Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:14](=[CH2:19])[C:15]([O:17]C)=[O:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][CH3:13])=[N:5]2.C([O:24]O)(C)(C)C.CCCCCCCCC.CC(C)([O-])C.[K+]>C1COCC1>[F:1][C:2]1[C:3]([C:14]2([C:15]([OH:17])=[O:16])[CH2:19][O:24]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][CH3:13])=[N:5]2
Reactant: C=C(C(=O)OC)c1c(F)ccc2ncc(OC)nc12
Reactant: CC(C)(C)OO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCCCCC
Product: COc1cnc2ccc(F)c(C3(C(=O)O)CO3)c2n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
A solution of methyl 2-[6-fluoro-3-(methyloxy)-5-quinoxalinyl]-2-propenoate (5.45 g, 0.02 mol) (for a preparation, see Example 1(l)) in THF (150 ml) was cooled to 0° C. A 6M solution tert-butyl hydrogen peroxide in nonane (5.2 mL, 0.03 mol) was added dropwise followed by a 1M solution of potassium tert-butoxide (10.39 mL, 0.01 mol). During the addition the temperature was kept at 0° C. The reaction mixture was kept at 0° C. for 16 hours. Another 0.5 equivalent of the 1M solution of potassium tert-butoxide (10.39 mL, 0.01 mol) was added at 0° C. and the reaction mixture was kept for a further 2 hours. The reaction was quenched by addition of a 1M solution of HCl in methanol (20 mL). The reaction mixture was evaporated to dryness. The residue was partially dissolved in methanol. The organic layer was dried over magnesium sulphate, filtered, evaporated under vacuum and chromatographed on silica (required repeated chromatography), eluting with a 0-30% methanol in dichloromethane gradient to afford the product as a white solid (3.22 g, 59%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH:22]([N:25]=[C:26]=[S:27])([CH3:24])[CH3:23]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[S:27])(=[O:14])=[O:13]
Reactant: CC(C)N=C=S
Reactant: CS(=O)(=O)c1ccc(S(N)(=O)=O)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)NC(=S)NS(=O)(=O)c1ccc(S(C)(=O)=O)cc1N
Temperature: 50 °C

Procedure:
A mixture of 2-amino-4-methanesulfonylbenzenesulfonamide (2.5 g), potassium carbonate (1.66 g) and isopropyl isothiocyanate (1.22 g) in 20 ml of dry acetone was heated at 50° C. for 18 h. Then the reaction mixture was evaporated in vacuo and the residue was dissolved in 25 ml of water. Then the solution was adjusted to pH 2 by dropwise addition of 4 M HCl at 0° C. with stirring. After stirring for 2 h the product was filtered off and dried, yielding the title compound as white crystals; m.p. 151-153° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[C:30]([CH3:36])=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1>>[CH3:36][C:30]1[C:29]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@@:13]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)=[CH:34][CH:33]=[C:32]([CH3:35])[N:31]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1ccc(Br)c(C)n1
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c(C)n1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 3-bromo-2,6-dimethylpyridine in Step 4. LC-MS Method 2 tR=1.012, m/z=463.1; 1H NMR (CDCl3) 1.32 (m, 2H), 1.49 (d, 3H), 1.62 (m, 2H), 1.86-1.96 (m, 2H), 2.17-2.29 (m, 3H), 2.31 (s, 3H), 2.49 (s, 3H), 2.93 (m, 1H), 3.51 (m, 2H), 5.68 (m, 1H), 6.88-7.03 (m, 7H), 7.25 (m, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH:9]([O:23][CH3:24])[CH:10]([S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][N+:12]([O-])=O.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:16]([S:15][CH:10]([CH:9]([O:8][CH3:7])[O:23][CH3:24])[CH2:11][NH2:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(OC)C(C[N+](=O)[O-])SCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(OC)C(CN)SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a suspension of lithium aluminum hydride (13.0 g) in tetrahydrofuran (60 ml) was added dropwise a solution (76 ml) of ({[2,2-dimethoxy-1-(nitromethyl)ethyl]thio}methyl)benzene (18.6 g) in tetrahydrofuran at 0° C. The reaction mixture was allowed to warm to room temperature, and stirred at room temperature for 1 hr. Water and 2N aqueous sodium hydroxide solution were added to the reaction solution, and the mixture was diluted with ethyl acetate. The mixture was filtrated through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=30:70-100:0) to give the title compound (12.6 g, yield 76%) as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[N:9][NH:8][C:7](=[O:11])[C:6]=1[Cl:12].[F:13][C:14]1[CH:28]=[CH:27][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1.[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C(N(CC)CC)C.CN(C)C=O>[F:13][C:14]1[CH:28]=[CH:27][C:17]2[C:18]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][NH:4][C:5]4[CH:10]=[N:9][NH:8][C:7](=[O:11])[C:6]=4[Cl:12])[CH2:25][CH2:26]3)=[N:19][O:20][C:16]=2[CH:15]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=c1[nH]ncc(NCCBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: O=c1[nH]ncc(NCCN2CCC(c3noc4cc(F)ccc34)CC2)c1Cl
Temperature: 60 °C
Yield: 77.6 %

