Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH2:10]([SH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([S:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N+:3]=1[O-:9]
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: CCCCCCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCSc1cccc(Cl)[n+]1[O-]

Procedure:
The 2.01 g (0.0122 moles) of 2,6-dichloropyridine N-oxide and 2.10 g (85%) (0.0122 moles) of 1-octylmercaptan was reacted with 0.488 g (0.0122 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 80° C. for 6 hours to give 2-chloro-6-octylthiopyridine N-oxide. It was reacted with 1.47 g (0.0367 moles) of ground sodium, hydroxide at 80° C. for 3 hours to give 1-hydroxy-6-octylthiopyridine-2(1H)-one. After cooling, it was added 180 ml of water and was adjusted with 6N HCL to pH 3. The precipitate was filtered, washed with water and washed with 150 ml of petroleum ether to give 1.34 g (43%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f19) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[C:17]=2[CH2:18][C:19](O)=[O:20])=[CH:4][CH:3]=1.[CH2:22]([NH:29][CH2:30][CH2:31]OC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]([CH2:30][CH3:31])[C:19](=[O:20])[CH2:18][C:17]1[N:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(-c2nc3cc(C)ccn3c2CC(=O)O)cc1
Reactant: COCCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)Cc1c(-c2ccc(C)cc2)nc2cc(C)ccn12
Yield: 54.6 %

Procedure:
According to the method of Example 13, 2-(4-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-benzyl-2-methoxyethylamine were used as raw materials for synthesis, to obtain yellow solid powder, yield 54.6%. m.p. 220-222° C., ESm/z: 398[M+H]+, 1H NMR(CDCl3, 400 MHz)δ: 1.14(t, 1.5H, J=7.00 Hz), 1.17(t, 1.5H, J=7.00 Hz), 2.36(s, 1.5H), 2.37(s, 1.5H), 2.52(s, 1.5H), 2.54(s, 1.5H), 3.35(q, 1H, J=7.00 Hz), 3.52(q, 1H, J=7.00 Hz), 4.15(s, 1H), 4.24(s, 1H), 4.57(s, 1H), 4.61(s, 1H), 7.05-7.19(m, 1H), 7.22-7.36(m, 9H), 7.47-7.62(m, 1H), 8.13-8.29(m, 1H).
Reaction SMILES: CN(C)C1C=CC=CC=1.ON=C(C1C=CC=CC=1)C#N.C(Cl)(Cl)=O.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=1.Cl[C:36]([O:38][N:39]=[C:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:41]#[N:42])=[O:37]>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:32][C:36]([O:38][N:39]=[C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:41]#[N:42])=[O:37])=[CH:29][CH:28]=1
Reactant: N#CC(=NOC(=O)Cl)c1ccccc1
Reactant: COc1ccc(CO)cc1
Agent: N#CC(=NO)c1ccccc1
Agent: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(COC(=O)ON=C(C#N)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
A solution of dimethylaniline (6.0 ml.) in benzene (15 ml.) was added dropwise to a suspension of 2-hydroxyimino-2-phenylacetonitrile (7.3 g.) and phosgene (5.0 g.) in benzene (50 ml.) for 40 minutes under ice-cooling. The mixture was stirred for 2 hours at the same temperature and allowed to stand overnight. A solution of 4-methoxybenzyl alcohol (6.9 g.) and pyridine (4.0 ml.) in benzene (20 ml.) was added dropwise, for 30 minutes under ice-cooling, to the mixture containing 2-chlorocarbonyloxyimino-2-phenyl-acetonitrile. The mixture was stirred for 7 hours at room temperature. The reaction mixture was then washed with water, 1N hydrochloric acid, water, a sodium bicarbonate aqueous solution and water, and dried over magnesium sulfate. The solution was concentrated and the residual crystals were triturated in n-hexane and collected by filtration. The crystals were recrystallized from a mixture of ethyl acetate and n-hexane to give 2-(4-methoxybenzyl)oxycarbonyloxyimino-2-phenylacetonitrile (3.1 g.). Mp 112° to 113° C. The mother liquor was concentrated to give the desired compound (2.4 g.). Total yield (5.5 g.).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][C:3]1=[CH:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1>CO.CC(N(C)C)=O.[Pd]>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH:3]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH2:4]1
Reactant: COC(=O)c1ccc(C=C2COc3ccccc3C2=O)cc1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COC(=O)c1ccc(CC2COc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
Pd/C 10% was added to a suspension of 260 (200 mg, 0.68 mmol) in MeOH (40 ml) and DMA (10 ml) which was previously purged under vacuum. The reaction mixture was stirred during 4 h at room temperature. After evaporation of the MeOH, water was added to the oily residue and the precipitate obtained was filtered. The crude residue was then purified by flash chromatography on silica gel (5-8% AcOEt/Hex) to afford the title compound 263 (114 mg, 59%) as a white solid. LRMS: 282.1 (Calc.); 283.0 (found).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[N:49]([CH:50]2[CH2:52][CH2:51]2)[N:48]=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:49]([CH:50]4[CH2:52][CH2:51]4)[N:48]=[N:47][N:46]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1nnnn1C1CC1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3nnnn3C3CC3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-cyclopropyl-1H-tetrazole and isolated as red gum. MS (m/e): 405.3 (MH+).
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:17][C:8]2=[CH:9][NH:10][C:11]3[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([C:7]=32)[C:5]1([OH:19])[CH3:18])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:27][C:28](Cl)=[O:29]>C(OCC)(=O)C>[CH2:1]([N:3]1[C@@H:4]2[CH2:17][C:8]3[C:7]4[C:11]([NH:10][CH:9]=3)=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:6]=4[C@@:5]2([CH3:18])[O:19][CH2:27][C:28]1=[O:29])[CH3:2]
Reactant: CCNC1Cc2c[nH]c3ccc(OC)c(c23)C1(C)O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCN1C(=O)CO[C@]2(C)c3c(OC)ccc4[nH]cc(c34)C[C@@H]12
Yield: 72 %

