Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC[S-]
Reactant: O=C(Nc1ccc(C(F)(F)F)cn1)c1ncccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cccnc1C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
0.33 g of sodium ethanethiolate was added to a mixture of 0.45 g of 3-chloro-N-(5-trifluoromethylpyridin-2-yl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. Water was poured to the reaction mixture cooled to room temperature, and the precipitated solid was taken by filtration and dried under reduced pressure to obtain 0.42 g of 3-ethylsulfanyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 2).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH3:23])=[C:11]([NH:24][C:25]([C:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[O:26])[CH:10]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH3:23])=[C:11]([NH:24][C:25]([C:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[O:26])[CH:10]=1
Reactant: CCOc1ccccc1-c1ccc(CNC(=O)OC(C)(C)C)cc1NC(=O)c1c[nH]c2ccccc2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccccc1-c1ccc(CN)cc1NC(=O)c1c[nH]c2ccccc2c1=O

Procedure:
{2′-Ethoxy-2-[(4-oxo-1,4-dihydroquinoline-3-carbonyl)-amino]-biphenyl-4-ylmethyl}-carbamic acid tert-butyl ester (304) (40 mg, 0.078 mmol) was stirred in a CH2Cl2/TFA mixture (3:1, 20 mL) at room temperature for 1 h. The volatiles were removed on a rotary evaporator. The crude product was purified by preparative HPLC to afford 4-oxo-1,4-dihydroquinoline-3-carboxylix acid (4-aminomethyl-2′-ethoxybiphenyl-2-yl)amine (163) as a tan solid (14 mg. 43%). 1H NMR (300 MHz, DMSO-d6) δ 12.87 (d, J=6.3 Hz, 1H), 11.83 (s, 1H), 8.76 (d, J=6.3 Hz, 1H), 8.40 (s, 1H), 8.26 (br s, 2H), 8.01 (dd, J=8.4 Hz, J=1.5 Hz, 1H), 7.75 (dt, J=8.1 Hz, J=1.2 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.47-7.37 (m, 2H), 7.24 (s, 2H), 7.15 (dd, J=7.5 Hz, J=1.8 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 7.02 (dt, J=7.5 Hz, J=0.9 Hz, 1H), 4.09 (m, 2H), 4.04 (q, J=6.9 Hz, 2H), 1.09 (t, J=6.9 Hz, 3H); HPLC ret. time 1.71 min, 10-100% CH3CN, 5 min gradient; ESI-MS 414.1 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][S:6][CH2:7][C:8](OC)=[O:9].CCCCCC.[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([CH:4]1[C:8](=[O:9])[CH2:7][S:6][CH2:5]1)=[O:12]
Reactant: COC(=O)CCSCC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C1CSCC1=O
Yield: 35.4 %

Procedure:
A solution of 3-methoxycarbonylmethylsulfanyl-propionic acid methyl ester (32) (58 g, 300 mmol) in dry T HF (800 mL) was added slowly within 4 h to a refluxing solution of hexane washed NaH (60% in mineral oil, 13.24 g, 331 mmol) in THF. The solution was further refluxed for 5 h. The solution was cooled and the solvent was evaporated. The residue was taken in water, acidified to pH˜1 by cold HCl solution, and extracted by CH2Cl2. The combined organic phase was dried over MgSO4 and concentrated under vacuum to get a viscous residue. The residue was purified by flash chromatography eluting with hexane to yield 17 g (35%) of 4-oxo-tetrahydro-thiophene-3-carboxylic acid methyl ester as colorless viscous oil which solidified on keeping overnight under vacuum. MP 51° C.; 1H NMR (400 MHz, CDCl3) δ 3.17-3.82 (m, 6.5 H), 10.94 (s, 0.5H) ppm. The isomeric mixture was used to next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([S:8](=[O:19])(=[O:18])[N:9]([CH3:17])[CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:6][N:7]=1.C1(C)C=CC=CC=1.[CH3:27][N:28]=[C:29]=[O:30]>C(OCC)(=O)C>[CH3:1][N:2]([C:3]1[S:4][C:5]([S:8](=[O:19])(=[O:18])[N:9]([CH3:17])[CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:6][N:7]=1)[C:29]([NH:28][CH3:27])=[O:30]
Reactant: CNc1nnc(S(=O)(=O)N(C)Cc2cccnc2)s1
Reactant: CN=C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)c1nnc(S(=O)(=O)N(C)Cc2cccnc2)s1

