 (2H), 3.15 (2H), 1.94 (3H).
Reaction SMILES: CS[C:3](=[N:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:6].[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([Cl:46])[C:38]=1[NH:39][C:40](=[O:45])[CH2:41][N:42]([CH3:44])[CH3:43])[CH2:34][NH2:35]>C(N(CC)CC)C>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([Cl:46])[C:38]=1[NH:39][C:40](=[O:45])[CH2:41][N:42]([CH3:43])[CH3:44])[CH2:34][NH:35][C:3]([NH:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:6])=[N:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)[C@H]1CCCN1c1ccc(C(F)(F)F)cc1
Reactant: CN(C)CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)Nc1c(Cl)cc(CNC(=NC(=O)OC(C)(C)C)NC(=O)[C@H]2CCCN2c2ccc(C(F)(F)F)cc2)cc1Cl
Yield: 54.5 %

Procedure:
A solution of (R)-tert-butyl methylthio(1-(4-(trifluoromethyl)-phenyl)pyrrolidine-2-carboxamido)methylenecarbamate (6 mg), 3,5-dichloro-4-(2-(dimethylamino)acetamido)-benzylamine (10 mg) and triethylamine (50 μL) was heated at 56° C. for 12 h. The crude reaction mixture was purified directly by preparative TLC eluting with 10% methanol/89% dichloromethane/1% ammonia hydroxide to give the title compound as a colorless oil (5 mg). retention time: 2.03 min (method A). MS (ESI) (M+Na)+ 659.19.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:11]([N+:17]([O-])=O)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O1CCOCC1.[Fe]>[NH2:17][C:11]1[N:10]=[CH:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: NS(=O)(=O)c1c([N+](=O)[O-])ncn1Cc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Nc1ncn(Cc2ccccc2)c1S(N)(=O)=O
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A solution of the product of Example 312E (434 mg, 1.54 mmol) in acetic acid (4.3 mL) and dioxane (4.3 mL) was reacted with iron powder (343 mg, 6.15 mmol) at 50° C. for 3 hours. The reaction mixture was cooled to 25° C., filtered through a pad of celite® (diatomaceous earth) and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (2×) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel using a gradient of methanol in dichloromethane (0-5%) to give the title compound (180 mg, 46%). MS (ESI+) m/z 253 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.24 (s, 2H), 7.22-7.39 (m, 5H), 7.43 (s, 1H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[CH2:15][CH2:16]2)=[CH:11][CH:10]=3)[CH2:7][CH2:6]1)[CH3:4].[H-].[Na+].[CH3:33][C:34]1([O:37][CH2:36]1)[CH3:35].C(OCC)C>CN(C)C=O>[OH:37][C:34]([CH3:36])([CH3:35])[CH2:33][O:1][N:2]=[C:3]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[CH2:15][CH2:16]2)=[CH:11][CH:10]=3)[CH2:7][CH2:6]1)[CH3:4]
Reactant: CC(=NO)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC1(C)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=NOCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A portion (606 mg) of the 20-hydroxyimino-3β-(2-tetrahydropyranyloxy)-5,7-pregnadiene obtained in (a) was dissolved in 10 ml of dry dimethylformamide, and after addition of 100 mg of sodium hydride (60% in oil), the solution was vigorously stirred for 30 minutes at room temperature. After addition of 0.5 ml of isobutylene oxide, the mixture was heated on an oil bath (80°-100° C.) for 1 hour. After cooling, diethyl ether was added, and the mixture was washed with water and dried, followed by the distilling off of the solvent under vacuum. The residue was subjected to silica gel column chromatography to obtain 271 mg of 20-(2-hydroxy-2-methylpropyloxyimino)-3β-(2-tetrahydropyranyloxy)-5,7pregnadiene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.Cl.[CH3:34][N:35]([CH3:42])[CH2:36][CH2:37][CH2:38][C:39](O)=[O:40].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:34][N:35]([CH3:42])[CH2:36][CH2:37][CH2:38][C:39]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:40]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: CN(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)CCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), 4-(dimethylamino)butanoic acid hydrochloride salt (0.24 g, 1.43 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.30 mmol) were combined in DMF (4 ml), The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then concentrated in vacuo, suspended in ethyl acetate:acetonitrile (1:1) and filtered. The solids were dissolved in a minimum amount of methanol and submitted directly to purification via chromatography (silica gel, 1 to 20% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white solid (0.195 g), melting point: 148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.CN(C)C(=O)C.S(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:19])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Product: ClCCc1ccc(Cl)cc1
Temperature: 58 °C
Reaction time: 2.5 h