Procedure:
To a solution of 3,4-dihydro-4-ethylamino-5-hydroxy-6-methoxy-5-methyl-5H-benz[cd]indole (646 mg 2.48 mmol) in ethyl acetate (25 ml) was added a saturated aqueous solution of sodium carbonate (24 ml). To the mixture was added, while stirring vigorously, chloroacetyl chloride (1.2 equivalent). After completion of the reaction, the organic layer was separated and washed with an aqueous saline solution, followed by drying (anhydrous Na2SO4). The solvent was distilled off under reduced pressure. The residue was cyclized and, then, purified by means of silica gel column chromatography (eluting with n-hexane-ethyl acetate (2:7)) to afford 517 mg (72%) of the title compound as an amorphous crystalline product.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>>[CH3:36][N:37]([CH3:41])[C:38]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:39]
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Reactant: CN(C)C(=O)Cl
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)N(C)C)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available dimethylcarbamyl chloride (Aldrich) via the parallel synthesis described above. MS−base peak at m/z=549 by positive ion CI
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][O:25][CH3:26]>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:23][CH2:24][O:25][CH3:26])[C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: COc1ccc(Cl)c2nc(-c3ccc(C(C)C)cc3)[nH]c12
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Cl)ccc(OC)c21

Procedure:
The title compound is prepared starting from 4-chloro-2-(4-isopropyl-phenyl)-7-methoxy-1H-benzoimidazole and (2-bromoethyl)-methyl ether using the same reaction conditions as described in Example 1. The title compound is obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[N:38]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH2:36]([C:29]1[CH:30]=[C:31]([OH:35])[C:32]([F:34])=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]2[C:27]([C:19]([C:17]3[NH:16][C:13]4[CH2:14][CH2:15][N:10]([C:8]([C:5]5[CH:4]=[N:3][C:2]([NH:45][CH2:44][CH2:43][N:38]6[CH2:42][CH2:41][CH2:40][CH2:39]6)=[CH:7][N:6]=5)=[O:9])[CH2:11][C:12]=4[N:18]=3)=[N:20][NH:21]2)=[CH:26][CH:25]=1)[CH3:37]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Reactant: NCCN1CCCC1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(NCCN5CCCC5)cn3)C4)n[nH]c2c1
Yield: 52 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (50 mg, 96 μmol) and (2-(pyrrolidin-1-yl)ethanamine, 50 mg, 132 μmol) using the method of Example 32. The crude material was purified by HPLC Method E to afford (30 mg, 52%) of the title compound.
Reaction SMILES: C([NH:11][CH2:12][C:13]([NH:15][C:16]1[S:17][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[N:19][N:20]=1)=[O:14])(OCC1C=CC=CC=1)=O.[BrH:25].C(OCC)C>C(O)(=O)C>[BrH:25].[NH2:11][CH2:12][C:13]([NH:15][C:16]1[S:17][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[N:19][N:20]=1)=[O:14]
Reactant: NS(=O)(=O)c1nnc(NC(=O)CNC(=O)OCc2ccccc2)s1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NCC(=O)Nc1nnc(S(N)(=O)=O)s1
