Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:19]=2[CH:18]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41]>C(#N)C.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:25][C:19]=2[CH:18]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(O)ccc2s1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCOCCOc1ccc2sc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1
Temperature: 100 °C

Procedure:
To a solution of 77 mg (0.20 mmol) {2-[(5-Hydroxy-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (4) in 3 ml acetonitrile was added 200 mg potassium carbonate and 0.3 ml 1-bromo-2-(2-methoxyethoxy)-ethane. The reaction mixture was heated at 100° C. for 90 min and poured into brine. The aqueous phase was extracted with ethyl acetate and the organic phase was dried over sodium sulfate, the solvent was evaporated and the residue subjected to silica gel chromatography (petrolether/ethyl acetate 2:1 and then 1:1). The product (28) (80 mg, 0.164 mmol) was obtained as a colorless oil.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[F:8][C:9]([F:18])([F:17])[C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=1.C(O)(=O)C>O.CO>[F:18][C:9]([F:8])([F:17])[C:10]1[CH:15]=[C:14]([NH:16][C:1]2[CH2:5][CH2:4][C:3](=[O:6])[CH:2]=2)[CH:13]=[CH:12][N:11]=1
Reactant: O=C1CCC(=O)C1
Reactant: Nc1ccnc(C(F)(F)F)c1
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C1C=C(Nc2ccnc(C(F)(F)F)c2)CC1
Temperature: 130 °C

Procedure:
A mixture of cyclopentane-1,3-dione (1.51 g, 15.4 mmol), 2-(trifluoromethyl)pyridin-4-amine (2.50 g, 15.4 mmol) and acetic acid (7.5 mL) is heated at 130° C. for 5 h, cooled at room temperature, diluted with water and methanol, and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% formic acid). Yield: 2.26 g; ESI mass spectrum [M+H]+=243; Retention time HPLC: 0.77 min (Z018_S04).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH3:16])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][C:28](=O)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:29][CH:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[CH3:16])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=2)[CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Cc1cc2c(cc1N)N1C(=NNC(=O)C1C)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 44 %

Procedure:
A solution of 6-amino-4,7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one ((Example #54, Step E, 0.060 g, 0.24 mmol) and 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (0.083 g, 0.41 mmol) in MeOH (4.5 mL) and acetic acid (0.5 mL) was stirred at ambient temperature for 1 h. Sodium cyanoborohydride (0.031 g, 0.41 mmol) was added and the resulting dark solution was stirred at ambient temperature for 14 h. The solvent was removed in vacuo to give the crude product, which was purified by preparative TLC (eluting with 33% EtOAc in petroleum ether) to give 3-(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.042 g, 44%) as an off-white solid. LC/MS (Table 1, Method 2) Rt=1.065 min.; MS m/z: 424 [M+23]+.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[CH2:3].ClC(OCC)=O.C(N(CC)CC)C.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>O.C(#N)C>[NH2:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])=[CH:26][CH:25]=1)(=[O:28])=[O:29]
Reactant: C=C(C)C(=O)O
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: C=C(C)C(=O)Nc1ccc(S(N)(=O)=O)cc1
Temperature: 70 °C
Yield: 65.1 %

Procedure:
To a 500 ml volume three-necked flask equipped with a stirring machine, a cooling tube and a dropping funnel, there were added 31.0 g (0.36 mole) of methacrylic acid, 39.1 g (0.36 mole) of ethyl chloroformate and 200 ml of acetonitrile and then the resulting mixture was stirred while cooling it in an ice-water bath. To this mixture, there was dropwise added 36.4 g (0.36 mole) of triethylamine through the dropping funnel over about one hour. After the completion of the dropwise addition, the ice-water bath was removed and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture, there was added 51.7 g (0.30 mole) of p-aminobenzene sulfonamide and the resulting mixture was stirred over one hour while warming the mixture at 70° C. in an oil bath. After the completion of the reaction, the mixture was introduced into 1 L of water while stirring the water and the resulting mixture was stirred for 30 minutes. This mixture was filtered to recover the precipitates, followed by addition of 500 ml of water to the precipitates to give a slurry, filtration of the slurry and drying the resulting solid to give N-(p-aminosulfonylphenyl) methacrylamide as a white solid (yield 46.9 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23](I)[CH3:24]>CN(C=O)C>[CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]([CH2:23][CH3:24])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: c1ccc(CN2CCc3[nH]c4ccccc4c3C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c2c(c3ccccc31)CN(Cc1ccccc1)CC2
Yield: 85 %