Procedure:
Into a 250-mL round-bottom flask equipped with magnetic stirring, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, was charged 2-(4-chlorophenyl)ethanol (25.033 g, 160 mmol). N,N-Dimethylacetamide (0.749 mL, 7.99 mmol) was added and the mixture was heated in oil bath to 58° C. Thionyl Chloride (12.25 mL, 168 mmol) was charged over 1 h while the reaction temperature was maintained at <66° C. The resulting brown solution was stirred at 60 to 64° C. for 2.5 h and then allowed to gradually cool to room temperature leaving a dark brown oil.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[S:21][CH:20]=[C:19](Br)[C:18]=3[CH:23]=2)=[O:12])=[CH:9][CH:8]=1.[CH:26]1[C:34]2[N:29]([CH:30]=[CH:31][C:32](=O)[CH:33]=2)[CH2:28][CH:27]=1>C(OCC)C>[F:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[S:21][CH:20]=[C:19]([C:32]4[CH2:33][CH:34]5[N:29]([CH2:28][CH2:27][CH2:26]5)[CH2:30][CH:31]=4)[C:18]=3[CH:23]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=c1ccn2c(c1)C=CC2
Reactant: O=C(Nc1ccc2scc(Br)c2c1)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(Nc1ccc2scc(C3=CCN4CCCC4C3)c2c1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1.55 mL n-butyllithium in diethyl ether is cooled to -78° C. under a nitrogen atmosphere. To this cooled solution is added a solution of N-(4-fluorobenzoyl)-3-bromo-5-aminobenzothiophene (0.90 eq.) in diethyl ether. The reaction mixture is stirred at -78° C. for 1 hour and then to it is added dropwise a solution of 7-indolizinone (1.08 eq.) in diethyl ether. The reaction is stirred an additional 2 hours at -78° C. and is then gradually warmed to -20° C. over 55 minutes. The reaction mixture is then quenched with saturated aqueous sodium bicarbonate, diluted with additional diethyl ether and the phases separated. The organic phase is washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in aqueous potassium hydroxide (10% in water) and heated to reflux for 15 hours. The mixture is concentrated in vacuo and the residue is subjected to flash silica gel chromatography. Fractions shown to contain product are combined and then concentrated under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1>C1COCC1>[Cl:1][C:2]1[C:11]([C@H:12]([OH:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(=O)c1cc2cccc(F)c2nc1Cl
Solvent: C1CCOC1
Product: C[C@@H](O)c1cc2cccc(F)c2nc1Cl
Temperature: -55 °C
Reaction time: 1 h

Procedure:
In a round bottomed flask was dissolved (+)-dip-chloride(tm) (4418 mg, 13773 μmol) in anhydrous THF (50 mL) and the solution was cooled to −55° C. (using a dry ice/MeCN bath). To this solution was added 1-(2-chloro-8-fluoroquinolin-3-yl)ethanone (1.4 g, 6.3 mmol) as a solution in THF (10 mL). The reaction was allowed to warm to +10° C. over 5 h. The reaction was quenched with 10 mL acetone and 20 ml, of 10% Na2CO3 and allowed to stir for 1 h at rt. Ethyl acetate (200 mL) was added and the layers were separated. The organic phase was washed with three times with a 50% saturated sodium bicarbonate solution and once with brine. The organic layer was dried over MgSO4, filtered, and concentrated to provide 5 g of crude material. The crude material was purified using 7:3 hexanes:ethyl acetate on 120 g silica gel column to afford (R)-1-(2-chloro-8-fluoroquinolin-3-yl)ethanol. Chiral HPLC (10% IPA in hexanes, chiralcel AD) shows product to be 96.0% ee. 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (br s), 7.64 (br d, J=8.2 Hz, 1H), 7.50 (td, J=7.8, 4.7 Hz, 1H), 7.41 (ddd, J=10.2, 7.8, 1.2 Hz, 1H), 5.40 (qd, J=5.9, 0.8 Hz, 1H), 2.22 (br s, 1H), 1.62 (d, J=6.3 Hz, 3H). Mass Spectrum (ESI) m/e=226.0 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=[O:4].[CH3:26][NH2:27]>CCO>[CH3:26][NH:27][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=[O:4]
Reactant: CN
Reactant: COC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Solvent: CCO
Product: CNC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 80 °C

