Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH2:1].[O:2]=[C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]2[S:15][C:16]([C:24]#[N:25])=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:5]=[CH:4]1>N1C=CC=CC=1.C(N(CC)CC)C>[O:2]=[C:3]1[N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7]2[S:15][C:16]([C:24](=[S:1])[NH2:25])=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:5]=[CH:4]1
Reactant: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Reaction time: 60 h
Yield: 40 %

Procedure:
Hydrogen sulphide was bubbled through a solution of the compound of Example 77 (539 mg, 1.64 mmol) in pyridine (1 0 mL) and triethylamine (0.5 mL) for 30 minutes. The reaction was left to stand for 60 h at r.t. and then nitrogen bubbled through the mixture to ensure the solution was purged of H2S. The solution was diluted with DCM and washed with water (×2), 2M HCl(aq) (×2) and brine. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was recrystallised from DCM-hexane to give the title compound as a solid (327 mg, 40%). δH (DMSO-d6) 9.70 (1H, s), 7.70–7.47 (9H, m), 7.45 (2H, m), 7.38 (1H, d J 9.6 Hz), 6.52 (1H, d, J 9.6 Hz). LCMS (ES+) RT 3.33 minutes, 385 (M+Na)+, 363 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)(=[O:22])=[O:21]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])=[CH:6][CH:5]=[C:4]([NH:29][CH:26]2[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: Nc1nc(Cl)ccc1C(=O)c1c(F)cccc1F
Product: CS(=O)(=O)N1CCC(Nc2ccc(C(=O)c3c(F)cccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2,6-difluoro-phenyl)-methanone (Example 51) and 1-methanesulfonyl-piperidin-4-ylamine (Step A. Example 6) using the procedure described in Step B. Example 6. HRMS, observed: 411.1298, Calcd for (M+H)+: 411.1297.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A solution of 6-bromonaphthalen-2-ol (5.0 g, 22.4 mmol) and imidazole (2.3 g, 33.6 mmole) in N,N-dimethylformamide (DMF) (5.0 mL) was added t-butyldimethylsilyl chloride (TBDMSCI) (3.7 g, 24.6 mmole) in one portion at 0° C. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was partitioned between EtOAc (500 mL) and water (300 mL). The aqueous layer was separated and extracted with EtOAc (2×100 mL) and the combined organic extracts were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes) to afford (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane (28, 7.4 g, 98%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J=1.8 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.48 (dd, J=8.7, 1.8 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.09 (dd, J=9.0, 2.4 Hz, 1H), 1.01 (s, 9H), 0.24 (s, 6H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][C@@H:36]4[CH3:41])[C:25]4[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.CO.C(O)(=O)C>[Pd]>[C:32]([N:29]1[CH2:30][CH2:31][C:25]2[C:24]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][C@@H:36]3[CH3:41])=[N:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]([NH:15][C:13]4[NH:14][C:9](=[O:8])[CH:10]=[CH:11][CH:12]=4)=[CH:17][CH:18]=3)=[N:27][C:26]=2[CH2:28]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCc2c(nc(-c3ccc(Nc4cccc(OCc5ccccc5)n4)cc3)nc2N2CCOC[C@@H]2C)C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N1CCc2c(nc(-c3ccc(Nc4cccc(=O)[nH]4)cc3)nc2N2CCOC[C@@H]2C)C1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Step 2—Synthesis of compound wf: (S)-1-(2-(4-(6-(benzyloxy)pyridin-2-ylamino)phenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethanone (0.098 g, 0.00018 mol), Palladium on Carbon 10% (0.1:0.9, Palladium:carbon black, 0.103 g), dry Methanol (5.00 mL, 0.123 mol) and Acetic acid (0.300 mL, 0.00528 mol) were combined under nitrogen then purged with hydrogen, heated at 65° C., and stirred overnight. The reaction mixture was purged with nitrogen, added celite, filtered through celite, concentrated, and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 9.13 (s, 1H), 8.21 (d, J=8.6, 2H), 7.78 (s, 2H), 7.42 (t, J=7.9, 1H), 6.32 (s, 1H), 5.99 (s, 1H), 4.71-4.43 (m, 2H), 4.10 (s, 1H), 3.88 (d, J=11.2, 1H), 3.82-3.56 (m, 5H), 3.44 (dd, J=26.9, 16.5, 2H), 2.75 (s, 1H), 2.62 (s, 1H), 2.13 (s, 3H), 1.26 (t, J=5.9, 3H). LC/MS-m/z+461.2 (M+H)+
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][C:12]2[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=3)=[CH:9][CH:10]=1)=[O:5])C.[OH-].[Li+].Cl>O1CCOCC1>[C:4]([C:6]1[O:7][C:8]([CH2:11][C:12]2[N:13]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:16][CH:15]=3)=[CH:9][CH:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(Cc2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc2c(c1)cc(Cc1ccc(C(=O)O)o1)n2Cc1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of the compound obtained in Example 30. (6) (0.003 g) in 1,4-dioxane (0.5 ml), a 10% aqueous lithium hydroxide solution (0.5 ml) was added at −5° C. under argon atmosphere and the mixture was stirred for 2 hours. To the reaction solution was then added a 10% aqueous hydrochloric acid solution and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain 0.001 g of the desired product.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].C(O)C.[OH-].[Na+]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(S(C)(=O)=O)cc3)nc21

