Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1C=CC2C(C3C(O)=CC=C4C=3C=CC=C4)=C(O)C=CC=2C=1.O.[OH-].[Na+:49].[O-]CC.[Na+]>C(OC)(C)(C)C.C(OC(=O)C)C>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+:49]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: CC[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 2.5 °C

Procedure:
Esomeprazole-BINOL inclusion complex (100 g; 158.3 mmol; ee of 98.2%) was suspended in a mixture of methyl t-butyl ether (1300 ml) and DM water (400 ml). Aqueous sodium hydroxide solution (5 w/w; 133 g) was added to the suspended mass at 20-30° C. and stirred till clear solution was obtained. Thereafter, organic layer was separated and the aqueous layer was washed with methyl t-butyl ether. Thereafter, 20% aqueous ammonium formate solution (60 ml) was added and extracted with methylene chloride (300 ml). The organic layer was washed with DM water and concentrated under reduced pressure to yield a foamy mass. The concentrated mass was dissolved in ethylacetate (400 ml) and cooled to 0-5° C. To the solution, sodium ethoxide (10.77 g, mmol) was added and stirred at 20-30° C. for 90 min. The separated solid mass was filtered, washed with ethyl acetate and dried under reduced pressure at 40° C. to yield esomeprazole sodium.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@@H:15]([C@@H:16]([OH:30])[C@@H:17]([N+:27]([O-])=O)[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[CH2:14][O:13][C@H:12]([O:31][CH2:32][CH3:33])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.[Ni](Cl)Cl>[C:3]([O:7][C:8]([N:10]1[C@@H:15]([C@@H:16]([OH:30])[C@@H:17]([NH2:27])[CH2:18][C:19]2[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=2)[CH2:14][O:13][C@H:12]([O:31][CH2:32][CH3:33])[CH2:11]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)[N+](=O)[O-])CO1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Yield: 70.2 %

Procedure:
Add sodium borohydride (0.061 g, 1.62 mmol) portionwise to a solution of (2S,5R)-5-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-2-nitropropyl]-2-ethoxymorpholine-4-carboxylic acid tert-butyl ester (0.145 g, 0.325 mmol) and nickel (II) chloride (0.063 g, 0.487 mmol) at room temperature in methanol (5 mL) and stir 30 for min. Add water (˜3 mL) and concentrate. Dilute with ethyl acetate and filter through a filtering agent. Partition the filtrate between ethyl acetate and water, dry (magnesium sulfate) and concentrate to give the title compound as a white solid (95 mg, 70%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=2)=O)=[C:4]1[CH3:23])[CH3:2].[C:24]1([C:30]2[C:31]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:32][N:33]3[C:38]=2[CH:37]=[CH:36][CH:35]=[CH:34]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OC(=O)C)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([C:32]3[N:33]4[C:38]([CH:37]=[CH:36][CH:35]=[CH:34]4)=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:31]=3[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:20](=[O:21])[O:22]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: c1ccc(-c2cn3ccccc3c2-c2ccccc2)cc1
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3c(-c4ccccc4)c(-c4ccccc4)c4ccccn34)OC(=O)c3cccnc32)c2ccccc21

Procedure:
A mixture of 1.6 grams of (1-ethyl-2-methylindol-3-yl)(3-carboxypyridin-2-yl)ketone, 1.85 grams of 1,2-diphenylindolizine and 10 ml. of acetic anhydride was heated at about 40° C. for 104 minutes and then cooled in an ice bath. The reaction mixture was filtered and the product was repeatedly recrystallized from a toluene-petroleum ether mixture until a constant melting point of 206.5°-207.5° C. was obtained. A chloroform solution of the final product produced a blue color when applied to a record sheet material coated with a zinc-modified phenolic resin.
Reaction SMILES: C(OC([N:8]([C:28]1[C:33]([O:34][CH3:35])=[N:32][C:31]([CH3:36])=[CH:30][N:29]=1)[S:9]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)=[N:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])=O)C(C)C.[I-].[K+].C(OC1C=CC(B(O)O)=CC=1)(C)C>>[CH:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([S:9]([NH:8][C:28]3[C:33]([O:34][CH3:35])=[N:32][C:31]([CH3:36])=[CH:30][N:29]=3)(=[O:11])=[O:10])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:19][CH:20]=1)([CH3:27])[CH3:26]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(OC(C)C)cc1
Agent: CC(C)Oc1ccc(B(O)O)cc1
Agent: [I-]
Agent: [K+]
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(OC(C)C)cc1

