Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=[O:4])[CH2:2][OH:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:37][CH2:38][CH:39]([OH:64])[CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][C:50]([C:52]2[S:53][C:54]([CH3:63])=[C:55]3[CH2:60][C:59]([CH3:62])([CH3:61])[CH2:58][CH2:57][C:56]=23)=[O:51])=[CH:44][CH:43]=1>C(Cl)Cl>[OH:4][CH2:1][C:2]([NH:37][CH2:38][CH:39]([OH:64])[CH2:40][O:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:48][CH2:49][C:50](=[O:51])[C:52]2[S:53][C:54]([CH3:63])=[C:55]3[CH2:60][C:59]([CH3:61])([CH3:62])[CH2:58][CH2:57][C:56]=23)=[CH:46][CH:47]=1)=[O:3]
Reactant: Cc1sc(C(=O)CCc2ccc(OCC(O)CN)cc2)c2c1CC(C)(C)CC2
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1sc(C(=O)CCc2ccc(OCC(O)CNC(=O)CO)cc2)c2c1CC(C)(C)CC2

Procedure:
To a solution of glycolic acid (1.5 eq.) in DCM (10 mL), TBTU (1.3 eq.) and DIPEA (4.0 eq.) is added. The mixture is stirred at rt for 10 min before the appropriate 3-[4-(3-amino-2-hydroxy-propoxy)-phenyl]-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (0.5-1.0 mmol, 1. eq.) is added. Stirring is continued at rt for 1 h before another portion of glycolic acid (0.7 eq.) and TBTU (0.6 eq.) is added. The mixture is stirred for another hour, is diluted with DCM and washed with sat. aq. NaHCO3 solution. The wash solutions are extracted back with DCM. The combined organic extracts are dried over MgSO4, filtered and the solvent is evaporated. The crude product is purified by chromatography on prep. TLC plates using DCM containing 5% of methanol to give the desired 2-hydroxy-N-(2-hydroxy-3-{4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenoxy}-propyl)-acetamide as an almost colourless foam.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[N:5]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:4](=[O:29])[C:3]=1[C:30]([O:32]CC)=O.[CH:35]1([NH2:39])[CH2:38][CH2:37][CH2:36]1>>[CH:35]1([NH:39][C:30]([C:3]2[C:4](=[O:29])[N:5]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=3)=[O:32])[CH2:38][CH2:37][CH2:36]1
Reactant: NC1CCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc([N+](=O)[O-])cc2)c1=O
Product: O=C(NC1CCC1)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-1-[(4-nitrophenyl)methyl]-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.91 (1H, d, J=7.6 Hz), 8.21 (1H, s), 8.10 (2H, d, J=8.6 Hz), 7.35 (2H, d, J=8.6 Hz), 7.29 (1H, s), 7.14 (3H, m), 7.08 (2H, m), 5.47 (2H, br s), 4.40 (1H, m), 3.91 (2H, s), 2.24 (2H, m), 1.86 (2H, m), 1.67 (2H, m); HRMS calcd for C27H24N4O5+H+: 485.1825. Found: 485.1815.
Reaction SMILES: [C:1]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([C:18]2[CH:19]=[C:20]([C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[CH:21]=[CH:22][C:23]=2[O:24]CC2C=CC=CC=2)=[O:17])[C:9]2[O:13][N:12]=[C:11]([CH3:14])[N:10]=2)=[CH:3][CH:2]=1.B(Br)(Br)Br>>[C:1]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([C:18]2[CH:19]=[C:20]([C:32]3[CH:33]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=3)[CH:21]=[CH:22][C:23]=2[OH:24])=[O:17])[C:9]2[O:13][N:12]=[C:11]([CH3:14])[N:10]=2)=[CH:5][CH:6]=1
Reactant: Cc1noc([C@@H](Cc2ccc(-c3ccccc3)cc2)NC(=O)c2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2OCc2ccccc2)n1
Agent: BrB(Br)Br
Product: Cc1noc([C@@H](Cc2ccc(-c3ccccc3)cc2)NC(=O)c2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2O)n1
Yield: 86.7 %