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 1-(1-methylethyl)-6-[4-(methylsulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (260 mg, 0.671 mmol), Ethanol (4 mL), THF (1 mL) and sodium hydroxide (2N, 1.118 mL, 3.36 mmol). The final product was collected as 231 mg (96%). LCMS E-S (M+H)=360.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.8 Hz, 6H), 3.30 (s, 3H), 5.34-5.49 (m, 1H), 8.11 (d, J=8.6 Hz, 2H), 8.30 (s, 1H), 8.44 (s, 1H), 8.51 (d, J=8.6 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].C(#N)C>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 80.8 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1H- indazole (3.5 g, 16 mmol), K2CO3 (2.2 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (3.8 g, 16 mmol) and acetonitrile (90 ml) was refluxed for 16 hours. The reaction was poured into water and the resulting white solid, which precipitated from solution, was collected to afford 5.5 g of the desired product. The compound was recrystallized from dimethylformamide (twice) to afford 3.0 g (44%) of 1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]-methoxyphenyl]ethanone as a white solid, m.p.=202°-204° C.
Reaction SMILES: CC[O-].[Na+].[SH:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([CH3:14])[CH:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[N:7]=1.Cl[CH2:26][C:27]([NH2:29])=[O:28].O>C(O)C>[NH2:13][C:12]1[C:11]2[C:6](=[N:7][C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)=[CH:9][C:10]=2[CH3:14])[S:5][C:26]=1[C:27]([NH2:29])=[O:28]
Reactant: NC(=O)CCl
Reactant: COc1ccc(-c2cc(C)c(C#N)c(S)n2)cc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(C)c3c(N)c(C(N)=O)sc3n2)cc1OC
Yield: 94.3 %

Procedure:
2.1 g (31.4 mmol) sodium ethylate are dissolved in 40 ml absolute ethanol. 3.0 g (10.5 mmol) 2-mercapto-6-(3,4-dimethoxyphenyl)-4-methyl-pyridine-3-carbonitrile and 1.2 g (12.6 mmol) 2-chloroacetamide are added and refluxed for 1 h. Following cooling, 10 ml water are added and the precipitate is sucked off, suck dried and dried in vacuo at 50° C. 3.4 g (94%) 3-amino-6-(3,4-dimethoxyphenyl)-4-methyl-thieno[2,3-b]-pyridine-2-carboxamide is obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])(=[O:9])=[O:8])[CH2:3][CH2:2]1.S(Cl)([Cl:21])=O.C[O-].[Na+]>ClCCl.CO>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([Cl:21])=[O:13])(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1S(=O)(=O)N1CCOCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1S(=O)(=O)N1CCOCC1
Temperature: 60 °C
Yield: 113.2 %