Procedure:
To a solution of 5.7 g. of 2-methylamino-5-[N-methyl-N-(3-pyridylmethyl)sulfamoyl]-1,3,4-thiadiazole (from Preparation 4) in 100 ml. of toluene was added 3 g. of methyl isocyanate. The mixture was heated at reflux for about 5 hours. The mixture was cooled and concentrated in vacuo to yield a semisolid residue. A sample of the semisolid subjected to thin layer chromatography in ethyl acetate showed three spots. The semisolid was chromatographed on a silica gel column using ethyl acetate. The eluate corresponding to the second spot material was collected. The eluate was concentrated to dryness in vacuo, leaving a residue. The residue was recrystallized from ethyl acetate to yield white crystals having a melting point of about 169°-170° C., and weighing about 2.2 g. The product was identified by NMR spectrum and elemental analyses as 1,3-dimethyl-1-[5-[N-methyl-N-(3-pyridylmethylsulfamoyl]-1,3,4-thiadiazol-2-yl]urea.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:15][CH2:14][CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[O:9][C:10]=1[CH3:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCOCc1ccccc1
Reaction time: 0.08 h
Yield: 60 %

Procedure:
A solution of 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol (3.17 g, 11.2 mmol) in DMF (25 mL) was treated with NaH (0.67 g, 60% oil dispersion) at 0° C. and stirred for 5 min. Benzyl bromide (2.90 g, 16.9 mmol) was added, and the resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water, and the mixture was extracted with EtOAc (2×150 mL). The combined organics were dried (Na2SO4), concentrated, and purified by silica gel chromatography column (10% EtOAc/hexanes) to yield the title compound as an oil (2.50 g, 60%).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:33][C:34]([F:39])([F:38])[C@@H:35]([OH:37])[CH3:36]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:37][C@@H:35]([CH3:36])[C:34]([F:39])([F:38])[F:33])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: C[C@H](O)C(F)(F)F
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: C[C@H](Oc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)[C@H](C(=O)N3CC(F)(F)C3)C2)c(Cl)c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 134 using (1R,2R,4R)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amid (Example 119) and (S)-1,1,1-trifluoro-propan-2-ol. Off-white solid. MS (EI): 584.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)P(N(C)C)(N(C)C)=O.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5]2[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:3]=[C:2]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[C:9](=[O:11])[CH2:8]1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccn3)c2C1
Reactant: CCCC[Sn](CCCC)(CCCC)Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)CC(=O)c2c(Cc3ccccc3)cn(-c3ccccn3)c2C1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 3-bromo-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one (10 mg, 0.31 mmol), benzyltributylstannane (253 mg, 0.68 mmol) and dichlorobis(triphenylphosphine)palladium (50 mg, 0.08 mmol) in hexamethylphosphoramide (1 mL) was heated at 70° C. for 48 h. The mixture was cooled to room temperature, diluted with DCM (2 mL), and the solution chromatographed on silica gel, eluting with isohexane: EtOAc (4:1). The title compound (45 mg, 43%) was isolated as a colourless solid. mp 111-113° C. Found: C, 79.7; H, 6.7; N, 8.3%. Calc. C22H22N2O: C, 79.97; H, 6.71; N, 8.48%. 1H NMR (360 MHz, CDCl3) δ 1.11 (6H,s), 2.39 (2H,s), 2.93 (2H,s), 4.17 (2H,s), 6.61 (1H,s), 7.16-7.34 (7H,m), 7.77 (1H, d of t, J=7.7 and 1.9 Hz), 8.50-8.53 (1H,m). MS (ES+) 331 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:40])[C:29]([NH:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:40])[C:29]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To an ice-cooled solution of tert-butyl 2-[(2-{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}-2-oxoacetyl)amino]acetate (1.33 g, 2.41 mmol) in methylene chloride (25 mL) was added 12 mL (160 mmol) of trifluoroacetic acid. The reaction mixture was stirred for two hours at room temperature then concentrated. The residue was crystallized twice from isopropanol. It was dried for 15 hours at 95° C. to give the title compound as yellow solid (0.928 g, 77%), mp 211–2° C. (dec.). Mass spectrum (−ESI, [M−H]−) m/z 495; 1HNMR (500 MHz, DMSO-d6): δ12.5–13.0 (br, 1H), 9.05 (s, 1H), 8.95 (t, 1H, J=6.1 Hz), 8.5 (d, 1H, J=1.5 Hz), 7.75–7.8 (m, 2H), 7.7 (d, 1H, J=8.6 Hz), 7.6 (dd, 1H, J=8.6 Hz and 1.8 Hz), 7.45 (d, 2H, J=8.1 Hz), 7.25–7.35 (m, 5H), 5.65 (s, 2H), and 3.9 ppm (d, 2H, J=6.1 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[OH:25].[OH-].[K+]>C(#N)C>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Reactant: Cc1ccc(C)c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)ccc1C
Yield: 80.9 %

