Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:52])([F:51])[C:17]1[CH:18]=[C:19]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:20][N:21]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][NH:25][C:24]2[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]([CH3:33])=[CH:32][C:23]1=2.[CH3:53][O:54][C:55](=[O:65])[C:56]1[CH:61]=[C:60]([CH:62]=O)[CH:59]=[CH:58][C:57]=1[F:64].C(O)(=O)C>C(#N)C.ClCCl>[CH3:53][O:54][C:55](=[O:65])[C:56]1[CH:61]=[C:60]([CH2:62][N:25]2[CH2:26][CH2:27][CH2:28][C@H:22]([N:21]([CH2:20][C:19]3[CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=[C:17]([C:16]([F:51])([F:15])[F:52])[CH:18]=3)[C:38]3[N:39]=[N:40][N:41]([CH3:43])[N:42]=3)[C:23]3[CH:32]=[C:31]([CH3:33])[C:30]([C:34]([F:35])([F:36])[F:37])=[CH:29][C:24]2=3)[CH:59]=[CH:58][C:57]=1[F:64]
Reactant: COC(=O)c1cc(C=O)ccc1F
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)ccc1F
Reaction time: 24 h
Yield: 92.3 %

Procedure:
Add sodium triacetoxyborohydride (0.153 g, 0.724 mmol) portionwise to a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.100 g, 0.181 mmol), 2-fluoro-5-formyl-benzoic acid methyl ester (0.100 g, 0.543 mmol) and glacial acetic acid (1 mL) in acetonitrile (10 mL) at room temperature under an atmosphere of nitrogen and stir for 24 h. Quench the reaction with saturated sodium bicarbonate (5 mL) and dilute with dichloromethane (15 mL). Separate the layers and wash the organic layer with saturated sodium bicarbonate and brine (20 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as a white foam (0.120 g, 92%), 1H NMR (CDCl3, 300 MHz) δ 1.23-1.34 (m, 2H), 1.64-1.72 (m, 2H), 2.10-2.20 (m, 1H), 2.32 (s, 3H), 2.76-2.80 (m, 1H), 2.94-3.02 (m, 1H), 3.89 (s, 3H), 4.14 (s, 3H), 4.23-4.54 (m, 2H), 4.76-5.02 (m, 2H), 5.62-5.70 (m, 1H), 6.90 (s, 1H), 7.10 (m, 1H), 7.35-7.43 (m, 2H), 7.56-7.80 (m, 2H), 7.89-7.92 (m, 1H); ESI MS m/z 719 [C32H28F10N6O2+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1.O>CS(C)=O>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:16]2[CH:17]=[CH:18][C:19]([C:22](=[O:24])[CH3:23])=[CH:20][N:21]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(=O)c1ccc(Cl)nc1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To 4-hydroxy-boc-piperidine (1.55 g, 7.71 mmol) in DMSO (12 mL) was added 1M KtOBu (8.36 mL), followed by 1-(6-chloropyridin-3-yl)ethanone (1.00 g, 6.43 mmol). After overnight stirring at 100° C., the reaction was poured into water, extracted with dichloromethane, washed with brine, dried over sodium sulfate, and concentrated. The product was purified using a Single Step column (7:3 hexanes:ethyl acetate) to obtain 0.5 g (25%); MS m/z 321 (M+H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][CH:6]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9].C(=O)([O-])[O-].[Na+:17].[Na+].C(=O)=O>>[Br:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][C:6]=1[S:8]([O-:11])(=[O:10])=[O:9].[Na+:17]
Reactant: O=S(=O)(O)O
Reactant: Brc1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Product: O=S(=O)([O-])c1cc(Br)sc1Br
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Equal volumes of 2,5-dibromothiophene and 27°-30% fuming sulfuric acid were added to a 100 ml round bottom flask immersed in an ice bath. The mixture was stirred for five minutes and then added to 200 ml of ice water. Sodium carbonate was added until carbon dioxide evolution ceased. The mixture was filtered and the aqueous filtrate stripped of solvent under vacuum. The resulting solid was combined with 300 ml of ethanol and the mixture heated to reflux for 2.5 hours. The hot solution was filtered. A solid formed which was washed with ethyl acetate and dried to provide sodium 2,5-dibromo-3-thiophenesulfonate. The sulfonate was added to 150 ml of water and about 40 gm of 5% sodium/mercury amalgam was added over a 0.5 hour period. The temperature was maintained at 35° C. or below The aqueous layer was decanted from the mercury and filtered. The filtrate was neutralized with 1N HCl to a pH of 7. The solution was then stripped to dryness. The resulting solid was heated to reflux in 200 ml of ethanol. The hot liquid was filtered and the filtrate condensed to provide an off-white solid of sodium 3-thiophenesulfonate. Phosphorous oxychloride (20 ml) was mixed with this thiophenesulfonate (3.17 g) and stirred at reflux for about two hours under a drying tube. The reaction mixture was cooled to room temperature and slowly added to ice. The resulting mixture was extracted with two 200-ml aliquots of a mixture of ethyl acetate and ethyl ether and the resulting organic layer extracted with water. The organic layer was isolated and the solvent removed under vacuum. The resulting residue was combined with 50 ml of concentrated ammonium hydroxide and stirred at room temperature. THF (50 ml) was added to obtain a homogenous mixture. After two hours of stirring, the mixture was partially concentrated and acidified with concentrated HCl. The resulting mixture was extracted with two 200-ml aliquots of a mixture of ethyl acetate and ethyl ether. The organic layers were combined and dried over sodium sulfate, filtered, and concentrated to provide a solid product. The solid was crystallized from ethyl acetate and dried to provide 3-thiophenesulfonamide (1.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=1.C([O:18][CH:19]=[C:20]([C:26](=[O:37])[C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([Cl:35])[C:28]=1F)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>C(O)C>[C:12]([NH:11][C:4]1[N:3]=[C:2]([N:1]2[C:28]3[C:27](=[CH:32][C:31]([F:33])=[C:30]([F:34])[C:29]=3[Cl:35])[C:26](=[O:37])[CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]2=[O:18])[C:7]([C:8]#[N:9])=[CH:6][C:5]=1[F:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)Nc1nc(N)c(C#N)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: CCO
Product: CCOC(=O)C1C(=O)c2cc(F)c(F)c(Cl)c2N(c2nc(NC(C)(C)C)c(F)cc2C#N)C1=O
Reaction time: 8 h
Yield: 45.4 %

