Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:28])[N:17]([C@@H:19]([CH2:26]O)[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)[CH3:18])([CH3:14])([CH3:13])[CH3:12].[CH2:29]([N:31](CC)CC)C.C(O)(=O)C.CN.C(O)C.C([BH3-])#N.[Na+]>ClCCl>[C:11]([O:15][C:16](=[O:28])[N:17]([CH3:18])[C@H:19]([CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)[CH2:26][NH:31][CH3:29])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCN(CC)CC
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CO)Cc1cccs1
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CNC[C@@H](Cc1cccs1)N(C)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 43.5 %

Procedure:
A solution of oxalyl chloride (1.81 ml, 20.8 mmol) in dichloromethane (180 ml) was cooled to −78° C. A solution of dimethylsulfoxide (2.15 ml, 27.8 mmol) in dichloromethane (2 ml) was added dropwise. The solution was stirred for 15 min at −78° C. A solution of N-((1R)-1-(hydroxymethyl)-2-(2-thienyl)ethyl)-N-methylcarbamic acid tert-butyl ester (3.78 g, 13.9 mmol) in dichloromethane (10 ml) was added dropwise. The solution was stirred for 20 min at −78° C. Triethylamine (7.71 ml, 55.6 mmol) was added. The solution was stirred for 5 min at −78° C. and warmed to −35° C. As soon as −35° C. was reached it was cooled to −78° C. Acetic acid (3.50 ml, 61.2 mmol) was added. The solution was warmed to room temperature and was washed with brine (200 ml). The organic phase was dried over magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in methanol (180 ml). 4 A mol (20 g) sieves was added. Acetic acid (5.5 ml, 97.3 mmol) was added. An 8.0 M solution of methylamine in ethanol (5.2 ml, 41.7 mmol) was added. Solid sodium cyano borohydride (0.57 g, 9.1 mmol) was added. The solution was stirred at room temperature for 1 h, before another portion of solid sodium cyano borohydride (0.57 g, 9.1 mmol) was added. The reaction mixture was stirred for 16 h at room temperature and filtered through a plug of celite. The celite was washed with methanol (150 ml). The solvent of the filtrate was removed in vacuo. The residue was dissolved in 1 N sodium hydroxide solution (200 ml). The solution was extracted with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (150 g), using dichloromethane/methanol/25% aqueous ammonia 100:10:1 as eluent, to give 1.72 g of N-methyl-N-((1R)-2-methylamino-1-((2-thienyl)methyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: O[C:2]1([C:17]2[C:25]([CH2:26][OH:27])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]1=[O:16].C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[CH2:11]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:25]3[CH2:26][O:27]2)[C:3]1=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2CO)OCO3)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(OCc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 3-hydroxy-3-[6-(hydroxymethyl)-1,3-benzodioxol-5-yl]-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (45%) as a colorless solid: mp 113-115° C.; 1H NMR (300 MHz, CDCl3) δ7.24-7.33 (m, 1H), 7.12 (dd, 1H), 7.01 (t, 1H), 6.87 (d, 1H), 6.74 (s, 1H), 6.15 (s, 1H), 5.92 (dd, 2H), 5.48 (d, 1H), 5.27 (d, 1H), 3.76-3.56 (m, 2H), 1.71-1.64-(m, 2H), 1.37-1.27-(, 4H), 0.89-0.84 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 175.9, 148.7, 148.1, 143.6, 133.7, 132.1, 130.3, 129.8, 125.3, 125.0, 123.1, 113.5, 109.1, 108.7, 101.9, 101.7, 88.7, 74.4, 40.0, 29.7, 29.0, 25.3, 13.3; MS (ES+) m/z 352.1 (M+1).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:39])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([S:27]([CH2:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=2[Cl:38])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[NH:13][C:12]=1[CH3:40])=O.[NH:41]1[CH2:46][CH2:45][CH:44]([OH:47])[CH2:43][CH2:42]1>>[Cl:38][C:32]1[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=1[CH2:30][S:27]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:39])/[C:18]/2=[CH:17]\[C:14]1[NH:13][C:12]([CH3:40])=[C:11]([C:9]([N:41]2[CH2:46][CH2:45][CH:44]([OH:47])[CH2:43][CH2:42]2)=[O:8])[C:15]=1[CH3:16])(=[O:29])=[O:28]
Reactant: OC1CCNCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)ON1C(=O)CCC1=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)N1CCC(O)CC1
Yield: 25.5 %