Procedure:
A mixture of 1-benzyl-5-cyano-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (18 mg, 0.054 mmol) and methylamine (1 mL, 2M in THF) in EtOH (2 mL) was heated in a sealed tube at 80° C. for 16 h. After cooling to r.t., mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (0-2% MeOH/CH2Cl2) to give 10 mg of the title compound. MS: (−) m/z 333.30 (M−1).
Reaction SMILES: [C:1]([C:3]1[N:11]2[C:6]([C:7]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[O:8][C:9]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:10]=32)=[CH:5][CH:4]=1)#[N:2].[Br:29]N1C(=O)CCC1=O.C(C(N=NC(C)(C)C#N)(C)C)#N>C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]3[C:3]([C:1]#[N:2])=[CH:4][CH:5]=[C:6]3[C:7]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[O:8][C:9]=2[CH:15]=1
Reactant: Cc1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1ccc(C#N)n1-2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(CBr)ccc1-n1c(C#N)ccc12
Temperature: 80 °C
Yield: 47.6 %

Procedure:
tert-Butyl 1′-cyano-7′-methyl-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (200 mg, 0.527 mmol), 1-bromopyrrolidine-2,5-dione (93.8 mg, 0.527 mmol), and 2-(1-cyano-1-methyl-ethyl)azo-2-methyl-propanenitrile (8.66 mg, 0.0527 mmol) were combined in carbon tetrachloride (10 mL) and the mixture was heated at 80° C. for 4 hours. The mixture was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (50-100% CH2Cl2/hexanes) to yield tert-butyl 7′-(bromomethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (115 mg, 47%). ESI-MS m/z calc. 457.1, found 458.5 (M+1)+; Retention time 2.43 minutes (3 min run).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:8]=1.[CH3:21][NH:22][C:23](SC)=[CH:24][N+:25]([O-:27])=[O:26]>C(#N)C>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:23]([NH:22][CH3:21])=[CH:24][N+:25]([O-:27])=[O:26])[N:8]=1
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CC#N
Product: CNC(=C[N+](=O)[O-])NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Yield: 26.8 %

Procedure:
A solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylthio)pyrimidine (0.31 g.) in acetonitrile (5 ml.) was treated with 1-methylamino-1-methylthio-2-nitroethylene (0.15 g.) and the mixture heated under reflux for 18 hours. The hot solution was filtered and cooled and the solid which crystallised was collected and recrystallised from ethanol to give 1-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-ylthio)propylamino]-1-methylamino-2-nitroethylene (0.11 g.), m.p. 189°-191°.
Reaction SMILES: [NH2:1][S:2]([NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=4[CH:17]=[C:16]([C:26]([O:28]C)=[O:27])[CH2:15][N:14]3[C:30]=2[CH:31]=1)=[O:7])(=[O:4])=[O:3].CO.[OH-].[Na+].Cl>CO.O>[NH2:1][S:2]([NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=4[CH:17]=[C:16]([C:26]([OH:28])=[O:27])[CH2:15][N:14]3[C:30]=2[CH:31]=1)=[O:7])(=[O:3])=[O:4]
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(N)(=O)=O)cc3n2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(N)(=O)=O)cc21
Temperature: 60 °C
Yield: 93.5 %

