Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].O(C)[Na].CN([CH:12]=[C:13]1[C:19](=O)[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)[CH2:15][CH2:14]1)C>CO>[CH3:3][C:2]1[N:4]=[CH:12][C:13]2[CH2:14][CH2:15][N:16]([C:25](=[O:35])[C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]=2[N:5]=1
Reactant: CC(=N)N
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2C1=O
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Reaction time: 0.08 h
Yield: 99.7 %

Procedure:
To a stirred solution of 0.233 g of acetamidine hydrochloride in 36 ml of methyl alcohol under argon is added 0.133 g of NaOCH3. After 5 minutes, 0.600 g of 4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one is added and stirring continued for 18 hours. The volatiles are evaporated to a residue which is dissolved in ethyl acetate and passed through a pad of silica gel. The filtrate is evaporated in vacuo to give 590 mg of the desired product as tan crystals, m.p. 211°-212° C. HR FABMS: Exact mass (M+H):361.1295.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][N:20]([CH3:27])[CH2:21][CH2:22][CH2:23]C(Cl)=O.[CH2:28]([N:30]1[C:42]2[CH:41]=[CH:40][C:39]([NH2:43])=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:29]>>[CH3:19][N:20]([CH3:27])[CH2:21][CH2:22][CH2:23][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([NH:43][C:39]1[CH:40]=[CH:41][C:42]2[N:30]([CH2:28][CH3:29])[C:31]3[C:36]([C:37]=2[CH:38]=1)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:18])=[O:7]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CN(C)CCCC(=O)Cl
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOC)CN3C(=O)CCCN(C)C)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(dimethylamino)-butanoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 42% purity by LC/MS. MS(ESI+): m/z=464.2.
Reaction SMILES: [C:1](O)(=O)C.O.[CH:6](=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C=O>[CH2:1]=[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[O:14]
Reactant: CCCCCCCC=O
Reactant: CC(=O)O
Agent: C=O
Solvent: O
Product: C=C(C=O)CCCCCC
Temperature: 50 °C

Procedure:
A 5-liter flask fitted with an overhead stirrer and condenser was charged with di-N-butyl amine (61 g, 0.47 mol) and acetic acid (56 g, 0.9 mol). Roughly 900 ml of 37% formaldehyde solution in water (351 g formaldehyde, 11.7 mol) was then added and the resulting solution was heated to 50° C. with stirring. After this temperature was reached octanal (1000 g, 7.0 mol) was fed in over about 2 h. A slight exotherm was noticed during the feed. Monitoring by GC showed the consumption of octanal and the production of 2-methylene octanal, finally reaching roughly 95% conversion after the addition was complete. The reaction mixture was allowed to cool to room temperature, poured into a separatory funnel, and washed once with 5% HCl solution. The organic layer was then washed once with saturated sodium bicarbonate, then taken directly on to the next step.
Reaction SMILES: CCCCC.C[Sn:7]([CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11].[ClH:26].O>C1C=CC=CC=1>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][Sn:7]([Cl:26])([CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: Cl
Reactant: CC(C)(C)CC[Sn](C)(CCC(C)(C)C)CCC(C)(C)C
Solvent: CCCCC
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)CC[Sn](Cl)(CCC(C)(C)C)CCC(C)(C)C
Temperature: 25 °C
Yield: 90 %

