Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1.O.[K+].[Br-]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH2:1]([C:8]1[C:9]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2cnc(NC(=O)c3cccc(OC)c3)c(Cc3ccccc3)n2)cc1
Temperature: 50 °C
Reaction time: 22 h

Procedure:
To a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (800 mg, 2.75 mmol) in pyridine (10 mL) were successively added 4-(dimethylamino)pyridine (33.6 mg, 275 μmol) and m-anisoyl chloride (18) (773 μL, 5.50 mmol) at room temperature, and the mixture was heated with stirring at 50° C. for 22 hours. After cooling to room temperature, to the mixture was added water and the product was extracted with dichloromethane (×3). The combined organic extract was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residual pyridine was azeotropically removed with toluene (×3). The residue was purified by column chromatography (silica gel 100 g, dichloromethane/ethyl acetate=9/1). The residue was recrystallized from ethyl acetate to give Compound fly (967 mg, 2.27 mmol, 82.5%) as a colorless solid. Rf=0.63 (dichloromethane/ethyl acetate=9/1); 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 6H), 4.19 (s, 2H), 7.05-7.12 (AA′BB′, 2H), 7.14-7.28 (m, 6H), 7.42-7.49 (m, 2H), 7.53 (d, 1H, J=7.5 Hz), 8.06-8.12 (AA′BB′, 2H), 8.98 (s, 1H), 10.77 (s, 1H); 13C NMR (67.8 MHz, CDCl3) δ 41.5, 55.3, 55.4, 112.5, 114.3 (2C), 118.6, 119.3, 126.7 (2C), 128.1, 128.55, 128.61 (2C), 128.5 (2C), 129.6, 135.0, 136.8, 137.7, 143.3, 149.2, 149.9, 159.8, 160.9, 165.7; IR (KBr, cm−1) 700, 746, 833, 1022, 1040, 1117, 1179, 1254, 1300, 1325, 1373, 1416, 1441, 1501, 1607, 1655, 2936, 3265; Anal. Calcd. For C26H23N3O3: C, 73.39; H, 5.45; N, 9.88. Found: C, 73.55; H, 5.36; N, 9.86.
Reaction SMILES: [F:1][CH:2]([O:7][C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4].[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)(O)O>C(O)(=O)C>[N+:15]([C:13]1[CH:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[O:7][CH:2]([F:1])[C:3]([F:4])([F:5])[F:6])([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(OC(F)C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(OC(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20.8 g (0.10 moles) 3-tetrafluoroethoxytoluene is placed in 25 ml glacial acetic acid and nitrated at 5° C. with a mixture of 30 ml concentrated nitric acid and 35 ml concentrated sulfuric acid. The solution turns yellow as the nitrating acid is added dropwise. When the addition is terminated the cooling bath is removed and the solution is agitated for 31/2 hours at room temperature. The solution is then poured onto ice, the pecipitated oil separated and the aqueous solution is extracted with ethyl acetate. After drying over sodium sulfate and distilling the solvent, a yellow oil remains in quantitative yield, which according to the NMR spectrum, involves the 4-nitro-3-tetrafluoroethoxytoluene.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([OH:20])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:29])=[N-]>C1COCC1>[CH3:29][O:19][C:18](=[O:20])[CH:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C(c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a stirring solution of compound 90 (1.281 g, 3.62 mmol) in THF (40 mL) was added an excess of diazomethane at room temperature and the reaction mixture was stirred for 15 minutes. Nitrogen was bubbled into the reaction mixture for 15 minutes then it was concentrated to afford compound 91 (1.032 g, 77%) as a colorless oil after purification by ISCO (0 to 50% EtOAc in hexanes). LRMS (ESI): (calc) 367.44 (found) 368.16 (MH)+. 1H NMR (CD3OD-d4) δ (ppm):7.33-7.23 (m, 10H), 5.09 (s, 2H), 4.18-4.14 (m, 1H), 4.05-4.01 (m, 1H), 3.63 (s, 3H), 3.33-3.30 (m, 1H), 2.86-2.72 (m, 2H), 2.21 (qt, J=11.3, 3.5 Hz, 1H), 1.78 (d, J=12.7 Hz, 1H), 1.28-1.18 (m, 2H), 0.96 (qd, J=12.5, 4.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12](=O)[CH2:13][C:14]#[N:15].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][NH2:22])[CH3:18]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([NH:22][CH2:21][CH:20]([O:23][CH2:24][CH3:25])[O:19][CH2:17][CH3:18])=[CH:13][C:14]#[N:15]
Reactant: CCOC(CN)OCC
Reactant: N#CCC(=O)c1cc(C(F)(F)F)ccc1Cl
Solvent: Cc1ccccc1
Product: CCOC(CNC(=CC#N)c1cc(C(F)(F)F)ccc1Cl)OCC

