Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[N:6]1([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=S(=O)(Cl)Cl
Reactant: C1CCNCC1
Product: O=S(=O)(Cl)N1CCCCC1
Temperature: 25 °C

Procedure:
A solution of 4 g of sulfuryl chloride in acetronitrile was treated dropwise with 861 mg of piperidine at ambient temperature under an atmosphere of nitrogen. After complete addition, the mixture was refluxed for 18 h, cooled to room temperature and concentrated in vacuo to yield the title product as a red oil. TLC: Rf=0.86, CH2Cl2. (1H)-NMR (CDCl3) consistent with structure.
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[C:3]#[CH:4].[C:7]([NH:12][C:13]1[CH:14]=[C:15]([O:19][C:20](Cl)=[O:21])[CH:16]=[CH:17][CH:18]=1)([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:10]([O:9][C:7](=[O:8])[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20](=[O:21])[NH:6][C:2]([CH3:5])([CH3:1])[C:3]#[CH:4])[CH:14]=1)[CH3:11]
Reactant: CCOC(=O)Nc1cccc(OC(=O)Cl)c1
Reactant: C#CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C#CC(C)(C)NC(=O)Oc1cccc(NC(=O)OCC)c1
Reaction time: 0.5 h

Procedure:
Into a solution of 5.0 g (0.06 mole) of 1,1-dimethypropinylamine in 30 ml acetic ester is dropped, after addition of 50 ml water, at 10° to 15° C., while stirring, a solution of 14.6 g (0.06 mole) chloroformic acid-3-(N-carbethoxyamino)-phenyl ester in 30 ml acetic ester and simultaneously a solution of 8.3 g (0.06 mole) potassium carbonate in 30 ml water, the reaction product crystallizing out. Stirring is continued for 30 minutes while cooling with ice. The product is suction-filtered and washed with ether and water.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]1[CH2:8][CH2:7][N:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22]([O:24]C)=[O:23])=[CH:21][C:13]2=3)(=[O:11])=[O:10])[CH2:5][CH2:4]1.O.[OH-].[Li+].O>CO>[F:27][C:2]([F:1])([F:26])[CH:3]1[CH2:8][CH2:7][N:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22]([OH:24])=[O:23])=[CH:21][C:13]2=3)(=[O:10])=[O:11])[CH2:5][CH2:4]1
Reactant: COC(=O)c1cnc2c(c1)N(S(=O)(=O)N1CCC(C(F)(F)F)CC1)CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc2c(c1)N(S(=O)(=O)N1CCC(C(F)(F)F)CC1)CCO2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of methyl 1-(4-(trifluoromethyl)piperidin-1-ylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (0.280 g, 0.684 mmol) in MeOH (20 mL) was added lithium hydroxide monohydrate (0.144 g, 3.42 mmol) and water (4.00 mL) which provided a white suspension. The reaction was stirred at room temp for 2.5 h. The MeOH was removed under reduced pressure and the resulting aqueous solution was neutralized with concentrated HCl (400 mL) to provide a white solid. The suspension was extracted EtOAc (3×10 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo to provide 1-(4-(trifluoromethyl)piperidin-1-ylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acid as a white solid. The yield was assumed to be 100% for calculation purposes in subsequent reactions. LCMS (+ESI) m/z=396.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[OH:10].[C:11](O)(=[O:13])C>>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[OH:10])[CH:11]=[O:13]
Reactant: CCc1cccc(Br)c1O
Reactant: CC(=O)O
Product: CCc1cc(C=O)cc(Br)c1O
Yield: 46 %

