Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:6]1[C:10](=[O:11])[CH2:9][N:8]([CH2:12][CH2:13][CH3:14])[C:7]1=[O:15])(OCC)=O.C(#N)C.O=C1CC(=O)CN1>C(OCC)(=O)C>[CH2:12]([N:8]1[CH2:9][C:10](=[O:11])[CH2:6][C:7]1=[O:15])[CH2:13][CH3:14]
Reactant: CCCN1CC(=O)C(C(=O)OCC)C1=O
Agent: O=C1CNC(=O)C1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCN1CC(=O)CC1=O
Temperature: 25 °C

Procedure:
Freshly prepared 1-propyl-2,4-dioxopyrrolidine was prepared by heating together 3-carboethoxy-1-propyl-2,4-dioxopyrrolidine (1.16 g) (U.S. Pat. No. 4,511,568, Example 52d describes the preparation of the methoxy compound; the ethoxy compound may be prepared in a similar manner), and acetonitrile (100 ml). After heating for 1.5 hours the volatiles were removed under aspirator vacuum and the residue consisting of crude 2,4-dioxopyrrolidine was taken up in toluene (4 ml). This solution was added dropwise to a refluxing mixture of 2-amino-3-methylbenzonitrile from Example 1(0.48 g) and p-toluenesulfonic acid (36 mg) in toluene (10 ml). The refluxing mixture was surmounted with a Dean-Stark trap to collect water evolved in the reaction as the azeotrope with toluene. Following the addition of 2,4-dioxopyrrolidine (about 60 minutes), the mixture was heated for an additional 2 hours, then excess toluene was removed by distillation. After cooling to ambient temperature, the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. After separation of the layers, the ethyl acetate layer was washed once with brine, dried (MgSO4) and concentrated to leave an orange gum. Chromatographing the material over silica gel using ethyl acetate as the eluent afforded the desired product (0.70 g, 75%) as a white solid; tlc, Rf =0.21, silica gel, ethyl acetate.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:24]=[N:25][N:26](C(C)(C4C=CC=CC=4)C)[N:27]=3)=[CH:13][CH:12]=2)[C:8]([CH2:37][OH:38])=[C:7]([Cl:39])[N:6]=1)[CH2:2][CH2:3][CH3:4]>Br>[CH3:4][CH2:3][CH2:2][CH2:1][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:37][OH:38])=[C:7]([Cl:39])[N:6]=1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(C)(C)c3ccccc3)n2)cc1
Agent: Br
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 17.5 °C
Yield: 92.2 %

Procedure:
10 g (0.02 moles) of (2-butyl-5-chloro-3-{2′-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-biphenyl-4-ylmethyl}-3H-imidazol-4-yl)-methanol are dissolved in 50 ml of 40% aqueous hydrobromic acid under stirring at a temperature of 15-20° C. The mixture is stirred for a further 4 h, then washed 3 times with 25 ml of toluene. The aqueous phase is poured into a solution of 55 g of sodium acetate in water, the formed precipitate is filtered, thoroughly washed with water and dried under vacuum at 70° C., thereby obtaining 7.8 g of losartan.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:12].[CH3:13][O:14][C:15](=[O:27])[CH2:16][CH:17]1[C:21]2[CH:22]=[CH:23][C:24](O)=[CH:25][C:20]=2[O:19][CH2:18]1.C(P(CCCC)CCCC)CCC.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:27])[CH2:16][CH:17]1[C:21]2[CH:22]=[CH:23][C:24]([O:12][CH:6]3[C:7]4[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][C:8]=4[F:11])[CH2:4][CH2:5]3)=[CH:25][C:20]=2[O:19][CH2:18]1
Reactant: OC1CCc2c(Br)ccc(F)c21
Reactant: COC(=O)CC1COc2cc(O)ccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: ClCCl
Product: COC(=O)CC1COc2cc(OC3CCc4c(Br)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Reaction under argon atmosphere: to a solution of 15.3 g (66.3 mmol) of 4-bromo-7-fluoroindan-1-ol (product of step 1) and 11.0 g (53.0 mmol) of (6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester in 60.0 ml DCM are added 29.7 ml (116 mmol) of tributylphosphine. 24.4 ml (116 mmol) of diisopropylazodicarboxylate are added dropwise and under cooling in an ice/EtOH bath at 5° C.-15° C. over 20 min. It is stirred at r.t. for 1 h. The solvent is evaporated and the residue is chromatographed on silica gel (PE/EtOAc=100/0→95/5) to give the title compound. Yield: 16.9 g; LC (method 4): tR=4.84 min; Mass spectrum (ESI+): m/z=421 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C1(C)C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>CN(C=O)C.O>[CH3:1][N:2]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:3][CH2:4][OH:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCCO
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCO)C(=O)OCc1ccccc1
Yield: 54.1 %

