Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[C:20]([O:34][CH3:35])=[N:21][CH:22]=[C:23]([C:25]2[S:29][C:28]3=[N:30][CH:31]=[C:32](I)[N:27]3[N:26]=2)[CH:24]=1)(=[O:17])=[O:16].[N:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1>O1CCOCC1>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[C:20]([O:34][CH3:35])=[N:21][CH:22]=[C:23]([C:25]2[S:29][C:28]3=[N:30][CH:31]=[C:32]([C:40]4[CH:39]=[CH:38][N:37]=[N:36][CH:41]=4)[N:27]3[N:26]=2)[CH:24]=1)(=[O:17])=[O:16]
Reactant: CC1(C)OB(c2ccnnc2)OC1(C)C
Reactant: COc1ncc(-c2nn3c(I)cnc3s2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ncc(-c2nn3c(-c4ccnnc4)cnc3s2)cc1NS(=O)(=O)c1ccc(F)cc1F
Yield: 5.5 %

Procedure:
Dioxane (2 mL) and 2M aq Na2CO3 (0.5 mL) were added to 2,4-difluoro-N-[2-methoxy-5-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-pyridin-3-yl]-benzenesulfon-amide (100 mg) and pyridazin-4-boronic acid pinacol ester (80 mg), and the suspension was degassed under vacuum and filled with argon (2×). The catalyst (30 mg) was quickly added, and the reaction mixture was stirred at reflux for 2 h. Further boronate (50 mg) was added, and the mixture was degassed again, then more catalyst was added (25 mg) and stirring was continued at reflux for 4 h. The solvents were evaporated, and the residue was stirred in water for 36 h. The precipitate that had formed was removed by filtration, and the filtrate was concentrated and taken up in aq. NH4Cl. A precipitate formed overnight and was filtered off, washed with water followed by ether and dried. The solid was purified by flash chromatography (DCM/MeOH 98:2 to 9:1, affording 24 mg of crude product) and subsequently by preparative HPLC to give the desired product (5 mg). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.57 min, [M+H]+ m/z 502.1; 1H NMR (300 MHz, DMSO) δ=10.56 (s, 1H), 9.82 (s, 1H), 9.25 (d, J=5.5 Hz, 1H), 8.57 (s, 1H), 8.35-8.16 (m, 2H), 8.06 (s, 1H), 7.79 (dd, J=15.0, 8.6 Hz, 1H), 7.50 (s, 1H), 7.20 (t, J=8.3 Hz, 1H), 3.70 (s, 3H) ppm.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](O)[C:16]=1[CH:17]=[O:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[OH:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:13][CH2:12][C@@H:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]=1[CH:17]=[O:18]
Reactant: O=Cc1c(O)cccc1O
Reactant: OC[C@@H]1CCCN1c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1c(O)cccc1OC[C@@H]1CCCN1c1ccccc1
Reaction time: 0.17 h
Yield: 20.5 %

Procedure:
To a solution of (S)-(1-phenylpyrrolidin-2-yl)methanol (45 mg, 0.23 mmol) and 2,6-dihydroxybenzaldehyde (60 mg, 0.46 mmol) in THF (1 ml) was added PPh3 (0.12 g, 0.46 mmol), followed by DIAD (90 mg, 0.46 mmol) at room temperature. After stirrer for 10 min, the mixture was concentrated and the residue was purified by column (Hexanes/EtOAc=9:1) to give (S)-2-hydroxy-6-((1-phenylpyrrolidin-2-yl)methoxy)benzaldehyde (14 mg). 1H NMR (400 MHz, CDCl3 (ppm) 11.96 (s, 1H), 10.37 (s, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.25 (m, 2H), 6.73 (m, 3H), 6.53 (d, J=8.4 Hz, 1H), 6.33 (d, J=9.2 Hz, 1H), 4.21 (m, 1H), 4.15 (d, J=3.6 Hz, 1H), 3.83 (t, J=8.0 Hz, 1H), 3.53 (m, 1H), 3.22 (m, 1H), 2.11 (m, 4H); MS (ESI) m/z 298.4
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)CCC>>[S:26]1[CH:27]=[CH:28][N:29]=[C:25]1[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2nccs2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 5 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)thiazole. The title compound (9 mg) was obtained as a pale solid, m/z 348 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1)[CH3:2].[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]2=[O:31])=[N:22][C:21]=1[CH3:32])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][C:27](=[CH:8][C:6]3[S:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[C:26]2=[O:31])=[N:22][C:21]=1[CH3:32])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: CCc1ccc(C=O)s1
Product: CCc1ccc(C=C2CCCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)s1
Yield: 14 %