Procedure:
4-Hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid [2-biphenyl-4-yl-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (53 mg) was prepared from 4-benzyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid [2-biphenyl-4-yl-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (70 mg, 0.1 mmol) and boron tribromide (0.25 mL, 0.25 mmol, 1.0 M solution in DCM) following the general procedure P.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]=[C:7]([NH2:9])[NH:6][N:5]=1.[C:10]([C:12]([C:22](=O)[CH3:23])=[CH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)#[N:11].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([CH:13]2[N:6]3[N:5]=[C:4]([CH2:3][O:2][CH3:1])[N:8]=[C:7]3[NH:9][C:22]([CH3:23])=[C:12]2[C:10]#[N:11])=[CH:15][CH:16]=1)#[N:19]
Reactant: COCc1n[nH]c(N)n1
Reactant: CC(=O)C(C#N)=Cc1ccc(C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1nc2n(n1)C(c1ccc(C#N)cc1)C(C#N)=C(C)N2
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, 3-(methoxymethyl)-1H-1,2,4-triazole-5-amine (244 mg, 1.9 mmol) and 4-(2-cyano-3-oxobut-1-en-1-yl)benzonitrile (300 mg, 1.5 mmol, 0.8 eq.) were dissolved in DMF (3 ml), and solid sodium bicarbonate (803 mg, 9.6 mmol, 5 eq.) was added. The mixture was stirred at 55° C. for 12 h. The mixture was then filtered, and the DMF from the filtrate was distilled off under reduced pressure. The residue was acidified with 1 N hydrochloric acid and then purified by preparative HPLC (Kromasil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). The product was obtained as a solid (38.2 mg, 80% pure, 7% of theory).
Reaction SMILES: [Cl:1][C:2](Cl)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)[C:3](Cl)([Cl:5])[CH3:4].Cl>[Fe].C(O)C>[Cl:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)=[C:3]([Cl:5])[CH3:4]
Reactant: CC(Cl)(Cl)C(Cl)(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC(Cl)=C(Cl)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13 G. of 1,1,2,2-tetrachloro-1-(3-nitrophenyl) propane and 7.9 g. of iron powder is stirred vigorously under reflux in 465 ml. of 50% aqueous ethanol. 5.6 Ml of a solution prepared prejviously from 52 ml. of concentrated hydrochloric acid and 250 ml. of 50% aqueous ethanol are added dropwise over 5 minutes. After an additional 2 hours of stirring at reflux temperature, the hot reaction mixture is filtered, cooled to room temperature, diluted with enough chloroform to double the volume of the ethanol, and made basic with saturated aqueous sodium bicarbonate solution. The organic layer is separated, washed with water, dried and concentrated in vacuo to give a mixture of essentially pure cis and trans 1,2-dichloro-1-(3-aminophenyl)-1-propene as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=[C:14]([C:18](=O)[CH3:19])[C:15](=[O:17])[CH3:16])=[C:8]2[C:3]=1[C:4](=[O:22])[CH:5]=[C:6]([CH3:21])[O:7]2.[NH2:23]/[C:24](/[CH3:33])=[CH:25]\[C:26]([O:28][CH:29]1[CH2:32][CH2:31][CH2:30]1)=[O:27]>CC(O)C>[C:15]([C:14]1[CH:13]([C:9]2[CH:10]=[C:11]([F:12])[C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:21])=[CH:5][C:4]3=[O:22])[C:25]([C:26]([O:28][CH:29]2[CH2:32][CH2:31][CH2:30]2)=[O:27])=[C:24]([CH3:33])[NH:23][C:18]=1[CH3:19])(=[O:17])[CH3:16]
Reactant: CC(=O)C(=Cc1cc(F)c(F)c2c(=O)cc(C)oc12)C(C)=O
Reactant: C/C(N)=C/C(=O)OC1CCC1
Solvent: CC(C)O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)OC2CCC2)C1c1cc(F)c(F)c2c(=O)cc(C)oc12

Procedure:
80 mg (0.26 mmol) of 3-[(5,6-difluoro-2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione are dissolved with 40.4 mg (0.26 mmol) of cyclobutyl 3-aminocrotonate in 2 ml of 2-propanol and heated under reflux under argon for 12 h. The solvent is removed in vacuo, and the residue is purified by column chromatography (mobile phase: ethyl acetate/cyclohexane 1:2). 31.0 mg (27% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=O.P(Br)(Br)[Br:18].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Br:18][C:7]1[C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)c1cc(Br)c2[nH]ccc(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c2nccc(Br)c2c1
Reaction time: 0.5 h