Procedure:
To a suspension of 2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and NaH (1.1 equiv.) in DMF (10 mL) was added at 0° C., ethyl iodide (1 mmol) and stirred at RT overnight. The reaction mixture was quenched with a sat. solution of NH4Cl and extracted with EtOAc. The combined organic extracts were dried over anydrous Na2SO4 and purified by flash chromatography to afford 2-benzyl-5-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (85%).
Reaction SMILES: [CH2:1]([N:8]([CH3:41])[CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34]([OH:36])=O)[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[O:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[CH3:46][O:47][CH:48]([O:56][CH3:57])[CH2:49][N:50]([CH3:55])[S:51]([NH2:54])(=[O:53])=[O:52]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([N:8]([CH3:41])[CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34]([NH:54][S:51]([N:50]([CH2:49][CH:48]([O:47][CH3:46])[O:56][CH3:57])[CH3:55])(=[O:53])=[O:52])=[O:36])[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[O:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCOCC1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)Cc1ccccc1
Reactant: COC(CN(C)S(N)(=O)=O)OC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(COCCN(C)Cc1ccccc1)COc1ccccc1-3)OC
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of (7R or 7S)-7-({2-[benzyl(methyl)amino]ethoxy}methyl)-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid in dry DCM (0.06 M) was treated with DMAP (3 eq), EDC (1.5 eq) and N-(2,2-dimethoxyethyl)-N-methylsulfamide (prepared as described in example 1 step 1). The mixture was stirred at 40° C. for 2 h, and then diluted with EtOAc, washed with 1N HCl (aq), sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound. The crude material was used in the next step without further purification. (ES+) m/z 733 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([Cl:23])[CH:9]=1)=[O:6].[NH3:25]>CO>[Cl:23][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:25])=[O:2])[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: N
Solvent: CO
Product: NC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Yield: 100 %

Procedure:
Prepared in analogy to example 3 from N-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and 7M ammonia in methanol. Yield=100%. Colorless solid. MS: m/e=337.1 (M++H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[K+].C(O)=O>CS(C)=O.O>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(OC(C)(C)C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-methyl-3-pyridyloxy)-2-methylpropionate (Step A, 2.0 g, 8.9 mmol) in DMSO (20 mL) was added potassium hydroxide (1.0 g, 20 mmol) in 2 mL water. After stirring at room temperature for 2 h, the reaction was quenched by addition of formic acid (85%, 10 mmol) and poured into water (200 mL). The product was extracted with EtOAc (2×100 mL), and the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the title compound contaminated with DMSO (molar ratio 1:5, determined by NMR). 1H NMR (500 MHz, CD3OD): δ 8.06 (d, 1H), 7.38-7.22 (m, 2H), 2.47 (s, 3H), 1.58 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:14][CH3:15])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.Br[C:28]1[CH:32]=[CH:31][S:30][CH:29]=1>[Cl-].[Cl-].[Zn+2].Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:14]([CH:9]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:3][CH:4]=1)[CH3:15]
Reactant: Brc1ccsc1
Reactant: CCCCC(CC)Cc1ccc(Br)cc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCCCC(CC)Cc1ccc(-c2ccsc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A dry 250-mL three-neck round bottom flask, equipped with a condenser, was charged with 1-bromo-4-(2-ethylhexyl)-benzene (8 g, 0.03 mol) and purged with N2 followed by addition of anhydrous THF (50 mL) via a deoxygenated syringe. The reaction flask was cooled to −78° C. and n-butyllithium, a 2.5 M solution in hexane (12 mL, 0.03 mol), was added dropwise via syringe. The reaction mixture was stirred for 1 hour at −78° C. Anhydrous ZnCl2 (4.09 g, 0.03 mol) was added in one portion and completely dissolved after 30 minutes of stirring. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature, whereupon 3-bromothiophene (5.38 g, 0.03 mol) and Ni(dppp)Cl2 (0.32 g, 2 mol %) were added. The solution was heated up to reflux and maintained at that temperature for 12 hours, then cooled to ambient temperature, and quenched with cold HCl (10 mL, 1.0 N). The aqueous layer was separated and extracted with diethyl ether (3×100 mL). The organic phase was collected and dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was purified by recrystallization from methanol affording 5.3 g (65%) of white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C@@H:10]([O:39][Si](C(C)(C)C)(C)C)[CH2:11][C@@H:12]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[N:21]=2)=[CH:16][CH:15]=1)=O)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][CH2:6][NH:8][C@@H:9]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C@@H:10]([OH:39])[CH2:11][C@@H:12]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[N:21]=2)=[CH:16][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(-c2ccc(C[C@@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)NC(=O)OCc3ccccc3)cc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(C[C@@H](C[C@H](O)[C@H](Cc3ccccc3)NCOC(C)(C)C)NC(=O)OCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.1 %