Procedure:
A mixture of 3-[2-chloro-5-(trifluoromethyl)phenyl]-3-oxopropanenitrile (1.2 g, 4.8 mmol), 2-aminoacetaldehyde diethyl acetal (0.77 mL, 5.3 mmol) and toluene (30 mL) was stirred under reflux for 5 h under nitrogen atmosphere in the Dean-Stark apparatus. The mixture was evaporated in vacuo and used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH:7]=[CH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:2]=12.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[N+:1]1([O-:25])[CH:6]=[CH:5][CH:4]=[C:3]2[CH:7]=[CH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:2]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1c2ccccc2ccc2cccnc12
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2ccc2ccc[n+]([O-])c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
To a solution of 1.04 grams (0.005 mole) of benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 20 milliliters of chloroform was added 1.19 grams (0.0055 mole) of m-chloroperbenzoic acid and the resulting solution stirred at room temperature for 24 hours. At this time an additional 0.6 gram of m-chloroperbenzoic acid was added and the mixture stirred for 5 hours; thereafter, another 0.3 gram of m-chloroperbenzoic acid was added and the mixture stirred overnight. The resulting reaction mixture was then washed twice with 10 percent aqueous sodium hydroxide, twice with water and the washed solution dried over magnesium sulfate. The mixture was filtered to remove drying agent and the solvent removed under reduced pressure to obtain 0.75 gram of benzo[5,6]cyclohepta[1,2-b]pyridin-11-one N-oxide intermediate as residue.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[NH:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20](OC)=[O:21])[C:14]=2[CH:13]=[CH:12]1.C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>CCOCC>[NH:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:20][OH:21])[C:14]=2[CH:13]=[CH:12]1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OCc1cccc2[nH]ccc12
Temperature: -70 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
Diisobutylaluminum hydride (1 M in toluene; 1.3 mL, 1.3 mmol) was added to a solution of 1H-indole-4-carboxylic acid, methyl ester (85 mg, 0.49 mmol) in ether (1.6 mL) at −70° C. The solution was allowed to stir at −70° C. for 1 h, then at room temperature for 1 h. Ethyl acetate (20 mL) was added, and the solution was stirred with an aqueous solution of potassium sodium tartrate (30% w/v; 20 mL) for 30 min. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered, evaporated, and dried under high vacuum to give 1H-indole-4-methanol (73.2 mg, quantitative yield) which was used in the next step without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH2:39][NH2:40]>>[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH2:39][NH:40][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([C:11]2[O:12][C:8]([CH3:7])=[C:9]([CH2:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:24])=[O:25])[N:10]=2)=[CH:14][CH:15]=1
Reactant: Cn1ccnc1CN
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4nccn4C)cc3)oc2C)cc1
Yield: 69.9 %

