Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.Cl.O1CCOC[CH2:24]1>CO.O1CCOCC1>[CH3:24][O:20][C:19](=[O:21])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:17][CH:16]=1
Reactant: C1COCCO1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-3-nitro-pyridine (5.0 g, 31.4 mmol), (4-amino-phenyl)-acetic acid (4.75 g 31.4 mmol), and a 4 N solution of HCl in dioxane (7.85 mL, 31.4 mmol) in MeOH/dioxane (100 mL; 1:1, v/v) is stirred and refluxed for 30 h. (4-Amino-phenyl)-acetic acid (4.75 g 31.4 mmol) is added and the reaction mixture is stirred and refluxed for additional 18 h. The reaction mixture is allowed to cool to rt and concentrated in vacuo. The residue is dissolved in EtOAc, washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (Hexane/EtOAc, 85:15→60:40) provides the title compound as a red solid: ES-MS: 288.0 [M+H]+; tR=4.71 min (System 1); Rf=0.20 (Hexane/EtOAc, 4:1).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([CH2:11][OH:12])[O:6][CH:7]2[OH:10])[O:3]1.C(N(CC)CC)C.[C:21](Cl)([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)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([CH2:11][O:12][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:6][CH:7]2[OH:10])[O:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H]2[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)OC(O)[C@@H]2O1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2,3-O-Isopropylidene-D-ribofuranose (20 g, 105.2 mmol) was dissolved in dichloromethane (200 mL) at 0° C. Triethylamine (10.9 g, 107.5 mmol) and a catalytic. amount of pyridine were added to the reaction mixture, followed by the addition of trityl chloride (27.8 g, 0.1 mol). The mixture was stirred at 0° C. for 3 h and further 12 h at room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate (80 mL) and the phases were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvents were removed in vacuo. The crude product was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:14])=[N:8][N:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1)=[O:5])[CH3:2].[Br:15]N1C(=O)CCC1=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:14])=[N:8][N:9]([CH:11]([CH3:13])[CH3:12])[C:10]=1[Br:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)C)nc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1c(O)nn(C(C)C)c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 40.2 %

Procedure:
3-Hydroxy-1-isopropylpyrazole-4-carboxylic acid ethyl ester (10.5 g) was dissolved in dichloromethane (100 mL), and N-bromosuccinimide (14.1 g) was added to the solution under ice cooling. The mixture was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (5.9 g)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C@H:27]2[CH2:32][C@H:31]([N:33]3[CH2:38][CH2:37][N:36]([CH2:39][C:40]([NH:42][C:43]4[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][C:44]=4[CH3:50])=[O:41])[CH2:35][CH2:34]3)[CH2:30][CH2:29][NH:28]2)[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:28]1[CH2:29][CH2:30][C@@H:31]([N:33]2[CH2:34][CH2:35][N:36]([CH2:39][C:40]([NH:42][C:43]3[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][C:44]=3[CH3:50])=[O:41])[CH2:37][CH2:38]2)[CH2:32][C@@H:27]1[CH2:26][C:21]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=1)=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN[C@@H](Cc3ccc(Cl)c(Cl)c3)C2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3ccc(Cl)c(Cl)c3)C2)CC1
Reaction time: 0.08 h
Yield: 43.9 %

Procedure:
3,5 di(trifluormethyl)benzoyl chloride (0.0011 mol) was added to a mixture of (±)-trans-4-[2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (0.001 mol) in DCM (20ml). The mixture was stirred for 5 minutes. Triethylamine (2ml) was added. The mixture was stirred at RT for 3 hours, washed with a diluted NaOH solution and with water, and then dried. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 96/4). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.32 g (44%) of (±)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 139).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)[NH2:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:26][NH:25][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNc1cnccn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1cnccn1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with a suspension of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.200 g) in 1:1 CH2Cl2: AcOEt (25 mL). 2-Hydrazinopyrazine (0.062 g) was added at −40° C. followed by T3P (50%) (0.432 g) and DIPEA (0.147 g). The reaction mixture was stirred for 30 min at −40° C. before being concentrated under reduced pressure (35° C., 20 mmHg). The crude oil was purified by preparative TLC using 5% MeOH in CH2Cl2 as mobile phase (under ammonia atmosphere) to afford 40 mg (yield: 16%) of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyrazin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 10.53 (s, 1H), 9.59 (s, 1H), 9.14 (s, 1H), 8.53 (s, 2H), 8.29 (s, 1H), 8.13 (s, 1H), 8.06-8.07 (m, 1H), 7.92-7.93 (d, J=2.8 Hz, 1H), 7.51-7.53 (d, J=10.4 Hz, 1H), 6.07-6.10 (d, J=10.4 Hz, 1H); LCMS for C17H12F6N7O [M+H]+ predicted: 444.31. found: 444.49 (RT 2.70 min, purity: 95.78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[NH:14][C@H:13]2[CH3:18])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[Br:21][C:22]1[C:23]([CH2:29]Br)=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=1>C1COCC1>[Br:21][C:22]1[C:23]([CH2:29][N:14]2[C@@H:13]([CH3:18])[C@@H:12]([C:4]3[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([F:1])[CH:3]=3)[O:16][C:15]2=[O:17])=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(F)cc(C(F)(F)F)c1
Reactant: Clc1ccc(Br)c(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reaction time: 1.5 h