Procedure:
To a slurry of 2-(morpholinosulfonyl)benzoic acid (327 mg, 1.21 mmol) in dichloromethane (11 mL) was added thionyl chloride (0.220 mL, 3.01 mmol). The reaction was heated at 60° C. for 1 hour, after which LCMS analysis (sodium methoxide solution, 25% in methanol) revealed reaction completion. The reaction was concentrated to afford 2-(morpholinosulfonyl)benzoyl chloride (0.397 g, 1.37 mmol) as a viscous yellow residue and this was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[N:14]=[CH:13][CH:12]=[C:11]([F:15])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Li+].CC([N-]C(C)C)C.CCCCCCC.[Br:31]C(Br)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Br:31][C:12]1[CH:13]=[N:14][C:2]([F:1])=[C:3]([C:11]=1[F:15])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: ClC(Cl)(Cl)C(Cl)(Br)Br
Reactant: CC(C)(C)OC(=O)c1c(F)ccnc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(F)ncc(Br)c1F
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
Into a solution of tert-butyl 2,4-difluoronicotinate (0.95 g, 4.4 mmol) in THF (15 mL) at −78° C. was added a solution of LDA in heptane (1.5 M×3.5 mL, 5.3 mmol) dropwise. The mixture was stirred for 10 min. Then a solution of dibromotetrachloroethane (1.86 g, 5.7 mmol) in THF (4.0 mL) was added dropwise. After 15 min, the temperature was allowed to rise to room temperature slowly. The reaction was quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to give a residue, which was purified by silica chromatography (5-50% dichloromethane in hexanes) to give tert-butyl 5-bromo-2,4-difluoronicotinate (0.55 g, 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([S:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]O.C(OCC)(=O)C>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][O:20][C:19](=[O:21])[CH2:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1
Reactant: O=C(O)CSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCc1cccc(F)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(CSc1ccc(C(=O)Nc2ccc(F)cc2)cn1)OCc1cccc(F)c1
Yield: 26.5 %

Procedure:
A solution of [5-(4-fluorophenylcarbamoyl)pyridin-2-ylsulfanyl]acetic acid (0.030 g, 0.10 mmole), 3-fluorobenzyl alcohol (0.10 mL, 1.0 mmol), and sulfuric acid (1 drop) in toluene (5 mL) was heated at reflux. After 2 h the reaction mixture was poured into ethyl acetate and washed with saturated sodium bicarbonate and dried over sodium sulfate. Removal of the solvents provided a solid. Purification by trituration using ethyl acetate/hexanes gave 0.011 g (27%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s 1H); 8.86 (m, 1H); 8.12 (m, 1H); 7.74 (m, 2H); 7.51 (m, 1H); 7.35 (m, 1H); 7.15 (m, 5H); 5.16 (m, 2H), 4.18 (m, 2H); MS (EI) m/z 413.05 (M−H)−.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[SH:23]>>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Sc1ccc2ccccc2c1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc3ccccc3c2)s1

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.502 g, 2.45 mmol) and naphthalene-2-thiol (0.392 g, 2.45 mmol). The title compound was obtained as a cream colored solid (0.585 g, 73% yield). 1H NMR (300 MHz, CDCl3) δ: 8.23 (1H, m), 8.09 (1H, s), 7.99 (1H, d), 7.92 (2H, m), 7.63 (3H, m), 2.46 (3H, s).
Reaction SMILES: [ClH:1].FC1C=CC(F)=CC=1[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.Br[C:16]1[CH:17]=[C:18]([F:26])[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([F:25])[F:24]>>[ClH:1].[F:24][CH:23]([F:25])[O:22][C:21]1[CH:20]=[CH:19][C:18]([F:26])=[CH:17][C:16]=1[C@H:11]1[CH2:12][CH2:13][CH2:14][NH:10]1
Reactant: Fc1ccc(OC(F)F)c(Br)c1
Reactant: Fc1ccc(F)c(N2CCCC2)c1
Agent: Cl
Product: Fc1ccc(OC(F)F)c([C@H]2CCCN2)c1

