Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=S)[CH3:2].[N:5]([CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C@@H:10]1[C:22]([NH2:24])=[O:23])=[N+]=[N-]>CCOCC>[C:1]([NH:5][CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C@@H:10]1[C:22]([NH2:24])=[O:23])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: C[C@@H](c1ccccc1)N1CC[C@@H](CN=[N+]=[N-])[C@H]1C(N)=O
Solvent: CCOCC
Product: CC(=O)NC[C@@H]1CCN([C@@H](C)c2ccccc2)[C@@H]1C(N)=O
Reaction time: 16 h

Procedure:
Thioacetic acid (2.312 mmol) was added to (2S,3S)-3-azidomethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide (Stage 36.3) (0.578 mmol) at rt with the formation of nitrogen gas. After stirring for 16 h, the reaction mixture was diluted with Et2O, the solids were removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a light yellow oil (thiol odor). HPLC: tR=3.71 min (method H); LC-MS: tR=0.64 min, [M+H]+ 290 (method I); TLC: Rf=0.38 (200:20:1 CH2Cl2/MeOH/conc. NH4OH).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:27][C:28]([C:30]1[CH:34]=[CH:33][S:32][CH:31]=1)=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CN([CH:38]=[O:39])C>CCCCCC.C1COCC1.C(OCC)C.C(O)(=O)C>[CH2:13]([O:27][C:28]([C:30]1[CH:34]=[CH:33][S:32][C:31]=1[CH:38]=[O:39])=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCOC(=O)c1ccsc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CCCCCCCCCCCCCCOC(=O)c1ccsc1C=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL Schlenk flask were added 0.5 mL of diisopropyl amine and 20 mL of dry THF. The flask was cooled to −78° C. 3.5 mmol of n-butyl lithium in hexane was then added to the above solution. The mixture was stirred at −78° C. for 30 minutes. After stirring, 1.0 g of tetradecylthiophene-3-carboxylate in 10 mL THF was added dropwise to the solution. After stirring at −78° C. for another 2 hours, 0.7 mL of DMF was syringed into the reaction mixture. The reaction mixture was stirred for 5 h at −78° C. and 1 mL of acetic acid was added to the flask. The mixture was poured into a separation funnel and diethyl ether was added to the mixture. The organic layer was washed 3 times with 100 mL of water, dried with MgSO4, and the solvents were removed by rotary evaporation. The resulting residue was purified by column chromatography using a mixture of hexane and dichloromethane to give the desired compound. The NMR data were obtained and were consistent with those of the desired compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=O)[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)=O)=[CH:8]1>O1CCCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH:22]2[CH2:21][CH2:20][N:19]([CH2:17][CH2:16][C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[NH:7][CH:8]=3)[CH2:24][CH2:23]2)=[CH:31][CH:30]=1
Reactant: O=C(C(=O)N1CCC(Oc2ccc(F)cc2)CC1)c1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(OC2CCN(CCc3c[nH]c4ccccc34)CC2)cc1

Procedure:
By following the manipulative procedure described in Example 2(d), 2.6 g of lithium aluminum hydride in 80 ml. of tetrahydrofuran and 6.0 g of 1-(indol-3-ylglyoxyloyl)-4-(p-fluorophenoxy)piperidine in 60 ml. of tetrahydrofuran are allowed to react to produce a white solid. The solid is recrystallized from isopropanol, and then from an ethanol and water mixture to give colorless cubes of 3-{2-[4-(p-fluorophenoxy)piperidyl]ethyl}indole, m.p. 109°-111° C.
Reaction SMILES: [NH:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[Si:16]([O:10][CH2:9][CH2:8][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCNc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCNc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A solution of 2-anilinoethanol (5.82 g, TCI) in anhydrous DMF (50 ml) was added with imidazole (3.23 g, TCI), added dropwise with a solution of t-butyldiphenylsilyl chloride (12.48 g, TCI) in DMF (50 ml) under ice cooling, stirred for 30 minutes, then warmed to room temperature, and further stirred for 3.5 hours. The reaction mixture was added with water (100 ml), and extracted with ethyl acetate (100 ml). The organic layer was washed successively with water and saturated brine, and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (Intermediate 46, 15.61 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH3:20])[C:7]2[C:12]([C:13]=1[C:14](=[O:19])C(Cl)(Cl)Cl)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[OH-:21].[Na+].Cl>C1COCC1>[CH2:1]([C:5]1[N:6]([CH3:20])[C:7]2[C:12]([C:13]=1[C:14]([OH:19])=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCc1c(C(=O)C(Cl)(Cl)Cl)c2ccccc2n1C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1c(C(=O)O)c2ccccc2n1C
Yield: 101.2 %

