Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].C([O:6][C:7](=[O:28])[CH2:8][N:9]1[C:17]2[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=2)[CH:11]([CH2:21][CH2:22][C:23](OCC)=[O:24])[CH2:10]1)(C)(C)C>>[O:24]=[C:23]1[NH:18][C:13]2[C:12]3[CH:11]([CH2:10][N:9]([CH2:8][C:7]([OH:6])=[O:28])[C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH2:21][CH2:22]1
Reactant: CCOC(=O)CCC1CN(CC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c21
Agent: [Cl-]
Product: O=C(O)CN1CC2CCC(=O)Nc3cccc1c32

Procedure:
Essentially following the procedures described for Intermediate 34, but using (±)-ethyl 3-[1-(2-tert-butoxy-2-oxoethyl)-4-nitro-2,3-dihydro-1H-indol-3-yl]propanoate in place of ethyl 3-[1-(2-tert-butoxy-2-oxoethyl)-4-nitro-1H-indol-3-yl]propanoate, and resolving the racemate into pure enantiomers in analogy with Intermediate 42, the title compound was prepared. MS: m/z=303 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:9][O:10][C:11]1[C:12]([C:23](O)=O)=[CH:13][C:14]2[C:19]([CH:20]=1)=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][CH:15]=2.P(Cl)(Cl)(Cl)=O>>[CH3:9][O:10][C:11]1[C:12]([C:23]2[NH:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=2)=[CH:13][C:14]2[C:19]([CH:20]=1)=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][CH:15]=2
Reactant: Nc1ccncc1N
Reactant: COc1cc2c(OC)cccc2cc1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(OC)cccc2cc1-c1nc2cnccc2[nH]1

Procedure:
A solution of 4.1 g. of 3,4-diaminopyridine and 8.7 g. of 3,5-dimethoxy-2-naphthoic acid in 250 ml. of phosphorous oxychloride was heated at reflux for 18 hours. The reaction was cooled and evaporated in vacuo. The solid was dissolved in 2N hydrochloric acid, cooled, and adjusted to pH 8. The resulting solid was recovered by filtration and chrom;atographed over silica gel to afford 4.4 g. of the desired title compound, m.p. 178°-180° C.
Reaction SMILES: [H-].[Na+].[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][OH:11].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>O1CCCC1>[CH2:15]([O:11][CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][CH2:4][F:3])[CH:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1cccc(OCCF)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FCCOc1cccc(COCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Sodium hydride (0.24 g; 60% in oil) was suspended in 30 ml of dry tetrahydrofuran, and then 1.0 g of 3-(2-fluoroethoxy)benzyl alcohol was added. The mixture was stirred at 50° to 60° C. for 30 minutes, and 1.7 g of benzyl bromide was added. The mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure. The resulting crude ether was purified by silica gel (50 g) column chromatography (developing solvent: toluene) to give 1.2 g of 3-(2-fluoroethoxy)benzyl benzyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:24][C:19]=4[S:18][C:17]3=[N:29]C(=O)C(F)(F)F)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH:29]=[C:17]1[N:16]([CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)[C:20]2[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:24][C:19]=2[S:18]1
Reactant: O=C(N=c1sc2cc(C(F)(F)F)ccc2n1CCN1CCN(c2ccc(F)cc2)CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N=c1sc2cc(C(F)(F)F)ccc2n1CCN1CCN(c2ccc(F)cc2)CC1
Yield: 77.1 %

Procedure:
Using the procedure described in example 19 but starting with 3-{2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl}-2-trifluoroacetylimino-6-trifluoromethylbenzothiazoline (3.5 g), a 7% strength aqueous alcoholic solution (15 cc) of potassium carbonate and methanol (150 cc). 2-imino-3-{2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl}-6-trifluoromethylbenzothiazoline (2.2 g) m.p. 250° C. is obtained.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH2:6])[C:3]([NH2:7])=[CH:2]1.[Cl:8][CH2:9][C:10](OCC)(OCC)OCC.CCCCCC>C(COC)OC>[Cl:8][CH2:9][C:10]1[NH:7][C:3]2=[CH:2][S:1][CH:5]=[C:4]2[N:6]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Nc1cscc1N
Solvent: COCCOC
Solvent: CCCCCC
Product: ClCc1nc2cscc2[nH]1
Temperature: 95 °C
Reaction time: 24 h

