Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:22][S:21][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:20])[C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:23]([OH:25])=[O:24].CN1CCCC1=[O:32]>C(O)(C)C.CO>[CH3:1][C:2]1[CH2:22][S:21][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:20])[C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:23]([OH:25])=[O:24].[CH3:1][C:2]1[CH2:22][S:21][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:20])[C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:23]([OH:25])=[O:24].[OH2:32]
Reactant: CN1CCCC1=O
Agent: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccc(O)cc3)[C@H]2SC1
Solvent: CC(C)O
Solvent: CO
Product: O
Temperature: 10 °C

Procedure:
Cefadroxil 1-methyl-2-pyrrolidone solvate (30 g) was slurried in a mixture of 110 ml isopropyl alcohol and 40 ml of methanol kept at 45°-48° C. for 100'. After cooling to 10° C. the mixture was filtered, the product washed with acetone and dried at 40° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[NH:27][C:28]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)=[O:29]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:34]([C:33]3[CH:32]=[CH:31][C:30]([C:28]([NH:27][C:19]4[NH:18][C:26]5[C:21]([CH:20]=4)=[CH:22][CH:23]=[CH:24][CH:25]=5)=[O:29])=[CH:37][CH:36]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: O=Cc1ccc(C(=O)Nc2cc3ccccc3[nH]2)cc1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4cc5ccccc5[nH]4)cc3)[nH]c2c1

Procedure:
Compound 663 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(2-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C25H22N4O3: 427.17; found: 426.99.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:51])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[N:28][N:27](COCC[Si](C)(C)C)[C:24]3=[N:25][CH:26]=2)=[CH:17][C:16]=1[C:46](=[O:50])[N:47]([CH3:49])[CH3:48])=O)(C)(C)C>Cl(O)(=O)(=O)=O.C(O)(=O)C>[CH3:49][N:47]([CH3:48])[C:46]([C:16]1[CH:17]=[C:18]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[N:28][NH:27][C:24]3=[N:25][CH:26]=2)[CH:19]=[CH:20][C:15]=1[NH:14][C:13]([CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[O:51])=[O:50]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)C4CCCN4C(=O)OC(C)(C)C)c(C(=O)N(C)C)c3)cc12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(NC(=O)C4CCCN4)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
2-{2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenylcarbamoyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (103 mg, 0.14 mmol) obtained in step 1 was dissolved in 1 ml of a 5% v/v solution of 70% perchloric acid in acetic acid and stirred overnight at room temperature. The crude was filtered and purified by reverse phase HPLC, lyophilized to afford pyrrolidine-2-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-amide (24 mg, 35% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.76 (m, 2H), 1.91 (m, 1H), 2.19 (m, 1H), 2.89 (m, 1H), 2.95 (d, 6H), 3.01 (m, 1H), 3.10 (m, 1H), 3.85 (s, 3H), 7.10 (m, 1H), 7.22 (d, 1H), 7.47 (m, 1H), 7.65 (d, H), 7.72 (s, 1H), 7.83 (d, 1H), 7.96 (m, 1H), 8.36 (s, 1H), 8.88 (s, 1H). MS: m/z 485.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:11])([Cl:10])[Cl:9])=[CH:4][N:3]=1.[Cl:12]Cl>>[Cl:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([C:8]([Cl:9])([Cl:10])[Cl:11])=[CH:4][N:3]=1
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cn1
Reactant: ClCl
Product: Clc1cc(C(Cl)(Cl)Cl)cnc1Cl

Procedure:
In similar operations, various pressure and temperature conditions as described herein are employed when reacting 2-chloro-5-(trichloromethyl)pyridine with an effective amount of Cl2 in the absence of a catalyst resulting in the formation of 2,3-dichloro-5-(trichloromethyl)pyridine. The desired product can be isolated by distillation from the reaction mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](Cl)(Cl)=[S:11]>O.CO>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:10]([SH:11])=[N:1][C:2]=2[CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(Cl)ccc1O
Solvent: O
Solvent: CO
Product: Sc1nc2cc(Cl)ccc2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 179.9 %