Procedure:
5.6 g (22.2 millimoles) of 5-(2-bromoethylamino)-4-chloro-2H-pyridazine-3-one, 16 ml of anhydrous dimethyl formamide, 5.62 g (25.5 millimoles) of 6-fluoro-3-piperidine-4-yl-1,2-benzisoxazole, 8.85 ml of triethyl amine and 0.44 g of potassium iodide are admixed. The reaction mixture is heated at 60° C. for 2 hours, cooled to room temperature and a solution of 5.46 g of sodium carbonate and 50 ml of water is added dropwise. The mixture is stirred for half an hour, the suspension is filtered and the filtered product is washed three times with 20 ml of water each. The crude product thus obtained is dissolved in a 9:1 mixture of acetonitrile and water under heating to boiling, filtered warm and the mother lye is evaporated to one-third of its volume. The residual mother lye is stirred under cooling with icecold water for 2 hours. The precipitated crystals are filtered. Thus 6.75 g of the desired compound are obtained. Yield 77.6%. Mp.: 229–231° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:21]([N:22]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]3)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:13]1)=[O:11].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC.CCOC(C)=O>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:13][CH:14]([C:16]2[C:21]([N:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:15]1)=[O:11]
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(c2nccnc2N2CCC(O)CC2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1CCN(c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone (0.16 g, 0.42 mmol) was dissolved in anhydrous CH2Cl2 (20 mL), treated with Dess-Martin Periodinane (DMP) (195 mg, 0.46 mmol, 1.1 equiv) and stirred at RT until complete conversion controlled by TLC (Petro ether:EtOAc=1:1). The organic layer was washed with an aqueous solution of NaHCO3/Na2S2O3 (3×10 mL)), dried over Na2SO4, filtered and evaporated. The resulting residue was purified by flash chromatography (20% to 40% EtOAc in petroleum ether) to give 1-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-one (0.134 g, 0.36 mmol, 85% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>>[CH2:23]([O:22][C:20]([C:19]1[O:17][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:16][C:13]=2[CH:14]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2o1
Yield: 84 %

Procedure:
5-Benzyloxy-2-hydroxy-benzaldehyde ((21.5 g, 94.2 mmol) and ethyl bromoacetate (17.3 g, 103.6 mmol) and K2CO3 (19.5 g, 141.3 mmol) and DBU (14.3 g, 94.2 mmol) are reacted analogous to Example 18-A to give the title compound (23.5 g, 84%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[CH:37](O)[CH3:38]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:37]([C:31]3[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=3[Cl:29])[CH3:38])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CC(O)c1cc(Cl)ccc1Cl
Product: CC(Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1cc(Cl)ccc1Cl

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and 1-(2,5-dichloro-phenyl) ethanol. MS (ESI) m/z 553.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)(=O)C>[NH2:1][C@H:2]([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Temperature: 25 °C

Procedure:
The ketoamide (8) (227 mg, 0.5 mmol) was dissolved in ethyl acetate (10 mL) and cooled in an ice bath. Dry HCl gas was bubbled through until the solution was saturated and then the solution was stirred at r.t. until the starting material had been consumed as indicated by tlc (˜30 min). The solvent was removed under reduced pressure to give 22. To a solution of Ac—Tyr—Val—Ala—OH (197 mg, 0.5 mmol) in dry THF (10 mL) and DMF (2 mL) cooled to −15° C. was added N-methyl morpholine (51 mg, 55 μL, 0.5 mmol) followed by iso-butyl chlorofornate (68 mg, 65 μL, 0.5 mmol) and the solution stirred at −15° C. for 5 min. A previously prepared solution of 22 and N-methyl morpholine (51 mg, 55 μL, 0.5 mmol) in dry THF (5 mL) was added, the solution stirred at −15° C. for 15-30 min and then at r.t. for 16 h. The solution was filtered and the solvent removed under reduced pressure to yield the product which was recrystallized from methanol/ether to give 340 mg (93%) of Ac—Tyr—Val—Ala—Asp(Bzl)—CONH—CH2CH2Ph: mp 192-194° C.; 1H NMR (DMSO) δ0.77 (m, 6H, Val CH3's), 1.19 (m, 3H, Ala CH3), 1.74 (s, 3H, Ac CH3), 1.93 (m, 1H, Val β-CH), 2.62 (obs, 2H, CH2Ph), 2.77 & 3.18 (m, 4H, Tyr & Asp β-CH2's), 3.37 (m, 2H, NH-CH2), 3.75, 4.09, 4.19 & 4.53 (m, 4H, α-CH's), 5.06 (s, 2H, benzyl CH2), 6.62 & 7.01 (2xd, 4H, Tyr aromatic CH's), 7.20 (m, 5H, phenethyl aromatic CH's), 7.35 (s, 5H, benzyl aromatic CH's), 7.83 (m, 1H, NH), 8.04 (m, 4H, NH's), 9.15 (s, 1H, Tyr OH); FABMS m/e 730 (M++1).
Reaction SMILES: [F:1][S:2]([F:55])([F:54])([F:53])([F:52])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]4[N:29]=[N:30][N:31](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:32]=4)=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1.C(O)=O.O>O1CCCC1>[F:55][S:2]([F:1])([F:52])([F:53])([F:54])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]4[N:29]=[N:30][NH:31][CH:32]=4)=[CH:22][CH:23]=3)[N:15]=2)=[CH:7][CH:8]=1
Reactant: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nn4)cc3)co2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: O=CO
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCc4c[nH]nn4)cc3)co2)cc1
Temperature: 60 °C
Reaction time: 21 h

