Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1COCC1>[O:12]=[C:4]1[CH:3]=[C:2]([O:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1cc(O)c2ccccc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2cc(=O)oc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
A solution of 4-hydroxycoumarin (30.7 mmol, 4.98 g) and triethylamine (37.3 mmol, 5.2 mL) in THF (50 mL) is cooled to (0° C.). A THF solution (50 mL) of p-toluenesulfonyl chloride (33.5 mmol, 6.45 g) is added dropwise The mixture is stirred at 0° C. for 1.5 hrs., is filtered and the solid is washed with EtOAc. The filtrate is concentrated under reduced pressure and Et2O is added. The resulting precipitate is filtered, is washed with Et2O and is dried to afford the title compound (7.57 g, 79%); 1H NMR (CDCl3, 300 MHz) δ 7.91 (2H, m), 7.61 (2H, m), 7.34 (4H, m), 6.31 (1H, s), 1.55 (3H, s); MS (ESI, Pos.) calcd for C16H12O5S m/z [M+H]=317.0, found 317.0.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[CH2:5][CH2:4]1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C=O)C>[O:17]=[C:9]1[C:6]2([CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: O=C1Nc2ccccc2C12CCOCC2
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C2(CCOCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (8.00 mg of a 60% dispersion in mineral oil, 0.207 mmol) was added to a solution of 2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-2(1H)-one from Step A (35.0 mg, 0.172 mmol) in DMF (1 mL) at 0° C. After 1 hr, tert-butyl bromoacetate (0.280 mL, 0.189 mmol) was added and the reaction warmed to ambient temperature. After 18 h, the reaction was partitioned between CH2Cl2 (10 mL) and saturated NH4Cl (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=318 (M+1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)(=[O:17])=[O:16])[CH:13]=2)[NH:8][N:7]=1)=[O:4].Cl[C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl>[F:26][C:2]([F:1])([F:25])[C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)(=[O:16])=[O:17])[CH:13]=2)[N:8]([C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:7]=1)=[O:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1n[nH]c2ccc(S(=O)(=O)c3cccc(F)c3)cc12)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cccc(F)c3)cc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2,2,2-Trifluoro-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-acetamide, (17.93 g, 46.33 mmol) in dry dichloromethane (300 mL) was treated with chlorotriphenylmethane (14.22 g, 50.96 mmol) and triethylamine (14.2 mL, 102 mmol). After stirring at room temperature for two days, the reaction was washed with a solution of NH4Cl, dried and evaporated. The crude was used as such in the next step without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([F:35])=[CH:11][C:12]([F:34])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22]([F:26])[C:23]=3Br)[C:18](=[O:28])[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16]2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn]([C:49]#[C:50][Si:51]([CH3:54])([CH3:53])[CH3:52])(CCCC)CCCC)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([F:35])=[CH:11][C:12]([F:34])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22]([F:26])[C:23]=3[C:49]#[C:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:18](=[O:28])[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16]2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(F)c(F)cc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Yield: 74.4 %

Procedure:
Ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (6 g), tributylstannyltrimethylsilylacetylene (6 g) and tetrakis(triphenylphosphine)palladium (0.4 g) were added to dry toluene (30 ml). This suspension was heated under reflux overnight in a nitrogen atmosphere. After the temperature of the reaction mixture was given back to room temperature, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water. After an organic layer was collected and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resultant residue was subjected to column chromatography on silica gel (silica 240 cc/chloroform) to obtain the title compound (4.6 g) as a colorless powder.
