Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25](OCC)=[O:26])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:32][NH2:33].ClCCl.CO>O1CCCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:26])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1

Procedure:
The procedure described in Example 1 (step 1.4.) is used. Starting with 0.60 g (1.37 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{6-[3-(trifluoromethyl)phenyl]-3-pyridyl}-1-piperazinecarboxylate, obtained in step 7.5., and 3.40 ml (6.86 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 98/2 and then 97/3 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether, 0.36 g of pure product is obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]([NH:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=1)=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]1[O:24][C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)=[N:7][N:6]=1
Reactant: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Cl)ccc2Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Cl)ccc3Cl)o2)cc1
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Into a 250 ml flask fitted with a mechanical stirrer and thermometer was introduced 30 g (0.0686 mol) 2,5-dichlor-N′-[4-(octyloxy)benzoyl]benzohydrazide and 181 ml phosphorus oxychloride. This was refluxed and stirred for 8 hrs. About 100 ml of phosphorus oxychloride was distilled off under reduced pressure. The cooled residue was poured onto water and crushed ice with manual stirring and allowed to stand until the ice had melted. The precipitated white solid was collected by filtration, dried and recrystallized from ethanol. There was obtained 25.7 g (89% yield, mp 86° C.) of 2-(2,5-dichlorophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (2). The structure was confirmed unambiguously by 1D and 2D NMR techniques and gave the following: 1H-NMR (500 MHz, CDCl3) 0.89 (3H, t), 1.31 (8H, m), 1.46 (2H, q), 1.79 (2H, q), 6.97 (2H,d), 7.38 (1H, dd), 7.44 (1H, d), 8.01 (2H, d), 8.06 (1H, d); 13C-NMR (500 MHz, CDC 13.90 (C-28), 22.44, 25.79, 28.91, 29.01, 29.13, 31.59, 68.08 (C-21), 114.78 (C14 and C-16), 115.37 (C-12), 124.27 (C-6), 128.58 (C-13 and C-17), 130.23 (C-11), 130.87 (C-7), 131.75, 132.20, 132.87 (C-10), 161.03, 161.98 (C-15), 164.95 (C-5).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:47]([NH:54][C:21]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:10]([N:7]1[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]1)=[O:11])=[CH:20][CH:19]=2)=[O:23])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: NCc1ccccc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)NCc4ccccc4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), benzylamine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10](O)[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:15][CH2:16][C:17]([OH:19])=[O:18].C1C=CC=CC=1>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.CCOCC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CS
Reactant: CCCC(O)c1ccc2c(c1)OCO2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCC(SCC(=O)O)c1ccc2c(c1)OCO2
Yield: 89.3 %

Procedure:
A mixture of 103 g of 1-(1,3-benzodioxol-5-yl)-1-butanol, 73.3 g of mercaptoacetic acid, 0.1 g of D-10-camphorsulfonic acid and 500 ml of benzene was heated under reflux for 2 h. 2,000 ml of ether was added to the reaction mixture. After washing with water, the product was redissolved in 750 ml of 1N NaOH and then in 100 ml thereof. The solution thus obtained was washed with ether and then with chloroform, acidified with concentrated hydrochloric acid and extracted with 800 ml and then 400 ml of ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 132 g of the crude product. It was purified according to silica gel column chromatography (ethyl acetate/hexane/formic acid=100:900:1) to obtain 127 g of the intended compound in the form of a colorless oil. This oil was crystallized from n-hexane to obtain 115 g of the titled compound as a white crystalline powder. It was found to have a melting point of 59° to 61° C.
Reaction SMILES: [CH2:1]1[CH2:30][O:29][C:3]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([OH:18])[C@H:7]2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[O:2]1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])(C)C.N1C=CN=C1>CN(C=O)C>[CH2:30]1[CH2:1][O:2][C:3]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([O:18][SiH2:31][C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:7]2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[O:29]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCC1(CC[C@@H]2[C@H](CC(=O)OC)[C@@H](O)C[C@H]2OC2CCCCO2)OCCO1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCC1(CC[C@@H]2[C@H](CC(=O)OC)[C@@H](O[SiH2]C(C)(C)C)C[C@H]2OC2CCCCO2)OCCO1