Procedure:
1H NMR (CDCl3): 1.40 (d, 6H), 2.3 (s, 3H), 3.8 (s, 3H), 4.6 (m, 1H), 6.7 (br s, 1H), 6.9 (d, 2H), 7.2-7.35 (m, 3H), 7.5 (dd, 1H), 8.7 (dd, 1H), 8.8 (dd, 1H); mass spectrum (+ve ESP): 415 (M+H)+; starting from N-isobutoxycarbonyl-2-(4-isopropoxyphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide; 1H NMR (CDCl3): 0.7 (d, 6H), 1.40 (d, 6H), 1.7 (m, 1H), 2.5 (s, 3H), 3.8 (d, 3H), 4.0 (s, 3H), 4.6 (m, 1H), 6.9 (d, 2H), 7.45 (dd, 1H), 7.6 (d, 2H), 7.9 (s, 1H), 8.8 (dd, 1H), 8.95 (dd, 1H); mass spectrum (+ve ESP): 515 (M+H)+; itself obtained using an analogous procedure to that described in Example 1, part (iii) but with the addition of potassium iodide (1 molar equivalent) and using 4-isopropoxyphenylboronic acid which was prepared as described in European Patent Application, publication no. 569193.
Reaction SMILES: [NH4+:1].[OH-].[NH2:3][C:4]1[N:12]=[C:11]2[C:7](=[N:8][CH:9]=[N:10]2)[C:6](=[S:13])[N:5]=1>[OH-].[K+]>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([S:13][NH2:1])[N:5]=1
Reactant: [NH4+]
Reactant: NC1=NC(=S)C2=NC=NC2=N1
Agent: [K+]
Agent: [OH-]
Product: NSc1nc(N)nc2nc[nH]c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To an ice-cold 5.25% sodium hypochlorite solution (33.8 mL) was added 7N NH4OH (17.8 mL) and stirred for 10 minutes. A solution of 2-aminopurine-6-thione 1, see A. G. Beaman and R. K. Robins, J. Am. Chem. Soc., 83, 4038, (1961), (1.67 g, 22 mmol) in 2N KOH (11 mL) was added and continued stirring for 25 min at 0.C. The mixture was allowed to stand at 0° C. without stirring for 1.5 h. The precipitate was collected by filtration and washed with small amount of water and EtOH to obtain 1.45 g (36%) of the title compound, mp>250° C.: UV: λmax (pH 1) 325 nm (ε 6,400), 240 nm (sh): λmax (pH 7) 310 nm (ε 5,900), 237 nm (ε 6,800): λmax (pH 11) 312 nm (ε 5,900): 1H NMR (DMSO-d6): δ 5.78 (br s, 2, NH2, exchangeable in D2O), 7.73 (s, 1, C8H): Anal. Calcd for C5H6N6S.1/2 H2O (191.1): C, 31.41: H, 3.27: N, 43.98: S, 16.79. Found: C, 1.89: H, 3.27: N, 43.38: S, 17.19.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[CH:8]=[CH:9][C:10]=1[Cl:11])C=C.Cl.C(N(CC)[C:29]1[CH:34]=CC=C[CH:30]=1)C>>[CH2:34]([C:6]1[C:5]([OH:4])=[C:10]([Cl:11])[CH:9]=[CH:8][C:7]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]([CH3:23])[C:13]1=[O:24])[CH:29]=[CH2:30]
Reactant: C=CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reactant: CCN(CC)c1ccccc1
Agent: Cl
Product: C=CCc1c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc(Cl)c1O
Temperature: 180 °C
Reaction time: 3 h