Procedure:
5-[5-(2,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (120 mg, 0.2 mmol) was condensed with piperidin-4-ol (21 mg, 0.2 mmol) to give 30 mg the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>CN(C1C=CN=CC=1)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:24])[F:25])[CH:15]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccc(C(F)(F)F)c1
Yield: 100.4 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), 3-trifluoromethylbenzenesulfonyl chloride (200 mg, 0.83 mmol) and DMAP (cat.) gave the title compound (244 mg, 100%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:14]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:15][C:16](SC)=[N:17][CH:18]=2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CCO.[Ni]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2[C:14]([NH:21][CH2:22][C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[N:15][CH:16]=[N:17][CH:18]=2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CSc1ncc(C(=O)Nc2ccc(C(C)C)cc2)c(NCc2ccncc2)n1
Agent: [Ni]
Solvent: CCO
Product: CC(C)c1ccc(NC(=O)c2cncnc2NCc2ccncc2)cc1

Procedure:
A mixture of N-[4-(isopropyl)phenyl]{2-methylthio-4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamide (50 mg, 0.13 mmol, Step B) and Raney-Ni in EtOH (10 mL) was heated at reflux for 2 h. The resulting mixture was filtered, and the filtrate was concentrated to give the titled compound. MS (ES+): 348 (M+H)+; (ES−): 346 (M−H)−. Calc'd C20H21N5O-347.42.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]#[N:23]>CN(C)C=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:21][C:22]#[N:23]
Reactant: OCc1cccc(O)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCOc1cccc(CO)c1
Reaction time: 0.08 h

Procedure:
25.3 g (203.8 mmol) of 3-hydroxybenzyl alcohol are dissolved in 50 ml of dimethylformamide, and 400 ml of acetone and 28.17 g (203.8 mmol) of finely ground potassium carbonate are added. After 5 minutes of stirring, 24.45 g (203.8 mmol) of bromoacetonitrile are added, and the mixture is boiled under reflux for 72 hours. The mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed with 10% strength aqueous sodium hydroxide solution and then with water. The organic phase is dried over magnesium sulfate and filtered through a short silica gel column (mobile phase toluene->toluene/ethyl acetate=1:1). Evaporation gives 163.18 g (86% of theory) of an oil. Rf (SiO2, toluene/ethyl acetate=1:1)=0.41.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([F:13])([F:12])[CH2:6][NH:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]([F:13])([F:12])[CH2:6][N:7]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(F)(F)CNC1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
A solution of 17.76 g (0.086 mole) 3-cyclobutylamino-2,2-difluoropropionic acid ethyl ester in 10 mL of ethyl acetate was added dropwise to a mixture of 16.6 g (0.086 mole) of 2,4-dichloro-5-nitro-pyrimidine, 28.9 g (0.344 mole) of sodium bicarbonate and 100 mL of ethyl acetate at 0 degrees. The cooling bath was removed and the reaction was stirred at room temperature for 18 h. Activated charcoal was added, and the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography (elution with hexanes-ethyl acetate, gradient 100:0-50:50), to give 11.6 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-2,2-difluoro-prop ionic acid ethyl ester (IV-1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH3:10][NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1.CCO.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>[CH:8]([C:5]1[N:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:12]([NH:11][CH3:10])=[O:13])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)=[O:9]
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(Br)cn1
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: CCCCCC
Solvent: CCO
Product: CNC(=O)c1ccc(-c2ccc(C=O)nc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of 5-bromopicolinaldehyde (0.25 g, 1.34 mmol) in toluene (6 mL) and EtOH (5 mL) was added (4-(methylcarbamoyl)phenyl)boronic acid (0.36 g, 2.0 mmol), 2M Na2CO3 (2.5 mL, 4.03 mmol) and Pd(PPh3)4 (0.24 g, 0.2 mmol) under argon. The mixture was degassed, heated to 100° C., and stirred for 1 h. After completion of the reaction by monitoring with TLC (80% EtOAc\hexane), the resulting mixture was filtered using Celite® reagent. The filtrate was separated, concentrated, extracted with EtOAc (2×100 mL), washed with water (100 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel 100-200μ) using 60% ethyl acetate in hexane and isolated as a yellow solid (0.22 g, 62% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.0 (s, 1H), 9.20 (s, 1H), 8.53 (s, 2H), 8.39 (d, 2H), 7.9 (m, 3H); LC-MS: m/z 241.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH:11]([CH3:14])[C:10]([NH:15]C(OCC)=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH:11]([CH3:14])[C:10]([NH2:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NC1=NN(c2cccc(Cl)c2)C(=O)C1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1C(=O)N(c2cccc(Cl)c2)N=C1N