Procedure:
A solution of 300 mg of unpurified 2-amino-6-t-butylamino-3-cyano-5-fluoropyridine in 2 ml ethanol was added dropwise to a solution of 420 mg of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate in 2 ml ethanol at room temperature, and the mixture was stirred overnight. The solvent was distilled off the reaction solution, and to the residue were added 3 ml of N,N-dimethylformamide and 210 mg of potassium carbonate, and the mixture was stirred at room temperature for 90 minutes and 80° C. for 2 hours. The reaction solution was extracted by adding water and ethyl acetate, and the organic layer was collected and dried over magnesium sulfate. The solvent was distilled off, and the residue was collected by filtration using ethanol and washed with diethylether to obtain 280 mg of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:6]1[C:5]2[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][C:4]=2[C:9](=[O:10])[O:8][C:7]1=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccccc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
A solution of Compound 58 (4.9 g, 25 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 1.2 g, 30 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat benzyl bromide (3.78 mL, 30 mmol) was added and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 6.5 g (90%) of white solids. 1H NMR (DMSO-d6): δ 5.45 (s, 2H), 7.17 (d, J=8.7 Hz, 1H), 7.26-7.39 (m, 5H), 7.65 (dd, J=1.5, 8.7 Hz, 1H), 8.02 (d, J=1.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:6]([CH:11]=1)[N:7]([CH3:10])[CH:8]=O>C(O)(C)C>[F:1][C:2]1[CH:11]=[C:6]2[C:5]([C:12](=[O:18])[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][N:7]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Solvent: CC(C)O
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(F)cc21
Temperature: 25 °C