Procedure:
3,4-Thiophenediamine (0.5 g, Toronto Research Chemicals, Chemical Abstracts #90069-81-1) and 2-chloro-1,1,1-triethoxyethane (0.9 g) were combined in dimethoxyethane (7 mL) in a sealed tube and heated at 95° C. for one hour. After allowing to cool to room temperature and stirring for 24 hours, the mixture was treated with hexane (10 mL) and filtered. The filter cake was dried under reduced pressure to provide the title compound. MS (DCI/NH3) m/z 173 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH3:31]>>[CH3:31][N:30]([CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH:37]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CN(C)Cc1ccc(N)cc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(dimethylaminomethyl)-aniline Rf value: 0.7 (aluminium oxide, ethyl acetate/ethanol=20:1) C27H27N3O3
Reaction SMILES: C(NC(C)C)(C)C.[C:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:10][CH:9]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[NH4+].[Cl-]>C1COCC1.[Li]CCCC>[C:8]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])=[CH:10][CH:9]=1
Reactant: O=C(CCc1ccc(-c2ccccc2)cc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a solution of diisopropylamine (2.70 ml, 18.96 mmol) in THF (20 ml), BuLi in hexanes (11.85 ml, 18.96 mmol) was added under nitrogen at 0° C. After stirred for 0.5 hour at the same temperature, the solution was cooled to −78° C. and then a solution of benzyl 3-(biphenyl-4-yl)propanoate (5 g, 15.80 mmol) in THF (20 ml) was added. After stirred for 1.5 hour at the same temperature, tert-butyl bromoacetate (3.33 ml, 22.12 mmol) was added, and then the mixture was warmed up to 0° C. The reaction mixture was allowed to stir at 0° C. for 2 hours, and then stirred at room temperature for 14 hours. The reaction mixture was poured into 150 ml of saturated aq. NH4Cl. The product was extracted twice with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 10:1) to give the 1-benzyl 4-tert-butyl 2-(biphenyl-4-ylmethyl)succinate (2.97 g); Retention time=1.00 minutes (condition G); MS (m+1)=431.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl>C(O)C>[CH3:2][O:3][C:4]1[C:5]2[NH:10][C:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][C:15]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CN1CCC(=O)CC1
Reactant: COc1ccccc1NN
Agent: Cl
Solvent: CCO
Product: COc1cccc2c3c([nH]c12)CCN(C)C3
Temperature: 80 °C
Yield: 30.3 %

Procedure:
To a stirred solution of (2-methoxyphenyl)hydrazine hydrochloride (5 g, 0.0286 mol) and 1-methyl-4-piperidone (2.83 mL, 0.0229 mol) in ethanol (50 mL) was added ethanolic hydrochloric acid (5 mL). The reaction mixture was heated at 80° C. for 2 h. After completion, the reaction mixture was cooled to RT and solvent removed under reduced pressure. The residue was basified with 10% sodium hydroxide solution and extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel column chromatography (6% MeOH:DCM) to yield 6-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.5 g, 24% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>C(#N)C>[Cl:38][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7]
Reactant: COC(c1cc(C)no1)c1ccccc1CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(c1cc(C)no1)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a mixture of 1.24 g (5.3 mmol) of 5-(2-hydroxymethyl-α-methoxybenzyl)-3-methylisoxazole and 10 ml of acetonitrile was added 1.67 g (6.36 mmol) of triphenylphosphine and 1.23 ml (12.7 mmol) of carbon tetrachloride under ice-cooling and stirred at room temperature overnight. After completion of the reaction, the residue obtained by concentration under reduced pressure was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-(2-chloromethyl-α-methoxybenzyl)-3-methylisoxazole (1.03 g, 77.2%) as colorless oil.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12]>>[CH2:11]([CH:10]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:13][CH3:14])[CH3:12]
Reactant: CCC(Br)CC
Reactant: O=[N+]([O-])c1c[nH]cn1
Product: CCC(CC)n1cnc([N+](=O)[O-])c1

