Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([OH:22])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]=3[C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(O)c3c2c1COC
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3c(c2c1COC)C(=O)CCC3
Reaction time: 6 h
Yield: 15.3 %

Procedure:
0.7 g of 5-hydroxy-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester is hydrogenated in 50 ml of ethanol with 0.5 g of Raney nickel at a hydrogen pressure of 80 bars and a temperature of 100° C. for 6 hours. After filtering off of the catalyst, the solvent is evaporated in a vacuum. The residue is chromatographed on silica gel with dichloromethane and ethanol=10+1. 0.108 g of 4-methoxymethyl-5-oxo-5,6,7,8-tetrahydro-beta-carboline-3-carboxylic acid ethyl ester with a melting point of 249°-250° C. is obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([C:14]2[N:19]=[N:18][C:17]([NH2:20])=[N:16][C:15]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[CH:34]1[CH2:36][CH2:35]1)CCC>>[Cl:13][C:11]1[CH:10]=[C:9]([C:14]2[N:19]=[N:18][C:17]([NH2:20])=[N:16][C:15]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[C:7]([CH:34]2[CH2:36][CH2:35]2)[CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1CC1
Reactant: Nc1nnc(-c2cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c2)c(-c2ccccc2)n1
Product: Nc1nnc(-c2cc(Cl)cc(C3CC3)c2)c(-c2ccccc2)n1
Yield: 6.7 %

Procedure:
6-(3-Chloro-5-cyclopropylphenyl)-5-phenyl-1,2,4-triazin-3-amine (20 mg, 7%) was prepared from 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethane-sulfonate (0.40 g, 0.93 mmol) and tri-n-butyl(cyclopropyl) tin (0.37 g, 1.11 mmol) according to the general procedure for Example 4.
Reaction SMILES: C([O:8][C:9]1[C:33]([O:34][CH3:35])=[CH:32][C:12]2[C:13](=[O:31])[N:14]3[CH2:30][CH2:29][CH2:28][C@H:15]3[C@H:16]([OH:27])[N:17]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[C:11]=2[C:10]=1[O:36][CH3:37])C1C=CC=CC=1>[Pd].CCO>[OH:8][C:9]1[C:33]([O:34][CH3:35])=[CH:32][C:12]2[C:13](=[O:31])[N:14]3[CH2:30][CH2:29][CH2:28][C@H:15]3[C@H:16]([OH:27])[N:17]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:24])[CH3:25])=[O:19])[C:11]=2[C:10]=1[O:36][CH3:37]
Reactant: COc1cc2c(c(OC)c1OCc1ccccc1)N(C(=O)OCC[Si](C)(C)C)[C@@H](O)[C@@H]1CCCN1C2=O
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(c(OC)c1O)N(C(=O)OCC[Si](C)(C)C)[C@@H](O)[C@@H]1CCCN1C2=O
Yield: 90.5 %

Procedure:
10% Pd/C catalyst (0.22 g) was added to a solution of the substrate 128 (0.95 g, 2.1 mmol) in absolute EtOH (200 mL). The reaction mixture was hydrogenated under pressure using a Parr hydrogenator at 55 psi H2 for 18 h. The reaction mixture was filtered through celite, and the celite washed with hot EtOH, taking care not to allow the filtration pad to dry out. Removal of excess solvent afforded the product as a colourless glass (0.84 g, 1.9 mmol, 92%); 1H NMR (270 MHz, CDCl3) δ0.07 (s, 9H), 0.91-0.97 (m, 2H), 2.07-2.20 (m, 4H), 3.52-3.75 (m, 2H), 3.98-4.26 (m, 9H), 5.65 (d, 1H, J=9.71 Hz), 6.26 (br s, 1H), 7.14 (s, 1H); 13C NMR (CDCl3) δ167.0, 157.3, 146.8, 143.4, 141.3, 124.9, 123.5, 105.5, 105.2, 85.8, 64.8, 64.6, 64.5, 61.2, 60.0, 56.4, 46.4, 28.9, 28.7, 23.1, 23.0, 17.3, −1.3, −1.5, −1.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]([OH:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:16][S:17]([O:15][CH:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(O)CSc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC(CSc1ccc(Cl)cc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 42.0 g (0.172 mole) of 1-(p-chlorophenylthio)hexan-2-ol and 21.6 g (0.189 mole) of methane sulfonyl chloride in 100 ml of toluene is slowly added 20.8 g (0.206 mole) of triethylamine over a 1/2 hour period at less than 15° C. When the addition is completed, the mixture is stirred for 1/2 hour, and is allowed to warm to ambient temperature.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:33]4[CH:32]=[CH:31][C:30]([CH2:29][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:35][CH:34]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(-c4ccc(CS(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methylsulfonylmethyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 6): tR=1.06 min; Mass spectrum (ESI+): m/z=487 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CC(O)(C)C>[I:8][C:5]1[N:4]=[N:3][C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1
Reactant: Clc1ccc(I)nn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(I)nn2)CC1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
3-chloro-6-iodopyridazine (510 mg, 2.1 mmol) and tert-butyl piperazine-1-carboxylate (415 mg, 2.23 mmol) were taken up in tBuOH (8 mL). iPr2NEt (480 μL, 2.8 mmol) was added and the stirred reaction mixture was heated to 100° C. After 48 h, the reaction mixture was cooled and was partitioned between EtOAc and water. The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-25% Et2O in DCM) to afford tert-butyl 4-(6-iodopyridazin-3-yl)piperazine-1-carboxylate 7.12. LCMS-ESI+ (m/z): [M+H—CO2tBu]+ calcd for C8H121 N4: 291.0; found: 291.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:29])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]([OH:26])[CH:24]=[CH2:25])=[C:17]([CH3:27])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:28]=1.C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:29])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]([O:26][C:37](=[O:39])[CH3:38])[CH:24]=[CH2:25])=[C:17]([CH3:27])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:28]=1
Reactant: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Reaction time: 0.02 h
Yield: 87 %