Procedure:
To a cold (ice/methanol bath) mixture of (4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 93) (5000 mg, 19.00 mmol) in THF (100 ml) was added sodium hydride (912 mg, 22.80 mmol) all at once. The resulting mixture was stirred cold (ice bath) for 1.5 hrs followed by addition of 3-bromo-2-(bromomethyl)-6-chloropyridine (INTERMEDIATE 30) (5963 mg, 20.90 mmol). The reaction mixture was allowed to slowly warm to ambient in 3 hrs. The reaction was cooled (ice bath) and quenched by HCl (1N, aq.). The resulting mixture was extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated under reduced pressure to afford an oil. This oil was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted by an ethyl acetate/hexanes mixture (0% to 40% ethyl acetate). Related fractions were pooled and concentrated in vacuo to afford a light amber gum of 8.2522 g as the titled compound. LCMS calc.=465.97. found=468.91.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].Cl>C1(C)C=CC=CC=1.C(#N)C>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:22]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 81.2 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 100 ml were charged 8.29 g (60.0 mmol) of potassium carbonate, 30 ml of acetonitrile, 8.09 g (60.0 mmol) of dimethyl malonate with a purity of 99% and 5.00 g (30.0 mmol) of 2,4-difluoronitrobenzene with a purity of 98% under argon atmosphere, and under stirring, the mixture was reacted at 70° C. for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, 50 ml of toluene was added to the mixture, and 7.5 ml (90 mmol) of 12 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 20 ml of water and 20 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, this organic layer was analyzed (absolute quantitative method) by high performance liquid chromatography, it was found that 6.61 g (reaction yield: 81%) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate was formed.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:33])=[C:18]([C:24]([O:30][CH2:31][CH3:32])=[C:25]([CH:27](O)[CH3:28])[CH:26]=1)[C:19]([NH:21][CH2:22][CH3:23])=[O:20]>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:33])=[C:18]([C:24]([O:30][CH2:31][CH3:32])=[C:25]([CH:27]([Cl:3])[CH3:28])[CH:26]=1)[C:19]([NH:21][CH2:22][CH3:23])=[O:20]
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)O)c1OCC
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)Cl)c1OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
A mixture of cyanuric chloride (0.15 g, 0.84 mmol) and N,N-dimethylformamide (0.065 mL, 0.84 mmol) was stirred at room temperature for 10 min and then a solution of 3-chloro-6-ethoxy-N-ethyl-5-(1-hydroxyethyl)-2-methylbenzamide (0.16 g, 0.56 mmol) in methylene chloride (3.1 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with water, concentrated and purified on silica gel (eluting with 0 to 40% EtOAc in hexanes) to give the desired product (0.13 g, 76%). LCMS calculated for C14H20Cl2NO2 (M+H)+: m/z=304.1; Found: 304.1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([NH:13][C:14](=[O:35])[C:15](=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)=[C:23]([O:33][CH3:34])[CH:22]=1)[CH2:16][CH2:17][CH2:18]Cl)([CH3:12])[CH3:11].O.C(OCC)(=O)C>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:13]1[CH2:18][CH2:17][CH2:16][C:15](=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[C:14]1=[O:35])([CH3:12])[CH3:11]
Reactant: COc1cc(C=C(CCCCl)C(=O)NC(C)(C)c2ccccc2F)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C=C2CCCN(C(C)(C)c3ccccc3F)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
IPEA (0.5 mL), EDC (192 mg) and HOBT (135 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (150 mg) and 1-(2-fluorophenyl)-1-methylethylamine (102 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2-fluorophenyl)-1-methylethyl)amide. Sodium hydride (containing mineral oil at 40%, 40 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2-fluorophenyl)-1-methylethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 20 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 70 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: C[O-:2].[Na+].C(N(CC)CC)C.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12].[O:24]1[CH2:28]C[CH2:26][CH2:25]1>>[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([O:22][CH2:26][C@@H:25]1[O:24][CH2:28]1)(=[O:2])=[O:21])([O-:13])=[O:12]
Reactant: C[O-]
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)OC[C@H]1CO1
Reaction time: 2 h
Yield: 46.6 %