Procedure:
A mixture of 98 mg 4-[4-(4-{2-[(E)-2-(-4-pentafluorosulfanyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1-trityl-1H-[1,2,3]triazole, 100 μl formic acid, 10 μl water and 1.0 ml tetrahydrofuran was stirred at 60° C. for 21 h. After removal of solvents in vacuo 4-[4-(4-{2-[(E)-2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole was obtained by HPLC-MS-purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([O:44][CH:45]([CH3:47])[CH3:46])[C:30]([F:43])=[C:31]([CH:42]=1)/[CH:32]=[N:33]/[C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1)[CH3:25]>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[N:33]([CH2:32][C:31]1[CH:42]=[C:27]([O:26][CH2:24][CH3:25])[CH:28]=[C:29]([O:44][CH:45]([CH3:47])[CH3:46])[C:30]=1[F:43])[C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1
Reactant: c1ccc(COCn2cnc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2nc3ccccc3n2COCc2ccccc2)c(F)c(OC(C)C)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
To a solution of Intermediate 10.1 (50.0 mg, 0.210 mmol) in 2 mL THF at −78° C. was added 1.6 M solution of BuLi in THF (144 μL, 0.231 mmol). The mixture was stirred at −78° C. for 15 min, then a solution of Intermediate 7.3 (69 mg, 0.210 mmol) in 0.6 mL THF was added dropwise. The mixture was stirred at −78° C. for 30 min, was allowed to warm to rt over 1 h, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 95 mg of Intermediate 10.2 as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH2:14](I)[CH2:15][CH2:16][CH3:17].Cl>C(O)C.O>[Cl:3][C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCCCI
Reactant: O=C(O)c1ccc(O)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc(C(=O)O)c(Cl)c1
Reaction time: 5 h
Yield: 71.7 %

Procedure:
9 g of caustic soda are dissolved in 200 ml of ethanol. To the thus-prepared solution there are added 17.25 g of 2-chloro-4-hydroxybenzoic acid and 18.4 g of butyl iodide. The resulting solution is heated at reflux under stirring for 5 hours, cooled, poured into 200 ml of water and acidified, to pH=1, with hydrochloric acid. The precipitate is filtered-off, washed with water and dried to give 16.4 g of ortho-chloro-para-n-butyoxybenzoic acid which is recrystallized from hexane. The yield of the recrystallized product is 13.8 g (60.5%), M.p. 92°-93° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[N:17]=[C:18]([CH2:21][OH:22])[NH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30]([Si:34]([CH3:37])([CH3:36])Cl)([CH3:33])([CH3:32])[CH3:31]>ClCCl.C(Cl)(Cl)Cl.O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[N:17]=[C:18]([CH2:21][O:22][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:37])[CH3:36])[NH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1nc(CNC2CCN(Cc3ccccc3)CC2)c[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1nc(CNC2CCN(Cc3ccccc3)CC2)c[nH]1
Yield: 51.7 %

