Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:47][C:48]([F:57])([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:49]O>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][CH2:49][C:48]([F:57])([F:47])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: OCC(F)(F)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC(F)(F)c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a stirred mixture of 0.23 g of g of cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester, 0.54 g of 1.1′-(azodicarbonyl)-dipiperidine and 20 mL of benzene was added 0.4 g of tri-n-butyl-phosphine and 1.3 g (8 equivalents) of 2,2-difluoro-2-phenyl-ethanol. The mixture was heated to 60° C. overnight, then an additional 0.5 g of 1.1′-(azodicarbonyl)-dipiperidine and 0.4 g of tri-n-butyl-phosphine was added and heating continued for another 24 h. The mixture was cooled, diluted with 25 mL of toluene, filtered and the filter pad washed with 5 mL of toluene. The filtrate was purified by chromatography on silica gel eluting with a gradient of 0%-20% ethyl acetate in hexane gave 0.15 g of product as a resin: 1H NMR (400 MHz, CDCl3) 7.5 (m, 5H), 3.95 (m, 2H), 3.4 (m, 1H), 1.95 (m, 2H), 1.6 (m, 6H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[N:7]=3.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:24])[CH:23]=[N:16][C:14]([C:8]1[N:7]=[C:6]2[N:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Cl:1])[N:18]=[CH:17][C:5]=32)[CH:9]=1)=[O:15]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Solvent: Cc1ccccc1
Product: CN(C)C=NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Temperature: 95 °C

Procedure:
To a solution of 8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylic acid amide (2.40 g, 0.00907 mol) in Toluene (40 mL) was added 1,1-Dimethoxy-N,N-dimethylmethanamine (4.82 mL, 0.0363 mol). The flask was sealed and heated to 95° C. for 8 h. The reaction was deemed complete by TLC. The solvent was removed in vacuo to give 8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-methylideneamide which was used crude. MS (ESI+) 320.1
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][C:9]([CH:12]=O)=[CH:10][N:11]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][C:9]([CH2:12][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]2)=[CH:10][N:11]=1
Reactant: O=Cc1cnc(-c2ccccn2)s1
Reactant: OCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: OCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
The compound prepared in Example 139 (0.569 g), piperidin-4-ylmethanol (0.689 g) and sodium triacetoxyborohydride (1.902 g) were suspended in 1,2-dichloroethane (15 mL) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution, ammonium chloride solution and brine. The organics were then dried over magnesium sulfate, filtered and concentrated under reduced pressure and to afford the crude material, which was purified by flash column chromatography (eluant: 10% (9:1 methanol/concentrated ammonium hydroxide)/ethyl acetate) to furnish the title compound (0.571 g) having the following physical properties.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:20])=[CH:14][C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:20][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[O:16][C:15](=[O:19])[CH:14]=1
Reactant: O=c1cc(O)c2ccc(OCc3ccccc3)cc2o1
Agent: [Pd]
Solvent: CO
Product: O=c1cc(O)c2ccc(O)cc2o1
Yield: 90 %

Procedure:
A 300 cc autoclave was charged with 7-benzyloxy-4-hydroxycoumarin (3 g, 3.7 mmol), prepared in accordance with Example 5, 5% Pd on carbon (0.18 g) and 85 mL of methanol and the autoclave was purged with N2. The autoclave was pressurized with H2 to a pressure of about 100 psi and maintained at that pressure. The exothermic reaction was carried out at ~50° C. for ~2hrs. After the completion of hydrogenolysis, the reactor was flushed with N2 and the contents were transferred into a beaker using a long pipet. The mixture containing Pd/C was dried over MgSO4 and filtered through a frit. The filtrate was evaporated to dryness and finally dried overnight at 45° C. The purity of the material as determined by LC was 95%; yield ~90%. The product was characterized by NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([NH:16][C@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[CH2:19][CH2:18]2)[C:13]([N+:28]([O-:30])=[O:29])=[CH:12][N:11]=1.[CH:31](OC)(OC)OC>CO.C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:31][N:9]([C:10]3[N:15]=[C:14]([NH:16][C@H:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20](=[O:27])[CH2:19][CH2:18]4)[C:13]([N+:28]([O-:30])=[O:29])=[CH:12][N:11]=3)[C:3]=2[CH:4]=1
Reactant: COC(OC)OC
Reactant: Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCC(=O)c3ccccc32)n1
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CC[C@@H](Nc2nc(-n3cnc4ccc(F)cc43)ncc2[N+](=O)[O-])c2ccccc21