Procedure:
4-nitroimidazole was alkylated with 3-bromopentane to provide the title compound: 1H NMR (400 MHz, CDCl3) 0.84-0.90 (m, 6H), 1.71-1.82 (m, 2H), 1.86-1.96 (m, 2H), 3.79 (p, 1H, J=4.8 Hz), 7.41 (d, 1H, J=1.6 Hz), 7.73 (d, 1H, J=1.3 Hz); MS 184.2 m/z (M+1)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:30])[CH2:10][C:11]1([C:24]2[S:25][C:26](Br)=[CH:27][CH:28]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:30])[CH2:10][C:11]1([C:24]2[S:25][C:26]([C:36]3[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)=[CH:27][CH:28]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]1
Reactant: CS(=O)(=O)N1CCC(CC(=O)NOC2CCCCO2)(c2ccc(Br)s2)S(=O)(=O)CC1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2ccc(C3(CC(=O)NOC4CCCCO4)CCN(S(C)(=O)=O)CCS3(=O)=O)s2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
A mixture of N-(2-tetrahydropyranyloxy)-2-[7-(5-bromo-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (200 mg), 4-methoxyphenylboronic acid (83.6 mg) and tetrakis(triphenylphosphine)palladium(0) (21.2 mg) in a mixture of 1,2-dimethoxyethane (2 ml) and aqueous 2M sodium carbonate (0.75 ml) was stirred for 2 hours at 80° C. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue was purified with silica gel column chromatography (eluent; 0.5-3% methanol in chloroform) to give N-(2-tetrahydropyranyloxy)-2-[7-(5-(4-methoxyphenyl)-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (130 mg) as an amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C[C:16]([N:18]([CH3:20])[CH3:19])=O.CN(C=O)C>O>[F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6](/[CH:8]=[CH:16]/[N:18]([CH3:20])[CH3:19])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(=O)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 62.7 %

Procedure:
A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol), DMA (12 g, 100 mmol) and DMF (50 mL) was heated at 100° C. for 4 h. The solution was cooled and poured into water. The precipitated red solid was collected, washed with water, and dried to give (E)-2-(5-fluoro-2,4-dinitrophenyl)-N,N-dimethylethenamine (8.0 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=2)[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[C:6]1=[O:15].[F:26][CH2:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[F:26][CH:27]([S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30])[C:7]1([OH:14])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:4][C:3]2[CH:16]=[CH:17][C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:19][C:2]=2[F:1])[C:6]1=[O:15]
Reactant: O=S(=O)(CF)c1ccccc1
Reactant: Cn1cc(-c2ccc(CN3C(=O)C(=O)c4ccccc43)c(F)c2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(CN3C(=O)C(O)(C(F)S(=O)(=O)c4ccccc4)c4ccccc43)c(F)c2)cn1
Temperature: -78 °C

Procedure:
1-(2-Fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)indoline-2,3-dione (1 g, 3.0 mmol) was added to a flame-dried round bottom flask with stir bar and dissolved in THF (30 mL). Next, ((fluoromethyl)sulfonyl)benzene (780 mg, 4.5 mmol) was added, and the mixture was cooled to −78° C. Lithium hexamethyldisilazide (1M in THF, 4.5 mL, 4.5 mmol) was added dropwise to the cooled solution, and the mixture was allowed to gradually warm to room temperature overnight. The reaction was quenched by addition of excess saturated brine, and then extracted with 3×50 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, evaporated and purified by silica gel chromatography (30-100% EtOAc in hexanes gradient) to afford 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one as a yellowish foam. To a scintillation vial containing a magnetic stir bar was added 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one (305 mg, 0.6 mmol), followed by DMF (6 mL), magnesium powder (150 mg, 6 mmol), and 3 mL of an acetic acid/sodium acetate (1:1) buffer solution (8 mol/L). The vial was sealed and allowed to stir at room temperature overnight. The mixture was diluted with water (100 mL), and then extracted with 5×25 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, evaporated, and purified by reversed-phase HPLC using 0.1% TFA in water/acetonitrile as a mobile phase to afford the title compound. LCMS: RT=0.67 min, >99% @ 254 nm, >99% @ 215 nm; m/z (M+1)+=370. 1HNMR (400 MHz, CDCl3, δ (ppm)): 7.53 (s, 1H), 7.47 (s, 1H), 7.3 (dt, J=7.8, 1.1 Hz, 1H), 7.2-7.1 (m, 2H), 7.1-7.0 (m, 2H), 6.9 (d, J=7.9 Hz, 1H), 5.0 (d, J=15.8 Hz, 1H), 4.9 (d, J=15.8 Hz, 1H), 4.8 (quartet, J=3.6 Hz, 1H), 4.6 (quartet, J=9.1, 4.0 Hz, 1H), 3.9 (s, 3H), HRMS calculated for C20H18N3O2F2 (M+H)+ m/z: 370.1367, measured: 370.1366.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].O.[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:17])=[O:7])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: O
Solvent: CO
Product: CCOc1cc([N+](=O)[O-])ccc1C(=O)OC
Yield: 311 %