Procedure:
A solution of 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide (1.0 g), prepared in a similar manner to that described in Example 11, in isopropyl alcohol (20 ml) was heated to reflux for 3.5 hours. The mixture was cooled to ambient temperature and the product collected by filtration and dried in vacuo at 50° to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p. 234.5°-235° (0.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:8]([C@H:9]4[C@@:13]([CH2:16][CH2:17]3)([CH2:14][CH3:15])[C:12](=[O:22])[CH:11]=[CH:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>O1CCCC1.CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:8]([C@H:9]4[C@@:13]([CH2:16][CH2:17]3)([CH2:14][CH3:15])[C@@H:12]([OH:22])[CH:11]=[CH:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1C=CC2=O
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1C=C[C@@H]2O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
4.7 g of 3-methoxy-18-methyl-1,3,5(10),15-estratetraen-17-one in 30 ml of tetrahydrofuran and 45 ml of methanol are mixed with 6.8 g of cerium(III)-chloride heptahydrate. At 0° C., 1.0 g of sodium borohydride is added, in portions. After 1 hour, the reaction mixture is put in ice/water. The precipitated product is suctioned off, dissolved in ethyl acetate, washed with water and dried. 4.5 g of 3-methoxy-18-methyl-1,3,5(10),15-estratetraen-17β-ol is obtained as a foam.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:23]=[CH:22][C:8]2[CH:9]=[C:10]([C:17]([O:19]CC)=[O:18])[CH:11]([C:13]([F:16])([F:15])[F:14])[O:12][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].F>>[CH3:4][C:2]([C:5]1[CH:23]=[CH:22][C:8]2[CH:9]=[C:10]([C:17]([OH:19])=[O:18])[CH:11]([C:13]([F:14])([F:15])[F:16])[O:12][C:7]=2[CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)C)cc2OC1C(F)(F)F
Agent: F
Product: CC(C)(C)c1ccc2c(c1)OC(C(F)(F)F)C(C(=O)O)=C2

Procedure:
Ethyl 7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 8, Step 2) was hydrolyzed to the carboxylic acid is a procedure similar to that described in Example 1, Step 2: mp 165.6-166.8° C. 1H NMR (acetone-d6 /300 MHz) 7.86 (s, 1H), 7.38 (d, 1H, J=8.1 Hz), 7.1) (dd, 1H, J=1.8 Hz, and J=7.8 Hz), 7.05 (bs, 1H), 5.79 (q H-F, 1H, J=7.2 Hz), 1.32 (s, 9H). FABHRMS m/z 301.1033 (M+H, Calc'd 301.1051). Anal. Calc'd for C15H15F3O3 : C, 60.00; H, 5.04. Found: C, 59.80; H, 5.10.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[O-]CC.[Na+].CCCCCC>C1COCC1>[OH:17]/[C:11](=[CH:9]\[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:10])/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(=O)c1cncc(C)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)/C(O)=C/C(=O)c1cncc(C)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-2 (0.5 g, 3.70 mmol) and diethyl oxalate (1.010 ml, 7.40 mmol) in THF (15 ml) was added sodium ethoxide (3.45 ml, 21% wt. in ethanol, 9.25 mmol). The resulting mixture was heated at 60° C. for 1 h followed by stirring at rt overnight. The reaction mixture was poured into cold hexane and the desire product 1-3 was collected as a light yellow solid: ESI+ MS [M+H]+ C12H14NO4=236.1.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:22])[CH:15]([F:21])[CH:16]([F:20])[C:17]([OH:19])=[O:18].C([N-]C(C)C)(C)C.[Li+].[CH2:31](Br)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:22])[CH:15]([F:21])[C:16]([F:20])([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:17]([OH:19])=[O:18]
Reactant: O=C(O)C(F)C(F)C(=O)c1ccc2oc3ccccc3c2c1
Reactant: BrCCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccc2oc3ccccc3c2c1)C(F)C(F)(CCc1ccccc1)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-dibenzofuran-2-yl-2,3-difluoro-4-oxo-butyric acid (1 equivalent, Example 6) in tetrahydrofuran cooled to -78° C. is added dropwise a solution of lithium diisopropylamide (2 equivalents). After stirring at -78° C. for 30 minutes, a solution of phenethyl bromide (1 equivalent) in tetrahydrofuran is added. The cooling bath is removed, and the reaction mixture gradually warms to room temperature and is stirred overnight. To this solution is added aqueous HCl (1 M) and ethyl acetate. The layers are separated, and the organic portion is washed with brine, dried (MgSO4), and concentrated in vacuo. The title compound is obtained by separation from the reaction by-product using silica gel chromatography (elution with chloroform/methanol).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([I:26])[CH:21]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:27]I>O1CCCC1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[OH-].[Na+]>[Cl:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:27])[C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([I:26])[CH:21]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc2[nH]c(=O)cc(-c3cccc(I)c3)c2c1)c1ccc(Cl)s1
Reactant: CI
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)cc(-c2cccc(I)c2)c2cc(C(=O)c3ccc(Cl)s3)ccc21
Reaction time: 24 h