Procedure:
To a 100 mL round bottom flask equipped with a magnetic stir bar was added 2-(2,6-dichloro-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.175 g, 0.409 mmol), THF (5 mL), triethylamine (60 μL, 0.43 mmol) and acetic anhydride (1 mL). To the stirring suspension was then added N,N-dimethylaminopyridine (2 mg, 0.016 mmol). The reaction mixture became clear in 1 minute, and TLC analysis indicated that all starting material had been consumed. The reaction mixture was concentrated in vacuo and the residue was further purified by silica gel chromatography, eluting with methanol:dichloromethane (0-10%) to provide acetic acid 1-[2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (0.168 g, 87%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.42 (s, 1H), 7.80-7.76 (m, 4H), 7.57 (t, 1H, J=8.2 Hz), 6.34 (d, 1H, J=6.3 Hz), 6.21-6.13 (m, 1H), 5.41 (d, 1H, J=17.2 Hz), 5.33 (d, 1H, J=10.2 Hz), 4.25 (s, 3H), 2.33 (s, 3H), 2.12 (s, 3H); ESMS (m/z): found, 471.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(ON=O)CC(C)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](N)=[C:19]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:26]=2[Cl:35])[CH:18]=1>C(#N)C.O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:19]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][C:26]=2[Cl:35])[CH:18]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2N)c(Cl)c1
Reactant: CCOC(=O)CS
Agent: CC(C)CCON=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CSc1ccc(Cl)cc1Oc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 60 °C

Procedure:
Ethyl mercaptoacetate (0.11 ml) followed by isoamylnitrite (0.16 ml) were added to a solution of the product from example 15 step (i) (0.5 g) in dry acetonitrile (20 ml) and heated at 60° C. for 10 h. The mixture was diluted with water, extracted with diethylether, the organics dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with dichloromethane, yield 0.60 g.
Reaction SMILES: C[O:2][C:3](=[O:21])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[N:5]/[OH:6].CO.[OH-].[Na+].Cl>O>[OH:6]/[N:5]=[C:4](\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)/[C:3]([OH:21])=[O:2]
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(Oc2ccccc2/C(=N\O)C(=O)O)cc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To E-α-hydroxyimino-2-(4-methylphenoxy)phenylacetic acid methyl ester (1.00 g, 0.0035 mole) were added methanol (3.5 ml), water (3.5 ml), sodium hydroxide (0.31 g, 0.0077 mole) and the mixture was heated under reflux for one hour. After cooling to room temperature,-the resultant was adjusted to pH 1 with 5% of hydrochloric acid. After stirring at room temperature, the crystals were filtered off and washed with water to obtain colorless crystals of E-α-hydroxyimino-2-(4-methylphenoxy)phenylacetic acid (0.90 g, yield: 94.7%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:38][CH:39]=2)[CH2:29][CH2:28]1>C(Cl)Cl.CO>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:23]([C:20]3[CH:21]=[CH:22][C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[CH:15]4)=[O:24])=[N:38][CH:39]=2)[CH2:29][CH2:28]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture for 20 h at rt. Title compound: ESI-MS: 566.1 [M+H]+; TLC: Rf=0.22 (DCM/MeOH, 9:1).
Reaction SMILES: [CH2:1]([C:10]1([C:19](Cl)=[O:20])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:24]=1[NH2:25]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:10]1([C:19]([NH:25][C:24]2[C:23]([F:22])=[CH:29][C:28]([F:30])=[CH:27][C:26]=2[F:31])=[O:20])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCC1(C(=O)Cl)Cc2ccccc2C1
Reactant: Nc1c(F)cc(F)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC1(C(=O)Nc2c(F)cc(F)cc2F)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 44 h
Yield: 54 %