Procedure:
Following the procedure as described in Example 10, making variations as required to use 5-ethylthiophene-2-carbaldehyde in place of benzaldehyde to react with N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 14% yield: mp 171-172° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.42-7.22 (m, 5H), 7.16 (d, J=3.7 Hz, 1H), 6.83 (dd, J=0.7, 3.7 Hz, 1H), 5.98 (t, J=5.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.32-4.25 (m, 2H), 2.93-2.81 (m, 4H), 2.65 (s, 3H), 2.15-2.02 (m, 2H), 1.32 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 164.8, 162.7, 157.5, 153.7, 152.4, 137.9, 136.4, 133.6, 132.9, 128.8, 127.9, 127.6, 124.5, 122.7, 119.5, 46.9, 44.1, 25.9, 23.8, 21.9, 17.4, 15.7; MS (ES+) m/z 452.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[CH:12]1[C:13]([NH:14][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=[C:10]([Cl:9])[CH:11]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Clc1ccc(Nc2ccc(Cl)cc2)cc1
Reaction time: 0.67 h
Yield: 35 %

Procedure:
p-Chloroiodobenzene (14 g), p-chloroaniline (11.23 g), potassium carbonate (12.15 g), and cuprous chloride (1.16 g) were suspended in dimethylsulfoxide (15 ml), and heated with stirring at 180°-190° C. for 3 hours and 40 minutes. After cooling the reaction mixture, ethyl acetate was added thereto, and washed with conc. aqueous ammonia 2 times, and with aqueous sodium chloride solution 3 times, and then, the mixture was concentrated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixed solvent of chloroform/n-hexane [1:2 (v/v)] to give 4,4'-dichlorodiphenylamine (4.89 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[NH:24])[NH:22][OH:23])=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47](Cl)=O)=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>CC(=O)OCC>[C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:24]=[C:34]([C:35]3[CH:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=4)=[CH:37][CH:36]=3)[O:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN(Cc1ccc(C(=N)NO)cc1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(Cc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 43 %

Procedure:
Prepared using General Procedure 20. To a stirring solution of methyl 2-((tert-butoxycarbonyl)(4-(N-hydroxycarbamimidoyl)benzyl)amino)acetate INT-75 (786 mg, 2.33 mmol) and DIEA (448 μL, 2.56 mmol) in dioxanes (15 mL) was added 4′-methyl-[1,1′-biphenyl]-4-carbonyl chloride (591 mg, 2.56 mmol), at room temperature. After 30 min the reaction mixture was heated to 120° C. for 3 h. The reaction mixture was diluted with EA (150 mL) and washed with brine (100 mL). The organics were concentrated in vacuo and the crude product purified by chromatography (MeCN/DCM) to afford 518 mg (43%) of methyl 2-((tert-butoxycarbonyl)(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)amino)acetate INT-76 as a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([O:8][CH2:9][O:10][CH3:11])[CH2:5]1)([CH3:3])[CH3:2].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>CCOCC>[O:18]([CH2:5][CH:6]([O:8][CH2:9][O:10][CH3:11])[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COCOC1CN(C(C)C)C1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COCOC(CNC(C)C)COc1ccccc1
Temperature: 180 °C
Yield: 67 %