Procedure:
A mixture of 1-(2-butyl-1-methyl-1H-indol-3-yl)-2,2,2-trichloro-ethanone (4.87 g, 14.7 mmol), prepared in the previous step, and 1 N NaOH (73.5 mL, 73.5 mmol) in 350 mL of THF was refluxed under nitrogen for 2.25 h. After cooling to room temperature 1 N HCl (80 mL, 80 mmol) was added and then the solvent was removed under reduced pressure. The residue was partitioned between 1 N HCl and methylene chloride. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-1-methyl-1H-indole-3-carboxylic acid (3.44 g, 100%) as a brown solid, mp 163-165° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:57][C:58]1[NH:59][C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=1>C(Cl)Cl>[NH:59]1[C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=[C:58]1[NH:57][C:14](=[O:15])[CH:13]([C:5]1[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:3]([C:1]#[N:2])[CH:4]=1)[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Reactant: Nc1nc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3[nH]2)cc1C#N
Yield: 95 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 26, 100 mg, 0.311 mmol), triethylamine (0.13 mL, 0.933 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (206 mg, 0.467 mmol), and 2-aminobenzimidazole (62 mg, 0.467 mmol) in methylene chloride (3 mL) was stirred at 25° C. for 3 h. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40S, Silica, 1/3 h-hexanes/ethyl acetate) to afford N-(1H-benzoimidazol-2-yl)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (129 mg, 95%) as a yellow solid: mp 148-152° C.; EI-HRMS m/e calcd for C23H24N4O3S (M+) 436.1569, found 436.1573.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F.C(OCC)(=O)C>CN(C=O)C.CCCCCC>[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH:2]([C:1]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
Benzyl ethyl malonate (2.9 g, 12.6 mmol) in dry DMF (20 ml) was cooled in an ice bath and the temperature monitored whilst sodium hydride (504 mg, 12.6 mmol) was added portionwise. This was stirred at room temperature for 10 minutes until H2 evolution ceased. 3,4-Difluoronitrobenzene (2 g, 12.6 mmol) was added under an argon atmosphere and gave a dark red colour change. The reaction mixture was heated at 100° C. for 20 hours under argon. Thin layer chromatography (20% ethyl acetate in hexane) showed completion of the reaction. The reaction mixture was cooled to room temperature and partitioned between 2N Hydrochloric acid (75 ml) and ethyl acetate (75 ml). The aqueous layer was extracted with ethyl acetate (2×75 ml) and the combined organic fractions were evaporated to a yellow oil. Purification by chromatography on silica gel eluting with 0-20% ethyl acetate in hexane gave the title compound as a yellow oil (3.86 g, 10.6 mmol).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH2:31]([NH2:34])[CH2:32][CH3:33]>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH2:31][CH2:32][CH3:33])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: CCCN
Product: CCCNCC1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1