Procedure:
Reaction of oxalyl chloride (75 λL, 0.86 mmol) and benzoic acid 4 (212 mg, 0.57 mmol) with subsequent coupling to (1-methyl-1H-imidazol-2-yl)methylamine (70 mg, 0.63 mmol) gave benzamide 14 (185 mg, 70%) as a white powder: mp (EtOAc) 190-192° C.; 1H NMR δ 9.05 (t, J=5.5Hz, 1 H, CONH), 8.00 (dd, J=8.6, 1.8Hz, 2 H, H-2, H-6), 7.87 (dd, J=8.6, 1.8Hz, 2H, H-3, H-5), 7.67 (d, J=8.3Hz, 2 H, H-2′, H-6′), 7.42 (d, J=8.3Hz, 2 H, H-3′, H-5′), 7.08 (d, J=1.1Hz, 1 H, H-5″), 6.80 (d, J=1.1Hz, 1 H, H-4″), 4.62 (s, 2 H, CH2SO2), 4.54 (d, J=5.5 Hz, 2 H, CH2N), 3.66 (s, 3 H, NCH3), 2.40 (s, 3 H, CH3), 2.13 (s, 3 H, CH3); 13C NMR δ 165.2, 158.0, 149.9, 144.5 (2), 135.6, 135.3, 129.6 (2), 128.8, 128.3 (2), 128.2 (2), 126.4, 126.0, 125.3 (2), 121.8, 53.0, 35.5, 32.4, 21.0, 9.6; MS m/z 462.5 (MH+, 100%). Anal. calcd for C24H24N4O4S: C, 62.05; H, 5.21; N, 12.06. Found: C, 61.76; H, 5.09; N, 11.76%.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:19]3[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OCC)(=O)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:19]3[O:18][CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2cccc3c2OCCNC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A mixture of tert-butyl 9-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (210 mg, 0.534 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (143 mg, 81.3%) as a solid.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][O:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][N:4]=[CH:3]1.O[CH2:15][CH2:16]N1C=CN=C1.[H-].[Na+].ClCC(OCC)=O>CN(C)C=O>[CH2:15]([O:12][C:11](=[O:13])[CH2:10][O:9][CH2:8][CH2:7][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1)[CH3:16]
Reactant: O=C(O)COCCn1ccnc1
Reactant: OCCn1ccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(=O)CCl
Product: CCOC(=O)COCCn1ccnc1

Procedure:
The 5-(imidazol-1-yl)-3-oxa-pentanoic acid-hydrochloride used as the starting material is prepared in the following manner: 1-(2-hydroxyethyl)imidazole (J. Chem. Soc. 1977, 1272) is reacted in the presence of sodium hydride with ethyl chloroacetate in dimethyl formamide to form 5-(imidazol-1-yl)-3-oxa-pentanoic acid-ethyl ester (oil) and the desired acid is obtained from it by heating with 6 N hydrochloric acid.
Reaction SMILES: [O-]CC.[Ca+2].[O-]CC.[CH2:8]1[O:12][CH:9]1[CH2:10][CH3:11].[I:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[OH:21].Cl>>[I:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:8][CH:9]([OH:12])[CH2:10][CH3:11]
Reactant: Oc1ccc(I)cc1I
Reactant: CCC1CO1
Agent: CC[O-]
Agent: Cl
Agent: [Ca+2]
Product: CCC(O)COc1ccc(I)cc1I
Temperature: 80 °C
Yield: 65.7 %

Procedure:
A suspension of calcium ethoxide (816 mg, 6.3 mmol), butene oxide (5.2 mL, 93 mmol) and 2,4-diiodophenol (2.17 g, 6.3 mmol) is heated in a sealed flask at 80° C. for 18 h. The reaction mixture is allowed to cool, poured into 1N HCl and extracted three times with CH2Cl2. The combined organic extracts are dried (Na2SO4), filtered and concentrated in vacuo. The resulting material is purified by column chromatography (two columns, step gradient of 30-40-50% CH2Cl2 in hexanes) to give 1-(2,4-diiodophenoxy)butan-2-ol as a clear oil (1.73 g, 67%).1H NMR (400 MHz, CDCl3) δ 8.04, 7.56, 6.57, 4.03, 3.9, 3.84, 2.42, 1.65, 1.04.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[N:16]1([CH2:25][C:26]#[N:27])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1>>[N:16]1(/[C:25](=[CH:12]/[C:11]2[C:2]([Cl:1])=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][C:7]([O:14][CH3:15])=[CH:6][CH:5]=3)/[C:26]#[N:27])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: N#CCn1nnc2ccccc21
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Product: COc1ccc2nc(Cl)c(/C=C(\C#N)n3nnc4ccccc43)cc2c1
Yield: 71.4 %