Procedure:
The title compound was prepared according to the procedure described in Example 65, except that 398 mg (1.3 mmple) 2-n-nonylindane-2-carbonyl chloride, 220 mg (1.5 mmole) 2,4,6-trifluoroaniline, and 187 mg (1.5 mmole) 4-dimethylaminopyridine in 12 ml methylene chloride were stirred at room temperature for 44 hours. There was obtained 290 mg product. 54% yield. IR(CHCl3): 1693 cm-1. 1H NMR: δ0.86 (t, 3H); 1.23 (c, 12H); 1.41 (c, 2H); 1.78 (c, 2H); 3.02 (d, 2H); 3.5 (d, 2H); 6.7 (c, 3H); 7.18 (c, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:29])([CH3:28])[C:25](O)=[O:26])=[CH:20][C:19]=1[C:30]([F:33])([F:32])[F:31].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:29])([CH3:28])[C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C:16]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]2=3)=[O:26])=[CH:20][C:19]=1[C:30]([F:31])([F:32])[F:33]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.8 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.030 g, 0.11 mmol), 2-[4-chloro-3-(trifluoromethyl)phenyl]-2-methyl-propanoic acid (0.030 g, 0.11 mmol) and NEt3 (0.070 mL, 0.50 mmol) in DMF (0.6 mL) was added HATU (0.060 g, 0.15 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water, and partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.005 g, 10%). 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.30-7.51 (m, 4H), 7.14 (dd, J=8.8, 8.4 Hz, 2H), 3.22 (m, 2H), 2.69 (t, J=6.4 Hz, 2H), 1.64 (s, 6H); 1.62 (m, 2H); MS: (ES) m/z calculated for C23H20ClF4N3O [M+H]+ 466.1, found 466.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:53]1([S:59]([C:62]2[CH:63]=[C:64](Br)[CH:65]=[CH:66][CH:67]=2)(=[O:61])=[O:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.[C:69]([O:73][C:74]([N:76]1[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]1)=[O:75])([CH3:72])([CH3:71])[CH3:70]>O1CCOCC1>[C:53]1([S:59]([C:62]2[CH:63]=[C:64]([N:79]3[CH2:78][CH2:77][N:76]([C:74]([O:73][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:75])[CH2:81][CH2:80]3)[CH:65]=[CH:66][CH:67]=2)(=[O:61])=[O:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=S(=O)(c1ccccc1)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(S(=O)(=O)c3ccccc3)c2)CC1
Temperature: 100 °C
Yield: 71.2 %

Procedure:
A solution of 2 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (62 mg, 0.1 mmol) and cesium carbonate (329 mg, 1.01 mmol) in dry dioxane (2 ml) were sonicated for 45 min, under argon. To this solution was added 3-phenylsulfonylbromobenzene (D2) (200 mg, 0.67 mmol) and 1-(tert-butyloxycarbonyl)piperazine (314 mg, 1.68 mmol) and the reaction heated at 100° C. for 18 h. The reaction mixture was evaporated in vacuo and the residue partitioned between water (50 ml) and dichloromethane (50 ml). The organic layer was washed with sat. sodium hydrogen carbonate (50 ml), 10% citric acid (50 ml), brine (50 ml) and then dried (MgSO4). Solvents evaporated in vacuo and the residue purified by column chromatography (silica gel; 0-60% ethyl acetate/petroleum ether) to give the product as a colourless oil (192 mg, 71%)
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:5]=1>[OH-].[Na+]>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:7]2[C:8]([S:10](=[O:12])(=[O:13])[NH2:11])=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][C:6]=2[N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(N2CCCC2)c(Oc2ccc(C)cc2)c(S(N)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(Oc2c(N3CCCC3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The methyl ester obtained according to (e) os suspended in 1 N NaOH and heated on the steam bath until a clear solution has formed. The whole is filtered and acidified to pH 3. The 4-(4'-methylphenoxy)-3-(1-pyrrolidinyl)-5-sulphamoylbenzoic acid that has precipitated is recrystallised from methanol; light yellow crystals melting at 230°-233° C with decomposition.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:30][CH3:31])=[C:11]([OH:29])[C:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]1([CH2:38][CH2:39]O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[C:11]([O:29][CH2:39][CH2:38][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:10]=1[CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Reactant: OCCC1CCCCC1
Product: CCc1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1OCCC1CCCCC1