Procedure:
To a solution of methyl 2-[(1S,2R,3R,5S)-2-(3,3-ethylenedioxyoctyl)-3-(tetrahydropyranyloxy)-5-hydroxycyclopentyl]acetate (61) in DMF (80 ml) were added t-butyldimethylsilyl chloride (2.11 g) and imidazol (0.95 g), and the resultant mixture was stirred. The crude product obtained by treating in the conventional manner was subjected to silica gel column chromatography to give the title compound (62).
Reaction SMILES: [OH2:1].[NH2:2][NH2:3].[C:4]([NH:6][C:7](SC)=[N:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1O[C:15]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=1)#[N:5]>C(O)C>[CH3:20][N:19]([CH2:18][C:15]1[O:1][C:13]([CH2:12][S:11][CH2:10][CH2:9][NH:8][C:7]2[NH:3][N:2]=[C:4]([NH2:5])[N:6]=2)=[CH:17][CH:16]=1)[CH3:21]
Reactant: NN
Reactant: O
Reactant: CSC(=NCCSCc1ccc(CN(C)C)o1)NC#N
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNc2nc(N)n[nH]2)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Hydrazine hydrate (3.5 ml) was added to a solution of N-cyano-N'-[2-[[[5-(dimethylamino) methyl-2-furanyl]methyl]thio]ethyl]carbamimidothioic acid, methyl ester (5.47 g) in ethanol (40 ml). After stirring for 3 days at room temperature the solvent was removed and the residual oil crystallised from water to give the title compound as white needles (2.95 g) m.p. 76°-78.5°.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>>[CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][N:5]([S:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)(=[O:40])=[O:39])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(C=O)cn(S(=O)(=O)c2ccccn2)c1-c1ccccc1

Procedure:
By a reaction under similar conditions as in Reference Example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and 2-pyridinesulfonyl chloride (231 mg) instead of 3-pyridinesulfonyl chloride hydrochloride, the title compound was obtained as an amorphous form (yield 262 mg, 80%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[CH:27]=[CH:28]\[CH:29]([OH:31])C)[C:21]=1[CH3:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33](N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:33])=[CH:28]\[CH2:29][O:31][S:41]([CH3:40])(=[O:43])=[O:42])[C:21]=1[CH3:32])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: Cc1ccc(/C=C\C(C)O)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: ClCCl
Product: C/C(=C/COS(C)(=O)=O)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a mixture of 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-hydroxy-3-methyl-1-propenyl)benzene (120 mg) and triethylamine (32.8 mg) in dichloromethane (1.2 ml) was dropwise added methanesulfonyl chloride (34 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. The mixture was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-methanesulfonyloxy-1-methyl-1-propenyl)benzene (132 mg) as colorless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][NH2:20])[N:14]=[CH:13]1>>[NH:12]1[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][NH:20][C:9](=[O:11])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:14]=[CH:13]1
Reactant: NCCCc1c[nH]cn1
Reactant: O=C(O)CCc1ccccc1
Product: O=C(CCc1ccccc1)NCCCc1c[nH]cn1

Procedure:
The preparation is carried out as in Example 1 with 10 mmol of 3-phenylpropanoic acid and 3-(1H-imidazol-4-yl)propanamine as the amine component. The title compound is purified by chromatography and recrystallized in the hydrogenmaleate form from ethyl acetate/acetonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]([NH2:26])=[O:25])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[F:15])=[CH:11][C:10]([C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])=[CH:9][CH:8]=3.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CO>[F:15][C:14]1[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[CH:11]=3)[NH:6][C:5]=2[C:4]([C:24]([NH2:26])=[O:25])=[CH:3][C:2]=1[C:32]1[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1
Reactant: NC(=O)c1cc(Br)c(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Reactant: COc1ccc(B(O)O)cc1
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: CO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4ccc(C(=O)N5CCOCC5)cc4c3c2F)cc1
Temperature: 105 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
3-Bromo-4-fluoro-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (25 mg, 0.059 mmol), 4-methoxyphenylboronic acid (13.56 mg, 0.089 mmol), Pd(Ph3P)4 (6.87 mg, 5.95 μmol) and Na2CO3(2M) (0.074 mL, 0.149 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was stirred at 105° C. for 3 hrs. The mixture was filtered through an ACRODISC® PTFE membrane (0.45 um) and purified using preparative HPLC to give 12.2 mg of titled product. MS (ESI) m/z 448.06 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.86 (bs, 1H), 8.31 (bs, 1H), 8.16 (d, 1H, J=9.1), 8.14 (s, 1H), 7.83 (d, 1H, J=8.6), 7.66 (d, 2H, J=8.2), 7.55(m, 2H), 7.11 (d, 2H, J=8.5), 3.84 (s, 3H), 3.7-3.5 (bm, 8H).
Reaction SMILES: CS(Cl)(=O)=[O:3].[C:6]([NH:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C>ClCCl>[C:17]([O-:18])(=[O:3])[CH3:14].[C:6]([NH:13][CH:14]([CH2:15][OH:16])[CH2:17][OH:18])([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7]
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)NC(CO)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)[O-]
Temperature: 20 °C
Reaction time: 20 h

