Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)cc1F
Temperature: 40 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a solution of 2-fluoro-4-hydroxy-benzoic acid (5.32 g, 34.1 mmol) in methanol (21 mL) was added thionyl chloride (4.86 g, 3 mL, 40.9 mmol) dropwise and the reaction mixture was stirred at 40° C. for 3 hours. The reaction mixture was concentrated in vacuo and diluted with DCM (100 mL) and washed with aqueous saturated NaHCO3 (2×50 mL) solution. The organics were separated and dried with MgSO4, filtered and concentrated in vacuo to give methyl 2-fluoro-4-hydroxy-benzoate (2.3 g, 40%). ESI-MS m/z calc. 170.1. Found 171.3 (M+1)+; Retention time: 0.84 minutes (3 min run).
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][C:27]=1[O:37][CH3:38]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([N:6]2[CH2:5][CH2:4][S:3][C:2]2=[S:1])=[O:35])=[CH:28][C:27]=1[O:37][CH3:38]
Reactant: COCOc1ccc(CCC(=O)O)cc1OC
Reactant: SC1=NCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1ccc(CCC(=O)N2CCSC2=S)cc1OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In an atmosphere of argon 4.03 g of 3-(4-methoxymethoxy-3-methoxyphenyl)propionic acid and 1.79 g of 2-mercaptothiazoline were dissolved in 80 ml of dichloromethane followed by the addition of 3.10 g of dicyclohexylcarbodiimide and 0.21 g of 4-dimethylaminopyridine. The mixture was stirred at room temperature for 15 hours, and the reaction mixture was filtered. The filtrate was washed with a 1N aqueous sodium hydroxide, water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue subjected to column chromatography on silica gel. From the fraction eluted with methylene chloride was obtained 5.07 g of N-[3-(4-methoxymethoxy-3-methoxyphenyl)propanoyl]-thiazolidine-2thione.
Reaction SMILES: [C:1]([N:9]([C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:27][CH2:26][C@@H:24]([OH:25])[C@@H:22]([OH:23])[C@H:20]1[OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:28]([N:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:27][CH2:26][C@@H:24]([OH:25])[C@@H:22]([OH:23])[C@H:20]1[O:21][C:36](=[O:37])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(c1ccccc1)N(C(=O)c1ccccc1)c1ncnc2c1ncn2[C@@H]1OC[C@@H](O)[C@@H](O)[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O[C@@H]1[C@H](O)[C@H](O)CO[C@H]1n1cnc2c(N(C(=O)c3ccccc3)C(=O)c3ccccc3)ncnc21)c1ccccc1
Temperature: -88.5 °C
Reaction time: 60 h
Yield: 72.1 %