Procedure:
A solution of 2-bromo-6-ethylphenol 1 (3.8 g, 18.8 mmol) hexamethylene tetraamine (10.6 g, 75.4 mmol), and acetic acid (120 mL) was heated at reflux for 12 h. Most of the solvent was removed under reduced pressure, and the residue was poured into water (500 nL), and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 until gas evolution ceased. The organic layer was washed with brine (1×100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (SiO2, gradient elution 5 to 10% ethyl acetate/hexanes) to yield 2.0 g (46%) of 3-bromo-5-ethyl-4-hydroxybenzaldehyde 2 as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[OH-].[Na+]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:11]3[C:16]([CH:9]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc(-c2cc3ccccc3[nH]2)cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To 47.2 g of polyphosphoric acid was added 13.62 g (0.10 mol) of 4′-hydroxyacetophenone and 10.0 mL (0.10 mol) of phenylhydrazine at room temperature. The mixture was heated at 150° C. (oil bath temp) for 1 h. After cooling to room temperature an ice-cold H2O (250 mL) was added and the dark brown mixture was stirred overnight. This was then neutralized with 5.0 N NaOH (100 mL) and extracted with EtOAc (1 L×4) which was washed with saturated aqueous NaHCO3 and brine (500 mL each). Organic layers were dried over MgSO4, filtered through a pad of diatomaceous earth, and concentrated to ca. 200-300 mL. This was treated with charcoal, filtered and concentrated. The crude 2-(4-hydroxyphenyl)indole 12.02 g (57%) was obtained. The crude phenolic indole (10.7 g; 51 mmol) was treated with 33.32 g (0.10 mol) of Cs2CO3 and 6.7 mL (56 mmol) of benzyl bromide in ca. 250 mL of DMF at room temperature overnight. The mixture was filtered through a pad of diatomaceous earth with thorough EtOAc rinse. The filtrate was taken up in to 1 L of EtOAc and washed with H2O (500 mL×2) and brine (500 mL) which were back-extracted with EtOAc (1 L×3). Combined organic layers were dried over MgSO4, concentrated and purified by PrepLC with 10:90 benzene-hexanes and 10:10:80 benzene-Et2O-hexanes to obtain 5.34 g (27%) of N,O-dibenzylated product and 1.94 g (13%) of the named benzyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][NH:25]2.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:13]([F:16])([F:15])[F:14])([OH:17])[CH:11]2[NH:20][C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[N:24][NH:25]3)=[CH:4][CH:3]=1
Reactant: Nc1cccc2[nH]ncc12
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccc(Cl)cc1
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]ncc23)c2cc(Cl)ccc21
Yield: 6 %

Procedure:
Analogously to Example 2, the corresponding imine is produced starting from 350 mg of 4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 158 mg of 4-aminoindazole. By reaction of 50 mg of imine with 1.8 ml of BBr3 (1N in dichloromethane), 29 mg of the title compound is obtained.
Reaction SMILES: [C:1]([O:15]C)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+:18]>O>[C:1]([O-:15])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na+:18]
Reactant: CCCCCCCCCCCCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCC(=O)[O-]

Procedure:
A mixture of methyl tridecanoate isomers, 95% pure and containing 65% methyl n-tridecanoate, was subjected to partial hydrolysis under basic conditions. A 10 ml amount of the isomer mixture was placed with 10 ml water in a flask equipped with a reflux condenser, along with 0.15 gram sodium hydroxide. The mixture was heated to reflux with stirring. After forty minutes, a sample was taken from the organic phase and a sodium tridecanoate white crystalline solid formed therein upon cooling. The sample was acidified with sulfuric acid and solids were separated by filtration and washed three times with water. By gas chromatographic analysis it was determined that the material was 64.9% hydrolyzed, and that 97.5% of the tridecanoic acid was n-tridecanoic acids, representing a substantial enrichment from the original 65%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C@H:12]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][C@H:13]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:10].C[C:27]([N:29](C)C)=O>C(OCC)(=O)C.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.[C-]#N.[Zn+2].[C-]#N>[C:27]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C@H:12]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][C@H:13]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:10])#[N:29]
Reactant: CC(=O)N(C)C
Reactant: CC1(C)OC[C@H](NC(=O)Nc2ccccc2Br)[C@H](c2ccccc2)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](NC(=O)Nc2ccccc2C#N)[C@H](c2ccccc2)O1
Temperature: 80 °C

Procedure:
A mixture of the product from Example 19 (355 mg, 0.88 mmol), tetrakis(triphenylphosphine)palladium(0) (102 mg, 10 mol %) and zinc cyanide (103 mg, 0.88 mmol) in dimethylacetamide (8.0 mL) was heated at 80° C. for 8 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (25 mL). The organic layer was washed with water, separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to afford 309 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:35])[N:27]([CH2:31][CH2:32][O:33][NH2:34])[CH:28]([CH3:30])[CH3:29])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:35])[N:27]([CH2:31][CH2:32][O:33][NH:34][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])[CH:28]([CH3:30])[CH3:29])([CH3:22])([CH3:24])[CH3:23]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)N(CCON)C(=O)OC(C)(C)C
Product: CC(C)N(CCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 80.9 %

