Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 97.7 %

Procedure:
4-Fluoro-2-methyl-1-nitrobenzene (2 g), piperazine-1-carboxylic acid tert-butyl ester (4.8 g), potassium carbonate (3.57 g) and dimethyl sulfoxide (20 ml) were heated together at 80° C. under nitrogen for 15 hours. The mixture was then cooled, diluted with ethyl acetate (200 ml), washed with 2M aqueous hydrochloric acid (200 ml), dried (MgSO4), and concentrated to give the sub-title compound (4.05 g).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14]O)=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:12]1[O:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][N:11]=1
Reactant: CC1(c2cnc(CO)o2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2cnc(CCl)o2)OCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-yl]-methanol (35 mg, 0.19 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with Et3N (0.03 mL, 0.25 mmol) followed by DMAP (2.3 mg, 0.02 mmol) and Ms-Cl (0.02 mL, 0.23 mmol). After stirring at rt for 30 min, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 2-chloromethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-oxazole as a yellow oil. A solution of this crude 2-chloromethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-oxazole (38 mg, 0.19 mmol) in acetone (1.0 mL) was treated with 5-nitro-1H-pyrazole (21 mg, 0.19 mmol) and TBA bromide (12 mg, 0.04 mmol) followed by K2CO3 (77 mg, 0.56 mmol). The reaction mixture was stirred at rt until completion. The solvent was removed under reduced pressure and water (10 mL) followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a colorless oil. TLC: rf (4:6 hept-EA)=0.15. LC-MS-conditions 02: tR=0.83 min; [M+H]+=281.05.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[CH3:2].[OH:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH2:41][CH2:42]CC2=O.B(F)(F)F>ClCCl>[C:8]([O:7][C@@H:6]1[C@H:28]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:26]([CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:27][C@H:5]1[O:4][C:1]1[CH:2]=[CH:42][CH:41]=[C:40]2[C:45]=1[CH2:46][CH2:47][CH2:48][C:39]2=[O:38])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Product: O=C(OC[C@H]1O[C@@H](Oc2cccc3c2CCCC3=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 67.7 %

Procedure:
A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (426 mg, 0.84 mmol), 5-hydroxy-1-tetralone (122 mg, 0.75 mmol) and boron trifluoride diethyletherate (120 mg, 0.84 mmol, 106 μl) in dichloromethane (4 ml) was stirred at room temperature, under argon for 19 hours. Work-up as for Stage 1 in Example 1 then flash chromatography on silica gel (eluting with 2% acetone in toluene) gave the title compound as a colourless oil (308 mg of approx. 51% purity).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2.[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]Cl.O>CN(C)C=O>[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2
Reactant: Fc1ccccc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(O)ccc3c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4ccccc4F)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
Sodium hydride (60%, oily, 36.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propionate (360 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 2-Fluorobenzyl chloride (0.119 ml) was added to this mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[1-[6-(2-fluorobenzyloxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (404 mg, yield: 88%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])#[N:2].N[C:22]1[C:27]([OH:28])=[CH:26][CH:25]=[CH:24][N:23]=1>>[O:28]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:2]=[C:1]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Nc1ncccc1O
Reactant: CCCCCCCCCCCCCCCCCCC#N
Product: CCCCCCCCCCCCCCCCCCc1nc2ncccc2o1
Yield: 30 %