Procedure:
The title compound was prepared (0.092 g, 84%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.13 g, 0.28 mmol) and propylamine (0.165 g, 2.80 mmol). mp >250° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.CO.Cl.O>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: O=C1NCCCc2cc(I)ccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Ic1ccc2c(c1)CCCNC2
Temperature: 75 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
7-Iodo-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (Preparation 1) (550 mg, 1.916 mmol) was dissolved in dry THF (70 ml) and treated with borane-THF complex (1M) (11.49 ml, 11.49 mmol) and heated at reflux for 4 hours. Then the reaction was left standing overnight. Additional borane-THF complex (1M, 2 ml) was added and the reaction heated at reflux temperature for a further 2 hours and 30 minutes. Methanol was carefully added to the cooled reaction mixture. The reaction was stirred until fizzing stopped. Then 2N HCl (aq) (20 ml) was carefully added portion-wise and, after fizzing had subsided, the solution heated at 75° C. for 30 minutes. LC/MS showed one major product. The reaction mixture was cooled and water was added (20 ml). The mixture was washed with EtOAc (40 ml), basified with 2 N NaOH (aq) and extracted with EtOAc (50 ml). The EtOAc layer was dried over anhydrous MgSO4 and evaporated to yield the title compound (400 mg) as a white solid. MS (ES) C10H12IN requires 273: found 274 (M+H)+.
Reaction SMILES: [CH:1]#[C:2][C@@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:9][C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[CH:1]
Reactant: C1=COCCC1
Reactant: C#C[C@@H](O)CCCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: C#C[C@H](CCCCC)OC1CCCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (3S)-1-octyn-3-ol (63 g., 0.5 mole) and dihydropyran (63 g., 0.75 mole) is cooled to 5° in an ice bath and stirred while concentrated sulfuric acid (0.5 ml.) is added dropwise. The resulting solution is allowed to warm to room temperature and stand for 24 hours. The solution is then treated with solid anhydrous sodium carbonate, filtered, and distilled to yield (3S)-3-(2-tetrahydropyranyloxy)-1-octyne.
Reaction SMILES: [K+].[CH3:2][N:3]([CH3:20])[C:4]1[CH:19]=[CH:18][C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([O-])=[O:16])=[CH:11][C:9]=3[S:10][C:6]=2[CH:5]=1.C(Cl)(=O)C([Cl:24])=O>C1C=CC=CC=1>[CH3:2][N:3]([CH3:20])[C:4]1[CH:19]=[CH:18][C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([Cl:24])=[O:16])=[CH:11][C:9]=3[S:10][C:6]=2[CH:5]=1
Reactant: CN(C)c1ccc2c(c1)sc1cc(C(=O)[O-])ccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: c1ccccc1
Product: CN(C)c1ccc2c(c1)sc1cc(C(=O)Cl)ccc12

Procedure:
To a suspension of 1.9 g. of 7-dimethylaminodibenzothiophene-3-carboxylic acid potassium salt in 100 ml. of refluxing benzene was added over a period of 20 minutes a solution of 1.2 g. of oxalyl chloride in 25 ml. of benzene. The solution was then stirred and refluxed for 3 hours. The hot solution was filtered, and the filtrate was distilled to dryness in vacuo (steam bath, rotary evaporator). The residue of crude 7-dimethylaminodibenzothiophene-3-carbonyl chloride weighed 1.8 g.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([CH:8]1[CH2:12][CH:11]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]3[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=3[CH:26]=2)=[O:15])[CH2:10][N:9]1[CH2:27][CH:28]1[CH2:41][C:40]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:42][CH3:43])[CH:38]=3)[N:33]=[CH:32][C:31]=2[O:30][CH2:29]1)=[O:7]>O1CCCC1.O>[CH3:43][O:42][C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][C:31]1[O:30][CH2:29][CH:28]([CH2:27][N:9]3[CH2:10][CH:11]([NH:13][C:14]([C:16]4[CH:17]=[CH:18][C:19]5[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=5[CH:26]=4)=[O:15])[CH2:12][CH:8]3[C:6]([OH:7])=[O:5])[CH2:41][C:40]2=1
Reactant: COC(=O)C1CC(NC(=O)c2ccc3c(c2)NC(=O)CS3)CN1CC1COc2cnc3ccc(OC)cc3c2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2ncc3c(c2c1)CC(CN1CC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1C(=O)O)CO3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide monohydrate (5.5 mg, 0.13 mmol, 1.5 eq) is added at room temperature to a stirred solution of 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester (70 mg, 0.09 mmol, 1.0 eq) in tetrahydrofuran (2 mL) and water (1 mL). After 1 hour stirring at room temperature, the reaction mixture is concentrated and purified by preparative HPLC to afford 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-pyrrolidine-2-carboxylic acid as a white lyophilized powder (14 mg, 28% yield).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(C)=O.Cl[CH2:10][C:11]1[N:12]=[C:13]([NH:16][C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[O:18])[S:14][CH:15]=1>O>[N:1]([CH2:10][C:11]1[N:12]=[C:13]([NH:16][C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[O:18])[S:14][CH:15]=1)=[N+:2]=[N-:3]
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CCl)cs1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1csc(NC(=O)NCc2cccc(F)c2)n1
Reaction time: 4 h