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21](=O)[O:22]C4C=CC=CC=4)=[CH:14][CH:13]=3)[N:10]=[C:9]([C:30]([F:33])([F:32])[F:31])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:35]=1>>[C:1]1([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:43][S:40]([C:36]4[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=4)(=[O:42])=[O:41])=[O:22])=[CH:16][CH:17]=3)[N:10]=[C:9]([C:30]([F:33])([F:32])[F:31])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1cccnc1
Reactant: O=C(NCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1)Oc1ccccc1
Product: O=C(NCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1)NS(=O)(=O)c1cccnc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 0.42 from phenyl 2-{4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 4) and pyridine-3-sulfonamide: 1H-NMR (CDCl3) δ 9.04 (1H, d, J=2.0 Hz), 8.78 (1H, d, J=3.7 Hz), 8.08-8.04 (1H, m), 7.48-7.44 (1H, m), 7.34-7.10 (9H, m), 6.76 (1H, s), 6.28 (1H, br.s), 3.48-3.42 (2H, m), 2.83-2.78 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([OH:10])=[C:4]([CH2:11]C)[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([O:10][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)=[C:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: FC(F)(F)Oc1ccc(OCCCBr)cc1
Reactant: CCc1cc(Br)cc(CC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)cc(C)c1OCCCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
To a mixture of 10 g of 4-bromo-2,6-diethylphenol, 13.5 g of l-(3-bromopropyloxy)-4-trifluoromethoxybenzene and 100 ml of N,N-dimethylformamide was added 6.6 g of potassium carbonate, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water, and extracted twice with 200 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 14.8 g of 4-bromo-2-ethyl-6-methyl-1-[3-(4-trifluoromethoxyphenoxy)propyloxy]benzene (76% yield).
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:5])[CH:3]=O.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:5][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:1])[CH2:3][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C1CCNC1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CN2CCCC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (22 mg), pyrrolidine (0.02 ml), acetic acid (0.01 ml) in methylene chloride (1 ml) was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (28 mg) was added. The mixture was stirred at room temperature for at least two days. The mixture was quenched with diluted NaOH and extracted with methylene chloride. The organic layer was separated, concentrated to dryness and the residue was purified by silica gel column chromatography using 35% to 65% ethyl acetate in hexane as eluent to give the title compound. The title compound was prepared as the corresponding HCl salt by adding HCl/doxane, followed by concentration to give a solid. LC_MS retention time 2.0 min M+1=480.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:39]=[CH:38][C:13]([CH2:14][N:15]([C:25]3[CH:37]=[CH:36][C:28]4[O:29]C(C)(C)[O:31][C:32](=[O:33])[C:27]=4[CH:26]=3)[C:16](=[O:24])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][N:15]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:25]3[CH:37]=[CH:36][C:28]([OH:29])=[C:27]([CH:26]=3)[C:32]([OH:33])=[O:31])=[CH:38][CH:39]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2cc(N(Cc3ccc(C#Cc4ccc(Cl)cc4)cc3)C(=O)c3cccc(F)c3)ccc2O1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(N(Cc2ccc(C#Cc3ccc(Cl)cc3)cc2)C(=O)c2cccc(F)c2)ccc1O

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-chlorophenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)-3-fluorobenzamide and NaOH as a white powder (56%). 1H NMR (MeOD, 300 MHz) δ 7.51 (m, 5H), 7.45-7.22 (m, 5H), 7.20-7.02 (m, 4H), 6.79 (d, J=9 Hz, 1H), 5.15 (s, 2H) M− (ESI): 497.9. HPLC. Rt: 4.92 min (Purity: 97.9%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[S:29](Cl)([CH3:32])(=[O:31])=[O:30].Cl>C(Cl)Cl>[CH3:32][S:29]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCO)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyl 2-[3-(3-hydroxypropyl)phenoxy]-2-methylpropionate (10.1 g, 34.3 mmol) was dissolved in methylene chloride (50 mL). Subsequently, triethylamine (6.94 g, 68.6 mmol) was added thereto. Mesyl chloride (4.71 g, 41.2 mmol) was added dropwise under ice-cooling, and the mixture was stirred for five hours at room temperature. Diluted hydrochloric acid was added thereto, the resultant mixture was extracted with chloroform. The reaction mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=4/1), whereby the target compound was obtained (7.8 g, 61%).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][C:12]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH3:19])=[N:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=O)=O.O[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]#[N:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH3:19])[O:13][C:9]=2[CH2:8][CH2:7][CH2:6][O:5][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]#[N:36])=[CH:30][CH:29]=2)=[CH:21][CH:22]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOS(C)(=O)=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccc(CC#N)cc2)o1