Procedure:
14.90 g of the diol compound obtained in (A) above was dissolved in 150 ml of tetrahydrofuran, and with ice cooling, 6.49 g of sodium methoxide was added. The mixture was stirred for 2 hours. To the reaction mixture was added 27.8 ml of triethylamine, and a solution of 22.2 g of o-nitrobenzenesulfonyl chloride in 50 ml of tetrahydrofuran was added dropwise. The mixture was stirred overnight. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography [solvent: benzene-chloroform (2:1)] to give 7.31 g (yield 46.6%) of the desired compound as a pale yellow viscous oil.
Reaction SMILES: C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O.C([O:23][C:24]1[CH:51]=[C:50]([C:52]2[CH:56]=[CH:55][O:54][CH:53]=2)[CH:49]=[CH:48][C:25]=1[C:26]([NH:28][C:29]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:38][C:30]=1[C:31]([O:33]C(C)(C)C)=[O:32])=[O:27])C1C=CC=CC=1>>[O:54]1[CH:55]=[CH:56][C:52]([C:50]2[CH:49]=[CH:48][C:25]([C:26]([NH:28][C:29]3[CH:41]=[C:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH:39]=[CH:38][C:30]=3[C:31]([OH:33])=[O:32])=[O:27])=[C:24]([OH:23])[CH:51]=2)=[CH:53]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccoc2)cc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(-c2ccoc2)cc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.8 %

Procedure:
Thioanisole (0.82 mL) and trifluoroacetic acid (2.6 mL) were added to the obtained tert-butyl 2-(2-(benzyloxy)-4-(furan-3-yl)benzamido)-4-phenylbenzoate (0.076 g), followed by stirring at room temperature for 3 hours and 20 minutes. The solvent was evaporated under reduced pressure, and a 2 mol/L aqueous solution of sodium hydroxide and toluene were added to the residue. The aqueous layer was separated and adjusted to a pH of 4.5 with 6 mol/L hydrochloric acid. The solid substance was collected by filtration to obtain 0.016 g of 2-(4-(furan-3-yl)-2-hydroxybenzamido)-4-phenylbenzoic acid as a brown solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[Na+].CN([CH:21]=[O:22])C>O>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:21]=[O:22])=[CH:12][NH:13]2)=[CH:9][CH:8]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(Cl)ccc12
Temperature: 37 °C
Reaction time: 0.75 h
Yield: 88 %

Procedure:
This Vilsmeyer reaction was performed according to H. G. O. Becker, Organikum, pp. 364-365, Johann Ambrosius Barth Verlag, Heidelberg-Leipzig (1996). To 5 mL DMF in a three-necked flask equipped with a thermometer, 1.8 mL POCl3 was added dropwise in a temperature range between 15° C. and 20° C. Then, a solution of 1 g (6.6 mMol) of 6-chloro-1H-indole in 2 mL DMF was added dropwise in a temperature range between 20° C. and 30° C. The reaction mixture was stirred for 45 minutes at 37° C. Afterwards, the reaction mixture was poured in a mixture of 15 g ice in 10 mL water under stirring. 3.4 g NaOH in 18 mL were added between in a temperature range between 20 and 30° C. The resulting mixture was then refluxed for 5 minutes. After cooling to room temperature, the precipitate was filtered off and washed with 10 mL cold water. Crystallization from ethanol yielded 6-chloro-1H-indole-3-carbaldehyde as a white solid (1.04 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].C(N(CC)CC)C.[C:25](#[N:28])[CH:26]=[CH2:27]>Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]([C:6]1[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH:27]=[CH:26][C:25]#[N:28])=[O:8]
Reactant: C=CC#N
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Product: N#CC=Cc1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
A solution of 5.0 g (14 mmol) of 5-chloro-2'-fluoro-2-iodobenzophenone, 2 mL (14.3 mmol) of triethylamine, 2 mL (30 mmol) of acrylonitrile and 35 mg (1.5 mmol) of palladium acetate was refluxed under an atomsphere of argon for 16 hr. The mixture was diluted with 100 ml of 1 N hydrochloric acid and the resulting precipitate was collected by filtration. The precipitate was washed with ether and air dried to give an off-white solid, mp 130°-133°.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[NH:10]([CH2:12][CH2:13][OH:14])[NH2:11]>C(O)C>[NH2:9][C:8]1[N:10]([CH2:12][CH2:13][OH:14])[N:11]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: CCOC=C(C#N)C#N
Reactant: NNCCO
Solvent: CCO
Product: N#Cc1cnn(CCO)c1N
Temperature: 95 °C
Reaction time: 10 h
Yield: 64.1 %