Procedure:
This compound was prepared by the method substantially similar to the preparation of 2,5-difluorophenyl pyrrolidine hydrochloride as mentioned in Example 1 step 5 using 3-bromo-4-(difluoromethoxy)-1-fluorobenzene (J. Med. Chem. 2003, 46, 1016-1030).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])=O)C.[NH2:20][C:21]([NH2:23])=[S:22].C([O-])([O-])=O.[K+].[K+].Cl>COCCO.O>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[NH:23][C:21](=[S:22])[NH:20][C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1OCCOC
Reactant: NC(N)=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCO
Solvent: O
Product: COCCOc1ccccc1-c1cc(=O)[nH]c(=S)[nH]1
Yield: 60.2 %

Procedure:
To a solution of 3-[2-(2-methoxy-ethoxy)-phenyl]-3-oxo-propionic acid ethyl ester (0.5 g, 1.88 mmol) in 2-methoxyethanol (5 mL) was added thiourea (0.22 g, 2.8 mmol) and K2CO3 (0.28 g, 2 mmol). The reaction mixture refluxed 3 h. After cooling, a mixture poured into water (10 mL) and adjusted to pH 3 with concentrated HCl. A precipitate formed that was filtered and washed with water and diethyl ether to obtained 0.315 g (60%) 6-[2-(2-methoxy-ethoxy)-phenyl]-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one as a cream solid.
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:39]=2)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)C(N)=O)CCOCC1
Temperature: 85 °C
Yield: 101.1 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 300 mg) and 3-(methylsulfonyl)phenylboronic acid (122 mg) in acetonitrile (8 mL) were treated with an aqueous solution of sodium carbonate (2M, 0.58 mL) and nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the reaction mixture was heated at 85° C. for 18 h. The mixture was purified by chromatography on silica eluting with 50-100% ethyl acetate/isohexane as eluent to yield the sub-titled compound (320 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH2:14]=O>O>[CH3:12][C:9]1([CH3:13])[C:5]2[C:6](=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][NH:11][CH2:10]1
Reactant: COc1cccc(C(C)(C)CN)c1
Reactant: C=O
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)CNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A mixture of 2-(3-methoxyphenyl)-2-methylpropylamine (7.5 g, 0.042 mol), 40% aqueous formaldehyde (3.2 g, 0.043 mol) and water (3.2 ml) was stirred at room temperature for 3 hours then heated on a steam bath for 0.5 hour. On cooling the mixture was partitioned between water (100 ml) and dichloromethane (50 ml) and the aqueous layer extracted with dichloromethane (3×50 ml). Combined extracts were dried (Na2SO4) and evaporated in vacuo. The residue was mixed with water (3.6 ml) and concentrated hydrochloric acid (5 ml) and heated on a steam bath under argon for 2 hours. On cooling, water (300 ml) was added and the mixture washed with dichloromethane (2×50 ml). The aqueous layer was basified with solid potassium carbonate and extracted into dichloromethane (3×75 ml). Combined extracts were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a pale yellow oil (6.5 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[N:20]1[NH:21][N:22]=[N:23][C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:20]=[N:21][NH:22][N:23]=2)=[CH:30][CH:29]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Reactant: NCc1ccc(-c2nn[nH]n2)cc1
Agent: Cl
Product: O=C(NCc1ccc(-c2nn[nH]n2)cc1)c1cc(Cl)ccc1Oc1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 75 from 5-chloro-2-(4-fluorophenoxy)benzoic acid (step 2 of Example 67) and 1-[4-(2H-tetrazol-5-yl)phenyl]methanamine hydrochloride: 1H-NMR (DMSO-d6) δ 9.01 (1H, t, J=6.0 Hz), 7.93 (2H, d, J=8.2 Hz), 7.70 (1H, d, J=2.6 Hz), 7.53–7.46 (3H, m), 7.29–7.10 (4H, m), 6.93 (1H, d, J=8.9 Hz), 4.52 (2H, d, J=6.1 Hz); MS (ESI) m/z 424 (M+H)+, 422 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:3]=1.[ClH:15]>C(O)C.[Pd]>[ClH:15].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:3]=1
Reactant: N#Cc1ccc(F)cc1-n1cncn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(F)cc1-n1cncn1
Yield: 99 %

