Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([C:5]([N:12]=C=O)([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])[CH2:3][CH3:4]>O>[ClH:1].[CH2:2]([C:5]([NH2:12])([CH2:6][CH2:7][CH3:8])[CH2:9][CH2:10][CH3:11])[CH2:3][CH3:4]
Reactant: CCCC(CCC)(CCC)N=C=O
Agent: Cl
Solvent: O
Product: CCCC(N)(CCC)CCC
Temperature: 90 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Into a three-necked flask equipped with a mechanical stirrer, a dropping-funnel, a thermometer and a condenser, were introduced 200 ml of water and 90 ml of concentrated hydrochloric acid (d=1.19). The acid solution was heated to 90° C. and then, under vigorous stirring, 105 g of 1,1-di-n-propyl-n-butylisocyanate, prepared as previously described, were slowly added. The operation of addition lasted one hour after which the reaction medium was heated for a further 4 hours at a temperature between about 95° and 100° C. The mixture was then cooled to about 0° C. and the colourless crystals so obtained were filtered off dried by exposure to the air and then in a dessicator in the presence of potassium hydroxide. In this manner, 99 g of 1,1-di-n-propyl-n-butylamine hydrochloride were isolated in the form of a white crystalline powder.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].Cl>O.CN(C)C=O>[CH2:27]([O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:17]=[CH:18][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1)[CH:26]=[CH2:25]
Reactant: CC(C)Oc1ccc(Oc2ccc(O)cc2)cc1
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccc(OC(C)C)cc2)cc1
Reaction time: 0.4 h
Yield: 69 %

Procedure:
To a mixture of 1.23 g of 4-(4-isopropoxyphenoxy)phenol, 1.4 g of potassium carbonate and 10 ml of N,N-dimethylformamide 0.65 ml of allyl bromide was added dropwise at room temperature with stirring. After 24 minutes, the reaction solution was poured into water, and acidified by adding 10% hydrochloric acid. The solution was extracted with 50 ml of diethyl ether, washed in turn with 10% hydrochloric acid, an aqueous 10% sodium hydroxide and a saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.98 g of 4-(4-isopropoxyphenoxy)phenyl allyl ether (yield, 69%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1)[CH3:36]>O1CCOCC1.C([O-])(O)=O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[CH:39]=[N:38][N:37]([CH2:35][CH3:36])[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1cc(-c2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)cn1
Temperature: 100 °C

Procedure:
A mixture of bis(triphenylphosphine)palladium chloride (14.01 mg, 0.020 mmol), tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.399 mmol), and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (177 mg, 0.798 mmol) in dioxane (4 mL) and saturated aqueous NaHCO3 (1 mL) was heated to 100° C. in a Biotage Initiator microwave for 1 hour. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). The resulting solution was stirred at room temperature for 20 minutes, concentrated, and purified by preparatory HPLC, eluting with a gradient of 10-25% ACN (0.035% TFA) and water (0.05% TFA). The collected fractions were combined and dried to give a TFA salt of the title compound as a white solid (87 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (t, J=7.3 Hz, 3H), 1.75-1.77 (m, 1H), 2.10-2.11 (m, 1H), 3.61-3.63 (m, 1H), 3.85-3.86 (m, 1H), 3.93-3.94 (m, 1H), 3.96-3.98 (m, 2H), 4.18 (q, J=7.32, 2H), 4.47-4.48 (m, 1H), 7.04-7.05 (m, 1H), 7.89-7.91 (m, 2H), 8.30 (s, 1H), 8.37 (s, 1H), 8.88 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C17H21FN6O2, 361. found, 361.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[C:30]4[O:29][CH2:28][CH2:27][N:26]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]>C(O)C>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[C:30]4[O:29][CH2:28][CH2:27][N:26]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(=O)CCCCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCN(CCCCC(=O)O)C4)no2)cc1C#N
Temperature: 60 °C
Yield: 30.2 %