Procedure:
If one were to take 3 mmole of quinolone 5 from Step D dissolved in tetrahydrofuran (THF) and treat it with 1.5 equivalents of methyl iodide, 0.5 equivalents of benzyltriethylammonium chloride in 10 N aqueous sodium hydroxide and stir the resulting mixture for 24 hours followed by organic extraction with methylene chloride one would produce the resulting product, 6-(5-chloro-thiophene-2-carbonyl)-4-(3-iodo-phenyl)-1-methyl-1H-quinolin-2-one (6).
Reaction SMILES: OO.[CH2:3]([SH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:12][C:13]([NH2:15])=[S:14].[ClH:16]>C(O)C.C(OCC)C.O>[ClH:16].[CH2:3]([S:11][S:14][C:13](=[NH:12])[NH2:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCS
Reactant: NC(N)=S
Agent: Cl
Agent: OO
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCSSC(=N)N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen peroxide (30% aqueous, 28.0 g) was added dropwise over 45 minutes to a stirred mixture of n-octanethiol (32.27 g, 0.221 mole), thiourea (20.1 g, 0.264 mole), concentrated hydrochloric acid (35 ml), water (35 ml) and ethanol (500 ml) maintained at 0°-10° C. After the addition was complete the reaction mixture was stirred at room temperature for 2 hours during which time a thick white precipitate formed. The mixture was filtered and the filtrate evaporated giving a solid residue. This was dissolved in ethanol (150 ml), diluted with diethyl ether (800 ml) and allowed to stand overnight at 0° C. Filtration gave white crystals of the product (46.3 g; 82%), melting point=77°-82° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]1=[O:15].[C:16](Cl)(=O)C(Cl)=O.CO.C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH3:16][O:13][C:12]([C:4]1[C:3](=[O:15])[N:2]([CH3:1])[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=1)=[O:14]
Reactant: Cn1c(C(F)(F)F)ccc(C(=O)O)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(F)(F)F)n(C)c1=O
Yield: 92.8 %

Procedure:
1,2-dihydro-1-methyl-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid (114.0 g, 0.52 mol) was dissolved in dichloromethane (500 mL), and oxalyl chloride (99 g, 0.78 mol) was added thereto at room temperature. Thereto, N,N′-dimethylformamide (1 mL) was added, and the mixture was refluxed for 2 hours under heating. The solvent was distilled off, acetonitrile (500 mL) was added, and a mixture of methanol (33 g, 1.03 mol) and triethylamine (104 g, 1.03 mol) was added dropwise under ice cooling. After the 2 hours reaction at room temperature, the solvent was distilled off, an aqueous sodium bicarbonate solution was added, and extraction with chloroform was subjected. The organic layer was washed with an aqueous solution of citric acid and water, dried, and concentrated. Thus obtained oily product was purified by column chromatography (elution solvent: hexane/ethyl acetate=4/1 to 1/1) to obtain 113.5 g of a desired product (yield: 94%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([Cl:13])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=1)=[O:16])[CH2:6]2.ClC1C(Cl)=C(Cl)C(Cl)=C2C=1[CH2:38][N:39](C(C(C)C)C(O)=O)C2.[OH-].[K+].S(OC(C#N)C1C=CC=C(OC2C=CC=CC=2)C=1)(=O)(=O)C>C(O)C.O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([Cl:13])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([O:17][CH:18]([C:38]#[N:39])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=1)=[O:16])[CH2:6]2
Reactant: CC(C)C(C(=O)O)N1Cc2c(Cl)c(Cl)c(Cl)c(Cl)c2C1
Reactant: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)N1Cc2c(Cl)c(Cl)c(Cl)c(Cl)c2C1
Agent: CS(=O)(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)N1Cc2c(Cl)c(Cl)c(Cl)c(Cl)c2C1