Procedure:
A 100-mL round-bottom flask was charged with 2-(ethoxymethylene)malononitrile (4.88 g, 39.96 mmol), ethanol (50 mL) and 2-hydrazinylethan-1-ol (4.4 g, 57.82 mmol). The resulting solution stirred for 10 h at 95° C. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 9:1, dichloromethane/methanol) to afford 5-amino-1-(2-hydroxyethyl)-1H-pyrazole-4-carbonitrile (3.9 g, 63%) as a yellow solid. MS (ESI, pos. ion) m/z 153 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[N:7][CH:8]=1.[NH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>C1C=CC=CC=1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[N:7][CH:8]=1
Reactant: NCCCN
Reactant: O=Cc1ccc(C(F)(F)F)cn1
Solvent: c1ccccc1
Product: NCCCNCc1ccc(C(F)(F)F)cn1
Yield: 75.1 %

Procedure:
5-Trifluoromethylpicolinealdehyde (3.5 g) was added dropwise at room temperature to a solution of trimethylenediamine (7.4 g) in benzene (70 ml). After the addition, the mixture was gradually heated with stirring, and then refluxed for 2 hours while removing water that azeotroped. Benzene was distilled off under reduced pressure. The residue was dissolved in ethanol (100 ml), and sodium borohydride (0.9 g) was added little by little while the solution was stirred at 10° to 15° C. The mixture was then stirred at room temperature for 2 hours, and ethanol was distilled off at less than 30° C. Dichloromethane was added to the residue, and a portion soluble in dichloromethane was separated. Dichloromethane was distilled off under reduced pressure, and volatile materials were removed at 1 mmHg and less than 60° C. to give N-(5-trifluoromethyl-2-pyridylmethyl)trimethylenediamine (3.5 g) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]([CH2:6][C:7]([OH:9])=O)=[CH:4][N:3]=[CH:2]1.[CH:10]1([O:14][C:15]2[CH:16]=[C:17]([N:23]3[CH2:28][CH2:27][NH:26][C@@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24]3)[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:13][CH2:12][CH2:11]1>>[CH:10]1([O:14][C:15]2[CH:16]=[C:17]([N:23]3[CH2:28][CH2:27][N:26]([C:7](=[O:9])[CH2:6][C:5]4[O:1][CH:2]=[N:3][CH:4]=4)[C@@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24]3)[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:11][CH2:12][CH2:13]1
Reactant: COc1ccc(N2CCN[C@@H](CC(C)C)C2)cc1OC1CCC1
Reactant: O=C(O)Cc1cnco1
Product: COc1ccc(N2CCN(C(=O)Cc3cnco3)[C@@H](CC(C)C)C2)cc1OC1CCC1
Yield: 4 %

Procedure:
Prepared by the method outlined for Example 189 using 2-(oxazol-5-yl)acetic acid and (S)-1-(3-cyclobutlyoxy-4-methoxy-phenyl)-3-isobutyl-piperazine as starting material. Product was obtained as an oil (4%). LC/MS (Method B) 3.62 min, [M+1]+ 428.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:24])[NH:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1)(C)(C)C.[ClH:26]>CO.CC(O)C>[ClH:26].[ClH:26].[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:24])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)NCCN2CCCC2)cc1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: NCc1ccc(C(=O)NCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of [4-(2-Pyrrolidin-1-yl-ethylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester (400 mg, 1.15 mmol) in MeOH (30 mL) was added 6M HCl in IPA (25 mL). The mixture was stirred at ambient temperature for 5 h. After this time a precipitate had formed and was filtered and dried to yield the title compound. m/z (M+1) 248.34.