Procedure:
3-[4-(4-Chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl methanesulfonate (400 mg), 4-hydroxyphenylacetonitrile (200 mg), potassium carbonate (276 mg) and N,N-dimethylformamide (10 ml) was stirred at 100° C. for 4 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and 2-[4-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyloxy]phenyl]acetonitrile was obtained as a yellow oil (380 mg, 89%) from an ethyl acetate-hexane (2:1, v/v)-eluted fraction.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]2[N:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:29]=[C:28]5[C:23]([CH:24]=[CH:25][CH:26]=[N:27]5)=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)[C:10](=[O:13])[NH:11][N:12]=2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[N:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[N:39]1([C:45]([N:2]2[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]3[N:9]([C:14]4[CH:15]=[CH:16][C:17]([C:20]5[CH:29]=[C:28]6[C:23]([CH:24]=[CH:25][CH:26]=[N:27]6)=[CH:22][CH:21]=5)=[CH:18][CH:19]=4)[C:10](=[O:13])[NH:11][N:12]=3)[CH2:3]2)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(-c2ccc3cccnc3c2)cc1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N1CCOCC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 4 mL vial was placed 5-[(3S)-3-pyrrolidinylmethyl]-4-[4-(7-quinolinyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.147 mmol). Added in succession was dichloromethane (2 mL), N,N-diisopropylethylamine (0.458 mmol), and 4-morpholinecarbonyl chloride (0.157 mmol). The vial was capped and the solution was stirred at room temperature for 30 min. The solution was concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (23 mg, 31%). MS(ES)+ m/e 485.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1.[Na].[N:11]1([C:22](=[O:23])[C:21]2[NH:20][CH:19]=[N:18][C:17]=2[N:15]([CH3:16])[C:13]1=[O:14])[CH3:12]>C(O)(C)C>[CH3:9][C:7]1[O:6][N:5]=[C:4]([CH2:3][CH2:2][N:20]2[C:21]3[C:22](=[O:23])[N:11]([CH3:12])[C:13](=[O:14])[N:15]([CH3:16])[C:17]=3[N:18]=[CH:19]2)[N:8]=1
Reactant: Cc1nc(CCCl)no1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: [Na]
Solvent: CC(C)O
Product: Cc1nc(CCn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 91 %

Procedure:
2.92 g. of 3-(2-chloroethyl)-5-methyl-1,2,4-oxadiazole, 50 cm3 isopropylalcohol and 4.0 g. of theophylline sodium are heated for 8 hours. 5.3 g. (91% yield) 7-[2-(5-methyl-1,2,4-oxadiazol-3-yl)-ethan-1-yl]-theophylline are obtained, m.p.: 113°-114° C. (water).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16][CH:17]([NH2:18])[CH:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][S:29](Cl)(=[O:31])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][S:29]([NH:18][C@H:17]2[C@@H:11]3[CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[N:8]=4)[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16]2)(=[O:31])=[O:30])=[CH:26][CH:27]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Reactant: NC1CCN2CCN(c3cccc(C(F)(F)F)n3)CC12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1ccc(Cl)cc1)N[C@@H]1CCN2CCN(c3cccc(C(F)(F)F)n3)C[C@@H]12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 96B (100 mg, 0.349 mmol) in dry dichloromethane (2 mL) was added (4-chlorophenyl)methanesulfonyl chloride (118 mg, 0.524 mmol) and triethylamine (212 mg, 2.096 mmol). The mixture was stirred at room temperature for 16 hours and then concentrated. The residue was purified via HPLC (Gilson®, XBridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=254 nm) to give the title compound as the first eluting diastereomer. 1H NMR (500 MHz, methanol-d4) δ 1.57-1.66 (m, 1 H), 1.91-1.99 (m, 1 H), 2.21-2.29 (m, 2 H), 2.34 (q, 1H, J=8 Hz), 2.62 (dd, 1H, J=12, 10 Hz), 2.92 (td, 1H, J=12, 3 Hz), 3.00-3.06 (m, 2 H), 3.41 (td, 1H, J=9, 6 Hz), 4.33-4.40 (m, 3 H), 4.52 (dd, 1H, J=12, 1 Hz), 6.98 (t, 2H, J=7 Hz), 7.38-7.41 (m, 2 H), 7.44-7.48 (m, 2 H), 7.66-7.72 (m, 1 H); MS (DCI) m/z 475 (M+H)+.