Procedure:
The ester, m-phenoxybenzyl 2-(4,5,6,7-tetrachloro-2-isoindolinyl)-3-methylbutanoate is hydrolyzed to 2-(4,5,6,7-tetrachloro-2-isoindolinyl)-3-methylbutanoic acid using KOH in ethanol/water, which is reacted with α-cyano-m-phenoxybenzyl mesylate to yield α-cyano-m-phenoxybenzyl 2-(4,5,6,7-tetrachloro-2-isoindolinyl)-3-methylbutanoate.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.S(=O)(=O)(O)O.[C:19](=O)(O)[O-].[Na+]>CO>[OH:9][C:8]1[CH:10]=[CH:11][C:3]([CH2:2][C:1]([O:13][CH3:19])=[O:12])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(O)c(OC)c1
Yield: 94 %

Procedure:
A solution of homovanillic acid 10 (2 g, 11 mmol) and sulfuric acid (500 ml, 9.4 mmol) in methanol (100 ml) was refluxed for 3 hours. After cooling, a sodium bicarbonate solution was added to the reaction mixture. The product was extracted with CH2Cl2 (2×50 ml). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give methyl 4-hydroxy-3-methoxyphenylacetate 9 (2 g, 94%) in the form of a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.00-6.70 (m, 3H), 5.82 (br s, OH), 3.87 (s, 3H), 3.70 (s, 3H), 3.56 (s, 2H). 13C NMR (CDCl3, 75 MHz) δ 172.6, 146.6, 144.8, 125.7, 122.1, 114.5, 111.8, 55.9, 52.1, 40.8.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]CC)=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]3[CH2:39][CH2:38][CH2:37][N:36]([CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]3=[O:47])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]3[CH2:39][CH2:38][CH2:37][N:36]([CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]3=[O:47])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N3CCCN(Cc4ccccc4)C3=O)cc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccc(N3CCCN(Cc4ccccc4)C3=O)cc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazole and 1N sodium hydroxide solution in ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([O:22]C)[CH:21]=1)[C:5]([N:7]([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:9][C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)=[O:6].B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:5]([N:7]([CH:16]([CH3:17])[CH3:18])[CH2:8][CH2:9][C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)=[O:6]
Reactant: COc1cc(Cl)cc(C(=O)N(CCc2nnnn2C)C(C)C)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(C)N(CCc1nnnn1C)C(=O)c1cc(O)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
To a stirred solution of 3-chloro-N-isopropyl-5-methoxy-N-[2-(1-methyl-1H-tetrazol-5-yl)-ethyl]-benzamide (0.115 g) in anhydrous dichloromethane (5.0 ml) at −78° C. was added 1M boron tribromide solution in dichloromethane (1.36 ml). The reaction mixture was stirred at this temperature for 15 min. The reaction was allowed to warm to room temperature. After 24 h, the reaction was cooled to −78° C. and methanol (1 ml) added. The reaction was allowed to rewarm to room temperature and absorbed on to silica. This was loaded on to an already prepared flash column, eluting with ethyl acetate:petroleum ether (4:1 v/v) and 25:1 dichloromethane:methanol (25:1 v/v) to give the title compound as a white solid (0.072 g).
Reaction SMILES: C(O[C:9]([S:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:35])/[CH:20]=[CH:21]/[C:22]2[CH:23]=[N:24][N:25]([CH3:34])[C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.ClC[C:38]1[N:42]([CH2:43][CH2:44][CH3:45])[CH:41]=[N:40][N:39]=1.[OH-].[Na+]>C(O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]2[N:25]([CH3:34])[N:24]=[CH:23][C:22]=2/[CH:21]=[CH:20]/[C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([S:11][CH2:9][C:38]3[N:42]([CH2:43][CH2:44][CH3:45])[CH:41]=[N:40][N:39]=3)=[CH:17][CH:16]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(SC(=O)OCc3ccccc3)cc2)c1-c1ccc(F)cc1
Reactant: CCCn1cnnc1CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1cnnc1CSc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Yield: 65 %

Procedure:
A mixture of (2E)-N-{4-[(benzyloxycarbonyl)sulfanyl]phenyl}-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide (488 mg), 3-(chloromethyl)-4-propyl-4H-1,2,4-triazole (240 mg), a 1N aqueous sodium hydroxide solution (3 ml) and ethanol (30 ml) was stirred at room temperature for 3 hrs. The reaction mixture was concentrated, poured into water, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-(4-{[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]thio}phenyl)acrylamide (310 mg, 65%) as pale-yellow crystals.