Procedure:
Methyl 10-((aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate (725 mg, 1.39 mmol) was dissolved into MeOH//THF (1:1, 16 mL) and treated with 1M aqueous NaOH (3 mL). The reaction mixture was stirred and heated at 60° C. for 0.5 h and cooled to rt. The reaction solution was diluted with MeOH/H2O (2:1, 15 mL), neutralized with 1M aqueous HCl (3 mL) and concentrated to remove organic solvents. The resultant solids were collected by filtration, washed with H2O and dried under vacuum to yield 10-((aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (650 g, 1.3 mmol, 92%) as a bright yellow solid which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 1.16-2.22 (m, 10H), 2.82-2.96 (m, 1H), 3.94 (s, 3H), 4.07-4.29 (m, 1H), 5.57-5.80 (m, 1H), 7.14-7.23 (m, 2H), 7.55-7.63 (m, 2H), 7.88-7.94 (m 2H), 8.18 (s, 1H). LCMS: m/e 510 (M+H)+, ret time 2.85 min, column B, 4 minute gradient.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[CH:20][C:19]=1[F:29].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([F:29])[CH:20]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (1.00 g, 4.2 mmol) in CH2Cl2 (5 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-chloro-2-fluoro-4-((E)-2-nitro-vinyl)-benzene (0.68 g, 3.37 mmol) and trifluoroacetic acid (30 ul) in CH2Cl2 (5 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 0.78 g (55%) of the title compound as a colorless oil. ES-MS m/e: 335.2 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([O:20][Si](CC)(CC)CC)([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:8]=2)[NH:3]1.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]Cl)[CH:32]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C1COCC1>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:11]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:12]([F:14])([F:15])[F:13])=[CH:6][CH:5]=3)[CH2:10][CH:2]2[CH3:1])[CH:32]=1
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2)(C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cccc(CCl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3CC2C)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 56.4 %

Procedure:
To a solution of 94 mg (0.23 mmol) of 2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-1H-indole in 0.5 mL of DMF were added 104 mg (0.45 mmol) of 3-chloromethyl-benzoic acid methyl ester and the mixture was stirred at 80° C. for 10 hrs. After cooling to RT the mixture was treated with 0.5 mL of a 1M solution of TBAF in THF and stirred for an hour at 60° C. Evaporation of the solvent and chromatography on silica gel with EtOAc/n-heptane gave 58 mg (99%) of 3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-benzoic acid methyl ester, light red oil, MS: 448 (MH+).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.O.[CH:23](O)=[O:24]>>[CH:23]([O:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19]1)=[O:24]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=CO
Solvent: O
Product: C[C@]12CC[C@H](OC=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 60 °C

Procedure:
Following the procedure described by Ringold (H. J. Ringold, et al., J. Am. Chem. Soc. 78, 816, 1956), dehydroepiandrosterone (2.88 g, 10 mmol) dissolved in 85% formic acid (100 mL) is heated at 60 ° C. for 1 h. After cooling, the mixture is poured into iced water and after 16 h, crystals are filtered and dried in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][S:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=2)([C:14]([NH:16][OH:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:31]O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][S:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=2)=[O:31])([C:14]([NH:16][OH:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OO
Reactant: CC#CCOc1ccc(SCC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)CC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a slurry of tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl}methyl)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate (0.24 g, 0.55 mmol) at 0° C. in 7 mL of MeOH was added dropwise 3.5 mL of 30% hydrogen peroxide. The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was cooled to 0° C. and quenched with 3.5 mL of a saturated solution of Na2SO3. The organics were removed and the aqueous solution was extracted with CH2Cl2. The organics were washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether to provide 0.166 g (67%) of the desired product as an off white solid. Electrospray Mass Spec: 451.3 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][C@@H:17]4[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]4)[C:14]([CH2:24][O:25][CH2:26][CH3:27])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[CH3:22][C:19]1([CH3:23])[O:18][C@H:17]([CH2:16][N:15]2[C:6]3[C:5]4[CH:4]=[CH:3][C:2]([C:30]5[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=5)=[CH:11][C:10]=4[N:9]=[C:8]([NH2:12])[C:7]=3[N:13]=[C:14]2[CH2:24][O:25][CH2:26][CH3:27])[CH2:21][O:20]1
Reactant: OB(O)c1cccnc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1C[C@@H]1COC(C)(C)O1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1C[C@@H]1COC(C)(C)O1
Yield: 65.5 %

Procedure:
(R)-7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 6.9 mmol) and pyridine-3-boronic acid (1.02 g, 8.27 mmol) were coupled according to the method described in Examples 118-121. The work-up procedure described in Part F of Examples 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) followed by recrystallization from acetonitrile to provide 1.96 g of (R)-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 155-156° C.