Reaction time: 3 h

Procedure:
The desired compound is prepared by subjecting 2-(N-carbobenzyloxyglycylamino)-1,3,4-thiadiazole-5-sulfonamide (0.5 gram) suspended in glacial acetic acid (5 ml) to a solution of hydrogen bromide in glacial acetic acid (32% w/w, 8.0 ml) at room temperature for 1 hour with stirring. Diethyl ether (50 ml) is then added and the mixture set aside for three hours at 0° C. The solid precipitate is collected, washed with diethyl ether, and dried to give the desired product, 2-(glycylamino)-1,3,4-thiadiazole-5-sulfonamide hydrobromide, m.p. 207°-209° C. (0.4 gram).
Reaction SMILES: C(S([C:10]1[N:15]=[C:14]2[N:16]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:17](=[O:27])[N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH2:19][C:13]2=[CH:12][N:11]=1)=O)C1C=CC=CC=1.[NH2:34][C@@H:35]([CH3:38])[CH2:36][OH:37].ClCCl.CO>COCCOC>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:18]1[CH2:19][C:13]2[C:14](=[N:15][C:10]([NH:34][C@@H:35]([CH3:38])[CH2:36][OH:37])=[N:11][CH:12]=2)[N:16]([CH:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]2)[C:17]1=[O:27]
Reactant: O=C1N(c2ccccc2Cl)Cc2cnc(S(=O)Cc3ccccc3)nc2N1C1CCNCC1
Reactant: C[C@H](N)CO
Solvent: ClCCl
Solvent: COCCOC
Solvent: CO
Product: C[C@@H](CO)Nc1ncc2c(n1)N(C1CCNCC1)C(=O)N(c1ccccc1Cl)C2
Temperature: 100 °C
Yield: 63.3 %

Procedure:
To a suspension of 7-benzylsulfinyl-3-(2-chlorophenyl)-1-(piperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (650 mg, 1.136 mmol) in 1,2-dimethoxyethane (0.5mL) was added (S)-(+)-2-amino-1-propanol (250 mg, 3.33 mmol). The reaction was warmed to 100° C. under argon for 2 hours. The reaction was placed directly on a flash silica column using 92:8-90:10 dichloromethane/methanol as eluant to give 300 mg of the (S)-3-(2-chlorophenyl)-7-(2-hydroxy-1-methylethylamino)-1-(piperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one, which was redissolved in 5 mL of dichloromethane and 5 mL trifluoroacetic acid. After 5 hours the solvents were removed in vacuo and 5 mL of ethyl acetate and 5 mL of 10% sodium bicarbonate were added. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 130 mg of the title compound as a white foam that was dissolved in ethyl acetate and treated with 1 equivalent of hydrochloric acid in 1.0M ether. The precipitate was collected, washed with ether and dried in vacuo to give 115 mg of the hydrochloride salt of (S)-3-(2-chloro-phenyl)-7-(2-hydroxy-1-methylethylamino)-1-(piperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][N:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](=[O:19])[NH:11][C:10]1=[O:20])=[O:4].[OH-].[Na+]>O.CO>[C:3]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][N:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](=[O:19])[NH:11][C:10]1=[O:20])([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(Cn2c3c(c(=O)[nH]c2=O)CCCC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(Cn2c3c(c(=O)[nH]c2=O)CCCC3)c1
Yield: 82.1 %