Procedure:
To a mixture of 1.6 parts of 1-iso-propyl-3-methoxymethoxyazetidine and 9.4 parts of phenol 0.5 part of sodium hydroxide was addded, and the mixture was heated at 180° C. for 6 hours. The reaction mixture was cooled and 100 parts of ether were added thereto. Excessive phenol was removed by extraction with 2 N-sodium hydroxide aqueous solution, and the remaining ether layer was washed in water and dried over anhydrous sodium sulfate. After distillation of ether, the residue was subjected to distillation to yield 1.6 parts of 1-phenoxy-2-methoxymethoxy-3-(iso-propylamino)-propane boiling at 146°-149° C. under 2 mm Hg. The yield was 67%.
Reaction SMILES: C([O:8][NH:9][C:10]([CH2:12][N:13]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:14](=[O:25])[CH2:15][CH:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([NH:19][CH3:20])=[O:18])=[O:11])C1C=CC=CC=1.[K+].[Br-]>>[OH:8][NH:9][C:10]([CH2:12][N:13]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:14](=[O:25])[CH2:15][CH:16]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])=[O:11]
Reactant: CNC(=O)C(CC(=O)N(CC(=O)NOCc1ccccc1)CC(C)C)CC(C)C
Agent: [Br-]
Agent: [K+]
Product: CNC(=O)C(CC(=O)N(CC(=O)NO)CC(C)C)CC(C)C

Procedure:
N4 -(Benzyloxycarbamoyl-methyl)-2,N4 -diisobutyl-N1 -methyl-succinamide (0.30 g, 0.74 mmol) was deprotected by catalytic hydrogenolysis as described in Example 30 (Step I) then purified by column chromatography (silica gel, 5% methanol in dichloromethane) to give the product as a white hygroscopic solid. m.p. 60.5-61.5° C. 1H-NMR; δ (CD3OD), 4.16-3.62 (2H, br m), 3.31-2.82 (2H, br m), 2.69 (1H, m), 2.58 (4H, m), 2.30 (1H, m), 1.82 (1H, m), 1.42 (2H, m), 1.18 (1H, m) and 0.78 (12H, br m). 13C-NMR; δ (CD3OD), 178.6, 178.4,174.7, 174.5, 168.3, 167.9, 57.5, 55.4, 48.6, 43.1, 43.0, 42.6, 42.3, 37.0, 32.7, 28.9, 28.0, 27.0, 26.3, 23.6, 23.3, 22.6, 20.5, 20.3 and 14.4. IR (KBr) vmax 3309, 2957, 2871, 1681, 1636,1560 and 1490 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:21]=[CH:22][CH2:23][OH:24])[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:21]=[CH:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: ClCCN1CCOCC1
Reactant: O=C(NCc1ccc(Cl)cc1)c1c[nH]c2ccc(C=CCO)cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCOCC2)c2ccc(C=CCO)cc2c1=O
Temperature: 90 °C