Procedure:
2-Amino-4-chlorophenol (2.50 kg, 17.4 mol) was charged to a vessel and suspended in water (52 L) and methanol (10.4 L). High dilution was required to prevent slow and difficult filtration of the product. The mixture was stirred, cooled to 0° C., then thiophosgene (2.00 kg, 17.4 mol) was added to the suspension ensuring that the internal temperature remained at 5° C. throughout the addition. Water (8 L) and methanol (2 L) were added to aid stirring and the slurry was warmed to 13° C. for 1 h, followed by aging at 20° C. for a further 1 h. The slurry was then filtered and the solid washed with water (5 L). The batch was repeated and combined to dry in a vacuum oven (T=40° C.) for 15 h to give 9a (5.81 kg, 31.3 mol). The data corresponds to the commercially available material. 1H NMR (400 MHz, d6-DMSO): δ 7.51 (d, 1 H, J=9.2 Hz), 7.3 07.26 (m, 2 H), 13C NMR (100.6 MHz, d6-DMSO): δ 181.2, 147.4, 133.1, 129.7, 123.9, 111.6, 110.8. HRMS (ESI): m/z [M++H] calcd for C7H4ClNOS: 185.9780. found: 185.9785.
Reaction SMILES: [CH2:1]([CH:19]1[CH2:24][C:23](=[O:25])[O:22][C:20]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:26]([CH2:28][NH2:29])[OH:27]>>[OH:27][CH2:26][CH2:28][N:29]1[C:23](=[O:25])[CH2:24][CH:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:20]1=[O:22]
Reactant: CCCCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Reactant: NCCO
Product: CCCCCCCCCCCCCCCCCCC1CC(=O)N(CCO)C1=O
Yield: 53.7 %

Procedure:
A 50 mL reaction flask was charged with 17.6 g of octadecyl succinic anhydride (manufactured by Tokyo Chemical Industry Co., Ltd.) and 3.1 g of ethanolamine (manufactured by Tokyo Chemical Industry Co., Ltd.), and the resulting mixture was reacted at 160° C. for 4 hours under continuous nitrogen purging and with vigorous stirring. The reaction product was purified by silica gel column chromatography (mobile phase: ethyl acetate/hexane), yielding 10.6 g of N-(2-hydroxyethyl)octadecyl succinimide (yield: 54%).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[N:56]1[CH:61]=[CH:60][N:59]=[CH:58][C:57]=1[C:62](Cl)=[O:63]>>[CH3:3][O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][N:26]1[C:62]([C:57]1[CH:58]=[N:59][CH:60]=[CH:61][N:56]=1)=[O:63])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1cnccn1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1cnccn1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (25 mg) was reacted with pyrazine-2-carbonyl chloride according to General Procedure F. The reaction mixture was directly purified over silica (heaxnes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+4% MeOH). to give (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(pyrazine-2-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (12 mg). LCMS (m/z): 847.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[N:13][CH:14]=1)C1C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[F:23][C:16]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=1[C:12]1[N:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1ccc(F)c(-c2ncc(OCc3ccccc3)cc2CC(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(-c2ncc(O)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.5 %

Procedure:
To a solution of 5-(benzyloxy)-2-(2-fluoro-5-methoxyphenyl)-3-neopentylpyridine (2.95 g) in ethyl acetate (50 mL) was added 10% palladium-carbon (628 mg) and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 20 min. The catalyst was filtered and the filtrate was concentrated to give the title compound (2.26 g) as a white solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([F:29])([F:28])[F:27])=O)(=O)OC.O.[NH2:31][NH2:32]>>[F:25][C:23]1[CH:22]=[CH:21][C:20]([C:26]([F:29])([F:28])[F:27])=[C:19]([C:17]2[CH:16]=[C:3]3[C:2]([CH:1]4[CH2:7][CH:4]3[CH2:5][CH2:6]4)=[N:32][N:31]=2)[CH:24]=1
Reactant: NN
Reactant: O=C1C(=O)C2CCC1C2
Reactant: COP(=O)(CC(=O)c1cc(F)ccc1C(F)(F)F)OC
Solvent: O
Product: Fc1ccc(C(F)(F)F)c(-c2cc3c(nn2)C2CCC3C2)c1