Procedure:
A solution of 2-ethoxy-4-nitrobenzoic acid (2.035 g, 9.45 mmol, Aldrich) in methanol (40 ml) was treated with p-toluenesulfonic acid monohydrate (583.3 mg, 3.07 mmol) and heated at reflux under argon for 17 hrs. The solvent was removed and the residue was dissolved in ethyl acetate, washed with saturated Na2CO3, water and saturated NaCl and dried over Na2SO4, filtered and concentrated to give methyl 2-ethoxy-4-nitrobenzoate (2.15 g, 101%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@@H:19]([CH3:20])[CH2:18][C:17]2[C:16]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][CH:26]=[CH:25]4)=[N:15][CH:14]=[N:13][C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:31]([O:35][C:36]([N:38]1[C:42]([NH:43][C:44](OC2C=CC=CC=2)=[O:45])=[CH:41][C:40]([C:53]2([CH3:56])[CH2:55][CH2:54]2)=[N:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[C@@H:19]([CH3:20])[CH2:18][C:17]2[C:16]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:44](=[O:45])[NH:43][C:42]3[N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[N:39]=[C:40]([C:53]5([CH3:56])[CH2:55][CH2:54]5)[CH:41]=3)[CH:26]=[CH:25]4)=[N:15][CH:14]=[N:13][C:12]=2[CH2:11]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)n1nc(C2(C)CC2)cc1NC(=O)Oc1ccccc1
Reactant: C[C@H]1Cc2c(ncnc2Oc2ccc3[nH]ccc3c2)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C4(C)CC4)nn3C(=O)OC(C)(C)C)c2)CN1C(=O)OC(C)(C)C