Procedure:
26.4 g (55,5 mmol) of 3 were dissolved in 550 ml of anhydrous CH2Cl2 and 55 ml of pyridine (in each case stored over a molecular sieve) under an N2 atmosphere, treated with 0.73 g (5.55 mmol; 0.1 eq.) of DMAP and cooled to −87 to −90° C. 8.58 g (61 mmol; 1.1 eq.) of BzCl in 14 ml of pyridine were added dropwise in the course of 1 h and the mixture was left at −78° C. over a period of 60 h (week-end). The batch was concentrated, treated twice with 100 ml of toluene each time and evaporated in order to remove pyridine. Chromatography on silica gel 60 (20×10 cm) using gradients (AcOEt/heptane, 1:1 to 9:1) yielded 23.2 g of 4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:12]([OH:14])=O.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:12]([N:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([N:16]([CH3:34])[CH3:15])=[CH:22][CH:21]=1)[C:25]1[CH:26]=[CH:27][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=1)=[O:14]
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCOc2ccc(Br)cc21
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3ccc(Br)cc32)cc1
Yield: 48.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-bromochroman-4-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.57 g) as starting materials, 6-bromo-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (0.52 g) was obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]1.C([Li])CCC.[I:17]I>O1CCCC1>[I:17][C:5]1[O:1][C:2]([C:6]2([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]2)=[N:3][CH:4]=1
Reactant: II
Reactant: OC1(c2ncco2)CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ncc(I)o2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (−78° C.) solution of Example 48A (500 mg, 3.26 mmol) in tetrahydrofuran (50 mL) was added n-butyllithium (4.08 mL, 6.53 mmol, 1.6M in hexane) dropwise. After stirring for 30 min, a solution of iodine (0.829 g, 3.26 mmol) in tetrahydrofuran (5 mL) was added dropwise. After 2 h, the reaction was quenched by the addition of 10% Na2S2O3 solution (10 mL) and ethyl acetate (10 mL) and warmed to room temperature. The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×50 mL). The combined organics were washed with brine (1×50 mL), dried over Na2SO4, concentrated under reduced pressure, and purified by chromatography on SiO2 gel, eluting with 50% ethyl acetate in hexane, to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.65 (s, 2H), 1.79 (s, 2H), 1.89 (s, 2H), 2.02 (s, 2H), 5.50 (s, 1H), 7.22 (s, 1H).
Reaction SMILES: C([Si]([O:18][CH2:19][C:20]1C=CC=C[C:21]=1[CH2:26][S:27]([C:30]1C=CC(Cl)=CC=1)(=[O:29])=[O:28])(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1>[CH3:30][S:27]([CH2:26][CH2:21][CH2:20][CH2:19][OH:18])(=[O:29])=[O:28]
Reactant: CC(C)(C)[Si](OCc1ccccc1CS(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)CCCCO
Yield: 200.3 %

Procedure:
In toluene (5 ml) were dissolved t-butyl [[2-[[(4-chlorophenyl)sulfonyl]methyl]benzyl]oxy]diphenylsilane (350 mg, 0.654 mmol) and the 4-(methylsulfonyl)-1-butanol (200 mg, 1.31 mmol) obtained in Referential Example 3, followed by the addition of cyanomethylenetri-n-butylphosphorane (350 mg, 1.45 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, cyanomethylenetri-n-butylphosphorane (300 mg, 1.24 mmol) was added thereto. Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=3:2 was concentrated under reduced pressure, whereby the title compound (175 mg, 0.261 mmol, 40%) was obtained as a pale yellowish brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC>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.C1(C)C=CC=CC=1>[CH:12]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CCc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)CCC2=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a mixture of 5-bromo-2,3-dihydro-1H-inden-1-one (2 g, 9.48 mmol), tributyl(vinyl)stannane (3.32 mL, 11.37 mmol) and toluene (30 mL) in a sealed tube was added Pd(Ph3P)4 (0.548 g, 0.474 mmol). Nitrogen was bubbled through the reaction for 5 min., the vessel was sealed and heated at 100° C. for 20 hr. After cooling the reaction mixture to room temperature, ethyl acetate (20 mL), water (30 mL) and celite were added. The mixture was stirred at room temperature for 30 min. and filtered. The EtOAc layer was separated and the aqueous layer was re-extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under reduced pressure. Flash chromatography purification (40 g silica gel column, 5→50% ethyl acetate in hexanes) afforded 5-vinyl-2,3-dihydro-1H-inden-1-one (1.2 g, 7.59 mmol, 80% yield) as a yellow solid. The product had an HPLC ret. time=2.50 min. (condition C); LC/MS M+1=159.2.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:13]([N+:15]([O-])=O)[CH:14]=1)C1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O.C(Cl)(Cl)Cl>C(O)(=O)C.[C].[Pd]>[CH3:27][S:28]([NH:15][C:13]1[CH:14]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Oc2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(Oc2ccc(O)cc2NS(C)(=O)=O)cc1
Reaction time: 1 h
Yield: 119.4 %