Procedure:
(E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (20 g, 70.1 mmol) was reacted with 2,5-dimethylphenol (8.56 g, 1.0 eq) in 400 mL of acetonitrile (CH3CN) in the presence of potassium hydroxide (4.65 g, 1.1 eq) at room temperature for 4 hours, followed by removing the reaction solvent by concentration in a vacuum. The residue was stirred in water (200 mL) and the aqueous layer was extracted twice with 200 mL of dichloromethane. The organic layer thus obtained was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to remove the solvent. The residue was purified using silica gel chromatography to give (E)-methyl 2-(2-((2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white solid (18.5 g, yield 81%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]=[CH:12][C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C=Cc2ccc3cccc(O)c3n2)cc1
Temperature: 180 °C

Procedure:
A mixture of 8-hydroxyquinaldine (9.93 g) and p-anisaldehyde (20 mL) is heated at 180° C. overnight. The reaction is then cooled to room temperature and vacuum distilled. Once the majority of the p-anisaldehyde is distilled off (below 100° C.), the residue remaining in the flask is taken up in hot 95% EtOH. Any undissolved material is filtered off. H2O is added to the EtOH filtrate and the product is obtained as a yellow solid (3.42 g).
Reaction SMILES: CC1OC[C:5]([CH2:25][OH:26])([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[N:6]=1.[ClH:27].[CH2:28]([OH:30])[CH3:29]>>[ClH:27].[NH2:6][C:5]([O:30][CH2:28][CH3:29])([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:14]=1)[CH2:25][OH:26]
Reactant: CC1=NC(CO)(CCc2ccc(OCCOc3ccccc3)cc2)CO1
Reactant: CCO
Agent: Cl
Product: CCOC(N)(CO)CCc1ccc(OCCOc2ccccc2)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol (300 mg, 1.27 mmol) in DMF (5 ml) was added Cs2CO3 (1.2 g, 3.83 mmol) and 2-phenoxyethyl bromide (770 mg, 1.27 mmol). The reaction mixture was stirred at 85° C. for 4 hours. AcOEt and water were then added, the organic layer was separated and the aqueous phase was extracted with AcOEt (3×50 ml). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (AcOEt/Hx 9:1) afforded (2-Methyl-4-{2-[4-(2-phenoxy-ethoxy)phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol as colorless oil. To a solution of (2-methyl-4-{2-[4-(2-phenoxy-ethoxy)phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol (50 mg, 0.14 mmol) in ethanol (2 ml) was added conc. HCl (2 ml). The reaction mixture was stirred at 85° C. for 2 hours, then concentrated to dryness. The residue was re-dissolved in AcOEt and precipitated with hexanes. The solid was filtered off, washed with dry ether and dried in vacuo to afford 2-amino-4-{4-[2-phenoxy-ethoxy]-phenyl}-2-ethoxy-butan-1-ol hydrochloride as a colorless powder. ESI+MS: m/z=332.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18](=[O:38])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[CH:24]=[CH:23][C:22]=1O>>[CH3:16][O:17][C:18](=[O:38])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[CH:24]=[CH:23][C:22]=1[O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COC(=O)CCc1cc(C(=O)c2cccc(C#N)c2)ccc1O
Reactant: COc1ccc(C=CCCCCO)cc1
Product: COC(=O)CCc1cc(C(=O)c2cccc(C#N)c2)ccc1OCCCCC=Cc1ccc(OC)cc1
Yield: 34.1 %