Procedure:
Sodium hydride (0.024 g, 0.990 mmol; 60% in oil) is added to a solution of (S)-4-(1H-Indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester, Example 53-B-1, (0.126 g, 0.330 mmol) and DMF (7.5 mL) at rt. After 5 min 3-(1-Methyl-cyclopropyl)-5-phenoxycarbonylamino-pyrazole-1-carboxylic acid tert-butyl ester, Example 5-D, (0.178 g, 0.495 mmol) is then added. After 1 h the mixture is quenched by the addition of saturated aqueous NH4Cl and then concentrated. The residue is separated directly via FCC (20-70% EtOAc/heptane). MS (ESI) m/z 644.2 (M+1).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:17][CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>Cl.CO>[C:1]12([CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][NH2:23])=[CH:19][CH:20]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)NCCc1ccc(OCCCC23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Solvent: CO
Product: NCCc1ccc(OCCCC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Obtained from Intermediate 50 (1.2 g, 2.94 mmol) in hydrogen chloride 1.25 M in methanol by the same procedure described in Intermediate 17. The solvent was removed under reduced pressure and the title compound was obtained as a salt (0.62 g, 67%), which was used in the next step without further purification. MS (M+): 314.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:27][C@@H:26]([CH:28](C(C)(C)C(C)C)[O:29][SiH](C)C)[N:8]3[C:9]4[CH:10]=[CH:11][C:12]([O:16][CH:17]5[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]5)=[CH:13][C:14]=4[CH:15]=[C:7]3[C:6]2=[O:39])[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:1]1([CH2:4][N:5]2[CH2:27][C@@H:26]([CH2:28][OH:29])[N:8]3[C:9]4[CH:10]=[CH:11][C:12]([O:16][CH:17]5[CH2:18][CH2:19][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH2:22]5)=[CH:13][C:14]=4[CH:15]=[C:7]3[C:6]2=[O:39])[CH2:3][CH2:2]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C(O[SiH](C)C)C(C)(C)C(C)C)CN(CC3CC3)C2=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](CO)CN(CC3CC3)C2=O)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 12, from (S)-2-cyclopropylmethyl-4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one and tetra-n-butylammoniumfluoride, to give the desired product as a colorless oil (74%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[Cl:19][C:20]1[CH:21]=[N:22][C:23]([CH3:29])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>C1COCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:25]([C:24]2[C:23]([CH3:29])=[N:22][CH:21]=[C:20]([Cl:19])[CH:28]=2)=[O:26])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: Cc1ncc(Cl)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](NC(=O)c2cc(Cl)cnc2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trans-4-Amino-cyclohexanecarboxylic acid methyl ester (2.14 g, 11.05 mmol) is suspended in THF (50 mL) and Et3N (2.79 g, 27.6 mmol) and cooled to 0° C. 5-chloro-2-methylnicotinoyl chloride (step 1)(2.20 g, 11.05 mmol) is slowly added portionwise and the RM is stirred at r.t. for 2 hours. LCMS showed mainly product. The reaction mixture is partitioned between EtOAc and 1M HCl. The organic phase is washed with water and brine, dried over MgSO4, filtered and the solvent is removed in vacuo to afford the title product which is used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (1H, d), 7.42 (1H, 5), 7.80 (1H, d), 3.70 (1H, m), 3.60 (3H, s), 2.49 (3H, s), 2.29 (1H, m), 1.95 (4H, m), 1.42 (2H, m), 1.29 (2H, m); [MH]+ 311.26.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:26]([O:33][C:34]1[C:43]([CH:44](OC(N2C=CN=C2)=S)[C:45]([F:48])([F:47])[F:46])=[C:42]2[C:37]([C:38](=[O:74])[C:39]([CH3:73])=[C:40]([CH:57]3[CH2:62][CH2:61][N:60]([C:63]([O:65][CH2:66][C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[O:64])[CH2:59][CH2:58]3)[O:41]2)=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([O:33][C:34]1[C:43]([CH2:44][C:45]([F:46])([F:47])[F:48])=[C:42]2[C:37]([C:38](=[O:74])[C:39]([CH3:73])=[C:40]([CH:57]3[CH2:62][CH2:61][N:60]([C:63]([O:65][CH2:66][C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[O:64])[CH2:59][CH2:58]3)[O:41]2)=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1c(C2CCN(C(=O)OCc3ccccc3)CC2)oc2c(C(OC(=S)n3ccnc3)C(F)(F)F)c(OCc3ccccc3)ccc2c1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1c(C2CCN(C(=O)OCc3ccccc3)CC2)oc2c(CC(F)(F)F)c(OCc3ccccc3)ccc2c1=O
Yield: 92.8 %

Procedure:
Tri-n-butyltin hydride (104 μL, 0.39 mmol) and a catalytic amount of azobisisobutyronitrile were added to a solution of benzyl 4-[7-(benzyloxy)-3-methyl-4-oxo-8-{2,2,2-trifluoro-1-[(1H-imidazol-1-ylcarbonothioyl)oxy]ethyl}-4H-chromen-2-yl]piperidine-1-carboxylate (135 mg, 0.20 mmol) obtained in Example 36-3 in tetrahydrofuran (1.5 mL), and the mixture was heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=80/20→40/60) to obtain 105 mg of the title compound (yield: 95%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][C:5]=1[CH2:21][CH2:22][OH:23])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[CH2:21][CH2:22][O:23][C:33](=[O:34])[NH:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=1)[CH3:2]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCOC(=O)C(Cc1ccc(OCC)c(CCO)c1)OC(C)C
Product: CCOc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(OC)cc1

Procedure:
Using ethyl 3-[4-ethoxy-3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.