Procedure:
2M sodium hydroxide (0.347 mL, 0.694 mmol) was added to a stirred solution of ethyl 5-[9-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]pentanoate (Preparation 93) (70 mg, 0.139 mmol) in ethanol (5 mL) and the mixture was heated to 60° C. overnight. The reaction mixture was allowed to cool to room temperature and the solvent evaporated. The residue was diluted with water, acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to give the product as an off white solid (20 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[CH:20][C:21]([N+:23]([O-])=O)=[CH:22][C:14]1=2)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].O.NN>C(O)C.C(OCC)(=O)C.[Ni]>[NH2:23][C:21]1[CH:20]=[CH:19][C:15]2[S:16][CH2:17][CH2:18][N:13]([CH2:12][CH2:11][N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[C:14]=2[CH:22]=1
Reactant: CCN(CCN1CCSc2ccc([N+](=O)[O-])cc21)C(=O)OC(C)(C)C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CCN1CCSc2ccc(N)cc21)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
To a stirred solution of tert-butyl ethyl(2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (925 mg, 2.52 mmol) in ethanol (10 mL) was added Raney-Nickel (˜148 mg, 2.52 mmol) followed by hydrazine hydrate (1.225 mL, 25.2 mmol). The resulting mixture was stirred vigorously at 50° C. for 10 minutes. The mixture was then cooled to room temperature, diluted with ethyl acetate, and then washed sequentially with a 1:1 mixture of water and saturated sodium carbonate (3×) and saturated sodium carbonate. The organic phase was dried, filtered, and concentrated giving a red oil (810 mg, 95%); ESI-MS (m/z, %): 338 (MH+, 100), 282 (53), 238 (36).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[C:19]([OH:21])=[O:20]>CS(C)=O>[C:19]([CH:18]([NH:17][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)([OH:21])=[O:20]
Reactant: NC(Cc1cccc(F)c1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1NC(Cc1cccc(F)c1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(3-fluoro-phenyl)-propionic acid in DMSO to provide the title compound in good yield.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH:42]=[O:43]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([CH:42]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=2)[OH:43])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: O=Cc1ccccn1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3ccccn3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and pyridine-2-carboxaldehyde.
Reaction SMILES: C(N1C2C(=C(OCC3OC3)C(C)=CC=2)C=N1)(=O)C.C(N1C2C(=C(OCC3OC3)C=CC=2C)C=N1)(=O)C.[C:37]([N:40]1[C:48]2[C:43](=[C:44]([O:51][CH2:52][CH:53]3[O:55][CH2:54]3)[CH:45]=[C:46]([CH2:49]C)[CH:47]=2)[CH:42]=[N:41]1)(=[O:39])[CH3:38]>>[C:37]([N:40]1[C:48]2[C:43](=[C:44]([O:51][CH2:52][CH:53]3[O:55][CH2:54]3)[CH:45]=[C:46]([CH3:49])[CH:47]=2)[CH:42]=[N:41]1)(=[O:39])[CH3:38]
Reactant: CCc1cc(OCC2CO2)c2cnn(C(C)=O)c2c1
Agent: CC(=O)n1ncc2c(OCC3CO3)c(C)ccc21
Agent: CC(=O)n1ncc2c(OCC3CO3)ccc(C)c21
Product: CC(=O)n1ncc2c(OCC3CO3)cc(C)cc21

Procedure:
The following compounds are obtained in an analogous manner: 1-acetyl-4-(2,3-epoxypropoxy)-5-methyl-indazole (m.p. 75°-76° C.), 1-acetyl-4-(2,3-epoxypropoxy)-7-methyl-indazole (m.p. 108°-109° C.) and 1-acetyl-4-(2,3-epoxypropoxy)-6-ethylindazole (m.p. 77°-78° C.).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:31])[CH2:11][NH:12][CH:13]([CH3:30])[CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:34]=[O:35]>>[CH2:1]([O:8][CH2:9][CH:10]1[O:31][C:34](=[O:35])[N:12]([CH:13]([CH3:30])[CH2:14][O:15][C:16]2[CH:29]=[CH:28][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:18][CH:17]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)COCc1ccccc1
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)N1CC(COCc2ccccc2)OC1=O