Procedure:
A solution of 1-(3-methoxycarbonylbenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (2.3 g, 7.3 mmol) and NaOH (0.59 g, 14.7 mmol) in water-methanol (40 mL and 40 mL) was refluxed for 4 h. After the removal of methanol, the solution was adjusted to pH=2-3 by 3N hydrochloric acid (a.q). The mixture was filtered and the solid was washed by water, and dried to give the title compound (1.8 g, 82% yield) as yellow solid. MS: m/z 301.3 [M+H]+.
Reaction SMILES: [OH-].[Na+].C(OC([N:10]([C:30]1[C:35]([O:36][CH3:37])=[N:34][C:33]([CH3:38])=[CH:32][N:31]=1)[S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=2)=[N:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])=O)C(C)C.O.Cl>CO>[CH2:26]([C:23]1[CH:22]=[CH:21][C:20]([C:15]2[C:14]([S:11]([NH:10][C:30]3[C:35]([O:36][CH3:37])=[N:34][C:33]([CH3:38])=[CH:32][N:31]=3)(=[O:13])=[O:12])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:25][CH:24]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)C)cc1
Yield: 34.4 %

Procedure:
1M sodium hydroxide solution (11.2 ml) was added to a solution of N-(isobutoxycarbonyl)-2-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (2.6 g) in methanol (50 ml) and the mixture was stirred and heated under reflux for 30 minutes. Water (100 ml) was added and the mixture was acidified to pH 3 with 2M hydrochloric acid. This mixture was extracted with ethyl acetate (5×30 ml) and the extracts were washed with water (30 ml) and saturated sodium chloride solution and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 0-15% ethyl acetate/hexane through a silica gel Mega Bond Elut column followed by trituration with ether to give 2-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (720 mg) as a solid, m.p. 128-129° C.; 1H NMR (CDCl3): 0.95 (d, 6H), 1.9 (m, 1H), 2.3 (s, 3H), 2.55 (d, 2H), 3.8 (s, 3H), 6.6 (s, 1H), 7.1-7.3 (m, 4H), 7.35 (s, 1H), 7.5 (dd, 1H), 8.7 (dd, 1H), 8.8 (dd, 1H); mass spectrum (positive electrospray (+ve ESP)): 413 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17]O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:30])(=O)=O.O>ClCCl>[Cl:30][CH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc2c(ccn2-c2ccc(F)cc2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(-n2ccc3cc(CCl)ccc32)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 118.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-hydoxymethyl-1H-indole (10a) (21.5 g) and triethyl amine (21.5 mL) in dichloromethane a solution of methanesulfonyl chloride (15.3 g) in dichloromethane was added at 0-5° C. After stirring at 0-5° C. for 2 h, water (600 mL) was added the phases were separated and the aqueous phase was extracted with dichloromethane (500 mL). The combined organic phases were dried (MgSO4) and the solvents evaporated affording 5-chloromethyl-1-(4-fluorophenyl)-1H-indole as an oil (27.5 g). A solution of the crude chloromethyl derivative in dimethyl sulfoxide was added to a solution of sodium cyanide in dimethyl sulfoxide at 80° C. After heating of the reaction mixture at 80° C. for further 40 minutes, the reaction mixture was cooled to room temperature and water (900 ml) was added. The resulting mixture was extracted with diethyl ether (2×1.5 L) and the combined organic phases were washed with brine (2×1.5 L). Drying of the combined organic phases (Na2SO4), evaporation of the solvents and purification by column chromatography on silica gel (ethyl acetate/heptane 1:3) afforded pure 5-cyanomethyl-1-(4-fluorophenyl)-1H-indole as an oil (8.2 g): 1H NMR (CDCl3) δ 3.80 (s, 2H), 6.60 (d, 1H), 7.05-7.25 (m, 3H), 7.25 (d, 1H), 7.35-7.45 (m, 3H), 7.60 (broad s, 1H).
Reaction SMILES: [C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCO.[OH-].[Na+]>C1COCC1>[C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCOc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCCOc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 74.1 %