Procedure:
A solution of (R)-4-(2-(2-amino-5-fluorophenylamino)-5-nitropyrimidin-4-ylamino)-3,4-dihydronaphthalen-1(2H)-one (120 mg) and CH(OMe)3 (2.5 mL) in MeOH/THF (2.5 mL/10 mL) was stirred at room temperature overnight. Volatiles were removed in vacuo and the residue was purified by PTLC (EtOAc) to afford 80 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:9])[CH3:8])[CH:2]=1.[H-].[Na+].[C:12](OC)(=[O:14])[CH3:13]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:9])[CH2:8][C:12](=[O:14])[CH3:13])[CH:2]=1
Reactant: CC(=O)c1cccnc1
Reactant: COC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
To a solution of 1-(3-pyridyl)ethanone (15.0 g, 124 mmol) in DMF (100 mL) at 0° C. was added sodium hydride (5.9 g, 149 mmol). The reaction mixture was then stirred at room temperature for 10 minutes. After cooling to 0° C., methyl acetate (11.8 mL, 149 mmol) was slowly added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was quenched with the addition of saturated ammonium chloride (100 mL) and acidified to pH 5 with the addition of 1 N HCl. The mixture was then extracted with ethyl acetate (2×75 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The 16 grams of crude product were filtered through a plug of silica gel. The filtrate was concentrated under reduced pressure. The residue was taken up in a 1:9 solution of ethyl acetate/hexane (300 mL) at 65° C. The resulting solution was slowly allowed to cool to warm temperature while stirring. The precipitate was collected by vacuum filtration to provide 1-(3-pyridyl)butane-1,3-dione (7.7 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:27]=[CH:28][N:29]=[C:2]([N:34]4[CH2:35][CH2:36][CH:31]([CH3:30])[CH2:32][CH2:33]4)[CH:3]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Reactant: CC1CCNCC1
Product: CC1CCN(c2cc(C(=O)Nc3ccc(OCCN4CCOCC4)c4ccccc34)ccn2)CC1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and 4-methylpiperidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.26 (d, 1H), 8.22 (m, 1H), 7.84 (m, 1H), 7.57 (m, 2H), 7.45 (d, 1H), 7.39 (s, 1H), 7.13 (d, 1H), 7.05 (d, 1H), 4.41 (d, 2H), 4.31 (t, 2H), 3.60 (t, 4H), 2.88 (m, 4H), 2.57 (m, 4H), 1.68 (m, 4H), 1.11 (m, 1H), 0.95 (d, 3H). MS: 475.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10](O)=[O:11])[N:7]=[N:6]1.S(Cl)(Cl)=O.[NH3:22]>>[CH:15]1[CH:14]=[C:13]([F:17])[C:3]([CH2:4][N:5]2[N:6]=[N:7][C:8]([C:10]([NH2:22])=[O:11])=[CH:9]2)=[C:2]([F:1])[CH:16]=1
Reactant: O=C(O)c1cn(Cc2c(F)cccc2F)nn1
Reactant: N
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C