Procedure:
yellow gum. MS (EI): 308.0 (M+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(5-Fluoro-2-trifluoromethyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc([C@@H]2CCN(Cc3ccccc3)C2)c1
Solvent: CO
Product: Nc1cccc([C@@H]2CCN(Cc3ccccc3)C2)c1
Reaction time: 1.5 h
Yield: 84 %

Procedure:
(S)-1-Benzyl-3-(3-nitro-phenyl)-pyrrolidine (1 g, 3.54 mmol) was dissolved in methanol, 4.5 g of stannous dichloride (19.94 mmol) were added and the reaction mixture was stirred for 1.5 h under refluxing conditions. When the starting material was consumed, the solvent was evaporated under reduced pressure and the residue treated with a mixture of 1 N aqueous NaOH/ethyl acetate and filtered over celite. Phases were separated, the aqueous phase was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness to yield 0.75 g of a yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23]Cl.[H-].[Na+].C1(C)C=CC=CC=1>O>[CH3:19][N:20]([CH2:21][CH2:22][CH2:23][O:18][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:25]
Reactant: OC(CCCc1ccccc1)c1ccc(F)cc1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCCOC(CCCc1ccccc1)c1ccc(F)cc1

Procedure:
A mixture of 5.0 g of 1-(p-fluorophenyl)-4-phenyl-1-butanol, 10 g of γ-dimethylaminopropyl chloride, 2.0 g of sodium hydride (65%) and 100 ml of toluene was heated under refluxing for 30 minutes. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on silica gel to give 1-[3-(N,N-dimethylamino)propoxy]-1-(p-fluorophenyl)-4-phenylbutane. M.P., 80°-83° C. (fumarate).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([C:12](O)=[O:13])[CH2:9][CH2:8][CH2:7]2.ClCCl>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([CH2:12][OH:13])[CH2:9][CH2:8][CH2:7]2
Reactant: Cc1cccc2c1C(C(=O)O)CCC2
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc2c1C(CO)CCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
8-Methyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (J. Org. Chem. 1982, 47, 2590–2593) (0.066 g, 0.34 mmol) was dissolved in tetrahydrofuran (3 mL). To the solution was then added at 0° C. a 1.0M solution of borane-methyl sulfide complex in dichloromethane (0.7 mL, 0.69 mmol). The reaction mixture was stirred at room temperature for 15 minutes, refluxed for 2 hrs, then cooled down to 0° C. and quenched with methanol. The solvent was then evaporated in vacuo to yield a crude oil. The crude oil was partitioned with water and diethyl ether. The organic layer was dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield crude (8-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methanol as an oil which was used directly to the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:16]1([CH2:22][CH2:23][NH2:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: NCCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1CNCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-phenylethylamine.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH:8]/[CH:9]=[C:10](\[C:16]#[N:17])/[C:11]([O:13]CC)=O)(=[O:3])[CH3:2].C(NC1C=C(C=CC=1OC)N/C=C(/C#N)\C(OCC)=O)(=O)C.C1(C2C=CC=CC=2)C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[C:16]([C:10]1[C:11](=[O:13])[C:18]2[C:7](=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:20]([O:21][CH3:22])[CH:19]=2)[NH:8][CH:9]=1)#[N:17]
Reactant: CCOC(=O)/C(C#N)=C/Nc1ccc(OC)c(NC(C)=O)c1
Agent: CCOC(=O)/C(C#N)=C\Nc1ccc(OC)c(NC(C)=O)c1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: COc1cc2c(=O)c(C#N)c[nH]c2cc1NC(C)=O
Temperature: 256 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
An amount of 1 g (0.003 mol) of a mixture of ethyl (E)-3-[3-(acetylamino)-4-methoxyanilino]-2-cyano-2-propenoate and ethyl (Z)-3-[3-(acetylamino)-4-methoxyanilino]-2-cyano-2-propenoate was added to a stirring solution of biphenyl (16.3 mL, 0.10 mol) and phenyl ether (48.8 mL, 0.30 mol) at 256° C. After stirring for 2 hours at 256° C., the reaction mixture was cooled to room temperature, diluted with diethyl ether (130 mL), filtered, and evaporated to dryness to give a gray solid (0.53 g, 62% yield), mp 305-310° C.; 1H NMR (DMSO-d6) δ 12.80 (s, 1H), 9.58 (s, 1H), 8.62 (s, 1H), 8.58 (m, 1H), 7.52 (s, 1H), 3.97 (s, 3H), 2.20 (s, 3H); HRMS (EI) m/z 257.0793 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][NH:6][C:7](=[O:10])[CH2:8][CH3:9].Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]([N:20]2[C@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:21]2([CH3:30])[CH3:29])=[O:19])=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.O>C1COCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:13]2[C:12]([O:3][CH2:4][CH2:5][NH:6][C:7](=[O:10])[CH2:8][CH3:9])=[N:17][CH:16]=[C:15]([C:18]([N:20]3[C@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:21]3([CH3:30])[CH3:29])=[O:19])[CH:14]=2)=[CH:32][CH:33]=1
Reactant: CCC(=O)NCCO
Reactant: CC(C)C[C@@H]1COC(C)(C)N1C(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)NCCOc1ncc(C(=O)N2[C@H](CC(C)C)COC2(C)C)cc1-c1ccc(Cl)cc1
Reaction time: 6 h
Yield: 33.2 %