Procedure:
The title compound was prepared in a similar manner to those described in Example 2 using 3-benzyloxy-2-ethyl-6-(5-methyl-7-nitroindan-4-yloxy)phenol instead of ethyl N-[7-(3-ethyl-2-hydroxy-4-trifluoromethanesulfonyloxyphenoxy)-6-methylindan-4-yl]malonamate and using 2-cyclohexylethanol instead of 4-fluorobenzylalcohol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH:7]=1>CC(C)=O.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:7][CH2:8][C:9](=[O:12])[CH2:10][CH2:11]1
Reactant: O=C1CC=C(CCCCO)CC1
Agent: [Pd]
Solvent: CC(C)=O
Product: O=C1CCC(CCCCO)CC1
Reaction time: 3 h

Procedure:
To a solution of 4.63 g of 4-(4-hydroxybutyl)-cyclohex-3-ene-1-one in 130 mL acetone is added 0.46 of 10% palladium on carbon and the suspension is then hydrogenated at 3 atmospheres pressure for 3 hours. The catalyst is evaporated to dryness to give 4-(4-hydroxybutyl)cyclohexanone as an oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:30]>>[CH3:30][N:29]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:34][CH:33]=1)[CH3:28]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CN(C)C)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-(dimethylaminomethyl)-aniline
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH2:5]([SH:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:5]([S:17][CH2:2][CH2:3][OH:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCS
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCSCCO
Temperature: 22 °C
Reaction time: 10 h
Yield: 76.5 %

Procedure:
A mixture of 2-bromoethanol (6.08 g, 48.7 mmol), dodecanethiol (9.86 g, 48.7 mmol) and potassium carbonate (11 g) in dry N,N-dimethylformamide (100 ml) was stirred at 22° C. for 10 h. The reaction mixture was then diluted with toluene (400 ml) washed with water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the residue was filtered through a silica gel pad (toluene-ethyl acetate 95:5) and distilled under vacuum to give 9.18 g (77%) of 2-(dodecylthio)ethanol as a clear oil which solidified on standing: b.p. 100-105° C./0.01 torr (bulb to bulb distillation, air bath temperature); m.p. 31-32° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13]([CH3:14])=[C:12]([S:15](Cl)(=[O:17])=[O:16])[C:11]([CH3:19])=[N:10]1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:36][CH3:37])=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=2)[CH:26]=1>ClCCl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:36][CH3:37])=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C@H:33]([NH:35][S:15]([C:12]3[C:11]([CH3:19])=[N:10][N:9]([CH3:8])[C:13]=3[CH3:14])(=[O:17])=[O:16])[CH3:34])=[CH:29][CH:28]=2)[CH:26]=1
Reactant: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Reactant: COc1ccc(F)cc1-c1ccc([C@@H](C)N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2c(C)nn(C)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
Palladium acetate (56 mg, 0.25 mmol) was added to a mixture of 5-fluoro-2-methoxyphenylboronic acid (850 mg, 5.0 mmol) and (R)-1-(4-bromophenyl)ethylamine (500 mg, 2.5 mmol) in water (20 ml). This mixture was heated for 5 min at 200° C. in a Smithcreator microwave oven and then diluted with methanol (200 ml). The mixture was purified on a SCX column (20 g) using 2M ammonia in methanol to elute the intermediate amine. Evaporation of solvents under reduced pressure gave (R)-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine as a gum (580 mg, 2.37 mmol, 96.6%). Triethylamine (41.1 μl, 0.295 mmol) and 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (20.5 mg, 0.0984 mmol) were added to a solution of (R)-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20 mg, 0.082 mmol) in dichloromethane (1 ml) and the resulting solution shaken at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution (500 μl), the dichloromethane layer separated, dried over magnesium sulfate and the solvent evaporated. Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (13.8 mg, 0.033 mmol, 40%): 1H NMR (400 MHz, CDCl3): δ7.37, 7.14 (a/b, 4H), 7.02-6.87 (m, 3H), 4.68 (m, 1H), 4.48 (t, 1H), 3.78 (s, 3H), 3.55 (s, 3H), 2.35 (s, 3H), 2.22 (s, 3H), 1.50 (d, 3H) ppm; MS (ESI) m/z: 417 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([C:16](=O)/[CH:17]=[CH:18]/[N:19](C)C)=[N:12][CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Cl.[CH:24]1([NH:29]N)[CH2:28][CH2:27][CH2:26][CH2:25]1>CCO>[CH:24]1([N:29]2[C:16]([C:11]3[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:17][CH:18]=[N:19]2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CN(C)/C=C/C(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C
Reactant: NNC1CCCC1
Agent: Cl
Solvent: CCO
Product: OCc1cccnc1-c1ccnn1C1CCCC1
Temperature: 80 °C

Procedure:
To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 3.205 g, 10.0 mmol, 1 eq.) in EtOH (30 mL) was added cyclopentylhydrazine HCl salt (1.639 g, 12.0 mmol, 1.2 eq) at RT. The mixture was heated at 80° C. for 2 h, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give a mixture of regio-isomers, the less polar (2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol was obtained as a light brown oil (440 mg). MS (ESI) m/z 244.2 [M+H]+.