Procedure:
A procedure similar to that described in Example 4 was repeated, except that 200 mg of 5-{4-[2-(3-benzyloxy-2-hydroxypropylamino)propoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Example 15), 73 mg of N,N'-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography, using a gradient elution method, with mixtures of ethyl acetate and hexane in ratios ranging from 2:1 to 3:1 by volume as the eluent, to give 160 mg of the title compound as a pale yellow glassy solid which was a mixture of a less polar diastereomer having an Rf value of 0.49 (on silica gel thin layer chromatography, using a 3:1 by volume mixture of ethyl acetate and hexane as the developing solvent) and a polar diastereomer having an Rf value of 0.38 (on silica gel thin layer chromatography, using a 3:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:19])=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:31]([N:33]1[CH2:38][CH2:37][C:36]([F:40])([F:39])[CH2:35][CH2:34]1)=[O:32])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:40][C:36]1([F:39])[CH2:37][CH2:38][N:33]([C:31]([C:10]2[N:9]([CH2:8][CH2:7][OH:6])[C:17]3[C:12]([CH:11]=2)=[CH:13][C:14]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:19])=[CH:15][CH:16]=3)=[O:32])[CH2:34][CH2:35]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2n1CCO)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
The solution of 90 mg (0.15 mmol) [1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone in 3 mL dichloromethane was cooled to 0° C. and 1.0 mL (1.49 g, 13.1 mmol) trifluoroacetic acid were added. The cooling bath was removed and after stirring for 1 h at room temperature the pH of the solution was neutralized by adding 1M aqueous sodium hydroxide solution. The phases were separated and the aqueous phase was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash column chromatography on silica gel with dichloromethane:methanol as eluant (gradient 100:0 to 50:50) to give 41 mg (56%) of the desired compound as a white foam.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])[CH3:11])[CH:6]=[O:7])(=[O:3])[CH3:2].C(Cl)Cl.[BrH:31]>CC(O)=O>[C:1]([O:4][C@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])[CH3:11])[CH:6]=[O:7])(=[O:3])[CH3:2].[Br-:31]
Reactant: Br
Agent: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: [Br-]
Reaction time: 0.5 h

Procedure:
To a 500 ml flask was added 50 g of glucose pentaacetate (C6H22O11) and 80 ml of methylene chloride. The mixture was stirred at ice-water bath for 20 min HBr in HOAc (33%, 50 ml) was added to the reaction mixture. After stirring for 2.5 hr another 5 ml of HBr was added to the mixture. After another 30 min, the mixture was added 600 ml of methylene chloride. The organic mixture was washed with cold water (200 ml×2), Saturated NaHCO3(200 ml×2), water (200 ml) and brine (200 ml×2). The organic layer was dried over Na2SO4 and the mixture was evaporated at RT to give white solid as final product, bromide derivative, IntD1 (˜95% yield). C14H19BrO9, TLC Rf=0.49, SiO2, 40% ethyl acetate/60% hexanes; Exact Mass 410.02.
Reaction SMILES: [C:1]1([C:7]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][C:11]=3[C:10]([C:20]#[N:21])=[C:9]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1C[O:33]CC1>>[O:33]=[C:12]1[C:11]2[C:10]([C:20]#[N:21])=[C:9]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccccc2)c2c1Cc1ccccc1-2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccccc2)c2c1C(=O)c1ccccc1-2
Temperature: 2.5 °C

Procedure:
A solution of 4-phenyl-2(piperidin-1-yl)-9H-fluorene-1-carbonitrile (350 mg) in THF was added sodium hydride (27 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Light red solid; mp 220-222° C.; ESIMS 365 (M++1); IR (KBr) 2220 (CN), 1709 cm−1 CO).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:26]([O:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH2:27][CH3:28]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:33][CH2:32][CH2:31][CH2:30][O:29][CH2:26][CH2:27][CH3:28])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: CCCOCCCN
Product: CCCOCCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-propoxypropylamine employing methods similar to those described in Example 2 and was obtained a white solid: 1H NMR (d6-DMSO) δ 11.83 (1H, br s), 10.26 (1H, br s), 8.48 (1H, br s), 7.43 (1H, s), 7.30-7.26 (2H, m), 7.16-7.11 (2H, m), 4.09 (2H, s), 3.42-3.38 (4H, m), 3.30-3.28 (2H, m), 1.76-1.71 (2H, m), 1.49 (2H, q, J=7 Hz), 0.83 (3H, t, J=7.3 Hz); HRMS calcd for C22H24FN3O4+H+: 414.1829. Found 414.1844.
Reaction SMILES: [Sn].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=O)=O)=[CH:5][C:4]=1[N+:13]([O-])=O>Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][C:4]=1[NH2:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Agent: [Sn]
Product: Nc1cc(S)ccc1Cl
Temperature: 0 °C
Yield: 73.9 %