Procedure:
1.8 g of 5-benzyloxy-2-(4-methoxyphenoxy)nitrobenzene was dissolved in 40 ml of acetic acid. 200 mg of 5% palladium-carbon was added thereto. The mixture was subjected to hydrogenation at room temperature at atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration and the solvent was removed by distillation under reduced pressure. The residue was mixed with 7 ml of methylene chloride and 1.10 ml of pyridine to obtain a solution. Thereto was dropwise added 400 mg of methanesulfonyl chloride in 5 minutes at 5°-10° C. Stirring was conducted for 1 hour at the same temperature. 20 ml of water and 20 ml of chloroform were added thereto. The resulting organic layer was separated and washed with 20 ml of 2N hydrochloric acid and 200 ml of water. The organic layer was mixed with a 5% aqueous sodium hydroxide solution. The aqueous layer was separated and adjusted to pH 2 with 6N hydrochloric acid. 50 ml of ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography [eluant: a 10 : 1 mixture of toluene and ethyl acetate] to obtain 1.29 g (yield: 81.6%) of 3-methylsulfonylamino-4-(4-methoxyphenoxy)phenol.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.S(Cl)([Cl:35])=O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([Cl:35])=[O:29])=[CH:26][CH:25]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Yield: 108 %

Procedure:
To a stirred solution of 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (0.400 g, 0.93 mmol) in anhydrous chloroform (20 mL) was added thionyl chloride (0.27 mL, 3.7 mmol). The solution was heated at reflux for 2 h and concentrated in vacuo to afford 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoyl chloride (0.45 g) as a pale yellow solid. To a solution of 2-fluoroaniline (0.1 mL, 1.0 mmol) and triethylamine (0.43 mL, 3.1 mmol) in anhydrous dichloromethane (10 mL) at 0° C. under nitrogen was added 4-((2′-oxo-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indoline]-1′-yl)methyl)benzoyl chloride (0.46 g, 1.0 mmol). The reaction mixture was stirred at ambient temperature for 42 h and was washed with 10% w/v hydrochloric acid (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with hexanes/ethyl acetate (1/1) to afford N-(2-fluorophenyl)-4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.262 g, 49%) as a colorless solid: mp 245-251° C.; 1H NMR (300 MHz, CDCl3) δ 8.48-8.43 (m, 1H), 8.11-8.04 (m, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 7.24-7.02 (m, 6H), 6.75 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 5.16 (d, J=15.9 Hz, 1H), 4.95 (d, J=8.7 Hz, 1H), 4.89 (d, J=15.9 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.21-4.10 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.6, 164.9, 155.3, 152.7 (d, J=241.4 Hz), 144.7, 141.7, 140.0, 138.3, 134.1, 132.2, 128.8, 127.8 (d, J=4.1 Hz), 126.4 (d, J=9.8 Hz), 124.7-124.6 (m), 124.1, 123.7, 121.8, 120.8, 114.8 (d, J=19.1 Hz), 111.4, 109.1, 99.5, 80.1, 64.5, 63.9, 58.0, 43.8; MS (ES+) m/z 523.0 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=O)=[N+:8]=[N-:9].[NH2:20][C:21]1[CH:22]=[C:23]([C:34]([CH3:41])([CH3:40])[CH2:35][O:36][C:37](=[O:39])[CH3:38])[CH:24]=[C:25]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:26]=1[O:27][CH3:28].N1C(C)=CC=CC=1C>C(Cl)Cl.C1COCC1.CN(C=O)C.C1COCC1.C(Cl)Cl>[N:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([NH:20][C:21]1[CH:22]=[C:23]([C:34]([CH3:41])([CH3:40])[CH2:35][O:36][C:37](=[O:39])[CH3:38])[CH:24]=[C:25]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:26]=1[O:27][CH3:28])=[O:15])=[N+:8]=[N-:9]
Reactant: COc1c(N)cc(C(C)(C)COC(C)=O)cc1NS(C)(=O)=O
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)COC(C)=O)cc1NS(C)(=O)=O
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Oxalyl chloride (0.11 mL, 1.3 mmol) was added to a stirring suspension of 148 mg (0.84 mmol) of 3-azido-4-methyl benzoic acid in 5 mL of 1:1 CH2Cl2/THF followed by 1 drop of 10% DMF in THF. After stirring for 1 h, the now homogeneous mixture was concentrated to provide a dark oil. The acid chloride was dissolved in 5 mL of CH2Cl2 and 185 mg (0.56 mmol) of acetic acid 2-(3-amino-5-methanesulfonylamino-4-methoxy-phenyl)-2-methyl-propyl ester was added along with 0.2 mL (1.7 mmol) of 2,6-lutidine. The mixture was stirred overnight, then was diluted with 10 mL of CH2Cl2, and washed with 1 M NaHSO4 (2×), saturated NaHCO3, and brine. The organic portion was dried with Na2SO4, filtered, and concentrated to provide acetic acid 2-[3-(3-azido-4-methyl-benzoylamino)-5-methanesulfonylamino-4-methoxy-phenyl]-2-methyl-propyl ester (238 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(=Nc3ccccc3)CC2)cc1
Yield: 64.8 %