Procedure:
To a solution of (4-(((1-benzyl-4-piperidinyl)amino)methyl)-1H-imidazol-2-yl)methanol (0.28 g) obtained in Example 83f) and triethylamine (0.26 ml) in dichloromethane (5 ml) was added tert-butyl dimethylchlorosilane (0.17 g), and mixed at room temperature for 3 hours. The reaction solution was diluted with chloroform and water. The organic layer was collected by separation, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate:ethanol=10:1) to obtain the title compound as a pale yellow oil (0.20 g, 52%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([C@H:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([F:19])=[CH:13][C:14]=3[F:18])[CH2:9]2)[C:6](=[S:20])[NH:5][CH:4]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](O)=[O:28].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[F:18][C:14]1[CH:13]=[C:12]([F:19])[CH:11]=[C:10]2[C:15]=1[CH2:16][CH2:17][C@H:8]([N:7]1[C:3]([CH2:2][NH:1][C:27](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)=[CH:4][NH:5][C:6]1=[S:20])[CH2:9]2
Reactant: O=C(O)c1ccccn1
Reactant: NCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 20 %

Procedure:
A mixture of (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (295 mg, 1 mmol), prepared as in Example 31, picolinic acid (123 mg, 1 mmol) and PyBOP (620 mg, 1.2 mmol) in 10 mL of dry DMF was stirred under argon at approximately 25° C. for 5 minutes and then N,N-diisopropylethylamine (0.58 mL, 3.3 mmol) was added. The mixture was stirred for approximately 12 hours and then 10 mL of water was added. The aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined extracts were washed with water, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with hexane/THF (1:1 to 8:2) to give (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]picolinamide (80 mg, 0.2 mmol), m.p. 216°-217° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(OC)C)=[O:6].[CH3:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[Mg]Br>C1COCC1>[Br:1][C:2]1[C:3]([F:14])=[C:4]([C:5]([C:17]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=2[CH3:15])=[O:6])[CH:11]=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1cccc(Br)c1F
Reactant: COc1ccc([Mg]Br)c(C)c1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cccc(Br)c2F)c(C)c1

Procedure:
Prepared according to Method A step B from 3-bromo-2-fluoro-N-methoxy-N-methylbenzamide (8 g, 31 mmol) and 2-methyl-4-methoxyphenyl magnesium bromide ((70 ml, 0.5 M in THF) to give 3.58 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH2:29]([N:31](CC)CC)[CH3:30].BrCC#N>C(#N)C>[CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][N:19]1[CH2:30][C:29]#[N:31])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCN(CC)CC
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Agent: N#CCBr
Solvent: CC#N
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(CC#N)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 4.9 %

Procedure:
A stirred solution of crude 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (210 mg, 0.50 mmol, 1 equiv) and triethylamine (0.21 mL, 1.51 mmol, 3 equiv), in anhydrous acetonitrile (3 mL) was treated with bromoacetonitrile (42 μl, 0.60 mmol, 1.2 equiv), at rt and under nitrogen. The resulting reaction mixture was stirred at rt for 18 h, evaporated to dryness and purified by chromatography over silica gel, with an eluant of 2.5% methanol in dichloromethane. The desired fractions were pooled, evaporated to dryness, and lyophilized to furnish the title compound (11.2 mg, 10%) as a fluffy white powder: TLC Rf=0.2 (5% methanol in dichloromethane); 1H NMR (300 MHz, CD3OD) δ 5.44 (d, J=5.49, 1), 4.38-4.23 (m, 4), 2.29 (s, 3), 1.52 (m, 11), 1.16-1.09 (m, 12); MS (ESPOS): 458.5 [M+H]+, MS (ESNEG): 456.5 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:16])[CH2:14][CH3:15].[CH3:17][N:18]([CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:19]>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:16])[CH2:14][CH3:15])=[C:2]2[NH:27][CH:24]1[CH2:25][CH2:26][CH:21]([CH2:20][N:18]([CH3:19])[CH3:17])[CH2:22][CH2:23]1
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CCC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN(C)C)CC1
Yield: 93.4 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)propan-1-one (255 mg, 1.0 mmol) was reacted with trans-4-((dimethylamino)methyl)cyclohexanamine (310 mg, 2.0 mmol) to afford the product (350 mg, 93%) as a white solid: ESI MS m/z 375 [M+H]+.
Reaction SMILES: Cl.[C:2]1([CH2:8][C@H:9]([NH2:13])[CH2:10][O:11][CH3:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C.[Pt]=O>[CH:2]1([CH2:8][C@H:9]([NH2:13])[CH2:10][O:11][CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC[C@@H](N)Cc1ccccc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: COC[C@@H](N)CC1CCCCC1
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To a solution of (S)-3-phenyl-1-methoxy-2-propylamine hydrochloride (0.5 g) in ethanol (100 ml) was added concentrated HCl (0.32 mL), and platinum oxide (0.5 g), and the reaction was shaken under hydrogen gas (4 atm) for 18 h. The reaction was filtered, concentrated, diluted with water (50 mL) and neutralized with IM NaOH (to pH≈11). The mixture was washed with chloroform (3×50 mL), and the organic extracts were washed with brine (20 mL), dried (M.SO4), filtered and concentrated to give a colorless oil (400 mg).