Procedure:
To a suspension of methyl 8-bromo-4-oxo-1,4-dihydroquinoline-6-carboxylate (272 mg, 0.964 mmol) in DMF (5 mL) at room temperature was added slowly phosphorous tribromide (0.1 mL, 1.06 mmol). The resulting mixture was stirred under argon for 30 min. The reaction mixture was made basic by the addition of solid NaHCO3 until the pH was greater than 10, and then the reaction mixture was diluted with water and the solid collected by filtration. The product was washed with several portion of water and dried to yield methyl 4,8-dibromoquinoline-6-carboxylate. (M+H)+: 344, 346, 348.
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29]>ClCCl>[N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
To a chilled (0° C.) solution of 0.37 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine and 836 microliters of triethylamine in 5 ml of dichloromethane is added 0.761 g of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride. The mixture is stirred at room temperature under argon for 5 hours. An additional 420 microliters of triethylamine and 0.38 g of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride is added and the mixture stirred 16 hours. The mixture is diluted with 60 ml of dichloromethane and washed with 25 ml each of H2O, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered (twice) through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated to give a yellow glass (0.68 g) which is crystallized from ethyl acetate to give 0.38 g of white crystals, m.p. 250°-260° C.; mass spectrum (FABL) 442.4 (M+H).
Reaction SMILES: C[O:2][CH2:3][C:4]1([C:9]#[N:10])[CH2:7][C:6](=[CH2:8])[CH2:5]1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][CH2:3][C:4]1([C:9]#[N:10])[CH2:7][C:6](=[CH2:8])[CH2:5]1
Reactant: C=C1CC(C#N)(COC)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=C1CC(C#N)(CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a mixture of 1-(methoxymethyl)-3-methylenecyclobutanecarbonitrile (1.40 g, 0.0102 mol) in methylene chloride (30 mL, 0.4 mol) was added 1.0 M of boron tribromide in methylene chloride (12.8 mL) at −78° C. The reaction was stirred at rt for 2 h, quenched with aq. sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to dryness to give the desired product (1.26 g, 100%). 1H NMR (400 MHz, CDCl3): 4.81 (2H, m), 3.66 (2H, s), 3.10 (2H, m), 2.59 (2H, m) ppm.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([NH:18][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CCCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 50 parts of 4-chloro-3-nitrobenzoic acid and 222 parts of 1-butanamine was stirred for 3 hours at reflux temperature. After cooling and evaporation of the excess of 1-butanamine, the reaction mixture was acidified with a sulfuric acid solution 2N to pH 1. The precipitated product was filtered off and dried, yielding 59 parts (100%) of 4-(butylamino)-3-nitrobenzoic acid (int. 7).
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6]1)C.Cl.[NH2:14][C:15](=[NH:29])[N:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.C[O-].[Na+]>CO>[C:24]([O:23][C:22](=[O:28])[NH:21][C@@H:18]1[CH2:19][CH2:20][N:16]([C:15]2[N:14]=[CH:4][C:5]3[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][C:10]=3[N:29]=2)[CH2:17]1)([CH3:26])([CH3:25])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=N)N)C1
Reactant: CN(C)C=C1CN(C)CCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCc2nc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ncc2C1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
3-[(Dimethylamino)methylene]-1-methylpiperidin-4-one (9.04 g, 53.7 mmol) and tert-butyl {(3R)-1-[amino(imino)methyl]pyrrolidin-3-yl}carbamate hydrochloride (14.2 g, 53.7 mmol) were dissolved in methanol (100 mL) and to this was added dropwise sodium methoxide (9.66 g of a 30% solution in methanol). The reaction mixture was refluxed for 3 hours and then cooled to room temperature. The reaction mixture was then evaporated to dryness, and the residue was treated with water (50 mL). The precipitate was separated by filtration, washed with water (25 mL) and diethyl ether (50 mL) and dried to give the title compound 10.43 g (yield 58%). LCMS (ES+) M+H 334. 1H NMR (DMSO-d6) 1.39 (s, 9H) 1.85 (m, 1H) 2.13 (m, 1H) 2.33 (s, 3H) 2.60 (m, 2H) 2.67 (m, 2H) 3.23-3.26 (m, 1H) 3.31-3.37 (m, 3H) 3.40-3.536 (m, 1H) 3.63 (m, 1H) 4.04 (br s, 1H) 7.20 (br s, 1H) 8.04 (s, 1H).
Reaction SMILES: C([Li])CCC.[Br-].[C:7]1([C:13]([PH3+])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2C=CC=CC=2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([NH:37][C:38]([NH:40][S:41](C2C=CC=CC=2C(=O)C)(=[O:43])=[O:42])=[O:39])[N:30]=1>O1CCCC1>[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([NH:37][C:38]([NH:40][S:41]([C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:13]([CH3:7])=[CH2:14])(=[O:42])=[O:43])=[O:39])[N:30]=1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(C)=O)n1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 0.02 mol of n-butyllithium in 20 ml of anhydrous tetrahydrofuran is added 3.6 g of triphenylmethylphosphonium bromide. The above solution is stirred at room temperature for 4 hours. A slurry of 3.8 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-acetylbenzenesulfonamide in 30 ml of dry tetrahydrofuran is then added dropwise. The resulting mixture is refluxed overnight and allowed to cool to room temperature. The precipitate is removed by suction filtration and washed with methylene chloride. The combined filtrates are then washed with diluted hydrochloric acid, water, dried and evaporated to dryness to yield the desired product.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[CH:10]=1
Reactant: Cn1ccc(=O)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cn1ccc(=O)c(O)c1