Procedure:
Sodium azide (390 mg, 6.0 mmol) was added to a DMSO (5 mL) solution of Intermediate 4: 1-(4-(chloro-methyl)thiazol-2-yl)-3-(3-fluorobenzyl)urea (600 mg, 2 mmol). The mixture was stirred for 4 hours at 40 C. Upon completion of the reaction, water was added at 10 C and the mixture was extracted with EtOAc. Organics were washed with brine, dried and evaporated. Recrystallization from CH2Cl2/hexane afforded 1-(4-(azidomethyl)thiazol-2-yl)-3-(3-fluorobenzyl)urea. 1H NMR (400 MHz, CDCl3): δ 10.3 (1H, br), 7.27 (m, 1H), 7.1-6.9 (m, 3H), 6.74 (s, 1H), 4.50 (d, 2H), 4.27 (s, 2H). MS (ES+): M/Z 307 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12].[CH3:17][N:18]=[C:19]=[O:20].C(N(CC)CC)C>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:19]([NH:18][CH3:17])=[O:20])(=[O:13])=[O:12]
Reactant: CN=C=O
Reactant: NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Yield: 96.2 %

Procedure:
5.0 g of 2-(3,3,3-trifluoro-1-propen-1yl)phenylsulfonamide and 1.7 g of methyl isocyanate are suspended in 25 ml of methylene chloride and 3.0 g of triethylamine are added dropwise for 10 minutes, whereupon a clear solution forms. The solution is concentrated, the residue is dissolved in a 5% sodium carbonate solution, and insoluble constituents are removed by filtration. The clear solution is acidified with 10% hydrochloric acid, to give 5.9 g of N-[2-(3,3,3-trifluoro-1-propen-1-yl)phenylsulfonyl]-N'-methylurea as a colorless precipitate with a melting point of 190°-192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17]C)=[O:10])=[CH:5][CH:4]=1>ClCCl>[OH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:10]
Reactant: COc1ccc(C(=O)c2ccccc2OC)cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
2.61 g of (4-methoxyphenyl)(2-methoxyphenyl)methanone 52 are dissolved in dichloromethane. The mixture is cooled in an ice bath, and 3.71 g of boron tribromide-dimethyl sulfide complex are added. The mixture is warmed to room temperature and left to stir for 3 h. The reaction is then stopped by pouring into ice-water, the dichloromethane phase is separated off, and the aqueous phase is extracted several times with ethyl acetate. The combined organic phase is washed with water and sodium chloride solution, dried over sodium sulfate and concentrated. The crude product is chromatographed on silica gel with ethyl acetate/heptane. 1.26 g of the product are obtained. C14H12O3 (228.25) MS (DCl) 229.2 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:15](=[O:17])[CH3:16])[CH:3]=[N:4][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cncc(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.9 %