Procedure:
To a stirred and cooled (0° C.) solution of N-methyl ethanolamine (3.10 g, 41.27 mmol), Et3 N (11.80 mL, 84.66 mmol) in DMF-H2O (3:1, v/v, 40 mL) was added dropwise 30% toluene solution of benzyl chloroformate (25.40 g, 49.13 mmol) for over 15 min. The resulting mixture was stirred for 1 day at room temp. The mixture was extracted with EtOAc. The extract was washed with sat. NaHCO3, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with n-hexane:EtOAc (3:1, v/v) then CHCl3 as eluent to give 4.67 g (54%) N-methyl-N-(benzyloxy carbonyl)ethanolamine as a colorless oil. 1H-NMR (CDCl3) d 1.82 (bs, 1 H), 3.00 (s, 3 H), 3.46 (bs, 2 H), 3.77 (bs, 2 H), 5.13 (s, 2 H), 7.29–7.36 (m, 5 H).
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH2:20][C:21]2[CH:28]=[CH:27][C:24]([CH3:25])=[CH:23][CH:22]=2)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: Cc1ccc(CBr)cc1
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2ccc(C)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), 4-methylbenzylbromide (204 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.131 g (36.9%); MS m/z: 356.5 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.14 (t, 3H, 3J=7.6 Hz); 2.25 (s, 3H); 2.55 (q, 2H, 3J=7.6 Hz); 4.60 (s, 4H); 6.68 (br s, 1H); 6.72 (dd, 1H, 4J=1.8 Hz, 3J=8.9 Hz); 7.09-7.19 (m, 8H); 7.32 (d, 1H, 3J=8.9 Hz); 7.89 (s, 1H); 11.88 (br s, 1H); HPLC (METHOD [A]): rt 18.62 min (100%)
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH2:20][CH:21]([CH3:23])[CH3:22].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:1][C:2]2[CH:19]=[CH:18][C:5]([C:6]([N:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:13]3)=[O:7])=[CH:4][C:3]=2[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:27][CH:26]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1O
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccc(Cl)cc1
Yield: 42.9 %

Procedure:
As in the case of Example 18, 1-(4-hydroxy-3-isobutylbenzoyl)-4-isobutylpiperazine (1.59 g) was benzylated with 4-chlorobenzyl bromide (1.03 g), thereby yielding 0.95 g of the aimed compound.
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]([CH2:16][CH:17]=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:11][OH:12])[CH2:6][OH:7]
Reactant: CC(=O)NC(CC=Cc1ccccc1)(COC(C)=O)COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(CO)(CO)CC=Cc1ccccc1
Yield: 66.2 %

Procedure:
2-Acetamido-1,3-diacetoxy-2-(3-phenyl-2-propenyl)propane (170 mg) was dissolved in 6 ml of methanol and 6 ml of a 1 N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 3 hours. After the reaction, the solvent was distilled away and the residue was purified by silica gel column chromatography (methanol: chloroform=1:30-1:6) to give 70 mg of 2-amino-2-(3-phenyl-2-propenyl)-1,3-propanediol as pale brown crystals.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:28])[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][CH:16]=[CH:15][N:14]=3)=O)CCCCC1.O=P(Cl)(Cl)[Cl:31]>>[CH2:21]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:19]([Cl:31])=[C:10]([C:8]#[N:7])[C:11]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(NC1CCCCC1)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Product: N#Cc1c(Cl)c2cccnc2n(Cc2ccccc2)c1=O
Yield: 52 %