Procedure:
A mixture of 3-benzyloxy-1-methyl-1H-pyridin-4-one (14.1 g, 65.5 mmol) and 10% Pd/C (1.20 g) in methanol was subjected to hydrogenation in a Parr apparatus under 50 psi pressure of hydrogen for 70 min. The mixture was filtered through a pad of CELITE™, the filtrate was concentrated to dryness, and the residue was triturated with acetone. The solid was then collected by suction filtration. The title compound was obtained as a light-brown powder (7.13 g, 87% yield) after vacuum oven drying. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.49 (br. s, 1H), 7.38 (s, 1H), 6.12 (br. s, 1H) and 3.63 (s, 3H); MS-ESI (m/z): 125.7 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[S:31][N:30]=[C:29]([CH3:32])[C:28]=1[Cl:33]>ClC(Cl)C>[Cl:33][C:28]1[C:29]([CH3:32])=[N:30][S:31][C:27]=1[NH:26][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: Cc1nsc(N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)Cc2ccc(O)c([N+](=O)[O-])c2)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.1 %

Procedure:
4-Hydroxy-3-nitrophenylacetic acid (10 g, 0.05 mol) was suspended in dichloroethane (50 ml) and stirred at room temperature under a nitrogen atmosphere. N,N-Dimethylformamide (0.1 ml) was added followed by dropwise addition of oxalyl chloride (6.77 g, 0.05 mol) over 20 minutes. The mixture was stirred at room temperature for 25 minutes and then at 40° C. for 20 minutes. The reaction mixture was then heated under reflux while a solution of 5-amino-4-chloro-3-methylisotiazole (7.54 g, 0.05 mol) in dichloroethane (30 ml) was added over 30 minutes. The resultant pale orange suspension was stirred at reflux for 2 hours and then cooled to room temperature, to give a precipitate, which was collected by filtration and washed with dichloromethane. The solid was suspended in water (150 ml), treated with 10% (w/v) sodium hydroxide (50 ml) and the resulting red solution was washed with dichloromethane (2×50 ml). The combined washings were extracted with water (50 ml) and the combined aqueous layers were acidified to pH4-5 by addition of concentrated hydrochloric acid (approximately 10 ml). The resultant yellow suspension was filtered and the solid was washed with water and dried under suction to give N-(4-chloro-3-methyl-5-isothiazolyl)-4-hydrox-3-nitrophenylacetamide (14.6 g) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].C(N(CC)CC)C.[NH2:12][C:13]1[CH:18]=[C:17]([C:19]([Cl:22])([Cl:21])[Cl:20])[CH:16]=[CH:15][N:14]=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([Cl:21])([Cl:20])[Cl:22])[CH:16]=[CH:15][N:14]=1)=[O:4]
Reactant: Nc1cc(C(Cl)(Cl)Cl)ccn1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1cc(C(Cl)(Cl)Cl)ccn1
Reaction time: 4 h
Yield: 81.2 %