Procedure:
Intermediate 67, 4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile, (2.46 g, 13.13 mmol) was dissolved in hot ethanol (150 mL). To this was added 1N HCl (15 mL) followed by 10% Pd—C (200 mg). The mixture was treated with H2 at 55 psi for 4 h in a Parr shaker then filtered over Celite and the solvent removed under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The aqueous phase was separated and lyophilized to afford the title compound as a white powder (2.96 g, 99% yield). 1H NMR (500 MHz, CD3OD) δ ppm: 9.51 (1H, s), 8.63 (1H, s), 7.85 (1H, dd, J=8.5, 5.8 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz), 7.49 (1H, td, J=8.3, 2.4 Hz), 4.20 (2H, s). LCMS (M+H) calcd for C9H10N4F: 193.08; found: 193.16.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([N:8]1[CH2:31][CH2:30][CH2:29][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([C:19]([C:22]([C:25]([F:28])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.CN1CCOCC1.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][CH2:47][C:48](Cl)=[O:49])[CH:41]=1>C(Cl)Cl>[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][CH2:47][C:48]([NH:1][C@H:2]([C:6]([N:8]2[CH2:31][CH2:30][CH2:29][C@H:9]2[C:10]([NH:12][CH:13]([CH:14]([CH3:15])[CH3:16])[C:17](=[O:18])[C:19]([F:20])([F:21])[C:22]([F:23])([F:24])[C:25]([F:28])([F:26])[F:27])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5])=[O:49])[CH:41]=1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Reactant: O=C(Cl)CCc1cccnc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CCc1cccnc1)C(C)C)C(=O)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
Dissolve H-Val-Pro-Val-CF2CF2CF3.hydrochloride (185 mg, 0.37 mmol) in methylene chloride (10 mL) and cool to -20° C. while stirring. Add N-methylmorpholine (0.2 mL, 2.0 mmol) and immediately follow with a dropwise addition of 3-(3-pyridyl)propanoyl chloride in methylene chloride (5 mL) at such a rate as to maintain the internal reaction temperature at -10° C. or less. After completion of the addition, allow the reaction mixture to warm to room temperature. After 1.5 hours at room temperature, dilute the reaction mixture with methylene chloride (20 mL) and wash with 1N HCl (2×20 mL), saturated NaHCO3 (2×20 mL) and brine (1×20 mL). Dry (MgSO4) and concentrate in vacuo to give the title product in crude form. Immediately purify the crude product by flash chromatograpy (2×15 cm column eluted with 1:27 MeOH--CH2Cl2) to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[CH2:12](O)[CH2:13][OH:14].CC1C=CC(S(O)(=O)=O)=CC=1>C([O-])(O)=O.[Na+]>[CH3:2][C:1]1([C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])[O:14][CH2:13][CH2:12][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1cccc(C#N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(c2cccc(C#N)c2)OCCO1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A stirred solution of 3-acetylbenzonitrile (1.05 g, 7.2 mmol), ethylene glycol (0.81 mL, 14.5 mmol) and TsOH (0.65 g, 7.2 mmol) was heated at reflux with a Dean-Stark for 15 h during which time the reaction became dark brown suspension. The reaction mixture was cooled to room temperature and diluted with saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc in hexanes) to provide 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile (1.08 g, 79%).