Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].C(OCC)(=O)C.C[N:35](C)C=O>O>[C:1]1([CH:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:8]([NH:35][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: CCC(c1ccccc1)c1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CNC(C)C(c1ccccc1)c1ccccc1

Procedure:
2-Amino-1-(3,5-bis(trifiuoromethyl)phenyl)methyloxy)-3,3-diphenylpropane (0.365 g, Example 1f, liberated from its hydrochloride salt by partitioning between ethyl acetate and 10% aqueous sodium carbonate solution followed by drying (MgSO4) and evaporation in vacuo), K2CO3 (0.5 g), and methyl bromacetate (1.23 g) were stirred in dimethyl formamide (5 ml) for 30 minutes. Ethyl acetate (50 ml) and water (50 ml) were added and the organic phase was washed further with water (50 ml), saturated brine (50 ml) and dried (MgSO4). After evaporation the residue was chromatographed on silica gel (eluting with ethyl acetate: hexane (4:6)) to give 1-(3.5-bis(trifiuoromethyl)phenyl)methyloxy)-3,3-diphenyl-2-(N -((carbomethoxy)methyl)amino)propane as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1)#[N:2].[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1[S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:20]([C:12]2[S:11][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=[O:22])=[O:21])=[C:5]([NH:10][S:20]([C:12]2[S:11][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=[O:21])=[O:22])[CH:4]=1)#[N:2]
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: N#Cc1ccc(N)c(N)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1ccc(NS(=O)(=O)c2cc3ccccc3s2)c(NS(=O)(=O)c2cc3ccccc3s2)c1
Temperature: 80 °C
Yield: 35 %

Procedure:
To a solution of 4-cyanobenzene-1,2-diamine (1 mmol) in pyridine (4 mL), benzothiophene-2-sulfonyl chloride (2.2 mmol) was added in small portions. The reaction mixture was then heated at 80° C. with stirring until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with ethyl acetate (20 mL). The organic phase was washed with 10% aqueous HCl solution (15 mL), water (15 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 184 mg of N,N′-(4-cyano-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26](CCCCl)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22]N=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.ClC1C=[C:34](C=CC=1OCC1C=CC=C(F)C=1)[NH2:35].CN1CC[CH2:51][C:50]1=O.C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:18][C:19]3[CH2:51][CH2:50][N:21]4[CH:22]=[CH:34][N:35]=[C:24]([C:20]=34)[CH:25]=[N:26]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccn(CCCCl)c34)cc2Cl)c1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CN1CCCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Fc1cccc(COc2ccc(N3CC4=C5C(=NC=CN5CC4)C=N3)cc2Cl)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (839 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (1.10 g) and 1-methyl-2-pyrrolidone (5 mL) was stirred at 140° C. for 1 hr. The reaction mixture was poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (40 mL×3), and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=60:40→50:50) and further subjected to basic silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100). The object fraction was concentrated under reduced pressure. Chloroform-diisopropyl ether was added to the residue, and the solid was collected by filtration and dried. Recrystallization from ethyl acetate gave the title compound (74.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[C:22]=3[Cl:28])=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].C(O)=[O:34].O.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([OH:34])[C:22]=3[Cl:28])=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:29]([F:30])([F:31])[F:32]