Procedure:
Following the general procedure of Example 92B, 1.63 g of 6-(4-methoxyphenyl)-5-hexenyl alcohol were converted to its mesyl ester and reacted with 2.45 g of 5-(3-cyanobenzoyl)-2-hydroxybenzenepropanoic acid methyl ester to provide 1.34 g of 5-(3-cyanobenzoyl)-2{[6-(4-methoxyphenyl)-5-hexenyl]oxy]benzenepropanoic acid methyl ester, m.p. 65°-67° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[N:9]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.O>C(#N)C>[Br:17][C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][C:10]=1[Cl:14]
Reactant: Clc1ccc(CNc2cccc(Cl)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: Clc1ccc(CNc2ccc(Br)c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (4-chloro-benzyl)-(6-chloro-pyridin-2-yl)-amine (538, 4.00 g, 0.0158 mol) in acetonitrile (66.7 mL, 1.28 mol) under an atmosphere of nitrogen, N-bromosuccinimide (2.81 g, 0.0158 mol) in acetonitrile (20 mL) was added slowly. The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and crystallized with ethyl acetate in hexane to give a white solid (539, 2.60 g, 95.3%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][CH2:13][N:14]2[CH:18]=[C:17]([C:19]3[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:26]4[C:25](=[O:36])[N:24]([CH2:37][CH2:38][CH3:39])[C:23](=[O:40])[N:22]([CH2:41][CH2:42][CH3:43])[C:21]=4[N:20]=3)[CH:16]=[N:15]2)[CH:6]=1)C.[BH4-].[Na+].O>C1COCC1>[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]#[C:12][CH2:13][N:14]2[CH:18]=[C:17]([C:19]3[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:26]4[C:25](=[O:36])[N:24]([CH2:37][CH2:38][CH3:39])[C:23](=[O:40])[N:22]([CH2:41][CH2:42][CH3:43])[C:21]=4[N:20]=3)[CH:16]=[N:15]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4cccc(C(=O)OCC)c4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4cccc(CO)c4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
To a solution of 3-(3-{4-[2,6-dioxo-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-pyrazol-1-yl}-prop-1-ynyl)-benzoic acid ethyl ester (50 mg, 0.08 mmol) in THF (5 ml), NaBH4 (5 mg, 0.16 mmol) was added slowly at 0° C. It was stirred for 3 h at room temperature. Water was added to reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and then filtered and concentrated under vacuum. The residue obtained was purified by column chromatography to obtain 8-{1-[3-(3-hydroxymethyl-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (25 mg, 54%) as an yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:11][C:10](=[O:12])[N:9]([CH2:13][C:14]([OH:16])=[O:15])[C:8]2=[O:17])=[CH:3][CH:2]=1.[H][H].O>C(O)(=O)C.[Rh]>[NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:11][C:10](=[O:12])[N:9]([CH2:13][C:14]([OH:16])=[O:15])[C:8]2=[O:17])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(O)CN1C(=O)CC(c2ccncc2)C1=O
Agent: [Rh]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CN1C(=O)CC(C2CCNCC2)C1=O

Procedure:
2.8 g of [3-(4-pyridyl)-2,5-dioxopyrrolidin-1-yl]acetic acid are suspended in 160 ml of acetic acid and hydrogenated in an autoclave at 100° C. and a hydrogen pressure of 150 bar for 24 h using 100 mg of 5% rhodium on carbon as a catalyst. The catalyst is then filtered off and the filtrate is concentrated to dryness in vacuo. The product thus obtained is taken up in a little water and freeze-dried.
Reaction SMILES: O[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.NO.S(Cl)([Cl:22])=O>C1COCC1>[Cl:22][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: OCc1ccc(OCCN2CCCCC2)cc1
Reactant: O=S(Cl)Cl
Agent: NO
Solvent: C1CCOC1
Product: ClCc1ccc(OCCN2CCCCC2)cc1