Procedure:
This material was prepared in 30% yield from 1-cyanooctadecane (Mangold, H. K., et al., (1976) Chem. Phys. Lipids 17, 176-181) and 2-amino-3-hydroxypyridine using Method C3: mp 84-85° C.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][N:16]4[C:21]([N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]([C:39]5[CH:40]=[N:41][NH:42][CH:43]=5)=[N:18][C:17]=34)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:46]([O:49][CH2:50][CH2:51]Br)(=[O:48])[CH3:47]>CN(C=O)C>[C:46]([O:49][CH2:50][CH2:51][N:41]1[CH:40]=[C:39]([C:19]2[CH:20]=[C:21]([N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[N:16]3[N:15]=[CH:14][C:13]([C:10]4[CH:11]=[N:12][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)=[C:17]3[N:18]=2)[CH:43]=[N:42]1)(=[O:48])[CH3:47]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(-c2cn[nH]c2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCn1cc(-c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 2-5 mL pressure vial was charged 3-(6-phenylpyridin-3-yl)-5-(1H-pyrazol-4-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.38 mmol, 230 mg), DMF (4 mL), and sodium hydride (40% w/w in mineral oil, 0.56 mmol, 23 mg). This suspension was sonicaided and allowed to stir at room temperature for 15 minutes. At 15 minutes, 2-bromoethyl acetate (0.56 mmol, 62 μL). The vial was then sealed and the reaction was stirred at 80° C. for 18 hours. After 18 hours, the solvent was removed in vacuo, and the resulting residue was purified by flash chromatography to yield the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]([CH2:29][O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:22][S:23][CH2:24][CH2:25][C:26](O)=[O:27])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:50]([O:54][C:55](=[O:76])[C@H:56]([CH2:67][CH2:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[NH:57][C:58](=[O:66])[C:59]1[CH:64]=[CH:63][C:62]([NH2:65])=[CH:61][CH:60]=1)([CH3:53])([CH3:52])[CH3:51]>N1C=CC=CC=1.P(Cl)(Cl)Cl>[C:50]([O:54][C:55](=[O:76])[C@H:56]([CH2:67][CH2:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[NH:57][C:58](=[O:66])[C:59]1[CH:64]=[CH:63][C:62]([NH:65][C:26](=[O:27])[CH2:25][CH2:24][S:23][CH2:22][CH:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:29][O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:61][CH:60]=1)([CH3:52])([CH3:53])[CH3:51]
Reactant: O=C(O)CCSCC(COC(=O)CCCCCCCCCCCc1ccccc1)OC(=O)CCCCCCCCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(NC(=O)CCSCC(COC(=O)CCCCCCCCCCCc2ccccc2)OC(=O)CCCCCCCCCCCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 6,7-bis(12-phenyldodecanoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 34 (200 mg) and 4-aminobenzoyl-glutamic acid di-t-butyl ester (108 mg) in pyridine (6 ml), phosphorus trichloride (4 drops) was added drop by drop, followed by stirring at room temperature for 1 hour. After the solvent was concentrated, the residue was purified by silica gel column (n-hexane:ethyl acetate=2:1) to yield the title compound (282 mg, yield 93%) as a colorless oily substance.
Reaction SMILES: [C:1]1([CH2:9]Cl)[CH:6]=[CH:5][C:4]([CH2:7]Cl)=[CH:3][CH:2]=1.[Cl:11][CH2:12][CH2:13][OH:14]>>[Cl:11][CH2:12][CH2:13][O:14][CH2:9][C:1]1[CH:2]=[CH:3][C:4]([CH2:7][O:14][CH2:13][CH2:12][Cl:11])=[CH:5][CH:6]=1
Reactant: ClCc1ccc(CCl)cc1
Reactant: OCCCl
Product: ClCCOCc1ccc(COCCCl)cc1

Procedure:
To 5.0 g of p-xylylene dichloride was added 25 ml of 2-chloroethanol, and the mixture was refluxed for 24 hours. After the reaction, 2-chloroethanol was removed under reduce pressure at 100° C. The residue was applied to a silica gel column and eluted with hexane/chloroform (1:1) as eluent, and a relevant fraction was further purified by distillation to obtain 2.44 g of the title compound as a colorless liquid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]([OH:19])=O)[CH:7]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]([C:29]2[O:33][C:32]([CH2:34][CH2:35][NH2:36])=[CH:31][CH:30]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:29]2[O:33][C:32]([CH2:34][CH2:35][NH:36][C:17]([C:8]3[CH:7]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[N:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:9]=3)=[O:19])=[CH:31][CH:30]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: O=C(O)c1cc(-c2ccco2)n(-c2ccccc2)n1
Agent: Cl
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(-c2ccco2)n(-c2ccccc2)n1

Procedure:
The title compound was prepared as in Example 12 starting from 5-(2-furyl)-1-phenyl-1H-pyrazole-3-carboxylic acid and 2-[5-(3,4-dichlorophenyl)furan-2-yl]-ethylamine hydrochloride. The crude product was purified twice by flash chromatography using first CH2Cl2-MeOH as a gradient eluent (100:0-99:1). Then another purification by flash chromatography was done by using heptane/EtOAc (8:2) as an eluent. 1H NMR (400 MHz, DMSO-d6): 2.96 (2H, t), 3.58 (2H, m), 6.16 (1H, d), 6.34 (1H, d), 6.51 (1H, dd), 7.01 (1H, d), 7.07 (1H, s), 7.45-7.48 (2H, m), 7.54-7.56 (4H, m), 7.61 (1H, distorted dd), 7.73 (1H, d), 7.84 (1H, d), 8.49 (1H, t, 3J=5.9 Hz).
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2([C:34]([NH2:36])=[O:35])[CH2:33][CH2:32]2)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[N:8][CH:9]=1.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Cl:3][C:4]1[C:5]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2([C:34]([NH2:36])=[O:35])[CH2:32][CH2:33]2)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:37])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[N:8][CH:9]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2Cl)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cc2)CC1
Reaction time: 2.5 h
Yield: 25.9 %