Procedure:
Following a procedure analogous to Example 45, from the carboxylic acid (6b, 414 mg, 1.50 mmol) of Example 9 or 16 and tert-butyl(2-(aminooxy)ethyl)(isopropyl)carbamate (596 mg) described in Reference Example 17, 578.4 mg of the title compound was afforded (yield 81%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11](=[O:13])[CH3:12])[CH:9]=[CH:10][C:2]1=2.[H-].[Na+].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](OCC)=[O:23]>C1COCC1>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11](=[O:13])[CH2:12][C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)=[O:23])[CH:9]=[CH:10][C:2]1=2
Reactant: CCOC(=O)c1ccccn1
Reactant: CC(=O)c1ccc2c(c1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccccn1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone (XV) (1 eq) in THF was added slowly to a suspension of NaH (1.5 eq) in THF stirred under nitrogen at room temperature. The solution was further allowed to stir at room temperature until the evolution of gas was ceased. Ethyl picolinate (XIX) (1.1 eq) was added to the solution and refluxed overnight under nitrogen. The solution was cooled, poured into ice water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography over silica gel to produce 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyridin-2-yl)propane-1,3-dione 15 as a yellow solid (71% yield), 1H NMR (CDCl3, 400 MHz): δ ppm 4.13-4.43 (m, 4H), 6.94 (d, J=8.31 Hz, 1H), 7.42 (m, 1H), 7.44 (m, 1H) 7.59 (m, 2H), 7.85 (m, 1H), 8.14 (d, J=7.81, 1H), 8.65 (m, 1H); ESIMS found C16H13NO4 m/z 284 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[O:11]([NH2:13])[CH3:12]>>[CH3:12][O:11][N:13]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1]
Reactant: Cc1ccccc1C=O
Reactant: CON
Agent: Cl
Product: CON=Cc1ccccc1C
Yield: 96 %

Procedure:
Reaction of 2-methylbenzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (96% yield). HPLC indicated a 95:5 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 2.44 (3H, s, CH3), 4.01 (3H, s, OCH3), 7.19-7.28 (3H, m, aromatics), 7.73 (1H, m, aromatic), 8.36 (1H, s, CH).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.CN1CCOCC1.[F:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[F:38])[C:32](Cl)=[O:33].C(O)C(N)(CO)CO>CN(C)C=O>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:32]([C:31]3[CH:35]=[CH:36][C:37]([F:38])=[C:29]([F:28])[CH:30]=3)=[O:33])[CH2:2][CH2:3]2)[N:14]=1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: NC(CO)(CO)CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4ccc(F)c(F)c4)CC3)cccc2n1
Reaction time: 2 h
Yield: 157.8 %

Procedure:
5-(Piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was shaken for 60 hours at room temperature in the presence of 3-(morpholino)propyl polystyrene sulfonamide (PS-NMM) (160 mg; 0.4 mmol) and 3,4-difluorobenzoyl chloride (65.3 mg; 0.37 mmol) in 4 mL N,N-dimethylformamide. Tris-(2-aminoethyl)aminomethyl polystyrene (PS-Trisamine) (112 mg; 0.4 mmol) was then added to the mixture and continued to shake for an additional 2 hours. Resins were filtered off and rinsed with methanol. Filtrate was concentrated at reduced pressure, and residue was triturated with 2 mL 1 N NaOH and ethanol (1:1). Solids were collected by filtration to yield [4-(2,4-diamino-quinazolin-5-yloxymethyl)-piperidin-1-yl]-(3,4-difluorophenyl)-methanone (117.4 mg; 76% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.51 (m, 2H), 7.35 (t, J=8.4 Hz, 1H), 7.26 (m, 3H), 6.77 (d, J=8.4 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 5.94 (br s, 2H), 4.50 (br s, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.60 (br s, 1H), 3.11 (br s, 1H), 2.82 (br s, 1H), 2.22 (s, 1H), 1.87 (br s, 1H), 1.75 (br s, 1H), 1.31 (m, 2H). MS m/z (ESI) 414 (M+H)+.
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])=[C:12]([CH3:14])[CH3:13])[CH:3]=[CH2:4].N1C=CC=CC=1.P(Br)(Br)[Br:25]>CCCCCC>[Br:25][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])=[C:12]([CH3:14])[CH3:13]
Reactant: BrP(Br)Br
Reactant: C=CC(C)(O)CCC=C(C)CCC(C)=C(C)C
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(=CCBr)CCC=C(C)CCC(C)=C(C)C
Reaction time: 0.5 h