Reaction SMILES: CO.C([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH:12]([C:20]([O:22][CH3:23])=[O:21])[CH2:11]1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)(=O)C>[C:20]([OH:22])(=[O:21])[CH3:12].[OH:19][CH2:18][CH2:17][CH2:16][CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH:12]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1CCCO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1CNCCC1CCCO
Reaction time: 0.5 h

Procedure:
To 3 mL of a methanol solution containing 0.15 g of methyl 1-benzyl-4-(3-hydroxypropyl)piperidine-3-carboxylate, 0.12 mL of acetic acid and 0.15 g of palladium hydroxide were added, and the reaction mixture was stirred for 1 hour and 30 minutes under a hydrogen atmosphere. The insoluble material filtered off, and the solvent was removed under reduced pressure to obtain 0.12 g of a colorless oily substance, methyl 4-(3-hydroxypropyl)piperidine-3-carboxylate acetate. 1.34-1.41 (2H, m), 1.58-1.75 (4H, m), 1.87-1.95 (1H, m), 2.06 (3H, s), 2.80-2.90 (2H, m), 3.01 (1H, dd, J=3.7, 13.7 Hz), 3.20-3.28 (1H, m), 3.29-3.35 (1H, m), 3.65 (2H, t, J=6.3 Hz), 3.73 (3H, s)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:11][CH:12]1[CH2:17][CH:16]2[N:18](C(OC(C)(C)C)=O)[CH:13]1[CH2:14][CH2:15]2.[ClH:26]>O1CCOCC1.CC(O)C>[ClH:26].[CH:13]12[NH:18][CH:16]([CH2:15][CH2:14]1)[CH2:17][CH:12]2[NH:11][C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(Nc1cnc3ccccc3n1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: c1ccc2nc(NC3CC4CCC3N4)cnc2c1
Temperature: 70 °C

Procedure:
To the title compound from step A (343 mg, 1 mmol) in 1,4-dioxane (10 mL) was added 6N HCl in iPrOH (1 mL). The reaction was heated to 70° C. for 2 h, cooled to rt, concentrated and used without further purification in subsequent steps.
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6]C)=[O:5].[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Li+].[OH-]>C(Cl)Cl.O>[CH3:9][N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2](=[O:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(=O)Cl
Reactant: CNc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of methyl 3-chloro-3-oxopropanoate (1 mL, 9.32 mmol) and N-methyl aniline (1.01 mL, 9.32 mmol) in DCM (18.6 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue (N-methyl-N-phenyl-malonamic acid methyl ester, 2.55 g) was dissolved in THF (9 mL). A solution of LiOH×H2O (0.782 g, 18.64 mmol) in water (9 mL) was added and the mixture stirred for 1 h at room temperature. The THF was removed under reduced pressure and the remaining aqueous solution was acidified with 1N HCl (until pH-3) then extracted with EtOAc. The organic phase was concentrated under reduced pressure to afford the acid 31 (1.67 g, 93% yield) as a brown foam. MS (m/z): 194.0 (M+H).