Procedure:
Tris(3,3-dimethylbutyl)tin chloride was prepared by the gradual addition of stannic chloride (13.0 g., 0.05 mole) dissolved in 50 c.c. pentane to a solution containing 19.5 g. (0.05 mole) of methyl tris(3,3-dimethylbutyl)tin dissovled in 50 c.c. pentane. The addition required 20 minutes and was performed under a nitrogen atmosphere. External cooling was applied as necessary to maintain the temperature of the reaction mixture below 27° C. Following completion of the addition the resulant mixture was heated at the boiling point for 0.5 hour, then allowed to cool to ambient temperature. A solution containing 2 c.c. of 12 normal aqueous hydrochloric acid and 100 c.c. water was added to the reaction mixture over a three minute period, followed by 50 c.c. of benzene. The organic liquid phase was separated, combined with 102 c.c. of an aqueous hydrochloric acid solution as previously described, after which the organic solvent was separated, dried using a portion of anhydrous magnesium sulfate and the organic solvents removed under reduced pressure. A 10 g. portion of the resultant white solid residue, obtained in 90% yield, was recrystallized from 100 c.c. of hexane and exhibited the following analysis, by weight:
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:29]2[CH:30]=[C:25]([CH3:24])[CH:26]=[CH:27][CH:28]=2)=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C)c3)c2cc1OC
Reaction time: 3 h
Yield: 93.6 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 3-methylphenylboronic acid (136 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at +80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (72 mg, yield 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1)=[O:20].[C:32]([O-])(O)=O.[Na+].[Na+].[I-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[O:20])[CH2:11][CH2:10]1
Reactant: COc1ccccc1C1CCNCC1
Reactant: O=C([O-])O
Reactant: O=C(NCCCl)Nc1ccnc2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1C1CCN(CCNC(=O)Nc2cc(C)nc3ccccc23)CC1
Temperature: 70 °C
Reaction time: 144 h

Procedure:
To a solution of 4-(2-methoxy-phenyl)-piperidine (0.03 mmol) in dry THF (1 mL) is added 1-(2-chloro-ethyl)-3-quinolin-4-yl-urea (0.03 mmol), solid NaHCO3 (2.5 mg), and NaI (1 mg). The flask is tightly sealed, and shaken at 70° C. for 6 days. The reaction mixture is evaporated, taken up in aqueous formic acid, and purified by preparative HPLC to provide the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH:12]([O:15][CH3:16])[CH2:13][CH2:14][C:7]2=[N:6][C:5]=1[CH3:17].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1.CC(NC(C)C)C>CO>[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][C:4]4[C:9](=[O:10])[N:8]5[CH2:11][CH:12]([O:15][CH3:16])[CH2:13][CH2:14][C:7]5=[N:6][C:5]=4[CH3:17])[CH2:31][CH2:32]3)=[N:25][O:26][C:22]=2[CH:21]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COC1CCc2nc(C)c(CCCl)c(=O)n2C1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CO
Product: COC1CCc2nc(C)c(CCN3CCC(c4noc5cc(F)ccc45)CC3)c(=O)n2C1
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 6 parts of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-7-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 4.8 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole monohydrochloride, 6.1 parts of N-(1-methylethyl)-2-propanamine and 16 parts of methanol was stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 8.5 parts (100%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-7-methoxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one as an oily residue. (intermediate 5)
Reaction SMILES: N[C:2]1[C:10]2[N:9]([CH2:11][CH:12]([OH:14])[CH3:13])[N:8]=[C:7]3[CH2:15][CH2:16][CH2:17][C:5]([C:6]=23)=[CH:4][CH:3]=1.[OH:18]S(O)(=O)=O.O>>[OH:14][CH:12]([CH3:13])[CH2:11][N:9]1[C:10]2=[C:2]([OH:18])[CH:3]=[CH:4][C:5]3=[C:6]2[C:7]([CH2:15][CH2:16][CH2:17]3)=[N:8]1
Reactant: O=S(=O)(O)O
Reactant: CC(O)Cn1nc2c3c(ccc(N)c31)CCC2
Solvent: O
Product: CC(O)Cn1nc2c3c(ccc(O)c31)CCC2
Yield: 86 %