Procedure:
To a solution containing 223.9 g. of 3,7,10,11-tetramethyl-1,6,10-dodecatrien-3-ol in 570 ml. of hexane and 22.2 ml. of pyridine there was added dropwise at -7°C. over a period of two hours, 112 g. of phosphorous tribromide in 125 ml. of hexane. The resulting mixture was stirred for 30 minutes. After this, the reaction mixture was poured onto ice water and the reaction mixture was allowed to stand under constant stirring for 30 minutes. After 30 minutes, the reaction mixture was diluted with 1,000 ml. of hexane and the water layer was separated and the hexane layer was washed with water, aqueous sodium bicarbonate and finally with water. After washing, the hexane solution was dried over sodium sulfate and evaporated. There resulted 1-bromo-3,7,10,11-tetramethyl-2,6,10-dodecatriene.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:23][O:24]CC2C=CC=CC=2)[C:8]([N:10]2[C@@H:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.CN(C=O)C.[Pd]>[CH:1]1([CH2:6][C@H:7]([CH2:23][OH:24])[C:8]([N:10]2[C@@H:14]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](COCc1ccccc1)CC1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](CO)CC1CCCC1
Reaction time: 60 h
Yield: 99.9 %

Procedure:
A solution of (4S)-3-((2R)-3-cyclopentyl-2-{[(phenylmethyl)oxy]methyl}propanoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one (42.7 g, 0.1 mol) in ethanol (800 mL) and DMF (180 mL) was subjected to catalytic hydrogenation using 10% Pd/C (4 g) and a balloon of hydrogen. The reaction was 50% complete by LCMS after 24 h. The reaction was purged with nitrogen and a fresh balloon of hydrogen was introduced. After an additional 60 h, the reaction was again purged with nitrogen, was filtered, and the filtrate solvents were removed to provide (4S)-3-[(2R)-3-cyclopentyl-2-(hydroxymethyl)propanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (33.1 g, 100%). LCMS: (M+H)+: 332.3.
Reaction SMILES: F[C:2]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=O.S(Cl)(Cl)=O.[NH2:21][NH2:22].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH:7]([NH:6][C:4]1[C:3]2[C:2](=[CH:13][C:12]([N+:14]([O-:16])=[O:15])=[CH:11][CH:10]=2)[NH:22][N:21]=1)([CH3:9])[CH3:8]
Reactant: CC(C)NC(=O)c1ccc([N+](=O)[O-])cc1F
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Product: CC(C)Nc1n[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
2-Fluoro-N-isopropyl-4-nitro-benzamide (0.204 g, 0.902 mmol) and thionyl chloride (1 mL) were heated to 78° C. and stirred for three hours. The reaction mixture was cooled and concentrated to a white solid. NMP (1 mL), hydrazine (0.28 mL, 8.92 mmol) and powdered K2CO3 were added, and the reation mixture was heated to 90° C. and stirred for two hours. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (EtOAc/hexanes 0-33%) to give 0.075 g of Isopropyl-(6-nitro-1H-indazol-3-yl)-amine, MS (M+H)=249.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.CCO.O.[NH3:16]>>[Cl:11][C:4]1[N:3]=[C:2]([NH2:16])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCO
Solvent: O
Product: Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
2,6-Dichloro-3-nitropyridine 90 (10.0 g, 51.8 mmol) was dissolved in 37 ml of a 7N solution of NH3 in EtOH (0.26 mol, 5.0 eqv) and the solution was stirred at rt for 24 h. H2O (40 ml) was added and the resulting mixture was filtered to collect the crude yellow product. The solid material was dissolved in CH2Cl2 and then extracted with a 1N HCl solution. The aqueous extracts were combined and then neutralized with NaHCO3 before being re-extracted with CH2Cl2. The organic fractions were combined, dried (MgSO4), filtered, and concentrated in vacuo to yield 8.0 g of a yellow solid (89%): 1H NMR (400 MHz, d6-DMSO) d 6.77 (d, J=8.8 Hz, 1H), 8.27 (s, 2H), 8.39 (d, J=8.4 Hz, 1H); 13C NMR (125 MHz, d6-DMSO) d 111.89, 126.02, 138.28, 153.36, 154.88; HRMS (EI) Calcd for C5H4ClN3O2: 172.9997. Found 172.9996.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=1.C(OCC)(=O)C>[C].[Pd].CO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[N:17][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(N)cn1
Yield: 93.7 %