Procedure:
A 1000 ml round bottom flask affixed with a stirring bar, a Dean-Stark trap and a condenser was charged with 101.6 g of benzylpiperidone, 500 ml of toluene, 50 g of aniline and 500 mg of p-toluene sulfonic acid. The mixture was refluxed overnight. After removal of the solvent, the reaction mixture was poured into 600 ml of isopropyl ether. The resulting solution was filtered, and the filtrate concentrated and then vacuum distilled at 185°-190° C., 1.25 torr to obtain 91.9 g (about 65% yield) of product as a light yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:31]=[CH:32][C:33]([N+:38]([O-:40])=[O:39])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([OH:29])[CH:31]=[CH:32][C:33]=3[N+:38]([O-:40])=[O:39])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1ccc(O)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-hydroxy-2-nitro-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 528.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH3:19]OC(C1CCN(C(OC(C)(C)C)=O)CC1)=O>>[CH3:1][O:2][C:3]([C:5]1([CH2:18][CH3:19])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Product: CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using the method of 4-methylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester, the title compound is synthesized from piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester and isolated as a tan oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][C:19]([CH3:20])=[C:6]12)=[O:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1CCCCC1.C(OCC)(=O)C>[CH3:3][N:5]([CH2:11][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][C:19]([CH3:20])=[C:6]12)=[O:4])[CH3:6]
Reactant: C1CCNCC1
Reactant: Cc1scc2c1N(C(=O)CCl)c1ccccc1NC2=O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1scc2c1N(C(=O)CN1CCCCC1CN(C)C)c1ccccc1NC2=O

Procedure:
The title compound is prepared analogously to Example 2 from 4-(chloroacetyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-(dimethylamino)methyl]piperidine to give colorless crystals, mp. 172°-173° C. (cyclohexane/ethyl acetate 4:1 v/v).
Reaction SMILES: [CH2:1]([C:8]1[CH:22]=[CH:21][C:11]([C:12]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].S(=O)(=O)(O)O.[N+:28]([O-])([OH:30])=[O:29]>>[N+:28]([C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:8]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:12]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:13])([O-:30])=[O:29]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCc1ccc(C(=O)CCCCC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCCCCCCc1ccc(C(=O)CCCCC(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
5-(4-n-heptylbenzoyl)pentanoic acid (30.5 g; 0.1 mole) is added slowly to concentrated sulfuric acid (3 ml) while maintaining the mixture temperature below 5° C. with external cooling. A mixture of concentrated nitric acid (8 ml) and sulfuric acid (12 ml) is added dropwise over one hour with the reaction temperature maintained below 5° C. The reaction mixture is poured into ice water (1 liter). The precipitate is collected, dissolved in 2N potassium hydroxide (200 ml), diluted with water (to 400 ml) and washed with ether (2×100 ml). The aqueous phase is acidified with concentrated hydrochloric acid and the product extracted with ether (3×150 ml). The ether solution is dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on a silica gel column (hexane: ether: acetic acid, 74:25:1) to give 5-(3-nitro-4-n-heptylbenzoyl)pentanoic acid (5.25 g) which on recrystallization from heptane is obtained as pale yellow crystals, m.p. 53°-56° C.
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1[C:35]([O:37][CH:38]1[CH:43]([CH3:44])[CH2:42][CH2:41][CH2:40][CH:39]1[CH3:45])=[O:36])C1C=CC=CC=1>CO.[Pd]>[CH3:25][N:23]([CH3:24])[C:22]([C:12]1[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]([C:35]([O:37][CH:38]2[CH:43]([CH3:44])[CH2:42][CH2:41][CH2:40][CH:39]2[CH3:45])=[O:36])=[C:9]([OH:8])[C:13]=1[OH:14])=[O:26]
Reactant: COc1ccc(-n2c(C(=O)OC3C(C)CCCC3C)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-n2c(C(=O)OC3C(C)CCCC3C)c(O)c(O)c2C(=O)N(C)C)cc1
Yield: 29 %