Procedure:
The product from Step C (0.70 g, 3.2 mmol) was dissolved in H2SO4/H2O (1:2, 30 mL) and treated as described in Step E of Example 1 to provide a solid (0.60 g, 86%): m.p 162-163° C.; MS (ES) m/z 233(M+).
Reaction SMILES: [N+]([O-])([O-])=O.[K+].[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=[CH2:8].[C:12]([OH:15])(=[O:14])C>>[C:12]([OH:15])(=[O:14])/[CH:8]=[CH:7]\[C:6]([OH:11])=[O:10].[C:6]([OH:11])(=[O:10])/[C:7](=[CH:9]\[C:12]([OH:15])=[O:14])/[CH3:8]
Reactant: CC(=O)O
Reactant: C=C(C)C(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: C/C(=C/C(=O)O)C(=O)O
Product: O=C(O)/C=C\C(=O)O

Procedure:
A catalyst is prepared as described in Example 1 except that the addition of potassium nitrate is omitted. Under the test conditions of Example 1 and at a bath temperature of 310° C., the conversion is 69.9 mole %, and the selectivities with respect to methacrylic acid and acetic acid are 82.5 mole % and 3.7 mole % respectively. Maleic acid and citraconic acid are formed in a total amount of 1.2%.
Reaction SMILES: C([NH:6][NH:7][CH2:8][CH2:9][CH2:10][CH:11]1[NH:15]C(=O)N[C:12]1=[O:17])(OCC)=O.[OH2:18].O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O>[NH2:15][CH:11]([CH2:10][CH2:9][CH2:8][NH:7][NH2:6])[C:12]([OH:17])=[O:18]
Reactant: O
Reactant: CCOC(=O)NNCCCC1NC(=O)NC1=O
Agent: [Ba+2]
Agent: [OH-]
Product: NNCCCC(N)C(=O)O

Procedure:
Mix 5-[3-(carbethoxyhydrazino)-propyl]-hydantoin (2.44 g, 10 mmol), barium hydroxide octahydrate (18.15 g, 10 mmol) and water (55 mL). Reflux for 12 hours, remove the white solid by filtration and extract the filter cake with boiling water (25 ml) and finally wash with hot water (25 mL). Combine the filtrate and washings, treat with ammonium carbonate (5.7 g) and heat with stirring. Filter off the barium carbonate, wash the filter cake with hot water and evaporate the filtrate and washings in vacuo to give 2-amino-5-hydrazino-pentanoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=O)[C:3]=1[S:21]([CH3:23])=[O:22].Cl.[NH2:25][OH:26].N1C=CC=CC=1>CO>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:25][OH:26])[C:3]=1[S:21]([CH3:23])=[O:22]
Reactant: NO
Reactant: CS(=O)c1c(C=O)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Yield: 61.1 %