Procedure:
A mixture of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (25 gms) and thionyl chloride (63.5 gms) were stirred at 80° C. and maintained for 3 hours. The reaction mass was cooled to 50° C. and excess thionyl chloride was distilled off. To this reaction mass toluene (25 ml) was charged twice and it was distilled off under vacuum it was followed by addition of toulene (175 ml) to get clear solution. Aqueous ammonia (100 ml) charged into reaction mass at room temperature and maintained for 2 hours. The reaction mass was filtered. 10% sodium carbonate solution was added to above solid and stirred for 30 minutes. The solid was filtered and washed with water and cyclohexane (50 ml). Dried the crude material in a vacuum oven at 70-80° C. for 10 hours. Yield: 23.00 gm.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[CH3:28][O:29][CH2:30]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][C:10]=1[O:11][CH2:28][O:29][CH3:30])=[O:4]
Reactant: COCCl
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC1=C(C(=O)OC)CN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester (10 mmol, 2.71 g) and DIEA (1 mL) in DCM was added methoxymethyl chloride (1.3 mL) drop-wise and continued stirring for 16 h at room temperature. Volatiles were removed under reduced pressure, the resultant residue was taken up in ethyl acetate (50 mL), washed with water (25 mL), dried the organic layer, filtered and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography using mixture of hexanes and ethyl acetate to provide 4-methoxymethoxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester.
Reaction SMILES: [CH2:1]1[CH2:22][O:21][C:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH2:4][CH2:5][C@H:6]2[C@H:13]([OH:14])[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:2]1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]1[CH2:22][O:21][C:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH2:4][CH2:5][C@H:6]2[C@H:13]([O:14][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:2]1
Reactant: CCCCCC1(CC[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2O)OCCO1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCCCC1(CC[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2OC2CCCCO2)OCCO1

Procedure:
A solution of (1S,5R,6R,7R)-6-(3,3-ethylenedioxyoctyl)-7-hydroxy-2-oxabicyclo[3.3.0]octan-3-one (6a) (4.70 g) in dichloromethane (200 ml) was cooled on ice and dihydropyran (2.41 g) and p-toluenesulfonic acid (0.23 g) were added thereto and the resultant mixture was stirred for 1,5 hours. The crude product obtained by treating in the conventional manner was subjected to silica gel column chromatography to give the title compound (59).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)#[N:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[CH:4]([C:3]1[CH:6]=[C:7]([I:10])[CH:8]=[CH:9][C:2]=1[O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[CH:14][CH:15]=1)=[O:5]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=Cc1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(I)cc2C=O)cc1
Yield: 68 %

Procedure:
In a manner similar to the method described in Example 50a, 2-fluoro-5-iodobenzaldehyde (2 g, 8 mmol) (Aldrich) was reacted with 4-cyanophenol (1.43 g, 12 mmol) and K2CO3 in N,N-dimethylacetamide to give 4-(2-formyl-4-iodo-phenoxy)-benzonitrile as a light yellow solid (Yield 1.9 g, 70.4%).
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=O)[CH:12]=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[C:23]([OH:29])=[N:24][CH:25]=[CH:26][C:27]=1[OH:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:29][C:23]1[C:22]([NH:21][C:18]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:10]=2[N:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:17]=[CH:16]3)=[O:20])=[C:27]([OH:28])[CH:26]=[CH:25][N:24]=1
Reactant: Nc1c(O)ccnc1O
Reactant: O=C(O)c1cccc2ccc(Oc3ccccc3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1c(O)ccnc1O)c1cccc2ccc(Oc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-phenoxyquinoline-8-carboxylic acid (178c 217 mg, 0.818 mmol), 3-aminopyridine-2,4-diol (155 mg, 1.227 mmol), HATU (622 mg, 1.636 mmol), and DIPEA (438 μl, 2.454 mmol) in DMF (1636 μl) was stirred at RT for 1 h. Purification by silica gel (100% DCM to 5% MeOH/DCM) provided N-(2,4-dihydroxypyridin-3-yl)-2-phenoxyquinoline-8-carboxamide (179c) as a yellow solid. MS (ESI, pos. ion) m/z: 374.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([O:13][C:14](=[O:30])CC(C1C=CC(C2CCCCC2)=CC=1)=O)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:30])[CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:10])[CH3:12]
Reactant: CCOC(=O)CC(=O)c1ccc(C2CCCCC2)cc1
Reactant: CC(=O)c1cccc(F)c1
Product: CCOC(=O)CC(=O)c1cccc(F)c1
Yield: 91 %