Procedure:
Methanesulfonyl chloride (130 mmol) was added at 5° C. to a stirred solution of boc-serinol (40 mol) and triethylamine (25 ml) in dichloromethane (100 ml). The mixture was stirred at 5° C. for 5 h and at 20° C. for 20 h. Dichloromethane (200 ml) was added and the mixture was washed with an aqueous solution of sodium hydrogen carbonate (50 mM), dried (Na2SO4) and concentrated to dryness under vacuum. Chromatography of the residue on silicagel (1.2 L) eluting with hexane/ethyl:acetate (50:50) gave bis-(methanesulfonic acid ester) of boc-serinol.
Reaction SMILES: [C:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:15]Br>CC(O)=O>[Br:15][C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1]([NH:11][C:12](=[O:14])[CH3:13])=[CH:2][CH:3]=1
Reactant: CC(=O)Nc1cccc2c1CCCC2
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c2c1CCCC2
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a solution of compound 2A (2 g, 11 mmol) in AcOH (15 mL) cooled at 0° C. was added a solution of bromine (1.69 mL, 33 mmol) in AcOH (1.2 mL) slowly so that the reaction temperature was maintained below 17° C. After addition, the reaction mixture was stirred at rt until all the starting material was consumed (˜4 h). The reaction mixture was then poured into ice/water and the resulting suspension filtered. The collected solid was washed with H2O until the filtrate pH=6-7, and dried in a vacuum oven at 50° C. overnight to yield compound 2B (2.7 g) as an off-white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[C:34]([O:46][CH3:47])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:57])=[C:34]([O:46][CH3:47])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)c(OC)c2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)c(OC)c2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methoxy-4-[(3-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.39 g) was dissolved in methylene chloride (7.8 ml), a solution of m-chloroperbenzoic acid (152 mg) in methylene chloride (15.6 ml) was added to the mixture at −78° C., and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methoxy-4-[(3-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 240) (0.26 g).
Reaction SMILES: [C:1]([C:9]1[CH:19]=[C:18]([OH:20])[C:17]([O:21][CH3:22])=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[N+:26]([O-])([OH:28])=[O:27].O>[Cl-].[Na+].O>[C:1]([C:9]1[C:19]([N+:26]([O-:28])=[O:27])=[C:18]([OH:20])[C:17]([O:21][CH3:22])=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cc(OC)c(O)cc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1C(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a mixture of ethyl 2-benzoyl-4-hydroxy-5-methoxy-benzoate (reference example 17-1) (550 mg) and dichloromethane (10 mL) was added fuming nitric acid (85 μL) at room temperature. After stirring for 20 minutes, water and dichloromethane were added to the mixture. The separated organic layer was brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (806 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:6])[CH2:4][OH:5].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=O.[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N:24]2[N:28]=[CH:27][CH:26]=[N:25]2)=[C:19]([CH:23]=1)[C:20](O)=[O:21]>C1(C)C=CC=CC=1>[CH3:6][CH:3]1[CH2:4][O:5][CH:8]([C:7]([O:11][CH2:12][CH3:13])=[O:10])[N:1]([C:20](=[O:21])[C:19]2[CH:23]=[C:15]([CH3:14])[CH:16]=[CH:17][C:18]=2[N:24]2[N:28]=[CH:27][CH:26]=[N:25]2)[CH2:2]1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: CC(CN)CO
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1OCC(C)CN1C(=O)c1cc(C)ccc1-n1nccn1