Reaction SMILES: Br[C@H:2]([CH:16]([CH3:18])[CH3:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:7]=1[OH:15])=[O:4].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:16]([C@H:2]1[C:3](=[O:4])[NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:7]=2[O:15]1)([CH3:18])[CH3:17]
Reactant: CC(C)c1cccc(NC(=O)[C@H](Br)C(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc2c1O[C@@H](C(C)C)C(=O)N2
Yield: 80.1 %

Procedure:
A solution of (R)-2-(2-bromo-3-methylbutyryl)amino-6-isopropylphenol (18.5 g) in dimethylformamide (120 ml) was treated with powdered potassium carbonate (9.75 g) at room temperature for 3 hours. Dilution with water gave crystals, which were recrystallized from 2-propanol to yield (S)-2,8-diisopropyl-2H-1,4-benzoxazin-3(4H)-one as colorless prisms (11.0 g, 80.3%), mp 151°-152° C., [α]D23 -5.6° (c=1.0, MeOH).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]2[CH2:13][CH2:14][F:15])=[CH:4][N:3]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]2[CH2:13][CH2:14][F:15])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(CCF)c2c(Cl)c(Cl)ncc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(CCF)c2c(Cl)c(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
3.33 g (0.01 mol) of ethyl 7,8-dichloro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylate are heated at reflux in a mixture of 13 ml of acetic acid, 13 ml of water and 1.3 ml of concentrated sulphuric acid for two hours. The cooled mixture is put into ice-water, and the product is isolated and washed with water.
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]1[CH:19]=[CH:18][O:17][CH:16]=1)=[N+:12]=[N-:13]>>[ClH:1].[O:17]1[CH:18]=[CH:19][C:15]([CH2:14][N:11]2[CH:4]=[C:3]([CH2:2][C:5]3[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=3)[N:13]=[N:12]2)=[CH:16]1
Reactant: C#CCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1ccoc1
Agent: Cl
Product: Nc1nc(Cc2cn(Cc3ccoc3)nn2)c[nH]1
Yield: 42.9 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.101 g, 0.639 mmol) was reacted with 3-azidomethyl-furan (0.094 g, 0.767 mmol) following the general procedure for click reactions outlined above to produce 4-(1-Furan-3-ylmethyl-1H-[1,2,3]triazol-4-ylmethyl)-1H-imidazol-2-ylamine hydrochloride (0.077 g, 43%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.12 (s, 1H), δ 7.60 (s, 1H), δ 7.38 (s, 1H), δ 6.53 (s, 1H), δ 6.37 (s, 1H), δ 5.46 (s, 2H), δ 3.95 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.1, 145.3, 144.1, 141.0, 123.3, 123.1, 110.3, 110.2, 109.9, 51.3, 19.9 ppm; HRMS (ESI) calcd for C11H12N6O (M+) 244.1145. Found 244.1145.
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4].[SH:9][CH2:10][CH:11](O)[CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:4][C:3]1[O:5][CH:11]([CH3:12])[CH2:10][S:9][C:2]=1[CH2:6][CH2:7][Cl:8]
Reactant: CC(O)CS
Reactant: CC(=O)C(Cl)CCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1=C(CCCl)SCC(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of 0.1 mole (15.4 g.) 3,5-dichloro-2-pentanone, and 0.1 mole (9.2 g.) 1-mercapto-2-propanol was stirred in 100 ml toluene; 0.1 mole (10.4 g.) triethylamine was added dropwise. The mixture was stirred at room temperature overnight, then washed with dilute hydrochloric acid and reluxed with 0.5 g. PTSA, using a Dean-Stark trap to remove water for about 7 hours. The PTSA solution was washed with sodium bicarbonate, dried over magnesium sulfate and the solvent was removed. The product was distilled; bp 80°-82°/0.1 mm. Yield 47%.