Procedure:
This compound was prepared from m-fluoro acetophenone, in a manner analogous to the preparation of 3-(4cyclohexylphenyl)-3-oxo-propionic acid ethyl ester (Method A), except that the product was purified by vacuum distillation (bp 114-117° C. at 0.8-0.9 mmHg) in 91% yield.
Reaction SMILES: [C:1](=[O:40])([O:30]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH2:19][C@@H:18]2[C@@:6]([CH3:29])([C@@H:7]3[C@@H:15]([CH2:16][CH2:17]2)[C@:14]2([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]4[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=4)[CH2:12][CH2:13]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[N:41]1([CH2:46][CH2:47]O)[CH2:45][CH2:44][CH2:43][CH2:42]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1](=[O:40])([O:30][CH2:47][CH2:46][N:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1)[O:2][C@@H:3]1[CH2:19][C@@H:18]2[C@@:6]([CH3:29])([C@@H:7]3[C@@H:15]([CH2:16][CH2:17]2)[C@:14]2([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]4[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=4)[CH2:12][CH2:13]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1
Reactant: OCCN1CCCC1
Reactant: C[C@]12CC[C@H](OC(=O)Oc3ccc([N+](=O)[O-])cc3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@]12CC[C@H](OC(=O)OCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Yield: 86.1 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (24 mg, 0.044 mmol) in CH2Cl2 was added 2-(pyrrolidin-1-yl)ethanol (50.6 mg, 0.44 mmol, 10 eq), DIEA (22.7 mg, 0.176 mmol, 4 eq) and DMAP (19.7 mg, 0.176 mmol, 4 eq). The resultant mixture was stirred at 40° C. for 16 h and then purified via preparative TLC to afford (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(pyrrolidin-1-yl)ethyl carbonate (20 mg, 87.0%) as a white solid. LRMS (M+H+) m/z 528.4. 1H NMR (CD3OD, 400 MHz) δ 8.01 (dd, J=10.0, 2.4 Hz, 1H), 7.44 (m, 1H), 6.29 (d, J=10.0 Hz, 1H), 5.00 (m, 1H), 4.35 (t, J=5.4 Hz, 2H), 3.12 (m, 2H), 2.96 (m, 4H), 2.55-2.60 (m, 1H), 1.08-2.15 (m, 25H), 0.99 (s, 3H), 0.73 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11].[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13]>>[CH2:12]([NH:14][C:15]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11])=[S:16])[CH3:13]
Reactant: CCN=C=S
Reactant: Cc1ncoc1CSCCN
Product: CCNC(=S)NCCSCc1ocnc1C