Reactant: O=C(c1ccnc(Cl)c1Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccnc(O)c1Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 1 dram vial was charged with 4-chloro-N-[5-chloro-2-(2,3-dichloro-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (15 mg, 0.028 mmol), formic acid (0.39 mL) and water (0.13 mL). The heterogeneous solution was warmed to 100° C. and stirred overnight. The following day, starting material remained; therefore, an additional 0.26 mL of formic acid was added. The reaction was subsequently warmed to 110° C. and stirred overnight. The resultant mixture was neutralized with saturated aqueous sodium bicarbonate, diluted with EtOAc, and the organic layer washed with saturated sodium bicarbonate. The combined organics were dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to afford the desired hydroxypyridine: 1H NMR (400 MHz, CD3OD) δ 8.26-8.38 (m, 1H), 8.17-8.20 (m, 2H), 8.02-8.07 (m, 1H), 7.72-7.76 (m, 1H), 7.34-7.37 (m, 1H), 6.17-6.20 (m, 1H); MS (ES) (M+H)+ expected 525.9, found 525.9.
Reaction SMILES: C(Cl)(=O)C.[CH:5]1(O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:12][C@@:13]([NH:26][NH2:27])([C:23]([OH:25])=[O:24])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:22])=[C:19]([OH:21])[CH:20]=1>C(OCC)(=O)C>[OH:21][C:19]1[CH:20]=[C:15]([CH2:14][C@@:13]([NH:26][NH2:27])([CH3:12])[C:23]([O:25][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:24])[CH:16]=[CH:17][C:18]=1[OH:22]
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)O
Reactant: OC1CCCCC1
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)OC1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Acetyl chloride (1 mL) was slowly added to cyclohexanol (5 mL) at 0° C. After stirring at 0° C. for 10 min, carbidopa (294 mg, 1.5 mmol) was added slowly as solid. The resulting mixture was warmed to 50° C. for 16 h. After cooling to room temperature, ethyl acetate (40 mL) was added and product was extracted with water (4×5 mL), then the aqueous phase was lyophilized to give the crude product. HPLC of the crude product afforded 50 mg of the title compound as an oil. 1H NMR (CD3OD): δ 1.46 (s, 3H), 1.52–1.80 (m, 10H), 2.92 (dd, J=13.6 Hz, 2H,), 4.85 (m, 1H), 6.49 (d, J=7.6 Hz, 1H), 6.59 (s, 1H), 6.68 (d, J=7.6 Hz, 1H). MS (ESI) m/z 309.3 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][C:10](C)=[CH:11][C:6]2=[N:5][CH:4]=1.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.[CH2:22](N(CC)CC)C.CCOCC>C(O)C.ClCCl>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:2][C:3]2[N:7]3[CH:8]=[C:9]([CH3:22])[CH:10]=[CH:11][C:6]3=[N:5][CH:4]=2)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1ccn2c(CBr)cnc2c1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc2ncc(CSc3nc(C)cc(O)n3)n2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a mixture of 3-(bromomethyl)-7-methylimidazo[1,2-a]pyridine (1.0 g, 4.44 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (0.407 g, 2.88 mmol) in anhydrous ethanol (50 mL) at 0° C. was added triethylamine (0.898 g, 8.88 mmol). Then, the reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated to provide a crude residue. Ether was added to precipitate the triethylamine hydrochloride salt. The solid was filtered and washed with ether several times. The solvent was evaporated to provide a crude residue, which was purified by Combiflash using 0-10% methanol:dichloromethane to provide 6-methyl-2-[({6-methylimidazo[1,2-a]pyridin-3-yl}methyl)sulfanyl]pyrimidin-4-ol as a white solid (826 mg, 65% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.25 (s, 3H), 2.31 (s, 3H), 4.79 (s, 2H), 6.04 (bs, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.54 (s, 1H), 8.32 (s, 1H); M+ 286.5.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[CH2:2][CH3:3].Cl.[NH2:17][OH:18]>>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]1)[CH2:2][CH3:3]
Reactant: NO
Reactant: CCCOCCCCN1CCC(=O)CC1
Agent: Cl
Product: CCCOCCCCN1CCC(=NO)CC1