Procedure:
17 ml (0.3 mol) of methyl isocyanate and 1 ml of triethylamine were added to 21.2 g (0.1 mol) of 2-amino-4-trichloromethylpyridine and 400 ml of toluene at 25° C. After 4 hours at 80° C., the resulting solid was isolated. 21.8 g (82%) of the desired product were obtained. Mp.: 192°-195° C.; Active Ingredient Example 2.001
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCc1ccc(-c2ccccc2)cc1
Yield: 97.2 %

Procedure:
A solution of ethyl 4-(4-phenylphenyl)butanoate (21.0 g) and potassium hydroxide (9.65 g) in ethanol (50 ml) and water (50 ml) was heated under reflux for 2 hours. The resulting mixture was allowed to cool, diluted with water (150 ml), washed with ether (x2), acidified with concentrated hydrochloric acid, and extracted with ether. The extracts were washed with water, dried and concentrated to give crude 4-(4-phenylphenyl)butanoic acid [(3), 18.28 g] as a white solid, m.p. 111°-113° C. (D. H. Hey and R. Wilkinson, J. Chem. Soc., 1940, 1030, give a m.p. of 118°-119° C. for this acid).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:24][CH:23]=3)[C@H:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:43][C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46]>O1CCCC1>[CH3:43][C:44]([CH3:49])([CH3:48])[C:45]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:24][CH:23]=3)[C@H:7]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1)=[O:46]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Oc1ccc2c(c1)OC[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)OC[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of (±)-cis-7-hydroxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-3-(4-(trifluoromethyl)-phenyl)chromane (2.41 g, 4.98 mmol), triethylamine (3.40 ml, 24.4 mmol), 2,2-dimethylpropanoyl chloride (3.0 ml, 24.4 mmol) and tetrahydrofuran (150 ml) was stirred at room temperature for 4 days. The mixture was filtered to remove inorganic solids, the filter plug being washed with a little extra tetrahydrofuran. The solvents were then evaporated to give a colourless amorphous solid, which was recrystallised from 4:1 ethanol/water (20 ml) to give the product as colourless needles.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[N:8]([CH3:22])[N:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:22][N:8]1[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=2)=[CH:10][C:6]([CH2:4][OH:3])=[N:7]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)n(C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cn1nc(CO)cc1-c1ccc(OC(F)(F)F)cc1

Procedure:
In analogy to the procedure described for example 1 a], 1-methyl-5-(4-trifluoromethoxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (example 11 c]) was reduced with lithium aluminium hydride to give [1-methyl-5-(4-trifluoromethoxy-phenyl)-1H-pyrazol-3-yl]-methanol as brown solid.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([O:7][CH2:8]C)=[O:6])#[N:3].[CH:10](I)([CH3:12])[CH3:11]>CO>[CH:10]([CH:4]([C:2]#[N:3])[C:5]([O:7][CH3:8])=[O:6])([CH3:12])[CH3:11]
Reactant: CC(C)I
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C#N)C(C)C
Temperature: 25 °C

Procedure:
In 20 ml of absolute methanol was dissolved 520 mg of metallic sodium, and 2.12 g of ethyl cyanoacetate was added thereto with stirring at room temperature, after which 4.0 of isopropyl iodide was added dropwise over a period of 10 minutes. After completion of the dropwise addition, the resulting mixture was stirred at room temperature for 3 hours, refluxed for 1 hour, subjected to a conventional post-treatment, and then distilled under reduced pressure to obtain 2.1 g of methyl α-isopropylcyanoacetate.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:6][C:7]=1[CH2:8]C.[O:17]=[CH:18][C:19]1[CH:27]=[CH:26][C:24]([OH:25])=[C:21]([O:22][CH3:23])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:18]([C:19]1[CH:27]=[CH:26][C:24]([O:25][CH2:2][C:3]2[N:4]=[C:5](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:6][C:7]=2[CH3:8])=[C:21]([O:22][CH3:23])[CH:20]=1)=[O:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCOC(=O)/C=C/c1nc(CCl)c(CC)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1nc(COc2ccc(C=O)cc2OC)c(C)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.8 %

Procedure:
A mixture of ethyl (2E)-3-(4-chloromethyl-5-ethyl-1,3-oxazol-2-yl)-2-propenoate (11.62 g), vanillin (7.70 g), potassium carbonate (6.99 g) and N,N-dimethylformamide (200 mL) was stirred at room temperature for 15 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of ethyl (2E)-3-{4[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (12.15 g, yield 70%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 117-118° C.