Procedure:
The product from Example 113B (0.28 mmol) was treated with TBAF solution in THF (1.4 mL, 1N), stirred at 25° C. for 16 hours, concentrated and partitioned between ethyl acetate and water. The organic phase was washed with brined, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 20% ethyl acetate in dichloromethane, to give the title compound (0.055 g, 31% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:13]([SiH:16]([Cl:18])[Cl:17])[CH:14]=[CH2:15].[Cl-].[Na+]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:14]([CH3:15])[CH2:13][SiH:16]([Cl:18])[Cl:17])[CH3:2]
Reactant: CCc1ccccc1
Reactant: C=CC[SiH](Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: CCc1ccccc1C(C)C[SiH](Cl)Cl
Temperature: 50 °C
Yield: 77.6 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 27 g (255 mmol) of ethylbenzene and 1.1 g (9.0 mmol) of aluminum chloride were placed. The flask was then immersed in an ice water bath. To the reaction mixture was slowly added dropwise 12.0 g (85 mmol) of allyldichlorosilane and the solution was stirred for an hour. After confirming that no ethylbenzene was left by gas chromatography, 2.4 g, (413 mmol) of sodium chloride was added to reaction mixture, warmed up to 50° C. and stirred for two hours to deactivate the catalyst. Vacuum distillation of the reaction products gave 16.3 g (bp 80°-84° C./0.6 mmHg) of 3-(ethylphenyl)-1,1-dichloro-1-silabutane.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10](=[O:32])[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)[CH:15]([CH3:30])[C:14]1=[O:31].CC(C)=O.CC(O)=O>C1COCC1>[CH3:30][CH:15]1[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH:10]=[O:32])[C:14]1=[O:31]
Reactant: CON(C)C(=O)CCN1CCN(c2cccc(OC(F)(F)F)c2)C(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC1C(=O)N(CCC=O)CCN1c1cccc(OC(F)(F)F)c1
Temperature: -75 °C
Yield: 80.3 %

Procedure:
Lithium aluminum hydride solution (1 M in THF (0.46 mL, 0.46 mmol) was added dropwise at −30° C. to a solution of N-methoxy-N-methyl-3-[3-methyl-2-oxo-4-(3-trifluoromethoxy-phenyl)-piperazin-1-yl]-propionamide (180 mg, 0.46 mmol) in THF (10 mL). The reaction mixture was cooled to −75° C., then acetone (0.59 g, 10 mmol) and AcOH (44 mg, 0.93 mmol) were added dropwise. The reaction mixture was then partitioned between TBME and 1 M aq. KHSO4 solution. The organic layer was dried (MgSO4), filtered, and evaporated to afford the title compound (122 mg, 80%). Light yellow oil, MS: 331.1 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([S-:10])=[N:8][N:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Na+].Cl[CH2:13][C@H:14]1[O:19][C:18]([CH3:21])([CH3:20])[O:17][C@@H:16]([CH2:22][C:23]([O:25][C:26]([CH3:35])([CH3:34])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:24])[CH2:15]1>>[C:1]([N:5]1[C:9]([S:10][CH2:13][C@H:14]2[O:19][C:18]([CH3:20])([CH3:21])[O:17][C@@H:16]([CH2:22][C:23]([O:25][C:26]([CH3:34])([CH3:35])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:24])[CH2:15]2)=[N:8][N:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nnnc1[S-]
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Agent: [Na+]
Product: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CSc2nnnn2C(C)(C)C)OC(C)(C)O1

Procedure:
The procedure was carried out in the same manner as in Example 11, except that sodium 1-tert-butyl tetrazole-5-thiolate (3.6 g) prepared in Example 8 was used in place of sodium 1-phenyl-1H-tetrazole-5-thiolate, and 3.5 g of 2-methyl-1-phenylpropan-2-yl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate was used in place of 30 g thereof. The title compound was obtained (4.6 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:36](=[O:37])[N:11]3[CH2:12][CH2:13][N:14]([C@@H:17]([CH3:35])[CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=4[S:29]([F:34])([F:33])([F:32])([F:31])[F:30])[C:15](=[O:16])[C:10]3=[CH:9][CH:8]=2)[CH:6]=1.C(O)C.[Cl-].[NH4+]>O.[Fe]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][C@@H:17]([N:14]2[CH2:13][CH2:12][N:11]3[C:36](=[O:37])[C:7]([N:5]4[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]4)=[CH:8][CH:9]=[C:10]3[C:15]2=[O:16])[CH3:35])=[C:21]([S:29]([F:30])([F:34])([F:33])([F:32])[F:31])[CH:22]=1
Reactant: Cc1cn(-c2ccc3n(c2=O)CCN([C@@H](C)COc2ccc([N+](=O)[O-])cc2S(F)(F)(F)(F)F)C3=O)cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cn(-c2ccc3n(c2=O)CCN([C@@H](C)COc2ccc(N)cc2S(F)(F)(F)(F)F)C3=O)cn1
Temperature: 55 °C