Procedure:
2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (111 mg) was condensed with 1H-benzotriazole-1-acetonitrile (79 mg) through Method B (production step 3), to thereby yield the target product (yield: 129 mg, 71%).
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][O:13][C:14](=[O:24])[C:15]#[C:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1.C1(C)C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:38][N+:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[N:40]=1>C(#N)C>[CH3:12][O:13][C:14]([C:15]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[N:38][N:39]2[C:44]=1[CH:43]=[CH:42][C:41]([O:45][CH3:46])=[N:40]2)=[O:24]
Reactant: COc1ccc[n+](N)n1
Reactant: COC(=O)C#Cc1cccc(F)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)c1c(-c2cccc(F)c2)nn2nc(OC)ccc12
Reaction time: 1 h
Yield: 53.2 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (5 ml) was added to a stirred, chilled, mixture of (3-fluoro-phenyl)-propynoic acid methyl ester (2.67 g) and 1-amino-3-methoxy-pyridazin-1-ium mesitylene sulphonate (4.89 g) in acetonitrile (80 ml) and the mixture was stirred at 0° for 1 hour then at ambient temperature for 18 hours. The mixture was concentrated in vacuo, and partitioned between ethyl acetate (150 ml) and water (150 ml). The aqueous phase was separated and further extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with water (2×50 ml), brine (25 ml), dried (MgSO4), filtered and evaporated in vacuo to give a solid which was triturated with anhydrous ether: petroleum ether (1:0.5) to give the title compound as a brown solid (2.4 g, 53%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1.CO.O>[CH:11]([C:9]1[N:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][CH:8]=1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)c1csc(C(=O)O)n1

Procedure:
To a solution of 3.12 g (15.7 mmol) of 4-isopropylthiazole-2-carboxylic acid ethyl ester in 32 mL of 75% THF/MeOH, was added 110 mg (31.3 mmol) of LiOH in 8 mL of H2O. The mixture was stirred overnite, the solution adjusted to pH 5 using 1N aqueous HCl solution and concentrated in vacuo to afford 4-isopropylthiazole-2-carboxylic acid as a white solid (2.97 g including salts) which was used directly in Step E: 1H NMR (500 methanol-d4) δ ppm 1.29 (d, J=6.7 Hz, 6H), 3.20 (m, 1H), 7.39 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:19])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[C:27](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[OH:9][CH2:8][CH2:7][N:6]1[C:2]([NH:1][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:3]([NH:10][C:11](=[O:19])[O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1c(NC(=O)Oc2ccccc2)cnn1CCO
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cnn(CCO)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a stirred solution of phenyl [5-amino-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]carbamate (5.45 g) in N,N-dimethylformamide (55 ml) were added triethylamine (8.69 ml) and trityl chloride (6.37 g), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave a crude product, which was triturated with ethyl acetate-diisopropyl ether (1:2). The resulting solid was collected by filtration to give phenyl [1-(2-hydroxyethyl)-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (3.5 g).
Reaction SMILES: Br[N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=[O:8].O1C=CCC1.[NH2:14][C:15](N)=[S:16]>O>[NH2:14][C:15]1[S:16][C:5]([CH2:4][CH2:3][OH:8])=[CH:6][N:2]=1
Reactant: NC(N)=S
Reactant: O=C1CCC(=O)N1Br
Agent: C1=COCC1
Solvent: O
Product: Nc1ncc(CCO)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold suspension of 118.2 g of N-bromosuccinimide in 750 ml of water under a nitrogen atmosphere is added dropwise 75 ml of 2,3-dihydrofuran. The resulting solution is stirred at 0° C. for one hour. Thiourea, 50.5 g, is added and the solution refluxed under a nitrogen atmosphere overnight. The acidic solution is continuously extracted with ethyl acetate for 24 hours The ethyl acetate extract contains mostly succinimide. The aqueous phase is basified with concentrated ammonium hydroxide to a pH of 10-11 and continuously extracted with ethyl acetate for 72 hours. The ethyl acetate extract is cooled and acidified with ethereal hydrogen chloride. The hydrochloride salt oils out of solution and is crystallized from an ethanol-acetonitrile mixture to give 60.1 g of 2-amino-5-thiazoleethanol as the monohydrochloride salt; mp 125°-127° C. (lit. (a) mp 126°-127° C.) lit. (a) Farmaco. Ed. Sci., Vol. 41, pages 483-498 (1986).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)=[O:6].CCO>[Pt].C(Cl)Cl>[NH2:18][C:17]1[CH:16]=[CH:15][C:4]([C:5]([NH:7][CH:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Agent: [Pt]
Solvent: CCO
Solvent: ClCCl
Product: CN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Yield: 100.8 %