Procedure:
A solution of 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid cyclohexylamide (7) (1.3 g, 3.44 mmol) in neat POCl3 was heated overnight at 90° C. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in water, basified by saturated NaHCO3 solution and extracted by dichloromethane. The combined organic phase washed subsequently by a saturated NaHCO3 solution, water and brine, dried over Na2SO4, and evaporated. The residue was crystallized by acetone to yield 530 mg (52%) of 1-benzyl-4-chloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (8) as white solids. MP: 188° C.; 1H-NMR (DMSO-d6): δ 5.61 (s, 2H), 7.21-7.31 (m, 5H), 7.56 (dd, J=4.8, 8.0 Hz, 1H), 8.53 (dd, J=1.6, 8.0 Hz, 1H), 8.86 (dd, J=1.6, 8.0 Hz, 1H); EIMS: 296 (M+1).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][NH2:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>C(Cl)Cl>[C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][NH-:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(CCN)cc1OC
Agent: CCOC(=O)CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COc1ccc(CC[NH-])cc1OC
Reaction time: 0.5 h

Procedure:
To a solution of 15.35 g of monoethyl tert.butyl malonate in 200 ml of anhydrous CH2Cl2 are stirred, at ambient temperature, 15.88 g of N,N′-carbonyldiimidazole in small batches. After 30 minutes, 14.8 g of 2-(3,4-dimethoxyphenyl)ethylamine are added. After a further 15 hours the solvent is distilled off in vacuo. The residue is mixed with 200 ml of water, acidified with 2 N HCl and extracted with ethyl acetate. The organic phase is washed with water and concentrated by evaporation after drying over Na2SO4. The residue is triturated with petroleum ether (40 to 60° C.) and brought to crystallisation.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]12[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:14]3[C:15]1=[C:10]([CH:11]=[CH:12][CH:13]=3)[NH:9][C:8](=[O:25])[CH2:7]2)C.CC(C[AlH]CC(C)C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl.CC(C)=O>[O:25]=[C:8]1[CH2:7][C:6]2([CH2:5][CH:4]=[O:3])[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:14]3[C:15]2=[C:10]([CH:11]=[CH:12][CH:13]=3)[NH:9]1
Reactant: CCOC(=O)CC12CC(=O)Nc3cccc(c31)N(C(=O)OC(C)(C)C)C2
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(CC=O)CC(=O)Nc3cccc1c32
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 2a-(2-ethoxy-2-oxoethyl)-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-carboxylate, enantiomer A, from Step A (219 mg, 0.607 mmol) in CH2Cl2 (5 mL) at −78° C. was added DIBAL-H (1 M in CH2Cl2, 0.8 mL, 0.8 mmol) dropwise. After 1 h, DIBAL-H (1 M in CH2Cl2, 0.54 mL, 0.54 mmol) was added dropwise, and after an additional 1 h, more DIBAL-H (1 M in CH2Cl2, 0.65 mL, 0.65 mmol) was added dropwise. The mixture was stirred at −78° C. for 1 h, then quenched by addition of cold MeOH (1 mmol), then acetone (1 mL), then saturated aqueous potassium sodium tartrate (10 mL). The mixture was allowed to warm to ambient temperature and was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=317 (M+1).
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC(=C)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[C:29]([C@@H:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1)#N>>[CH2:29]=[C:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 87 %

Procedure:
The title compound II-ah was prepared in 87% yield from 3,3:17,17-bis(ethylendioxy)-6-methyleneandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.85 (m, 1H), 4.50 (m, 1H), 2.63-1.02 (m, 20H), 0.92 (s, 3H), 0.86 (s, 3H).
Reaction SMILES: IC.[Cl:3][C:4]1[C:5]([O:14][NH:15][C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:17])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[CH3:28]C(C)([O-])C.[K+]>>[Cl:3][C:4]1[C:5]([O:14][N:15]([CH3:28])[C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:17])=[N:6][CH:7]=[C:8]([C:10]([F:11])([F:13])[F:12])[CH:9]=1
Reactant: O=C(NOc1ncc(C(F)(F)F)cc1Cl)c1cccc2ccccc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Product: CN(Oc1ncc(C(F)(F)F)cc1Cl)C(=O)c1cccc2ccccc12
Reaction time: 48 h