Procedure:
1-(4-Propoxybutyl)-4-piperidone oxime is prepared from 1-(4-propoxybutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O:12][CH2:13][C:14]1[C:15](=[O:35])[N:16]2[C:28](=[CH:29][C:30]=1[C:31](=[O:34])[CH2:32][CH3:33])[C:19]1=[N:20][C:21]3[C:26]([CH:27]=[C:18]1[CH2:17]2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=O.[Cl-].[NH4+]>C1COCC1.[Zn]>[F:8][C:2]([F:9])([C:31]([OH:34])([C:30]1[CH:29]=[C:28]2[N:16]([CH2:17][C:18]3[C:19]2=[N:20][C:21]2[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15](=[O:35])[C:14]=1[CH2:13][OH:12])[CH2:32][CH3:33])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CCC(=O)c1cc2n(c(=O)c1COC=O)Cc1cc3ccccc3nc1-2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)(CC)c1cc2n(c(=O)c1CO)Cc1cc3ccccc3nc1-2
Temperature: 25 °C
Yield: 26 %

Procedure:
Approximately half of a total quantity of ethyl bromodifluoroacetate (1.8 ml, 14 mmol), (9-oxo-7-propionyl-9,11-dihydroindolizino[1,2-b]quinolin-8-yl)methyl formate (2.0 g, 5.75 mmol, as obtained in Stage 1.b.) in suspension in anhydrous THF (10 ml), are added dropwise under argon to a suspension of zinc (1.25 g, 17.2 mmol) in anhydrous THF under reflux (40 ml) then the remaining part of the ethyl bromodifluoroacetate is added. The reaction mixture is maintained under reflux for another half an hour. After cooling down to ambient temperature, the reaction is stopped by the addition of saturated ammonium chloride (20 ml) and the reaction mixture is extracted with dichloromethane (3×20 ml). The combined organic extracts are dried and concentrated. The residue is taken up in diethyl ether (10 ml), filtered and purified by column chromatography (SiO2, CH2Cl2/MeOH:98/2), which produces 664 mg (26%) of product in the form of a yellow solid, m.p. 208-209° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:29]CC1>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:12]([OH:29])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(-c3ccccc3)c2)CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(-c3ccccc3)c2)[C@@H](O)C1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of the title A compound, 4-biphenyl-3-yl-3,6,dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (2.57 g, 7.66 mmol) and 6 mL of dry THF is added dropwise under argon at 5° C. a 1M borane-tetrahydrofuran complex solution (11 mL, 11 mmol) within 15 min. The reaction mixture is stirred for 10 min. at 5° C. and for 1 h at RT. NaBO3 (3.38 g, 22 mmol) is then added in several portions followed by H2O (10 mL). After 2 h at RT, the reaction mixture is extracted twice with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography of the residue (SiO2, hexane/ethyl acetate) affords (3R*,4R*)-4-biphenyl-3-yl-3-hydroxy-piperidine-1-carboxylic acid t-butyl ester as a white amorphous solid: MS (after treatment with trifluoroacetic acid) 254.3 [M+H—C5H8O2]+; Rf 0.10 (hexane/ethyl acetate 8:2).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:4]2[N:3]=1.C(N(CC)CC)C.[F:28][C:29]([F:38])([F:37])[C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>C(O)CCC>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[C:30]([C:29]([F:28])([F:37])[F:38])[CH:31]=4)=[N:3][C:4]4[N:5]([N:17]=[C:18]([CH3:20])[CH:19]=4)[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: CCn1ncc2c1ncc1c(Cl)nc3cc(C)nn3c12
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCn1ncc2c1ncc1c(Nc3cccc(C(F)(F)F)c3)nc3cc(C)nn3c12
Yield: 72.9 %

Procedure:
5.8 g of 5-chloro-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine (0.02 mol), 3 g of triethylamine and 3.3 g of 3-trifluoromethylaniline are refluxed in butyl alcohol for 24 hours with stirring. The solvent is removed in vacuo and the residue treated with 20 ml of water and filtered off. Recrystallization from alcohol yields 6 g of 8-ethyl-2-methyl-N-[3-(trifluoromethyl)-phenyl]-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]-pyrimidin-5-amine; yield (73%) m.p. 205°-206°.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:5]([O:19][CH2:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Reaction time: 8 h

Procedure:
A solution of tert-butylchlorodiphenylsilane (5.56 mL, 21.36 mmol) in DCM (20 mL) was added dropwise to a stirred solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (CAS no. 142253-56-3) (4.0 g, 21 mmol) and anhydrous N-ethyl-N-isopropylpropan-2-amine (9.1 mL, 53 mmol) in DCM (45 mL) cooled to 10° C., over a period of 2 minutes under nitrogen. The resulting solution was stirred at ambient temperature for 3 hours 4-dimethylaminopyridine (100 mg) was added and the reaction was left overnight. The reaction mixture was concentrated and diluted with EtOAc (75 mL), and washed sequentially with saturated NaHCO3 (25 mL), water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the crude product (9.87 g) which was used without further purification.
Reaction SMILES: C(S)(=N)N.[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:11]([NH2:15])(=[O:14])[CH:12]=[CH2:13]>CCO>[N:5]1([CH2:13][CH2:12][C:11]([NH2:15])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C=CC(N)=O
Reactant: C1CCNCC1
Agent: N=C(N)S
Solvent: CCO
Product: NC(=O)CCN1CCCCC1
Yield: 75 %

Procedure:
Carbamimidothioic acid, N'-cyano-N-[3-[4-(diphenylmethylene)-1-piperidinyl]-propyl]-, methyl ester. A solution of piperidine, 4-(diphenylmethylene) (0.10 mole) and acrylamide (8.95 g, 0.062 mole) in EtOH (50 ml) was refluxed overnight. This reaction mixture was filtered and concentrated. The resulting while solid residue was dissolved in CHCl3, washed with H2O (3×150 ml), dried (Na2SO4) and the solvent removed to give thick yellow oil. Crystallization from CH2Cl2 -i-Pr2O afforded 29.01 g (75%) of 1-piperidinepropanamide, 4-(diphenylmethylene)-; mp 105°-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].OO.S([O-])([O-])=[O:30].[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:21])[CH:10]=[N+:11]([O-:30])[C:12]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]1=[O:22]
Reactant: O=S([O-])[O-]
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 100 °C

Procedure:
A mixture of ethyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (22 g, 58 mmol), glacial acetic acid (500 mL), and hydrogen peroxide (65.8 mL, 30% by weight in water) was heated at 100° C. for four hours. The resultant solution was cooled in an ice bath to 25° C. and treated with saturated aqueous sodium sulfite solution while keeping the reaction mixture below 40° C. When starch paper test showed complete consumption of residual peroxide, the solution was concentrated to two third of its volume, pH was adjusted to ˜3 with aqueous HCl and the solution was extracted with dichloromethane (3 times). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the title product as oil,
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[C:29]([OH:31])[CH:30]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[C:32](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C(OCc1ccccc1)c1cc(O)cc(OCCCCCCCCC2OCCO2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(OCCCCCCCCC2OCCO2)cc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.8 %