Procedure:
3-chloro-N-(1-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 56; 1.8 g, 6 mmol) hydrogenated over 2 hours with agitation at 298K and pressure of 5 bar using a 5% Pt/C catalyst and EtOH (50 mL) solvent. The catalyst was filtered and the filtrate concentrated to give a yellow crystalline solid which was dissolved in DCM and purified by column chromatography (5% MeOH/DCM) to give the title compound as a pale yellow crystalline solid (1.62 g, 100%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])=[CH:26][CH:25]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NCc1ccc(Cl)cc1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(Cl)cc4)cc3)c2)o1

Procedure:
N-(4-Chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-chlorobenzylamine using method N. NMR; δH [2H6]—DMSO 9.17,(1H, t), 7.99,(2H, d), 7.89,(1H, dd), 7.76,(1H, d), 7.56-7.52,(3H, m), 7.41-7.34,(4H, m), 4.49,(2H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.51 min, MH+ 418/420.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:16]=[CH:15][N:14]([CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=2[C:27]([F:30])([F:29])[F:28])[N:13]=1)=[O:10]>C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]([NH:11][C:12]1[CH:16]=[CH:15][N:14]([CH2:17][C:18]2[CH:26]=[CH:25][C:21]([CH2:22][OH:23])=[CH:20][C:19]=2[C:27]([F:28])([F:30])[F:29])[N:13]=1)=[O:10]
Reactant: O=C(O)c1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2ccc(CO)cc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[(3-{[(2,6-difluorophenyl)carbonyl]amino}-1H-pyrazol-1-yl)methyl]-3-(trifluoromethyl)benzoic acid (for a preparation see Intermediate 21)(0.340 g, 0.80 mmol) in THF (5 ml) at ambient temperature under nitrogen was added 1.0 M borane-tetrahydrofuran complex (1.3 ml, 1.30 mmol). The solution was stirred at ambient temperature under nitrogen for 1 h. To the suspension was added a further amount of 1.0 M borane-tetrahydrofuran complex (1.3 ml, 1.30 mmol). The solution was stirred for a further 2 h. The solvent was removed in vacuo to leave a colourless gum. The residue was re-dissolved in THF (5 ml). To the solution was added 1.0M boran-tetrahydrofuran complex (2 ml, 2 mmol) and stirred for 6 h. The solution was quenched with methanol (10 ml), stirred for 5 min and then the solvent removed in vacuo. The residue was loaded in dichloromethane and purified on silica (20 g) using 0-100% ethyl acetate-cyclohexane+0-20% methanol. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless gum (0.20 g);
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8]2([CH2:16][C:15](=[O:17])O[C:12](=[O:13])[CH2:11]2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].[NH3:18]>>[C:1]([CH:5]1[CH2:10][CH2:9][C:8]2([CH2:16][C:15](=[O:17])[NH:18][C:12](=[O:13])[CH2:11]2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1CCC2(CC1)CC(=O)OC(=O)C2
Reactant: N
Product: COC(=O)C1CCC2(CC1)CC(=O)NC(=O)C2
Reaction time: 1 h

Procedure:
A mixture of 4-carbomethoxycyclohexane-1,1-diacetic acid anhydride and concentrated aqueous ammonia solution was slowly heated with a free flame until the temperature reached 200° C. where it was kept for 1 hour. After cooling the product was ued in the next step without purification.