Procedure:
A mixture of N-(4-chlorobenzyl)-1,4-dihydro-6-[3-hydroxy-1-propenyl]-4-oxo-3-quinolinecarboxamide from Preparations No. 11 and 12 (0.52 g) is dissolved in DMF (4 mL), and potassium carbonate (0.78 g) and N-(2-chloroethyl)morpholine hydrochloride (0.52 g) are added. The mixture is heated at 90° C. for 2 h and then partitioned between water and chloroform. The organic layer is concentrated in vacuo to give a brown oil. Column chromatography (elution with 1-7% MeOH/CHCl3) followed by crystallization from EtOAc/hexane gave the title compound as a mixture of isomers. The mixture is then purified by HPLC chromatography on a 0.46×25 cm Chiralcel OD-H column eluting with EtOH at a rate of 0.5 mL/min. This gave 0.161 g of the alkene mixture as approximately a 2:1 mixture of the trans:cis isomers, which is crystallized from ethyl acetate to give 0.13 g of the title compound as a hydrate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].CS(O[CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)(=O)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:18]2[CH2:19][CH2:14][CH2:15][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(n2cc(Br)cn2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
4-Bromopyrazole (2.94 g, 20 mmol) dissolved in DMF (20 mL) was cooled to 0° C., sodium hydride (900 mg, 22.5 mmol) was added portion-wise over 1 h. After warmed to room temperature and stirred for 1 h, tert-butyl 3-(methylsulfonyloxy)-piperidine-1-carboxylate (5.03 g, 20 mmol) was added, and the reaction mixture was heated at 100° C. overnight. The reaction mixture was quenched with saturated NH4Cl, and extracted with EtOAc. The organic layer was washed with H2O, brine, dried and concentrated. Crude mixture was column purified with mixture of EtOAc and hexane to give tert-butyl 3-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.97 g) as white solid.
Reaction SMILES: CS([Cl:5])(=O)=O.[Cl-].[Li+].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[S:17]([O:20][C:21]1[C:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34]O)=[CH:30][C:29]=2[O:36][CH3:37])=[C:25]([CH3:38])[N:24]=[C:23]([NH2:39])[N:22]=1)(=[O:19])=[O:18]>C1COCC1.O>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[S:17]([O:20][C:21]1[C:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][Cl:5])=[CH:30][C:29]=2[O:36][CH3:37])=[C:25]([CH3:38])[N:24]=[C:23]([NH2:39])[N:22]=1)(=[O:19])=[O:18]
Reactant: COc1cc(CO)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (1.4 mL) was added to a mixture of lithium chloride (0.74 g) and the product from step (iv) (4.0 g) in THF (45 mL). The mixture was stirred at RT for 1.5 h, diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated under reduced pressure to afford the crude product as a pale yellow oil, which was used for next reaction without further purification; 1H NMR (300 MHz, CDCl3); 6.91 (2H, s), 6.83 (1H, s), 6.81-6.74 (2H, m), 4.69 (2H, br s), 4.54 (2H, s), 3.82 (3H, s), 3.80 (2H, s), 2.54 (6H, s), 2.29 (3H, s), 2.24 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([OH:49])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[N:34]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[O:49][C:46]1[CH:47]=[C:48]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][N:40]=[C:39]2[NH:38][C:35]1[CH:36]=[CH:37][N:33]([CH3:32])[N:34]=1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CN(C)CCCN(C)S(=O)(=O)c1cnc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)CCCN(C)S(=O)(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 67.3 %

Procedure:
5,6-Dichloro-N-[3-(dimethylamino)propyl]-N-methylpyridine-3-sulfonamide (122 mg, 0.37 mmol) and potassium tert-butoxide (58 mg, 0.52 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (50 mg, 0.21 mmol), and stirred under a nitrogen atmosphere at 100° C. for 2.5 hours. The reaction solution was cooled with ice, saline water was added, and extracted with chloroform/methanol (9:1). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate:chloroform to chloroform:methanol=2:4:1 to 100:2) to obtain the entitled compound (75 mg, yield: 68%) as a pale orange amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[C:11]([S:17](Cl)(=[O:19])=[O:18])=[C:12]([Cl:16])[S:13][C:14]=1[Cl:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:17]([C:11]1[C:10]([Br:9])=[C:14]([Cl:15])[S:13][C:12]=1[Cl:16])(=[O:19])=[O:18]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1c(Cl)sc(Cl)c1Br
Product: Cc1noc(NS(=O)(=O)c2c(Cl)sc(Cl)c2Br)c1Br
Yield: 58 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dichloro-4-bromothiophene-3-sulfonamide was prepared in the same manner as described in Example 1 from 5-amino-4-bromo-3-methylisoxazole and 4-bromo-2,5-dichlorothiophene-3-sulfonyl chloride in 58% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 146°-149° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.Br[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: Cl
Product: Cc1c(-c2cccnc2)n(Cc2ccc(C#N)cc2)c2ccccc12

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1) and 4-bromomethyl-benzonitrile are processed according to the method described in Example 25 to give 4-(3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile. 1H NMR (400 MHz, MeOD) δ ppm 2.32 (s, 3H), 5.43 (s, 2H), 6.99 (d, J=8.6 Hz, 2H), 7.13-7.21 (m, 1H), 7.25 (ddd, J=7.6, 1.3 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.54 (dd, J=8.0, 4.9 Hz, 2H), 7.58 (d, J=8.3 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.84 (dt, J=7.9, 2.0 Hz, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.59 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 324.1501 [(M+H)+ Calcd for C22H18N3: 324.1501].
Reaction SMILES: Cl.[CH2:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([OH:13])=[O:12])[CH:6]=1)[CH2:3][CH3:4].[H][H].C([O-])(=O)C>C(O)(=O)C.[Pt](=O)=O>[CH2:2]([CH:5]1[CH2:10][CH2:9][NH:8][CH:7]([C:11]([OH:13])=[O:12])[CH2:6]1)[CH2:3][CH3:4]
Reactant: CCCc1ccnc(C(=O)O)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: CCCC1CCNC(C(=O)O)C1
Yield: 1107.6 %