Procedure:
Iodomethane (0.82 g) was added to a stirred solution of the product from Example 13 (Compound 1012) (1.93 g) and potassium tert-butoxide (0.61 g) in tetahydrofuran (50 ml). The reaction mixture was stirred for 48 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was separated and extracted with 3 portions of ethyl acetate. The combined organic phases were dried, filtered and evaporated to give a residue which was purified by silica gel chromatography (ethyl acetate/petrol) to give the title compound, m/z (EI) 380 (M+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][SH:9].[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([N+]([O-])=O)=[C:21]([CH3:28])[N:20]=1)=[O:18].C(O)(=O)C>CN(C)C=O>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([C:4]([F:13])([F:14])[F:3])[CH:6]=2)=[C:21]([CH3:28])[N:20]=1)=[O:18]
Reactant: FC(F)(F)c1cccc(CS)c1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(SCc2cccc(C(F)(F)F)c2)c(C)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To the stirred suspension of 1.08 g of sodium hydride in 25 ml of dimethylformamide the solution of 9.0 g of m-trifluoromethylbenzylmercaptan in 50 ml of dimethylformamide is added during 3 minutes and the mixture stirred for 10 minutes. It is combined with 7.75 g of 6-methyl-5-nitropyridine-2-carboxylic acid methyl ester and the whole stirred on the steam bath for 30 minutes and allowed to stand overnight at room temperature. 2 ml of acetic acid are added and the solution is mixed with ice water to produce a dense, grainy precipitate. It is filtered off and recrystallized from isopropanol-diethyl ether, to yield the 6-methyl-5-(m-trifluoromethylbenzylmercapto)-pyridine-2-carboxylic acid methyl ester melting at 91°-93°.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:26])=O.Cl>CN(C)C=O.ClCCl>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([Cl:26])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A stirred mixture of triphenylacetic acid (21.7 g; 0.075 mol) and dry dimethylformamide (2 drops) in dry dichloromethane (100 cm3) was treated with oxalyl chloride (14 g; 0.11 mol) which was added in 4 approximately equal portions over ˜25 minutes. The mixture was stirred at 35° until evolution of hydrogen chloride had ceased (˜4 hrs). The resulting colourless solution was evaporated in vacuo at 40° to constant weight to give the title compound as a colourless crystalline solid. Yield=23.24 g (100.0%). The product was used directly in next stage.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[S:26][CH:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[CH:23]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:24]4[CH:23]=[C:22]([C:20](=[O:21])[C:19]([F:18])([F:36])[F:37])[S:26][CH:25]=4)[CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2csc(C(=O)C(F)(F)F)c2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2csc(C(=O)C(F)(F)F)c2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 17 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(2,2,2-trifluoroacetyl)thiophen-3-yl)benzoic acid as described in example 8 step 6 (30 mg, yield 17%). 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J=1.2 Hz, 1H), 8.43 (m, 1H), 8.16-8.12 (m, 2H), 8.00-7.97 (dd, J=9.0 Hz, 5.3 Hz, 2H), 7.92-7.90 (m, 2H), 7.84-7.82 (m, 1H), 7.57-7.53 (t, J=7.8 Hz, 1H), 7.30-7.25 (t, J=9.0 Hz, 2H), 3.56 (d, J=6.4 Hz, 2H), 1.34 (s, 6H). MS (ESI) m/z: Calculated for C26H20F4N2O3S: 516.11. found: 515.5 (M−H)−.
Reaction SMILES: [C:1]1([CH:7]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:8]([NH:10][CH:11]([CH:21]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[S:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[C:12]([O:14]CC[Si](C)(C)C)=[O:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[C:39]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([NH:10][CH:11]([CH:21]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[S:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[C:12]([OH:14])=[O:13])=[O:9])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: COc1cccc(SC(c2cccc(OC)c2)C(NC(=O)C(c2ccccc2)c2ccccc2)C(=O)OCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(SC(c2cccc(OC)c2)C(NC(=O)C(c2ccccc2)c2ccccc2)C(=O)O)c1