Procedure:
In 100 ml of N,N-diethylaniline, 8.0 g of 1-(3-allyloxy-4-chlorophenyl)-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione was dissolved, and the solution was stirred at 180° C. for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into diluted hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by silica gel chromatography, which afforded 6.3 g of the desired compound.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:22])[NH:18][CH2:19][CH2:20][OH:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(OC(N1CCC(C(Cl)=O)CC1)=O)C1C=CC=CC=1.OCCN>>[OH:21][CH2:20][CH2:19][NH:18][C:17]([CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[O:22]
Reactant: O=C(NCCO)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: NCCO
Product: O=C(NCCO)C1CCNCC1

Procedure:
1-Benzyloxycarbonyl-4-[N-(2-hydroxyethyl)carbamoyl]piperidine [6.24 g, m.p. 107°-108°, Found: C, 62.8; H, 7.2; N, 9.0; Calculated: C, 62.7; H, 7.2; N, 9.1; prepared similarly to Preparation C but starting from 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and 2-hydroxyethylamine] was hydrogenated as in Preparation G to give 4-[N-(2-hydroxyethyl)carbamoyl]piperidine. The i.r. and n.m.r. spectra were consistent with this structure and the product was used in Example 6 without further purification.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([N:15]=[C:16]=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CCCCCC>[CH2:7]([NH:15][C:16]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCN
Reactant: CCCCCCCCN=C=O
Solvent: CCCCCC
Product: CCCCCCCCNC(=O)NCCCCC
Reaction time: 8 h
Yield: 97 %

Procedure:
To 0.262 g (3.00 mmol) of pentylamine in 20 mL of hexane is added 0.53 mL (0.47 g, 3.0 mmol) of octylisocyanate with stirring to eventually produce a white crystalline solid. After standing overnight the mixture is cooled, the solid product collected, and washed with cold hexane. On air drying there is obtained 0.705 g (2.91 mmol, 97%) of 1-octyl-3-pentylurea as very fine white needles, mp 65.0-65.5° C. The material displays a 13C-NMR and a mass spectrum consistent with the assigned structure. 13C-NMR (CDCl3): δ 159.0 (C═O), 40.47 and 40.45 (C-1 and C-1′), 31.8 (C-6 and C-3′), 30.4 (C-2), 30.1 (C-2′), 29.3 (C-4), 29.2 (C-5), 27.0 (C-3), 22.5 (C-7), 22.4 (C-4′), 13.9 (C-8 and C-5′); important infrared absorption bands (KBr disc) are present at 3334 (s, N—H), 1617 (vs, C═O), and 1579 (vs, amide II) cm−1.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH:15](C)[C:16]2(C)O[SiH3])[C:11](=[O:46])[O:10][CH:9]([C:47]([CH3:61])=[CH:48][CH:49]2[CH2:54][CH2:53][CH:52]([NH:55][C:56](=[O:58])[CH3:57])[CH:51]([O:59][CH3:60])[CH2:50]2)[CH:8]([CH3:62])[CH:7](C(C)(C)C)[CH2:6][C:5]1=[O:67])[CH:2]=[CH2:3].F.C(OCC)(=[O:71])C>C(#N)C>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:46])[O:10][CH:9]([C:47]([CH3:61])=[CH:48][CH:49]2[CH2:54][CH2:53][CH:52]([NH:55][C:56](=[O:58])[CH3:57])[CH:51]([O:59][CH3:60])[CH2:50]2)[CH:8]([CH3:62])[CH:7]([OH:71])[CH2:6][C:5]1=[O:67])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3C(CCC(C)C3(C)O[SiH3])C(=O)OC(C(C)=CC3CCC(NC(C)=O)C(OC)C3)C(C)C(C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: CCOC(C)=O
Agent: F
Solvent: CC#N
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC(C)=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A portion of the product from step (a) (13 mg) was dissolved in acetonitrile (4 ml) and to this was added 40% aqueous hydrofluoric acid (0.1 ml). After stirring for 2 hours at room temperature the reaction mixture was poured into ethyl acetate and the separated organic extract was then washed with water, saturated aqueous sodium hydrogen carbonate solution and brine before being dried (MgSO4), filtered and evaporated to an oil in vacuo. Column chromatography on silica eluting with hexane/acetone [2:1] then gave the title compound (8 mg) as a foam.
Reaction SMILES: [CH2:1]([N:8]([CH3:25])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:24])[C:21]([OH:23])=[O:22])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CS(C)=O>O>[CH2:32]([O:22][C:21](=[O:23])[CH:20]([C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:13](=[O:14])[CH2:12][CH2:11][C:9](=[O:10])[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:25])[OH:24])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2RS)-2-[(2S)-1-[3-(N-benzyl-N-methlcarbamoyl)propanoyl]pyrrolidin-2-yl]-2-hydroxyacetic acid (134 mg), potassium carbonate (64 mg), benzyl bromide (51 μl) and DMSO (1 ml) was stirred for 1 hr at room temperature. Water was added to the mixture. The mixture was extracted with a mixture of hexane and EtOAc (1:1). The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (hexane-EtOAc) to give the title compound (141 mg) having the following physical data:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:30]4[CH:29]=[CH:28][N:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccnc(C(F)(F)F)c4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-(trifluoromethyl)pyridine-4-boronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.82 min; Mass spectrum (ESI+): m/z=450 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[O:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([O:22][C:23]2[C:28]([NH2:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:17]1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:29][C:28]3[C:23]([O:22][C@@H:18]4[CH2:19][CH2:20][CH2:21][O:16][CH2:17]4)=[N:24][CH:25]=[CH:26][CH:27]=3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1cccnc1O[C@@H]1CCCOC1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@@H]3CCCOC3)c2c1C