Procedure:
A mixture of 5-amino-1-[2,6dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde (2.74 g), hydroxylamine hydrochloride (0.99 g) and pyridine (1.68 g) was stirred in methanol at 46° C. for 2.8 hours, evaporated, washed (water) and crystallized from ethanol to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (1.74 g) as a white solid m.p.219-221° C. (decomposition). Compound 1
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][C:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23](C)(C)[CH3:24])=[O:21])[CH2:19][C:12]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].ClC(OCC)=O>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][C:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][C:12]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1cccc2c3c([nH]c12)CCN(C(=O)OC(C)(C)C)C3
Agent: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc2c3c([nH]c12)CCN(C(=O)OCC)C3
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
To a solution of tert-butyl 6-[(ethoxycarbonyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (8.7 g, 24.3 mmol) in CH2Cl2 (40 mL) at rt was added TFA (20 mL) and stirred at rt for 3 hours before the solvent was removed by the nitrogen stream. The solution was diluted with water (30 mL) and extracted with CH2Cl2 (2×30 mL). The combined extracts were dried over magnesium sulfate, and concentrated to afford an crude residue that was re-dissolved in CH2Cl2 (40 mL) followed by saturated K2CO3 (30 mL), ethyl chloroformate (2.4 mL, 4.0 mmol) and stirred at 25° C. for 0.5 hour. The solution was diluted with water (30 mL) and extracted with CH2Cl2 (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford ethyl 6-[(ethoxycarbonyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (4.5 g, 67%) as a clear oil. MS [M+H]+ 332. 1H NMR (CDCl3, 300 MHz): δ 7.00 (t, 1H, J=7.7 Hz), 6.82 (m, 1H), 6.71 (m, 1H), 4.62 (s, 2H), 4.02–4.31 (m, 4H), 3.82 (t, 1H, J=5.5 Hz), 2.82 (t, 1H, J=5.5 Hz), 1.20–1.24 (m, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[Br:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].C(N(CC)CC)C.O>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[Br:11])=[O:8]
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: Nc1ccccc1Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1Br)c1cncc(Br)c1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A mixture of 5-bromonicotinoyl chloride 5 (7.5 g, 33 mmol), 2-bromoaniline (5.86 g, 33 mmol) and triethylamine (14 mL, 100 mmol) in anhydrous dichloromethane (100 ml) was stirred under argon overnight. The resulting mixture was worked up with water and extracted with dichloromethane (200 mL×2). The organic phase was collected and dried over Na2SO4. After concentrated to 150 mL, white crystalline solid was crashed out. Filtration and washing with hexanes gave a white solid 6 (10.0 g, 85% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7](B(O)O)[CH:8]=1)=[O:2].[CH3:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21](Br)=[CH:20][C:18]=2[N:19]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.C1(C)C=CC=CC=1>[CH3:13][O:12][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][C:7]=1[C:21]1[CH:22]=[CH:23][C:17]2[O:16][C:15]([CH3:14])=[N:19][C:18]=2[CH:20]=1
Reactant: Cc1nc2cc(Br)ccc2o1
Reactant: COc1ccc(C=O)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C=O)cc1-c1ccc2oc(C)nc2c1
Yield: 89.6 %

Procedure:
A solution of 5-formyl-2-methoxybenzeneboronic acid (1 g, 5.6 mmol), 2-methyl-5-bromobenzoxazole (1 g, 4.72 mmol) and K2CO3 (1.63 g, 11.8 mmol) in ethanol (20 mL) and toluene (40 mL) was degassed prior to addition of Pd(Ph3)4 (55 mg, 0.047 mmol). The mixture was refluxed for 20 hours then cooled and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, extracted with ethyl acetate, washed with water and the organic layer dried over sodium sulphate. The crude was purified by column chromatography (heptane/ethyl acetate 7/3 to 6/4) to give 1.13 g of title compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9](=[O:18])[CH2:10][N:11]1[C:15](=O)[CH2:14][C:13]([CH3:17])=[N:12]1)[CH3:7].[OH-].[Na+].[C:21](=[O:24])([O-])O.[Na+]>CN(C=O)C>[CH2:6]([O:8][C:9](=[O:18])[CH2:10][N:11]1[C:15]([Cl:3])=[C:14]([CH:21]=[O:24])[C:13]([CH3:17])=[N:12]1)[CH3:7]
Reactant: CCOC(=O)CN1N=C(C)CC1=O
Reactant: O=C([O-])O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(C)c(C=O)c1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
DMF (2.01 mL) was cooled to 0° C. and phosphorus oxychloride (5.67 mL, 60.8 mmol) was added dropwise. This reaction mixture was warmed to room temperature, and then ethyl(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)acetate (1.60 g, 8.69 mmol) was added slowly, and then the mixture was stirred at 110° C. for 3.5 hours. After the reaction was completed, the mixture was poured into ice water, a 5N aqueous solution of sodium hydroxide and sodium hydrogencarbonate were added to the mixture for neutralization. The extraction with ethyl acetate was carried out, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain filtrate, and the solvent was distilled off under reduced pressure to yield a solid, and the obtained solid was washed with n-heptane/diisopropyl ether mixture (1:1), and dried to obtain the title compound 1.28 g (5.55 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([NH2:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[CH2:22]=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([N:20]=[CH2:22])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: C=O
Reactant: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Solvent: CC#N
Product: C=NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1