Procedure:
A solution of 0.40 g (0.65 mmol) of (R,S; R,S)-2- diphenylacetylamino-3-(3-methoxyphenyl)-3-(3-methoxyphenyl-sulfanyl) propionic acid, 2-trimethylsilylethyl ester of Example 34, 3.3 mL of N,N-dimethylformamide and 3.3 mL (3.3 retool) of 1M tetrabutylammonium fluoride in tetrahydrofuran is stirred at room temperature for 30 minutes. Ethyl acetate (100 mL) is added and the solution is washed with 80 mL of 1N hydrochloric acid and 80 mL of brine, dried (magnesium sulfate) and evaporated to give the product; wt 0.31 g (92%). Recrystallization from ethyl acetate-heptane gives product as a 9:1 mixture of diastereomers by NMR and hplc;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)(=[O:26])=[O:25])[C:20]=1[O:21][CH3:22])[C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)=[O:7].F[C:38](F)(F)[C:39]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:38]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)(=[O:26])=[O:25])[C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:10][CH:11]=1)[CH3:39]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)c1OC
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3cccc(C(F)(F)F)c3)c(OC)c(OC)c2)cc1

Procedure:
4-[3,4-Dimethoxy-5-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=523.1 (M−H), was prepared in analogy to example 31, steps A to D. Step C was performed using 3-trifluoromethyl-benzenesulfonyl chloride and yielded 4-[3,4-dimethoxy-5-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:21][C:22]([F:25])([F:24])[F:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]#[CH:33]>C1(C)C=CC=CC=1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]#[C:33][C:2]1[CH:3]=[C:4]([O:21][C:22]([F:24])([F:23])[F:25])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:14])([F:15])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2
Reactant: C#Cc1ccccn1
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(I)c2OC1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(C#Cc3ccccn3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 77 %

Procedure:
A mixture of ethyl 8-iodo-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 21a, Step 2 (1.00 g, 2.07 mmole), 2-pyridylacetylene (419 uL, 4.15 mmole), CuI (39 mg, 0.207 mmole), PdCl2(dppf)2-CH2Cl2 (169 mg, 0.207 mmole) and TEA (0.866 mL, 6.21 mmole) in anhydrous toluene (10 mL) was stirred at room temperature for 5 days under a N2 atmosphere. The mixture was then diluted with hexanes and purified by silica chromatography (0% to 75% EtOAc:hexanes gradient) to give 0.73 g (77% yield) the title product as a pale yellow crystalline solid: ESHRMS m/z 458.0849 (M+H, C21H14F6NO4, Calc'd 458.0822).
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([CH3:23])=[CH:17][N:16]=1>>[CH3:22][O:21][C:19]1[C:18]([CH3:23])=[CH:17][N:16]=[C:15]([CH2:14][S:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)[CH:20]=1
Reactant: Cc1nc(S)c2ccccc2n1
Reactant: COc1cc(CCl)ncc1C
Product: COc1cc(CSc2nc(C)nc3ccccc23)ncc1C
Yield: 1.5 %

Procedure:
The title compound(0.12 g) was prepared from 4-mercapto-2-methylquinazoline(4.48 g) and 2-chloromethyl-4-methoxy-5-methylpyridine(6.3 g).
Reaction SMILES: N1C2C=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=N1.OCCN1CCN(C2C=CC([C:25]3[NH:34][C:33](=O)[C:32]4[C:27](=[CH:28][C:29](OC)=[CH:30][C:31]=4OC)[N:26]=3)=CC=2)CC1.C=O>O>[N:3]1([CH2:33][N:34]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[CH:25]2)[CH2:4][CH2:9][CH2:8][CH2:7]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(CCO)CC4)cc3)nc2c1
Agent: C=O
Solvent: O
Product: c1ccc2c(c1)ncn2CN1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 1H-benzotriazole (10.0 g, 83.9 mmol) in water (84 mL) was added pyrrolidine 2 (6.3 mL, 226.6 mmol). After 10 minutes of vigorous stirring at room temperature, formaldehyde 37% aqueous solution was added. The reaction mixture was stirred for 1 hour, then the precipitate was filtered off, and washed with water to afford 1-pyrrolidin-1-ylmethyl-1H-benzoimidazole as an off-white solid. Yield: 14.58 g (85.9%).