Procedure:
Prepared analogously to example 1.1 from 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 2-[(R)-(Tetrahydro-pyran-3-yl)oxy]-pyridin-3-ylamine
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5](=[O:15])[CH:6]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[CH3:7].[S:17]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5](=[O:15])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:19]2[CH:20]=[CH:21][S:17][CH:18]=2)=[CH:10][CH:9]=1)[CH3:7]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)CNC(=O)C(C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CNC(=O)C(C)c1ccc(-c2ccsc2)cc1
Yield: 26.8 %

Procedure:
To a solution of N-2-methylpropyl-2-(4-bromophenyl)2-methylacetamide 1.1 g (3.9 mmol, part B above), 0.7 g (5.8 mmol) of thiophene-3-boronic acid and 0.8 g (5.8 mmol) of potassium carbonate in 12 mL of 3:1 dioxane/water was added 0.2 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium. The mixture was heated to reflux for 16 hours, cooled and diluted with 10 mL of water. The mixture was extracted three times with 10 mL each of dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Chromatography (65 g of silica gel, 35% ethyl acetate/hexanes) of the residue afforded 0.3 g (31%) of the final title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([CH:24]=C)=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.CC#N.O.C[N+]1([O-])CC[O:35]CC1>[Os](=O)(=O)(=O)=O.CC(C)=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([CH:24]=[O:35])=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: C=Cc1cc(OCc2ccc(C)nc2C)cc2scc(CC(=O)OC)c12
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)=O
Solvent: CC#N
Product: COC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)cc(C=O)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.5 %

Procedure:
To a mixture of methyl(6-((2,6-dimethylpyridin-3-yl)methoxy)-4-vinyl-1-benzothiophen-3-yl)acetate (459 mg), CH3CN (2 mL), water (2 mL) and acetone (2 mL) were added osmium(VIII) oxide (7% microcapsule, 907 mg) and NMO (439 mg) at room temperature. The mixture was stirred at room temperature for 20 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was poured into aqueous solution of Na2S2O3 at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. To a mixture of the residue, THF (3 mL) and water (3 mL) was added sodium periodate (802 mg) at 0° C. The mixture was stirred at room temperature for 1 h. The mixture was quenched with aqueous solution of Na2S2O3 at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine twice, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (293 mg).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:34])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].I[CH2:38][CH3:39]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([O:34][CH2:38][CH3:39])[C:19]2[S:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CCI
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CCOC(CCc1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
2-(2,3-Dichloro-4-(3-ethoxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid using 8 equivalents of sodium hydride and 2.1 equivalents of iodoethane according to general procedure H.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11](O)=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:51]1[O:55][C@@H:54]2[C@H:56]([O:59][N+:60]([O-:62])=[O:61])[CH2:57][O:58][C@@H:53]2[C@H:52]1[OH:63].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([O:63][C@H:52]2[CH2:51][O:55][C@@H:54]3[C@H:56]([O:59][N+:60]([O-:62])=[O:61])[CH2:57][O:58][C@H:53]23)=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCc1nc(Cl)c(C(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 48 h