Procedure:
Formaldehyde (37 wt % in H2O; 14 μL, 0.19 mmol) was added to a solution of 1-(2-(2-(5-chloro-2-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide (7) (30 mg, 63 μmol) in MeOH (5.0 mL) under an atmosphere of nitrogen. The resulting mixture was stirred for 10 minutes at room temperature before the addition of sodium triacetoxyborohydride (53 mg, 0.25 mmol). Stirring was continued for 2.5 hours at room temperature before the volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and the volatiles evaporated in vacuo. The residue was dissolved in acetone (0.5 mL) and petroleum benzine 40-60° C. (25 mL) was added. The resulting green precipitate was isolated by filtration and dried under high vacuum to give the title compound 8 as a green solid (8 mg, 26%); 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.41 (d, J=8.5 Hz, 2H), 7.34 (d, J=7.3 Hz, 1H), 7.30-7.23 (m, 3H), 7.12 (d, J=8.5 Hz, 2H), 5.55 (s, 1H), 5.25 (s, 1H), 3.13 (J m, 6H), 2.52-2.41 (m, 1H), 2.38 (s, 3H), 2.23 (t, J=11.8 Hz, 2H), 1.89 (dd, J=25.4, 12.3 Hz, 2H), 1.80 (d, J=12.3 Hz, 2H), 1.68 (s, 2H), 1.06 (s, 2H). LCMS-A: rt 4.611 min; m/z 491 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:23]1([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:29])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CC(c2ccccc2)c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CC(c1ccccc1)c1ccccc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.8 %

Procedure:
To a solution of 4-(3,3-diphenyl-propionyl)-piperazine-1-carboxylic acid tert-butyl ester (2.15 g, 5.45 mmol) in dry CH2Cl2 (60 ml) was added TFA (20 ml) and resulting mixture stirred at room temperature for 3 hrs. Solvent and excess TFA was then evaporated and the residue was dissolved in CH2Cl2 (150 ml) and washed with sat. NaHCO3 (2×) and dried over MgSO4. Evaporation of solvent gave 1.65 g of pure product.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[OH:23])[CH:18]=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8])[CH:18]=[O:19]
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(C=O)cc1Br
Temperature: 90 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (4.62 g), 3-bromo-4-hydroxybenzaldehyde (4.28 g), potassium carbonate (2.94 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 4 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzaldehyde as pale-brown crystals (5.20 g, yield 67%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 146-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24](O)=[O:25])[NH:13][C:12]43[CH2:29][C:28]([CH2:32][F:33])([CH2:30][F:31])[CH2:27]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C:42]([N:44]([CH3:46])[CH3:45])=[O:43])[CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([NH:35][C@H:36]4[CH2:37][CH2:38][C@H:39]([C:42](=[O:43])[N:44]([CH3:45])[CH3:46])[CH2:40][CH2:41]4)=[O:25])[NH:13][C:12]43[CH2:27][C:28]([CH2:30][F:31])([CH2:32][F:33])[CH2:29]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)[C@@H]1NC2(CC(CF)(CF)C2)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Agent: Cl
Product: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)[C@@H]2NC3(CC(CF)(CF)C3)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)CC1

Procedure:
The compound (70 mg, 0.14 mmol) obtained in Step 1 of Example 121 and trans-4-amino-N,N-dimethylcyclohexanecarboxamide hydrochloride (WO2008/068171) (29 mg, 0.17 mmol) were used as starting materials and treated in the same way as in Step 2 of Example 12 to give 62 mg (68%) of the title compound as a colorless amorphous solid.
Reaction SMILES: [CH3:1][C@H:2]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]#[CH:16])[CH:11]=2)[CH:6]=[N:5]1>C1(C)C=C(C)C=C(C)C=1>[CH3:1][C@H:2]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:13][CH2:14][CH:15]=[CH:16][C:11]3=2)[CH:6]=[N:5]1
Reactant: C#CCOc1ccc2cnn(C[C@H](C)NC(=O)OCc3ccccc3)c2c1
Solvent: Cc1cc(C)cc(C)c1
Product: C[C@@H](Cn1ncc2ccc3c(c21)C=CCO3)NC(=O)OCc1ccccc1