Procedure:
To a solution of 3-amino-5-bromopyridine (1.0 g, 5.78 mmol) and pyridine (1.3 mL, 12.9 mmol) in DCM (5 mL) is added acetic anhydride (0.6 mL, 6.358 mmol) dropwise. The mixture is stirred at room temperature for 17 h. The mixture is concentrated and the resulting crude product is purified by normal phase using 0-75% EtOAc in heptane as the gradient to afford N-(5-bromo-pyridin-3-yl)-acetamide (1.18 g, 95% yield).
Reaction SMILES: [N:1]1([CH:11]=[O:12])[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH:9]=O)[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>>[N+:18](/[CH:21]=[CH:9]/[C:7]1[CH:6]=[N:5][N:4]2[CH2:3][CH2:2][N:1]([CH:11]=[O:12])[C:8]=12)([O-:20])=[O:19]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cnn2c1N(C=O)CC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=CN1CCn2ncc(/C=C/[N+](=O)[O-])c21

Procedure:
A solution of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1,7-dicarbaldehyde (1 g) and ammonium acetate (653 mg) in nitromethane (20 ml) was refluxed for 4 hours. The reaction mixture was evaporated under reduced pressure and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 7-[(E)-2-nitroethenyl]-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-carbaldehyde (1.00 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=[NH:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:36]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[C@H]1C[C@@H](Oc2cccc(Cl)n2)CCN1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@@H](Oc2cccc(N=C(c3ccccc3)c3ccccc3)n2)CCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Combine 4-(6-chloro-pyridin-2-yloxy)-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 48, 0.725 g), benzhydrylideneamine (0.482 g), racemic-2,2′-bis(diphenylphosphino)-1,1′binaphthyl (55 mg) and sodium t-butoxide (0.299 g) in toluene (20 mL) and heat at 100° C. After 10 min., add tris(dibenzylidineacetone)-dipalladium(0) (41 mg) and heat at 100° C. After 2.5 hr., partition between ethyl acetate-hexane (1:4) and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a 10 g silica gel column eluting with dichloromethane-2M NH3 in methanol, gradient) to give the crude title compound (1.19 g). Mass spectrum (electrospray): m/z=472 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([OH:19])[C:5]2[N:6]=[CH:7][N:8]([C:17]=2[N:18]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>COCCO>[N:24]1([CH2:23][CH2:22][CH2:21][NH:20][C:2]2[NH:3][C:4](=[O:19])[C:5]3[N:6]=[CH:7][N:8]([C:17]=3[N:18]=2)[C@@H:9]2[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: NCCCn1ccnc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)nc(Cl)nc32)C[C@@H]1O
Solvent: COCCO
Product: O=c1[nH]c(NCCCn2ccnc2)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 0 °C

Procedure:
A solution of the nucleoside 102 (10.31 g, 36 mmol) and 1-(3-amino-propyl) imidazol (9 g, 72 mmole) in 2-methoxyethanol (60 ml) was heated in a steel bomb at 120° C. (oil bath) for 24 hrs. The bomb was cooled to 0° C., opened carefully and the precipitated solid was filtered. The solid was washed with methanol (50 ml) and acetone (50 ml), and dried over sodium hydroxide to give 9 g (67%) of pure 103. A small amount was recrystallized from DMF for analytical purposes. mp 245-47°.
Reaction SMILES: [CH:1]([C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4])=[CH2:2].[CH2:12]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=2)=[CH:9][CH:10]=1)=[O:4])=[CH2:2]
Reactant: C=CC(=O)c1ccc(O)cc1
Reactant: CCCCCc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)c1ccc(OC(=O)c2ccc(CCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.9 %

Procedure:
A mixture of 4-hydroxyphenyl vinyl ketone (c) (1.0 g), 4-pentylbenzoic acid (1.2 g), DCC (1.9 g), DMAP (0.1 g) and methylene chloride (30 mL) was stirred at room temperature for 12 hours. The white solid precipitated was filtrated out, and the solvent was evaporated away from the filtrate. The residue was dissolved in ethyl acetate, and washed with aqueous 2 M NaOH solution and then with water. The residue was purified through column chromatography (eluent: toluene) and then through recrystallization (ethanol) to obtain 0.4 g of colorless crystals, compound (1-5-11). The NMR and MS spectra of the compound well support the structure thereof.