Procedure:
Platinum(IV) oxide (79.8 mg, 0.35 mmol) was added to a solution of 1.05 g (5.22 mmol) of 4-propylpyridine-2-carboxylic acid hydrochloride synthetized according to a literature (J. Med. Chem. 1984, 27, 216.) in acetic acid (8 ml), and the mixture was stirred in a hydrogen atmosphere under the atmospheric pressure overnight. The reaction solution was filtered through Celite, and the solvent was then removed by distillation to give 9.90 g (yield 90%) of the title compound as acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[N:25][C:24]([Na])=[N:23]1.O>C(O)CC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]([CH3:13])([CH3:12])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:9])[CH2:10][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[CH:16][CH:17]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reactant: [Na]c1nc[nH]n1
Solvent: O
Solvent: CCCO
Product: CC(C)(Oc1ccc(Cl)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Reaction time: 48 h
Yield: 18.4 %

Procedure:
A solution of 30 g (0.093 mol) of 2-(4-chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane in 40 ml of n-propanol is added dropwise to a solution of 7.6 g (0.107 mol) of 1,2,4-triazolyl-sodium in 60 ml of n-propanol, at room temperature. The reaction mixture is stirred at the reflux temperature for a further 48 hours and is cooled, water is added and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo. The oily residue is purified by column chromatography. 6.7 g (18.4% of theory) of 3-(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-butan-2-ol are obtained. This is stirred with 20 ml of saturated hydrogen chloride/ether solution, at room temperature. The precipitate which separates out is filtered off under suction, rinsed with a small amount of ether and dried in vacuo at 40° C. 6.5 g (89% of theory, relative to base employed) of 3-(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-butan-2-ol hydrochloride of melting point 135° C. are obtained.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:29][CH:28]=2)[NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[N:10]=1)(C)(C)C.O.Cl>O1CCCC1>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH:15]([NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[C:11]2[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:46])=[O:5])[CH:14]=[CH:13][CH:12]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNc1cccc(C(Cc2ccc(-c3ccccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Temperature: 65 °C
Reaction time: 4.5 h
Yield: 41.4 %

Procedure:
To a solution of tert-butyl[tert-butoxycarbonyl(6-{[4-(pyridin-2-yl)benzyl]-(pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate (1.76 g) (containing 1.95 mmol of a pure content) obtained in Example 19-(a) in tetrahydrofuran (5.6 ml) were added water (5.6 ml) and concentrated hydrochloric acid (2.3 ml), followed by stirring at 65° C. for 4.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. After the concentrate was adjusted to pH 10.9 with a 1N aqueous sodium hydroxide solution, the insolubles were filtered off. The filtrate was then adjusted to pH 5.6 with 1N hydrochloric acid, followed by addition of ethyl acetate. A precipitated solid was collected by filtration, and then dried under reduced pressure to afford the title compound (553 mg) as a white solid. (Yield: 58%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH2:30]([NH:33][C:34](=[O:39])C(Cl)(Cl)Cl)[CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:34]([NH:33][CH2:30][CH2:31][CH3:32])=[O:39])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: CCCNC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Product: CCCNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(Cl)ccc1OC

Procedure:
4-(5-Chloro-2-methoxybenzamidomethyl)-6-(n-propylaminocarbonyl-aminosulfonyl)-7-methoxychroman ##STR33## 4-(5-Chloro-2-methoxybenzamidomethyl)-6-(n-propylaminocarbonylaminosulfonyl)-7methoxychroman is prepared analogously to Example 1 from 4-(5Chloro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-methoxychroman and N-(n-propyl)trichloroacetamide. Melting point: 159°-160° C.