Procedure:
Also, reacting 5-[(2-aminoethyl)thiomethyl]-4-methyloxazole with ethyl isothiocyanate by the procedure of Example 1 gives N-ethyl-N'-[2-((4-methyl-5-oxazolyl)-methylthio)ethyl]thiourea.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:25]3[CH2:31][CH2:30][CH:28]([CH:29]=2)[CH2:27][CH2:26]3)=[O:23])=[CH:17][C:16]=1[C:32]([F:35])([F:34])[F:33])([O-:14])=[O:13]>C(Cl)Cl>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]23[O:9][CH:29]2[CH:28]2[CH2:27][CH2:26][CH:25]3[CH2:31][CH2:30]2)=[O:23])=[CH:17][C:16]=1[C:32]([F:33])([F:34])[F:35])([O-:14])=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)C1=CC2CCC1CC2
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)C12OC1C1CCC2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
mCPBA (60% mixture, 518 mg, 3.00 mmol, 3 eq) was added to a solution of 11D (340 mg, 1.0 mmol, 1.0 eq) in CH2Cl2 (20 mL). The reaction mixture was stirred at rt overnight and then diluted with CH2Cl2 (40 mL). The organic solution was washed with sat. NaHCO3 (1×50 mL), brine (1×50 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 80% CH2Cl2/hexane gave 205 mg (0.58 mmol, 57.6%) of compound 11E. HPLC conditions: 95% at 3.70 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2% H3PO4, detecting at 220 nm). F. 3-Oxa-tricyclo[3.2.2.02,4]nonane-2-carboxylic acid N-(4-nitro-3-trifluoromethyl-phenyl)-hydrazide (11F)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52]([CH:57]([CH3:63])[C:58]([O:60][CH2:61][CH3:62])=[O:59])=[CH:51]2>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:47][C:48]4[CH:49]=[C:50]5[C:54](=[CH:55][CH:56]=4)[NH:53][C:52]([CH:57]([CH3:63])[C:58]([O:60][CH2:61][CH3:62])=[O:59])=[CH:51]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CCOC(=O)C(C)c1cc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.079 g, 0.384 mmol) in acetonitrile (1.5 mL) were added HBTU (0.146 g, 0.384 mmol) and Et3N (160 μL, 1.15 mmol) at room temperature. The mixture was allowed to stir at room temperature for 10 min before a solution of ethyl 2-(5-amino-1H-indol-2-yl)propanoate (0.089 g, 0.384 mmol) in acetonitrile (2.16 mL) was added. After addition, the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with 1 N HCl (1×3 mL) and then saturated aqueous NaHCO3(1×3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give ethyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)propanoate (0.081 g, 50%). 1 H NMR (400 MHz, CDCl3) δ 8.51(s, 1H), 7.67(s, 1H), 7.23-7.19(m, 2H), 7.04-7.01(m, 3H), 6.89(d, J=0.0 Hz, 1H), 6.28(s, 1H), 6.06(s, 2H), 4.25-4.17(m, 2H), 3.91(q, I=7.2 Hz, 1H), 1.72-1.70(m, 2H), 1.61(s, 2H), 1.29(t, J=7.1 Hz, 4H), 1.13-1.11(m, 2H).
Reaction SMILES: CS[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1>CO>[O:8]=[C:6]1[CH2:5][S:4][C:3]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]2)=[N:7]1
Reactant: O=C(O)C1CCNCC1
Reactant: CSC1=NC(=O)CS1
Solvent: CO
Product: O=C1CSC(N2CCC(C(=O)O)CC2)=N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methylsulfanyl-thiazol-4-one (4.4 g, 30 mmol) in MeOH (60 mL) was added piperidine-4-carboxylic acid (3.9 g, 30 mmol). The mixture was stirred at room temperature for 16 hours. The resulting solid was collected by filtration, washed with fresh MeOH and dried to give the title compound.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[N:5]=[CH:4][N:3]=1.[CH3:10][CH:11]1[CH2:16][CH:15]([CH3:17])[CH2:14][NH:13][CH2:12]1>C1(C)C=CC=CC=1>[F:9][C:6]1[C:7]([F:8])=[C:2]([N:13]2[CH2:14][CH:15]([CH3:17])[CH2:16][CH:11]([CH3:10])[CH2:12]2)[N:3]=[CH:4][N:5]=1
Reactant: Fc1ncnc(F)c1F
Reactant: CC1CNCC(C)C1
Solvent: Cc1ccccc1
Product: CC1CC(C)CN(c2ncnc(F)c2F)C1
Yield: 97.9 %

Procedure:
Into 6 ml of toluene solution of 0.5 g of 4,5,6-trifluoropyrimidine was added dropwise 1 ml toluene solution of 0.51 g of 3,5-dimethylpiperidine (cis/trans diastereomer=about 4/1) at 0° C., and the mixture was stirred for one-and-half hour at same temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.83 g of 4,5-difluoro-6-(3,5-dimethylpiperidino)pyrimidine. This compound had the cis/trans diastereomers originated two methyls on the piperidine ring. The ratio of the cis/trans diastereomer was about 5/1.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:14]2[N:13]3[N:15]=[C:16]([CH3:27])[C:17]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=4[CH3:26])=[C:12]3[N:11]=[C:10]([CH3:28])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].O>CN1CCCC1=O>[CH2:1]([CH:3]([N:6]1[C:14]2[N:13]3[N:15]=[C:16]([CH3:27])[C:17]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=4[CH3:26])=[C:12]3[N:11]=[C:10]([CH3:28])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(CC)n1ccc2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Yield: 36.2 %

Procedure:
A solution of 8-(1-ethylpropyl)-3-mesityl-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (468 mg, 1,24 mmol) in N-methyl-2-pyrrolidinone (10 mL) was heated at 200° C. for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column cromatography (10% ethyl acetate/hexane), to give the title compound (168 mg, 36%) as pale yellow crystals.