Procedure:
Sodium hydride dispersion in oil (˜55%, 72 mg) was added in portions to a well stirred solution of N-(2-hydroxyethyl)propionamide (71 mg, 0.6 mmol) in THF (13 mL). After stirring the mixture for 15 min at RT [6-Chloro-5-(4-chloro-phenyl)-pyridin-3-yl]-((R)-4-isobutyl-2,2-dimethyl-oxazolidin-3-yl)-methanone (225 mg, 0.55 mmol) was added and stirring continued for 6 h at RT. The mixture was poured into water and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (cyclohexane/ethyl acetate 8:1) to yield 89 mg of the title compound as a white solid, MS (ISP) 488.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[N:14]=[N:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:12]3[CH2:11][CH2:10][CH2:9][C:8]=2[CH:22]=1.[OH-].[Na+]>C1COCC1.CO>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[N:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:12]3[CH2:11][CH2:10][CH2:9][C:8]=2[CH:22]=1
Reactant: CCOC(=O)c1nnn2c1CCCc1cc(OC(F)(F)F)ccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nnn2c1CCCc1cc(OC(F)(F)F)ccc1-2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of ethyl 8-(trifluoromethoxy)-5,6-dihydro-4H-benzo[f][1,2,3]triazolo[1,5-a]azepine-3-carboxylate (384 mg, 1.125 mmol) in THF (5 mL) and methanol (3 mL) was added 2M NaOH (aq) (2.81 mL, 5.63 mmol) and the mixture was stirred at RT for 45 mins. The resulting mixture was concentrated under reduced pressure to give a residue that was partitioned between EtOAc and water. The layers were separated and the aqueous layer was washed with EtOAc. The organic portions were discarded and the aqueous layer was treated with 2M HCl (aq) until acidic. The resulting solution was extracted with EtOAc and the organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)=[O:13].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C:11]([F:10])([F:21])[F:22])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C1CCN(C(=O)C(F)(F)F)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(N1CCC(NCc2ccc(F)cc2)CC1)C(F)(F)F
Reaction time: 0.08 h
Yield: 36.9 %