Procedure:
A mixture of 2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-nitropyridine (13.4 g), palladium-carbon (5%, 1.5 g) and ethyl acetate (200 ml)-methanol (150 ml) was subjected catalytic hydrogenation at room temperature under one atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residual crystals were collected by filtration to obtain 5-amino-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (11.4 g, 93%). Recrystallization from ethyl acetate-hexane gave brown crystals, m.p.107.0-108.0° C.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.ClC[C:13]1[CH:14]=[CH:15][C:16]2[S:21][C:20]3[N:22]=[CH:23][CH:24]=[N:25][C:19]=3[NH:18][C:17]=2[CH:26]=1.C(OCC)C>CCCCCC>[CH2:9]([O:8][P:1]([C:13]1[CH:14]=[CH:15][C:16]2[S:21][C:20]3[N:22]=[CH:23][CH:24]=[N:25][C:19]=3[NH:18][C:17]=2[CH:26]=1)(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: ClCc1ccc2c(c1)Nc1nccnc1S2
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOP(=O)(OCC)c1ccc2c(c1)Nc1nccnc1S2
Temperature: 160 °C

Procedure:
To 2 ml of triethyl phosphite was added 0.374 g of 8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and the resulting mixture was heated to 160° C. for 3 hours. Then the reaction mixture was brought back to room temperature and diethyl ether (10 ml) and n-hexane (20 ml) were added thereto. The precipitate was taken up by filtration and washed several times with n-hexane to thereby give 0.413 g of the title compound as a yellow powder.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].S(C1C=CC(C)=CC=1)(O[CH2:18][C@@H:19]1[CH2:33][C@H:32]2[C@@H:22]([CH2:23][C:24]3[C:34]4[C:27](=[CH:28][CH:29]=[CH:30][C:31]2=4)[NH:26][CH:25]=3)[N:21]([CH3:35])[CH2:20]1)(=O)=O>CN(C)C=O>[CH3:3][C:4]1[N:5]=[CH:6][N:7]([CH2:18][C@@H:19]2[CH2:33][C@H:32]3[C@@H:22]([CH2:23][C:24]4[C:34]5[C:27](=[CH:28][CH:29]=[CH:30][C:31]3=5)[NH:26][CH:25]=4)[N:21]([CH3:35])[CH2:20]2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1[nH]cnc1C
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)ncn1C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h

Procedure:
1.6 g of 50% sodium hydride in an oil was added in small portions to a mixture of 10 g of ethyl 4-methyl-5-imidazolecarboxylate and 70 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 4.1 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 2 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to alumina column chromatography eluting with ethyl acetate to obtain ethyl 4-methyl-1-(6-methylergolin-8β-ylmethyl)-5-imidazolecarboxylate from the first fraction. The product was recrystallized from dichloromethane-diethyl ether and was colorless prisms having a melting point of 225°-227° C. Yield, 0.7 g. This compound is hereinafter referred to as Compound 15A.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=3[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:29]#[N:30]>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:22]2[C:17](=[CH:18][C:19]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=3[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:29]#[N:30]
Reactant: COc1ccc2cc3ncc(C#N)c(Cl)c3cc2c1
Reactant: Nc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cc3ncc(C#N)c(Nc4ccc(Cl)cc4Cl)c3cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
According to the procedure of Example 14, a reaction mixture of 657.8 mg (4.06 mmol) of 2,4-dichloroaniline and 162.4 mg (4.06 mmol) of sodium hydride in 18 mL of anhydrous DMF is stirred at room temperature for 0.5 hour. To the mixture is added 494.0 mg (1.84 mmol) of 4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile. The resulting mixture is heated at 55° C. for 1 hour. After work up, 624.6 mg (86.2%) of 4-(2,4-dichloroanilino)-7-methoxybenzo[g]quinoline-3-carbonitrile is obtained as a yellow solid, mp 215–217° C.