Procedure:
A mixture of 7-(4-methyl-1H-imidazol-1-yl)-2-{(2S)-1-[4-nitro-2-(pentafluoro-λ6-sulfanyl)phenoxy]propan-2-yl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (C55) (790 mg, 1.44 mmol) and ethanol (10 mL) was heated to 55° C. Iron powder (99%, 243 mg, 4.31 mmol) and a solution of ammonium chloride (462 mg, 8.64 mmol) in water (2.5 mL) were added, and the reaction mixture was stirred at reflux for 3 hours. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo, treated with ethyl acetate and saturated aqueous sodium bicarbonate solution and filtered through Celite. The filter pad was rinsed with water and ethyl acetate; the organic portion of the filtrate was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 5% to 10% methanol in ethyl acetate) provided the product as a light yellow foam. Yield: 507 mg, 0.98 mmol, 68%. LCMS m/z 520.2 (M+1). 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 1.48 (d, J=7.2 Hz, 3H), 3.71-3.79 (m, 1H) 3.85-3.92 (m, 1H), 4.05 (dd, J=9.6, 5.5 Hz, 1H), 4.99-5.08 (m, 1H), 6.80 (dd, half of ABX pattern, J=8.8, 2.6 Hz, 1H), 6.86 (br d, half of AB quartet, J=8.8 Hz, 1H), 7.06 (d, J=2.6 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][NH:19][CH:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:30][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:21]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][NH:19][CH:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[OH:30])[CH2:21]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC(NCc1nc(-c3ccccc3)c(-c3ccccc3)o1)C2)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cccc2c1CCC(NCc1nc(-c3ccccc3)c(-c3ccccc3)o1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-amino-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (0.96 g), (4,5-diphenyloxazol-2-yl)methyl bromide (0.80 g) and potassium carbonate (0.41 g) in DMF (14 ml) was stirred for 3.5 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo to give crude 2-[(4,5-diphenyloxazol-2-yl)methylamino]-1,2,3,4-tetrahydro-5-t-butyldiphenylsilyloxynaphthalene. To a solution of crude 2-[(4,5-diphenyloxazol-2-yl)methylamino]-1,2,3,4-tetrahydro-5-t-butyldiphenylsilyloxynaphthalene in THF (5 ml) was added 1M THF (3 ml) solution of tetrabutylammonium fluoride. After being stirred for 1 hour at room temperature, the mixture was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 2-[(4,5-diphenyloxazol-2-yl)methylamino]-1,2,3,4-tetrahydro-5-hydroxynaphthalene (0.66 g).
Reaction SMILES: C([O:4][CH2:5][CH:6]([N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:22](=[O:36])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)[C:13]1=[O:37])[CH2:7][O:8]C(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][NH:23][C:22]([C:18]2[C:19]3[CH:20]=[CH:21][N:12]([CH:6]([CH2:7][OH:8])[CH2:5][OH:4])[C:13](=[O:37])[C:14]=3[CH:15]=[CH:16][CH:17]=2)=[O:36])=[CH:26][C:27]=1[C:32]([F:35])([F:33])[F:34]
Reactant: CC(=O)OCC(COC(C)=O)n1ccc2c(C(=O)NCc3ccc(Cl)c(C(F)(F)F)c3)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(NCc1ccc(Cl)c(C(F)(F)F)c1)c1cccc2c(=O)n(C(CO)CO)ccc12

Procedure:
2-(5-(4-Chloro-3-(trifluoromethyl)benzylcarbamoyl)-1-oxoisoquinolin-2(1H)-yl)propane-1,3-diyl diacetate (100 mg, 0.0002 mol), potassium carbonate (80 mg, 0.0006 mol) and methanol (2 mL, 0.05 mol) were stirred at room temperature for 2 hours. The mixture was filtered and purified via flash chromatography (12 g fo silica gel, 0-10% MeOH/CH2Cl2) to give a white solid. 1H NMR (DMSO-d6) δ: 9.18 (br, 1H), 8.35 (d, J=7.6 Hz, 1H), 7.86-7.82 (m, 2H), 7.75-7.70 (m, 2H), 7.55-7.27 (m, 2H), 6.79 (d, J=7.9 Hz, 1H), 4.95-4.89 (m, 3H), 4.56 (d, J=5.9 Hz, 2H), 3.75-3.71 (m, 4H),
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.B.O1CCCC1.CO>C1COCC1>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(F)cc1CO
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of to 4,5-difluoro-2-nitrobenzoic acid (25.9 g) in THF (90 ml), cooled to 0° C., was carefully added borane-tetrahydrofuran complex (319 ml, 1M in THF). After the addition was complete, the mixture was stirred at 60° C. for 3 h. Methanol (150 ml) was added to the mixture at 0° C. and after 10 minutes the mixture was concentrated in vacuo. The residue was poured into water and extracted with ethyl acetate. The organic layer was washed with sat. aq. NaCl, dried (MgSO4), filtered and concentrated in vacuo.