Procedure:
A mixture of 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (Step A, Intermediate 4, 7.83 g, 16.5 mmol), isosorbide-5-mononitrate (1.55 g, 8.11 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.78 g, 19.7 mmol), 1-hydroxybenzotriazole (1.25 g, 8.16 mmol), 4-dimethylaminopyridine (0.10 g, 0.82 mmol), and N-methylmorpholine (9.0 mL, 82 mmol) was dissolved in dichloromethane (150 mL) and stirred for 2 days. It was then concentrated in vacuo and purified by reversed-phase mass-directed HPLC (Sunfire C-18) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 8.02 (dd, J=7.6, 1.0 Hz, 1H), 7.61 (td, J=7.6, 1.3 Hz, 1H), 7.55 (td, J=7.7, 1.1 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.7 Hz, 2H), 6.96 (d, J=7.8 Hz, 2H), 5.50 (s, 2H), 5.40 (td, J=5.4, 3.0 Hz, 1H), 5.32-5.30 (m, 1H), 4.99 (t, J=5.2 Hz, 1H), 4.51 (d, J=5.0 Hz, 1H), 4.06-4.02 (m, 3H), 3.99 (dd, J=11.4, 5.4 Hz, 1H), 2.68 (t, J=7.7 Hz, 2H), 1.69 (quintet, J=7.7 Hz, 2H), 1.36 (sextet, J=7.5 Hz, 2H), 0.89 (t, J=7.3 Hz, 3H); LC-MS: m/z 610.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:27])=[C:4]([F:26])[C:5]([NH:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][C:19]=2[F:25])=[C:6]([CH:16]=1)[C:7]([NH:9][O:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[O:8].C(N(CC)CC)C>O1CCCC1.[Ni]>[Br:1][C:2]1[C:3]([F:27])=[C:4]([F:26])[C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])=[C:6]([CH:16]=1)[C:7]([NH:9][O:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[O:8]
Reactant: O=C(NOCC(O)CO)c1cc(Br)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NOCC(O)CO)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Yield: 28.9 %

Procedure:
A solution of 5-bromo-N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (0.240 g, 0.429 mmol) and triethylamine (0.2 g, 1.98 mmol) in tetrahydrofuran (16 mL) was hydrogenated over Raney Nickel (0.12 g, pre-rinsed with tetrahydrofuran) at 10 psig at room temperature for a total of 7 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The afforded residue was partitioned between ethyl acetate and water. The organics were washed twice with water, twice with saturated brine, collected, dried over sodium sulfate, filtered and concentrated in vacuo. HPLC purification was performed using a YMC 30×100 mm 5 u (C18) column in 0-100% acetonitrile (3.0% n-propanol)/100-0% water (3.0% n-propanol)at 30 mL/min. The desired fractions were collected, concentrated and dried in a vacuum oven overnight at 50° C. to afford 5-bromo-N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-phenylamino)-benzamide as a white solid (0.054 g, 30%): m.p.=143.5-144.5° C.; 1NMR (400 MHz, DMSO-d6) δ 11.95 (bs, 1H), 8.74 (bs, 1H), 7.68 (d, 1H, J=6.1 Hz), 7.17 (t, 1H, J=9.8 Hz), 7.01-7.04 (m, 1H), 6.94 (m, 2H), 4.81 (m, 1H), 4.57 (m, 1H), 3.86 (m, 1H), 3.69-3.71 (m, 2H), 3.3, (2H, under HDO); MS(APCI+)=435.0/437.0.