Procedure:
The hydrolysis conditions described for 191 were employed. Thus, ethyl 4-({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)butanoate (217) (0.155 g, 0.39 mmol) was dissolved in THF and EtOH (1:1, 10 mL) and then treated with 1 N NaOH (2 ml) at 70° C. for 1 h. Upon acidification, work-up, and purification afforded 0.110 g (74%) of the title compound 218. 1H NMR (300 MHz, CD3OD): δ 7.02 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.1 Hz, 2H), 4.00 (t, J=6.3 Hz, 2H), 2.49 (t, J=7.5 Hz, 2H), 2.31 (br s, 4H), 2.05 (quintet, J1=13.5 Hz, J2=6.9 Hz, 2H), 1.60 (s, 8H). LCMS (ESI): m/z 379 (M−H)−. Anal. Calcd for C24H28O4, C, 75.76; H, 7.42; Found: C, 75.81; H, 7.64.
Reaction SMILES: CC(C[AlH]CC(C)C)C.CON(C)[C:13]([CH:15]1[CH2:18][CH:17]([CH2:19][C:20]2[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]3[CH:33]=[CH:34][C:35]([C:37]([F:40])([F:39])[F:38])=[CH:36][C:22]=3[N:21]=2)[CH2:16]1)=[O:14].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.CCOCC>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[CH:33][C:23]2[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[C:20]([CH2:19][CH:17]3[CH2:18][CH:15]([CH:13]=[O:14])[CH2:16]3)=[N:21][C:22]=2[CH:36]=1
Reactant: CON(C)C(=O)C1CC(Cc2nc3cc(C(F)(F)F)ccc3n2COCC[Si](C)(C)C)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(CC2CC(C=O)C2)nc2cc(C(F)(F)F)ccc21
Reaction time: 3 h
Yield: 87 %

Procedure:
DIBAL (0.69 ml, 0.69 mmol, 1M in THF) was added dropwise to a solution of N-methoxy-N-methyl-3-{[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutane-1-carboxamide in THF at −10° C. whilst stirring. The reaction was continued for 3 hours at −10° C. The reaction mixture was poured onto sat. aq. Rochelle's salt (20 ml), diluted with Et2O (50 ml) and stirred for 30 min. This was then separated and the organic layer was washed with Rochelle's salt (30 ml), sat. NaHCO3, (30 ml) and brine (30 ml). This was dried over Na2SO4, filtered and evaporated to give a colorless gum (190 mg, 87%); MS (ESI+) for C20H27F3N2O2Si m/z 413.6 [M+H]+; HPLC purirty 87% (ret. time, 2.25 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm −0.10-0.09 (9H, m), 0.88-1.00 (4H, m), 1.63-1.97 (2H, m), 2.07-2.23 (2H, m), 2.24-2.37 (0H, m), 2.37-2.42 (1H, m), 2.43-2.66 (2H, m), 2.93-3.34 (4H, m), 5.49-5.61 (2H, m), 7.16-7.31 (2H, m), 7.32-7.32 (2H, m), 7.49-7.61 (1H, m), 7.73 (1H, s), 7.83 (1H, d, J=8.35 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and p-anisidine (60 mg, 0.39 mmol). The title compound was obtained as a solid (42 mg, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.43 (1H, s), 9.00 (2H, s), 8.67 (1H, s), 7.56 (2H, m), 6.94 (2H, m), 3.73 (3H, s). MS m/z: 454.08, 456.02 [M+H]+.