Procedure:
The product from Step B (2.37 g, 6.53 mmol) was heated in mesitylene (40 mL) in a manner similar to that described in Example 4, Step B to give, following purification (silica, 20% to 50% ethyl acetate in hexane), an oil (1.01 g, 43%): LC/MS (+APCI) m/z 364 (M+H).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[CH3:14][CH2:15][CH2:16]I.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:14][CH2:15][CH3:16]
Reactant: NCCCNc1ccccn1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCN(CCCN)c1ccccn1
Reaction time: 8 h
Yield: 40.5 %

Procedure:
Sodium hydride (1.14 g) was dissolved in dimethylsulphoxide (DMSO) (20 ml) at 70°-75° C. The solution was cooled and 2-(3-aminopropylamino)pyridine (6.57 g) in DMSO (20 ml) was added at room temperature. N-Propyl iodide (8.13 g) in DMSO (10 ml) was added dropwise maintaining the temperature at 20°-25° C. After allowing the mixture to stand overnight, water (250 ml) was added and this mixture was extracted with ether. The ether extracts were washed with hydrochloric acid (2N) and the aqueous layers made alkaline to pH 10.5. The aqueous layer was extracted with ether and chloroform. The pH was adjusted to pH 14 and the aqueous layer was extracted again with ether. The final ether extract was dried (K2CO3O, and the ether was evaporated to give 2-[N-(3-aminopropyl)-N-propylamino]pyridine (3.4 g) as an oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:24]=1)=[O:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:33]2[CH2:34][CH2:35][CH:30]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:36])[CH:28]=[CH:27][C:26]=3[CH3:29])[CH2:31][CH2:32]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(Cc2ccc(Oc3ccc(F)c(F)c3)cc2)CC1
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 4-(3,4-Difluorophenoxy)benzaldehyde (41.0 mg, 0.170 mmol) and 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide (45.0 mg, 0.170 mmol) in 1,2-dichloroethane (5.00 mL) was added sodium triacetoxyborohydride (110 mg, 0.520 mmol) and ACOH (10.0 μL, 0.170 mmol) at room temperature. The mixture was stirred overnight. The reaction mixture was quenched by saturated NaHCO3 solution (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo. The crude product was purified by preparative TLC using 5% NH3 (2.0 M in MeOH) in CH2Cl2 to give the desired product N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (44.0 mg, 54.0%)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Mg+2].[CH2:12]=[O:13].Cl>C(#N)C.C(N(CC)CC)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH:12]=[O:13]
Reactant: C=O
Reactant: Oc1ccc(I)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=Cc1cc(I)ccc1O
Temperature: 25 °C
Yield: 66 %

Procedure:
To the mixture of 20 g (91 mmol) of 4-iodophenol and 25.1 g (264 mmol) anhydrous magnesium dichloride in 455 mL of anhydrous acetonitrile was added triethylamine and paraformaldehyde. The mixture was heated to reflux for 4 h, allowed to cool to rt and treated with 500 mL of 5% HCl. The solution was extracted three times with EtOAc. The combined organic extracts were washed with brine (3×) and dried over anhydrous magnesium sulfate. The dried organic solution was evaporated to afford an oil, which was purified by silica gel chromatography with EtOAc/hexane (2:8). Concentration of the desired fractions afforded 15 g (66%) of a yellow solid, which was used directly in the next step without further purification.
Reaction SMILES: [F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.[Cl:18][CH:19](Cl)[C:20](=O)[CH3:21]>C1(C)C=CC=CC=1>[Cl:18][CH2:19][C:20]1[N:13]=[C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([S:2]([F:14])([F:15])([F:16])([F:17])[F:1])=[CH:8][CH:7]=2)[O:12][CH:21]=1
Reactant: CC(=O)C(Cl)Cl
Reactant: NC(=O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
4.10 g (15.0 mmol) 3-(4-pentafluorosulfanyl-phenyl)-acrylamide, 2.37 g (18.7 mmol) dichloro acetone and 25.0 ml toluene were kept at reflux temperature for 12 h with continuous removal of water by use of a Dean-Stark trap (a water separator used in chemical reactions). The reaction mixture was evaporated and purified by chromatography on silica gel (eluent:heptane/ethyl acetate 5:1). All fractions containing the product were evaporated and the residue stirred with 10 ml isohexane, the crystallized material isolated by filtration dried. 4.40 g (85%) 4-Chloromethyl-2-[2-(4-pentafluoromsulfanyl-phenyl)-vinyl]-oxazole.