Procedure:
A solution of 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (5.0 g) and 37% formaldehyde solution (1.38 ml) in acetonitrile (150 ml) was stirred for 1.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (50 g) eluting with a mixture of chloroform and methanol (50:1). The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue was recrystallized from ethanol (200 ml) to give colorless crystals of 5-chloro-3-[(4-methyleneamino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (5.1 g).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:18]2[C@@H:9]([CH2:10][CH2:11][C:12]3[C@:17]2([CH3:19])[CH2:16][CH2:15][C:14](=[O:20])[CH:13]=3)[C@H:8]2[C@@:4]([CH3:26])([C@@:5]([OH:25])([C:21](=[O:24])CO)[CH2:6][CH2:7]2)[CH2:3]1.I(O)(O)(O)(O)(O)=[O:28]>CO.O>[OH:1][C@@H:2]1[C@H:18]2[C@@H:9]([CH2:10][CH2:11][C:12]3[C@:17]2([CH3:19])[CH2:16][CH2:15][C:14](=[O:20])[CH:13]=3)[C@H:8]2[C@@:4]([CH3:26])([C@@:5]([OH:25])([C:21]([OH:28])=[O:24])[CH2:6][CH2:7]2)[CH2:3]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: [O-][I+](O)(O)(O)(O)O
Solvent: O
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)O
Yield: 81 %

Procedure:
In a 1000 mL round-bottomed flask was suspended (8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (10.4 g, 28.69 mmol) in MeOH (200 mL) and a solution of orthoperiodic acid (9.81 g, 43.04 mmol) in water (200 mL) was added to give a colorless solution. The mixture was stirred for 45 minutes after which an additional 3 g of orthoperiodic acid was added and stirring was continued for another hour. MeOH was removed in vacuo and the residual aqueous mixture was diluted with 200 ml of water. The resulting solid was isolated by filtration and was air-dried on the sinter to yield 8.1 g of the desired compound as a white solid. APCI-MS m/z: 349 [MH+].
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23](F)[CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N1C(=O)C(CO[S:47]([CH3:50])(=O)=O)=CC(C2C=CC(SC)=CC=2)=N1)C(C)C.CN1CCNCC1>>[CH2:29]([N:16]1[C:15](=[O:33])[C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[C:19]([CH3:20])[C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:47][CH3:50])=[CH:23][CH:22]=2)=[N:17]1)[CH:30]([CH3:32])[CH3:31]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CSc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Agent: CN1CCNCC1
Product: CSc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C)CC3)c2C)cc1
Yield: 68.3 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 68.3%).
Reaction SMILES: [N:1]1([CH2:14][CH2:15][C:16]([O:18]CC)=O)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1COCC1.[CH3:26][NH2:27]>O>[N:1]1([CH2:14][CH2:15][C:16]([NH:27][CH3:26])=[O:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)CCn1cnc2cnc3ccccc3c21
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)CCn1cnc2cnc3ccccc3c21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 3-(1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.70 g, 17.5 mmol), THF (5 mL), and methylamine (available as a 40% solution in water, 10 mL) was sealed in a high-pressure vessel, stirred at 100° C. overnight, and concentrated under reduced pressure to provide 4.4 g of 3-(1H-imidazo[4,5-c]quinolin-1-yl)-N-methylpropanamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][OH:14])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][O:14][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccccc1
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A solution of {1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (2) (2.5 g, 10 mmol) in dichloromethyl (125 ml) was treated with benzoic acid (1.36 g, 11 mmol), EDCI (2.14 g, 11 mmol), HOBT (1.37 g, 10 mmol) and triethylamine (1.35 ml, 11 mmol) and stirred at room temperature overnight. Reaction mixture was washed with saturated sodium bicarbonate solution and then water and dried over Na2SO4. Solvent evaporated under reduced pressure, crude purified by mplc eluting with 1% triethylamine in 2:3 v/v ethyl acetate and heptane mixture to give yellow solid (850 mg); MS: MH+ 352.