Procedure:
4-Fluorobenzylamine (3.14 g, 25.9 mmol) was dissolved in methanol (150 mL). 1-(trifluoroacetyl)-4-piperidone (5.07 g, 25.9 mmol) was added and the pH was adjusted to ˜5 with acetic acid. The reaction mixture was stirred for 5 min and NaBH3CN (2.46 g, 38.9 mmol) was added slowly under stirring. After 20 h at room temperature the reaction was concentrated 2 M NaOH (100 mL) was added and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to give N-(4-fluorobenzyl)-1-(trifluoroacetyl)piperidin-4-amine (50ELH85, 2.91 g, 37%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[F:8][C:9]([F:45])([F:44])[O:10][C:11]1[CH:12]=[C:13]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26]C(C(F)(F)F)=[CH:24][CH:23]=3)[C:20](=[O:32])[C:19](NC3C=CC(C(F)(F)F)=CC=3)=[CH:18]2)[CH:14]=[CH:15][CH:16]=1.C[O:47]C1CCC(OC)O1>O.C(O)(=O)C.C(O)C>[OH:47][C:19]1[C:20](=[O:32])[N:21]([C:22]2[CH:27]=[CH:26][C:3]([C:2]([F:7])([F:6])[F:1])=[CH:24][CH:23]=2)[CH:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:9]([F:8])([F:45])[F:44])[CH:12]=2)[CH:18]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COC1CCC(OC)O1
Reactant: O=C1C(Nc2ccc(C(F)(F)F)cc2)=CC(c2cccc(OC(F)(F)F)c2)N1c1ccc(C(F)(F)F)cc1
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C1C(O)=CC(c2cccc(OC(F)(F)F)c2)N1c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 16.5 h

Procedure:
Mix ethanol (120 mL), glacial acetic acid (15 mL), water (3.0 mL, 164.7 mmol), trifluoroacetic acid (6.2 mL, 82.4 mmol), (±)-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-3-(4-trifluoromethyl-phenylamino)-1,5-dihydro-pyrrol-2-one (30.0 g, 54.9 mmol), and 2,5-dimethoxy-tetrahydrofuran (10.7 mL, 82.4 mmol). Warm the solution to 50° C. and stir the reaction mixture for 15-18 hours. Discontinue heating the solution, add water (35 mL), and cool the reaction mixture to −19° C. Filter the slurry and wash the solid with a 1:4 mixture of water-methanol (20 mL). Transfer the filtrate to a separatory funnel and wash with 6% brine (280 mL), then add 6% brine (100 mL), methanol (40 mL), diethyl ether (100 mL), and saturated sodium bicarbonate solution (43 mL) to the organic phase. Separate the layers, add methanol (60 mL) to the organic phase, and concentrate the solution to approximately 1 volume containing (±)-3-hydroxy-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:18]3[S:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:18]3[S:19][CH:20]=[C:21]([CH:23]([CH3:24])[CH3:25])[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:35][CH2:36][C:37]([OH:39])=[O:38]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccc(F)cc3)c3nc(C(C)C)cs3)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1csc(N(CCc2ccc(F)cc2)Cc2ccc(COc3ccc(CCC(=O)O)c(F)c3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Ethyl 3-{2-fluoro-4-[(4-{[[2-(4-fluorophenyl)ethyl](4-isopropyl-1,3-thiazol-2-yl)amino]methyl}benzyl)oxy]phenyl}-propanoate (485 mg) was dissolved in ethanol (5 mL), 2N aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.) and concentrated to give the title compound (354 mg, yield 75%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5]([CH2:7]Br)=[CH2:6])[CH3:2].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)C(C)C)C>CN(C)C=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:7][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])=[CH2:6])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=C(CBr)C(=O)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(CN1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
To a solution of 2-bromomethyl-acrylic acid ethyl ester (1.93 g, 10 mmol) in N,N-dimethylformamide (25 mL) was added piperazine-1-carboxylic acid tert-butyl ester (1.86 g, 10 mmol) and then, dropwise, ethyl-diisopropyl-amine (1.71 mL, 10 mmol). After stirring for 16 h at room temperature the solvent was removed under reduced pressure and water (50 mL) and dichloromethane (50 mL) were added. After stirring for 2 min the layers were separated, the organic was washed with water and brine, and dried over magnesium sulphate. The solvent was removed under reduced pressure to give crude 4-(2-ethoxycarbonyl-allyl)-piperazine-1-carboxylic acid tert-butyl ester (2.456 g, 82%).