Procedure:
To a mixture of concentrated hydrochloric acid (30 mL) and ice (25 g) was added tin (29.7 g) under ice-cooling, followed by adding 4-chloro-3-nitrobenzenesulfonyl chloride (6.4 g), and the mixture was stirred under ice-cooling for 1.5 hours, and then stirred at 90° C. for 2 hours. The insoluble material was removed by filtration, and the filtrate was stirred at room temperature overnight. The precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give the title compound (2.95 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CC(C[AlH]CC(C)C)C.C(=O)=O.CC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([CH2:15][OH:16])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cn1cc(Br)cc(Nc2ccc(CO)cn2)c1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
In a flask under N2, 186a (500 mg, 1.5 mmol) was suspended in methylene chloride and cooled to −78° C. in a dry ice/acetone bath. 1.0M DIBAL-H in methylene chloride (4.4 mL, 4.4 mmol) was slowly added via syringe. After the addition was complete the reaction was allowed to warm to −20° C. at which time the dry ice/acetone bath was exchanged for a ice/water bath and the reaction stirred an additional 0.5 hr at which time it was slowly quenched with 1N HCl (˜5 mL). The reaction was then diluted with ethyl acetate and allowed to stir and warm to room temp over ˜1 hr. The pH was adjusted to ˜7 with 1N NaOH and 50 mL of saturated aqueous Rochelle's salt was added and the mixture heated and stirred at 40° C. for 1 hr during which time the mixture cleared. The layers were separated, the organics washed with brine, dried over Na2SO4, filtered and concentrated to give 186b as a white solid (420 mg, 90% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[S:4][C:3]=1[C:14]([NH2:16])=[O:15].C[Si]([N:21]=[C:22]=[O:23])(C)C>>[NH2:21][C:22]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[S:4][C:3]=1[C:14]([NH2:16])=[O:15])=[O:23]
Reactant: NC(=O)c1sc(-c2ccccc2Cl)cc1N
Reactant: C[Si](C)(C)N=C=O
Product: NC(=O)Nc1cc(-c2ccccc2Cl)sc1C(N)=O

Procedure:
Prepared by the method of Example 1 from 3-amino-5-(2-chlorophenyl)-2-thiophenecarboxamide and trimethylsilylisocynate.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[F-].[Na+].O.C(N(CC)CC)C.ClC[C:35](Cl)=[O:36].Cl>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[CH2:11][O:13][CH2:14][C:35]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(CNCc1ccccc1)c1ccc(Br)cc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [F-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1COCC(c2ccc(Br)cc2)CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
To a solution of methyl 3-benzylamino-2-(4-bromophenyl)propionate (7.1 g, 20.5 mmol) in toluene (40 mL) at 0° C. under nitrogen atmosphere was added a 1M solution of diisobutylalminium hydride (DIBAH) in toluene (65 mL, 65 mmol) and the resulting mixture was stirred for 3 hours. After cooling to 0° C., sodium fluoride (10.9 g, 260 mmol) and water (3.5 mL, 195 mmol) was added to quench aluminum reagents. The white slurry was stirred for 30 minutes and filtered to remove solid materials. The organic solution was concentrated. The resulting residue was diluted with dichloromethane (80 mL) and cooled to 0° C. To the solution was added triethylamine (4.2 mL, 30 mmol) and chloroacetyl chloride (1.6 mL, 20 mmol) and stirred for one hour. The reaction mixture was poured into 1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The viscous residual oil was dissolved in 2-propanol (50 mL) and then potassium hydroxide pellet (2 g, 30 mmol) was added at room temperature. After vigorous stirring over night, the reaction solution was diluted with water and extracted with ethyl acetate. The organic solution was dried over anhydrous sodium sulfate and concentrated. The residual material was purified by flash column chromatography on silica gel (hexane/ethyl acetate=3/1 as an eluant) to afford 4-benzyl-6-(4-bromo-phenyl)-[1,4]oxazepan-3-one (3.0 g, 8.3 mmol, 41%) as brown oil.
Reaction SMILES: O[C:2]1[CH:12]=[C:11]2[C:5]([C:6](=[O:21])[N:7]([CH2:13][S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:8]2(=[O:10])=[O:9])=[C:4](C(C)C)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCCO)C1C=CC=CC=1>C1COCC1>[C:15]1([S:14][CH2:13][N:7]2[C:6](=[O:21])[C:5]3[C:11](=[CH:12][CH:2]=[CH:3][CH:4]=3)[S:8]2(=[O:10])=[O:9])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Agent: OCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2S(=O)(=O)N1CSc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-hydroxy-4-isopropyl-2-phenylthiomethylsaccharin (2.0 g, 5.5 mol) in THF (40 mL) were added triphenylphosphine (1.46 g, 5.56 mmol), 2-benzyloxyethanol (0.87g, 5.71 mmol) and triphenylphosphine (0.99 g, 5.68 mmol). The mixture was stirred at room temperature for 16 hours, the solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 20% EtOAc/hexane to afford 2.1 g (77%) of 4-isopropyl-6-[2-benzyloxy)ethoxy]-2-phenylthiomethylsaccharin, m.p. 98°-99° C.