Procedure:
A solution of 69 g (0.2 mole) of 1-m-chlorophenyl-3-carbethoxyamino-4-methyl-2-pyrazolin-5-one in 320 ml of 2.5 N sodium hydroxide was refluxed for 30 min. The solution was cooled and neutralized by addition of glacial acetic acid. The precipitate was dried under reduced pressure. Yield: 39 g (87%). Melting point: 138° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25]>ClCCl.CN(C)C1C=CN=CC=1.[Cl-].[NH4+]>[C:23]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCCC2
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCCc2cc(OC)c([N+](=O)[O-])cc21
Reaction time: 8 h

Procedure:
A mixture of 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (0.19 g, 0.91 mmol) and triethylamine (0.5 mL, 3.6 mmol, Aldrich) in dichloromethane was treated with dropwise addition of acryloyl chloride (0.3 mL, 3.7 mmol, Pfaltz and Bauer). A catalytic amount of 4-dimethylaminopyridine was added and the reaction stirred overnight. The mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 1-acryloyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline which was taken directly to the next step without determination of yield. ESIMS (M+H)+=263.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:34][CH:35]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CN1CCN(Cc2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(Cc2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 1-(4-bromo-benzyl)-4-methyl-piperazine (56.0 mg, 0.208 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a pale yellow foam (0.010 g, 12%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.4 Hz, 1H), 8.24 (d, J=8.2 Hz, 2H), 8.09 (d, J=8.2 Hz, 2H), 7.66 (d, J=7.1 Hz, 1H), 7.54 (d. J=7.8 Hz, 2H), 7.31 (d, J=7.9 Hz, 2H), 7.02 (t, J=6.7 Hz, 1H), 6.86 (s, 1H), 3.49 (s, 2H), 3.11 (s, 3H), 2.46 (br s, 8H), 2.29 (s, 3H). MS=477 (MH)+.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([S:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:25]([OH:35])[CH:24]=2)=[CH:16][C:15]=1[O:36][CH3:37])(=[O:12])=[O:11])[CH2:7][CH2:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH2:6]([S:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:25]([O:35][CH2:2][CH2:3][CH2:4][CH3:5])[CH:24]=2)=[CH:16][C:15]=1[O:36][CH3:37])(=[O:12])=[O:11])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)c(O)c2)cc1OC
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCOc1cc(CCCc2ccc(OS(=O)(=O)CCCC)c(OC)c2)ccc1CCC(=O)OC
Temperature: 70 °C
Yield: 40 %

Procedure:
ml (0.95 mmol) of iodobutane is added to a solution of 400 mg (0.86 mmol) of methyl 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-hydroxyphenyl)propanoate (prepared according to Example 10i) and 178 mg (1.29 mmol) of potassium carbonate in 10 ml of methyl ethyl ketone, and the reaction mixture is then heated at 70° C. for 18 hours. The reaction is treated by adding 20 ml of water and then extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 179 mg (40%) of methyl 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-butoxyphenyl)propanoate are obtained in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:4]=1[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[N:22](S(C3C=CC(C)=CC=3)(=O)=O)[C:23]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]([CH3:38])[CH:26]=3)=[CH:24][C:17]=12)[S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])=[O:8].[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:4]=1[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[NH:22][C:23]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]([CH3:38])[CH:26]=3)=[CH:24][C:17]=12)[S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2cccs2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(CN(Cc2ccnc3[nH]c(-c4cn(C)c5cc(OC)c(OC)cc45)cc23)S(=O)(=O)c2cccs2)c(OC)c1
Yield: 82.9 %

Procedure:
Thiophene-2-sulfonic acid (2,4-dimethoxybenzyl) [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide is prepared as described in Example 179a starting with 0.150 g of thiophene-2-sulfonic acid (2,4-dimethoxybenzyl) [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 1 cm3 of 5N potassium hydroxide. 0.100 g of thiophene-2-sulfonic acid (2,4-dimethoxybenzyl) [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C([O:35][C:36]1[CH:47]=[CH:46][C:39]([CH2:40][C@@H:41]([C:43]([OH:45])=[O:44])[NH2:42])=[CH:38][CH:37]=1)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([NH:42][C@H:41]([C:43]([OH:45])=[O:44])[CH2:40][C:39]2[CH:38]=[CH:37][C:36]([OH:35])=[CH:47][CH:46]=2)=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Product: COC1=C(OC)C(=O)C(CCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)=C(C)C1=O
Yield: 20.6 %