Procedure:
A solution of 2,6-dimethylcyclohexyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (45) (73 mg, 0.12 mmol) in MeOH (6 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 26° C. under H2 (full H2 mode). The output was concentrated in vacuo and the crude product was purified by preparative HPLC (Waters, Acidic (0.1% formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 5-95% MeCN in Water) to afford 2,6-dimethylcyclohexyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-113) (15 mg, 29%) as a yellow solid: m/z 431 (M+H)+ (ES+); 429 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.67-8.40 (m, 2H), 7.15-7.05 (m, 2H), 6.91-6.85 (m, 2H), 5.05 (br s, 1H), 3.76-3.75 (m, 3H), 2.82 (br s, 6H), 1.64-0.94 (m, 6H), 0.74-0.57 (m, 6H), 0.57-0.40 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)=[O:8])[CH:4]([CH3:6])[CH3:5].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2>>[ClH:22].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:2][C@@H:3]([C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH2:11][CH2:10]1)=[O:8])[CH:4]([CH3:5])[CH3:6])=[O:33])=[CH:26]2
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(C2CCN(C)CC2)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: CC(C)[C@@H](NC(=O)c1cc2cc(Cl)ccc2[nH]1)C(=O)N1CCC(C2CCN(C)CC2)CC1

Procedure:
Prepared from 1-D-valinyl-4-(1-methylpiperidin-4-yl)-piperidine hydrochloride and 5-chloroindole-2-carboxylic acid using methods substantially equivalent to General Coupling Method 2. Purified and converted to the hydrochloride salt from by preparative reverse phase HPLC (YMC ODSA C18 5μ column, 5-95% CH3CN in H2O with 0.01% HCl) to give the HCl salt.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][C:5]([Cl:12])=[CH:4][N:3]=1.[C:13](OC(=O)C)(=O)[CH3:14]>>[Cl:12][C:5]1[CH:4]=[N:3][C:2]2[NH:1][C:13]([CH3:14])=[N:11][S:8](=[O:9])(=[O:10])[C:7]=2[CH:6]=1
Reactant: Nc1ncc(Cl)cc1S(N)(=O)=O
Reactant: CC(=O)OC(C)=O
Product: CC1=NS(=O)(=O)c2cc(Cl)cnc2N1

Procedure:
A mixture of 1 g of 2-amino-5-chloropyridine-3- sulfonamide (Preparation 20) and 10 cm3 of acetic anhydride is brought to reflux for 6 hours. After cooling, the crystals are filtered off, washed with a small amount of acetic anhydride and then with diethyl ether and dried. The crystals are redissolved in 50 cm3 of 0.1N NaOH. The possible insoluble material is removed by filtration. The filtrate, adjusted to a pH of 4 using formic acid, allows crystals to precipitate. They are collected on a filter, washed with water and dried.