Procedure:
This material is prepared from the amino alcohol 1-[2-(4-Hydroxymethyl-phenoxy)-ethyl]piperidine by treatment with thionyl chloride in THF at 0° C. Resulting solid is used without further purification.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[O:7][C:8]2[C:14]([Cl:15])=[CH:13][C:12]([Br:16])=[CH:11][C:9]=2[CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Br:16][C:12]1[CH:13]=[C:14]([Cl:15])[C:8]2[O:7][C:6]([CH2:5][CH2:4][NH2:1])=[CH:10][C:9]=2[CH:11]=1
Reactant: [N-]=[N+]=NCCc1cc2cc(Br)cc(Cl)c2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCc1cc2cc(Br)cc(Cl)c2o1
Temperature: 65 °C
Yield: 85.1 %

Procedure:
To a solution of the product of step D (500 mg, 1.66 mmol) in THF (8 mL) was added triphenylphosphine (72 mg, 3.32 mmol) followed by water (3 mL). The reaction mixture was heated to 65° C. for 4 h and concentrated in vacuo. Purification by column chromatography (SiO2, 95:5 dichloromethane/methanol) provided 2-(5-bromo-7-chlorobenzofuran-2-yl)ethanamine (388 mg, 85%) as a colorless liquid: 1H NMR (CDCl3, 400 MHz) δ 7.51 (t, J=2.4 Hz, 1H), 7.36 (t, J=2.4 Hz, 1H), 6.45 (s, 1H), 3.12 (t, J=8.4 Hz, 2H), 2.94 (t, J=8.8 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]>ClCCl>[CH2:23]([O:22][C:20]([NH:1][C:2]12[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([CH2:5]3)[CH2:11]1)[CH2:9]2)=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)Cl
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)NC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h

Procedure:
1-Aminoadamantane (10 mmol; 1.51 g) and triethylamine (1.9 ml) in dry dichloromethane (30 ml) are stirred at 0°-5° C. and allyl chloroformate (1.1 ml) added dropwise. After 0.5 hour, the solution is washed with dilute sulfuric acid and water. After drying over anhydrous magnesium sulfate, the solution is evaporated to give 1-(allyloxycarbonylamino)adamantane, as a white solid, with a melting point of about 56°-58° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])(O)=O.[Na+].[CH3:14][CH2:15]O>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:14]=[CH:15][N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Br)ccn1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Product: Brc1ccn2ccnc2c1

Procedure:
4-Bromo-pyridin-2-ylamine (1 eq, 5.78 mmol, 1 g) is added to a solution of chloroacetic aldehyde (5 eq, 28.9 mmol, 5 ml) in EtOH (25 ml). NaHCO3 (2 eq, 11.6 mmol, 971 g) is then added and the reaction mixture is heated at reflux for 17 h. The solvent is then removed in vacuo and the product is purified by flash column chromatography eluting with 9:1 DCM/MeOH to afford 7-bromo-imidazo-[1,2-a]-pyridine as a brown solid; [M+H]+=198
Reaction SMILES: C([O-])(=O)C.[NH4+].C(O)(=O)C.O[N:11]=[C:12]([CH:18]([CH2:23][C:24](=O)[CH3:25])[CH:19]([CH3:22])[CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O>[CH:19]([C:18]1[CH:23]=[C:24]([CH3:25])[NH:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH2:20][CH3:21])[CH3:22]
Reactant: CCOC(=O)C(=NO)C(CC(C)=O)C(C)CC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1[nH]c(C)cc1C(C)CC
Temperature: 100 °C

Procedure:
Ammonium acetate (92.5 g) was added to the acetic acid solution (430 mL) of the compound prepared in Example 16 under argon gas atmosphere. The reaction mixture was stirred at 100° C. for an hour. Water was added to the reaction mixture, and the reaction mixture was stirred for an hour. A precipitate was filtrated. The precipitate which was filtrated was dissolved in methylene chloride again, and the solution was purified by column chromatography on silica gel (ethyl acetate:n-hexane=1:3) to obtain a title compound (44.1 g) having the following physical data.