Procedure:
By using 3-amino-2-methylpropan-1-ol (0.10 g, 1.1 mmol), ethyl glyoxylate (polymer type, a solution of 47% toluene) (2.0 mL, 9.7 mmol) and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (0.5 g, 2.5 mmol), the same procedure as in Reference Example 1 was carried out to obtain the title compound (0.13 g) (colorless oil).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O.[I-].[Na+].O.[NH2:26][NH2:27]>O>[C:11]1([C:10]2[CH:2]=[C:1]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:27][N:26]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NN
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
120 parts (1 mol) of acetophenone and 106 parts (0.5 mol) of benzaldehyde were simultaneously added dropwise at 25° C. to 980 parts (6 mol) of initially introduced 60% strength by weight sulfuric acid. The mixture was stirred at 25° C. for 30 minutes and the phases were then separated. The sulfuric acid phase was initially introduced with 2 parts (0.013 mol) of sodium iodide and the organic phase was simultaneously metered in in the course of 10 minutes with 62.5 parts (1 mol) of 80% strength by weight hydrazine hydrate. The mixture was stirred under refluxfor 4.5 hours, during the course of which the temperature fell from 123° C. to 119° C. After diluting with 500 parts of water, the mixture was cooled to room temperature and the solid was filtered off.The filter residue was washed with water until neutral and dried. 210.4 parts of 3,5-diphenylpyrazole having a purity of 97.5% (HPLC) were obtained, which corresponds to a yield of 93.2% of theory. M.p.: 198° C.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Na].CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:32][CH2:33][CH3:34]>O>[C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([O:15][CH2:32][CH2:33][CH3:34])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Reactant: CCCBr
Agent: [Na]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCOC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 28.2 parts of p-(2-thenoyl)hydratropic acid, sodium salt in 250 parts of hexamethylphosphoramide are added 49.2 parts of 1-bromopropane and the whole is stirred for 2 hours at room temperature. The reaction mixture is poured onto 1000 parts of water and the product is extracted three times with diisopropylether. The combined extracts are washed with 200 parts of water, dried, filtered and evaporated. The viscous residue is filtered off over hyflo, yielding propyl p-(2-thenoyl)hydratropate as a yellow oil.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[S:8]1[CH:12]=[CH:11][C:10]2[C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)=[CH:14][CH:15]=[CH:16][C:9]1=2.[CH3:27][NH:28][C:29]([C:31]1[N:32]=[C:33]([Cl:36])[S:34][CH:35]=1)=[O:30]>O>[ClH:36].[CH3:27][NH:28][C:29]([C:31]1[N:32]=[C:33]([O:26][CH2:25][CH2:24][CH2:23][N:20]2[CH2:19][CH2:18][N:17]([C:13]3[C:10]4[CH:11]=[CH:12][S:8][C:9]=4[CH:16]=[CH:15][CH:14]=3)[CH2:22][CH2:21]2)[S:34][CH:35]=1)=[O:30]
Reactant: OCCCN1CCN(c2cccc3sccc23)CC1
Reactant: CNC(=O)c1csc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1csc(OCCCN2CCN(c3cccc4sccc34)CC2)n1
Product: Cl
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 75.7 %

Procedure:
Sodium hydride (55%, oily, 90 mg, 2.2 mmol) was added to a DMF solution (2 ml) of 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propanol (0.2 g, 0.7 mmol) and N-methyl-2-chlorothiazole-4-carboxamide (0.26 g, 1.45 mmol) under ice cooling and the solution was stirred at 80° C. for 1.5 hours. After the reaction solution was cooled to room temperature and water was added thereto, it was extracted with ethyl acetate. The extraction solution with ethyl acetate was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=5:1→ethyl acetate). After the purified product was concentrated under reduced pressure, the residue was dissolved in ethyl acetate. A solution of 4N-hydrochloric acid/ethyl acetate was added to the solution and the insoluble matter precipitated was obtained by filtration and dried to obtain N-methyl-2-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]thiazole-4-carboxamide hydrochloride (0.24 g) as light yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[NH:9][C@H:10]([C:15]([O:17]C)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C[C@H](NC(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl N-{(4-bromophenyl) [4-(methylsulfonyl)phenyl]methyl}-L-leucinate from step 2 (81 mg, 0.17 mmol) in THF (1 mL) and MeOH (0.5 mL) was added 1N LiOH (0.3 mL, 0.3 mmol). The resulting mixture was stirred at room temperature for 18 hours and then partitioned between EtOAc and water+1N HCl (0.5 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a colorless gum.