Procedure:
Using p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionate (187 mg, 0.5 mmol) and O-benzyl-L-tyrosine (136 mg, 0.5 mmol) and following the procedure of Example 4, there was obtained 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionyl-L-tyrosine (43 mg), melting at 170° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[O:11][CH:10]([CH3:13])[CH2:9][C:8]=2[C:7]([CH3:14])=[C:6]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:5]=1[CH3:21])[CH3:2].Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH3:31])[CH:24]=1>>[CH2:1]([O:3][C:4]1[C:12]2[O:11][CH:10]([CH3:13])[CH2:9][C:8]=2[C:7]([CH3:14])=[C:6]([N:15]2[CH2:20][CH2:19][N:18]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH3:31])[CH:24]=3)[CH2:17][CH2:16]2)[C:5]=1[CH3:21])[CH3:2]
Reactant: COc1ccc(Br)cc1C
Reactant: CCOc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Product: CCOc1c(C)c(N2CCN(c3ccc(OC)c(C)c3)CC2)c(C)c2c1OC(C)C2
Yield: 45.7 %

Procedure:
By using 1-(7-ethoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (580 mg, 2.0 mmol) synthesized in Reference example 88 and 4-bromo-1-methoxy-2-methylbenzene (804 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 375 mg (yield 46%). Melting point was 80 to 83° C. (ethanol-water).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[S:22]([C:26]1[CH:34]=[CH:33][C:29]([CH2:30][CH2:31]Cl)=[CH:28][CH:27]=1)(=[O:25])(=[O:24])[NH2:23].C(=O)(O)[O-].[Na+].[I-].[K+]>O.C(#N)C>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:31][CH2:30][C:29]2[CH:28]=[CH:27][C:26]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:34][CH:33]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: NS(=O)(=O)c1ccc(CCCl)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc(S(N)(=O)=O)cc2)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g--see Preparation 8), 4-sulphamoylphenethyl chloride (0.23 g--see J. Pharm. Pharmacol., 16, 541, (1964)), sodium bicarbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 2 hours. A further portion of sodium bicarbonate (1 g) was added followed by potassium iodide (0.2 g) and the mixture was heated under reflux for 2 hours. On cooling to room temperature, water (60 ml) was added and the mixture was extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a glass which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.11 g.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17](SC)=[N:16][C:15]=2[CH:21]=1>CC(O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([N:4]3[CH:5]4[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]4)[CH2:2][CH2:3]3)=[N:16][C:15]=2[CH:21]=1
Reactant: CSc1nc2cc(Br)ccc2o1
Reactant: C1CN2CCC(CC2)N1
Solvent: CC(C)O
Product: Brc1ccc2oc(N3CCN4CCC3CC4)nc2c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 55.3 %

Procedure:
1,4-Diazabicyclo[3.2.2]nonane (57%, 731 mg, 3.31 mmol) was added to a solution of 5-bromo-2-methylsulfanyl-benzooxazole (538 mg, 2.20 mmol) in iPrOH (4.4 mL). The mixture was placed in an oil bath at 90° C. and the solvent was evaporated. The mixture was allowed to stir neat at 90° C. for 18 h. Upon cooling to RT the mixture was purified by chromatography (Biotage, 25M) eluting with 4% MeOH in CHCl3 with 20 drops of NH4OH per liter of eluent to afford 392 mg (55%) of the title compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 7.40 (t, 1H, J=1.2 Hz), 7.05 (d, 2H, J=1.2 Hz), 4.46-4.43 (m, 1H), 3.87 (t, 2H, J=5.8 Hz), 3.14-2.93 (m, 6H), 2.13-2.06 (m, 2H), 1.81-1.73 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 162.3, 148.0, 145.6, 122.9, 119.0, 116.8, 109.8, 57.2, 50.5, 46.5, 44.4, 27.0; MS (Cl) m/z 322.0 (M+1); HPLC retention time=3.36 min. The hydrochloride salt was prepared by diluting in ethyl acetate and adding a solution of 2.5 N HCl in ethyl acetate: mp>300° C.