Procedure:
To an ice-cooled solution of benzyl 3-((8-(1,3-dioxolan-2-yl)octyl)oxy)-5-hydroxybenzoate (1.94 g, 4.53 mmol) in dimethyl formamide (25 mL), was added potassium carbonate (0.93 g, 6.75 mmol) followed by iodomethane (0.42 mL, 6.75 mmol). The reaction mixture was allowed to warm to room temperature over 16 hours and stood at room temperature for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound (1.76 g, 88%).
Reaction SMILES: I[CH3:2].[H-].[Na+].[Br:5][C:6]1[CH:7]=[C:8]([C:23]([F:26])=[CH:24][CH:25]=1)[CH2:9][C@@H:10]([C:19]([O:21][CH3:22])=[O:20])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].O>O1CCCC1.C(OCC)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([C:23]([F:26])=[CH:24][CH:25]=1)[CH2:9][C@@H:10]([C:19]([O:21][CH3:22])=[O:20])[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:2]
Reactant: COC(=O)[C@H](Cc1cc(Br)ccc1F)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1cc(Br)ccc1F)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
49.8 g (350.86 mmol) of iodomethane and 2.28 g (57.01 mmol) of sodium hydride are added to a solution of 16.5 g (43.86 mmol) of methyl 3-bromo-N-(tert-butoxycarbonyl)-6-fluoro-L-phenylalaninate (Example 5O) in 220 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred at RT overnight. 1000 ml of water and 1000 ml of ethyl acetate are added to the mixture. The organic phase is washed successively with water and a saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane:ethyl acetate 3:1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:8]=1)#[CH:2].[N:17]([Si](C)(C)C)=[N+:18]=[N-:19].CN(C)C=O.CO>ClCCl>[NH:17]1[CH:2]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=3)[CH:8]=2)[N:19]=[N:18]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc2nc(C(=O)OCC)cn2c1
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cn2cc(-c3c[nH]nn3)ccc2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 220 mg of ethyl 6-ethynylimidazo[1,2-a]pyridine-2-carboxylate and 0.21 mL of azidotrimethylsilane in 4 mL of a mixture (9/1) of N,N-dimethylformamide and methanol are added 9.8 mg of cuprous iodide. The reaction mixture is stirred for 2 hours at 100° C. and then cooled, diluted with 4 mL of dichloromethane, filtered through alumina and concentrated to dryness. The residue is chromatographed on silica, eluting with a mixture of dichloromethane and ethanol (97/3). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 125 mg of ethyl 6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate in the form of an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].[CH3:18][N:19]=[C:20]=[O:21]>CO.O>[CH3:18][NH:19][C:20](=[O:21])[NH:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Reactant: CN=C=O
Solvent: CO
Solvent: O
Product: CNC(=O)NC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of 5'-amino-5'-deoxythymidine (2, 2.40 g, 9.95 mmol) in methanol-water (2.5:1, v/v) at 0° was added methyl isocyanate (0.63 g, 10.95 mmol). The reaction mixture was kept at 0° with stirring for 1 h, allowed to warm up to room temperature, and then clarified by filtration. The filtrate was evaporated to dryness under reduced pressure at a temperature not exceeding 35°, and the residue was then crystallized from methanol at 3° overnight to give 2.14 g (72%) of white fine needles: mp 238-239°. Anal. (C12H18N4O5) C, H, N.
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:3]1[CH2:7][CH:6]([CH2:8][S:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[O:5][C:4]1=[O:19].[OH-:37].[Li+]>O.C1COCC1>[CH3:1][N:2]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:3]([CH2:7][CH:6]([OH:5])[CH2:8][S:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[C:4]([OH:19])=[O:37]
Reactant: COc1ccc(-c2ccc(S(=O)(=O)N(C)C3CC(CSc4nc5ccccc5s4)OC3=O)cc2)cc1
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(S(=O)(=O)N(C)C(CC(O)CSc3nc4ccccc4s3)C(=O)O)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of N-methyl 3-[(4′-Methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-5-[[(2-benzothiazolyl)thio]methyl]-tetrahydrofuran 62c (1.00 g, 2.05 mmol) in water (5 mL) and THF (5 mL) is slowly added lithium hydroxide (0.49 g, 20.5 mmol). The reaction is stirred for 4 hr, then concentrated to dryness. The reaction mixture is diluted with water and then the mixture is extracted with ethy ether (2×25 mL) The ethyl ether layer is discarded and the aqueous layer is slowly acidified with 1N HCl to pH 5, and then extracted 3 times with ethyl acetate. The combined ethyl acetate layers are washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The white solid is then recrystallized with ethyl acetate/hexanes to give the desired product as a white solid.