Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([S:19][CH2:20][CH3:21])[N:17]=2)[C:12](=[O:23])[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10]1.ClC1C=CC=C(C(OO)=[O:37])C=1.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([S:19]([CH2:20][CH3:21])=[O:37])[N:17]=2)[C:12](=[O:23])[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(SCC)c(F)cc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(S(=O)CC)c(F)cc2c1=O
Yield: 77.9 %

Procedure:
In 10 ml of methylene chloride was dissolved 1.00 g of ethyl 1-(2,4-difluorophenyl)-7-ethylthio-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, and 580 mg of m-chloroperbenzoic acid (purity: 80%) was added thereto, after which the resulting mixture was subjected to reaction with ice-cooling for 5 hours. The precipitates were removed by filtration, and to the filtrate thus obtained was added 10 ml of water, after which the pH thereof was adjusted to 7.5 with saturated aqueous sodium hydrogencarbonate solution. The organic layer was thereafter separated, washed with 10 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: toluene-ethyl acetate (10:1 by volume)] to obtain 810 mg (yield 77.9%) of ethyl 1-(2,4-difluorophenyl)-7-ethylsulfinyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 150°-151° C. The physical properties of this compound were identical with those of the compound obtained in Example 44.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[C:6]([O:18][C:19]2[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([O:27][CH3:28])[N:20]=2)[CH:5]=[CH:4][CH:3]=1>C(O)C.C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:18][C:19]2[N:20]=[C:21]([O:27][CH3:28])[N:22]=[C:23]([O:25][CH3:26])[N:24]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COc1nc(OC)nc(Oc2cccc(Cl)c2C(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1nc(OC)nc(Oc2cccc(Cl)c2C(=O)O)n1
Yield: 83.4 %

Procedure:
A solution of 0.6 gram (0.001 mole) of phenylmethyl 6-chloro-2-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)benzoate in 50 mL of ethanol and 15 mL of acetic acid was hydrogenated in the presence of 5% palladium on charcoal using a Parr hydrogenation apparatus. Upon completion of the hydrogenation, the reaction mixture was filtered through diatomaceous earth. The diatomaceous earth filter cake was washed with tetrahydrofuran. The combined filtrate and wash was concentrated under reduced pressure to a residue. The residue was dissolved in 150 mL of methylene chloride and was washed with two 150 mL portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was stirred in 10 mL of diethyl ether containing a few drops of heptane. The resultant solid was collected by filtration and was washed with cold diethyl ether to yield 0.26 gram of 2-chloro-6-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)benzoic acid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([O:11][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[O:5]
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 89.8 %

Procedure:
To the solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester-2-ethyl ester (27) (1.8 g, 7 mmol) in dry pyridine (40 ml) was added p-toluenesulfonyl chloride (4.0 g, 21 mmol) under nitrogen at 0° C. The reaction mixture was kept refrigerated at 0° C. for 2 days. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using pet ether: EtOAc (1:1) to give 2.6 g of desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[C:6]([OH:14])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Br[C:25]1([CH3:28])[CH2:27][CH2:26]1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:12])[F:13])=[C:6]([O:14][CH2:28][CH:25]2[CH2:27][CH2:26]2)[CH:5]=1
Reactant: CC1(Br)CC1
Reactant: COC(=O)c1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 80 °C

Procedure:
3-hydroxy-4-(difluoromethoxy)-benzoic acid methyl ester (5 g, 22.9 mmol), K2CO3 (4.75 g, 34.4 mmol), NaI (0.34 g, 2.3 mmol) and bromo-methylcyclopropane (3.7 g, 27.5 mmol) were dissolved in DMF (25 ml), and the heterogeneous mixture was stirred and warmed at 80° C. for two hours. The suspension was cooled to room temperature, and water (50 ml) was added under stirring. The heterogeneous mixture was cooled to 0 to 5° C. for 60 to 90 minutes, and the solid filtered on a gooch funnel and washed with water (50 ml). An orange solid was obtained. It was dried under vacuum at room temperature. (yield 95.8%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]=[C:20]([Br:22])[CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:14]=3[NH:15][C:16]=2[CH:17]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O.CCOC(C)=O.CCCCCC>[Br:22][C:20]1[CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:14]2[NH:15][C:16]3[CH:17]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=3[C:13]=2[N:21]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(OCc3ccccc3)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(O)ccc12
Yield: 50.8 %

Procedure:
A solution of methyl 7-(benzyloxy)-2-bromo-5H-pyrido[3,2-b]indole-4-carboxylate (25 mg, 0.061 mmol) in TFA (0.5 mL) was heated at 80° C. for 20 min. The solvent was removed to leave a solid. This was suspended in a mixture of EtOAc and hexane and the solid was collected by filtration to give methyl 2-bromo-7-hydroxy-5H-pyrido[3,2-b]indole-4-carboxylate (10 mg, 0.031 mmol, 51% yield). MS (ESI) m/z 320.9 (M+H). 1H NMR (400 MHz, MeOD) δ ppm 8.03 (1H, d, J=8.56 Hz), 7.79 (1H, s), 6.99 (1H, d, J=1.76 Hz), 6.79 (1H, dd, J=8.56, 2.27 Hz), 4.00-4.07 (3H, m).
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([O:1][CH:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=3)[CH2:10][CH2:11]2)=[O:39])=[CH:33][CH:32]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(O)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(OC(=O)Cc3ccc(F)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxy-4-phenylbutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and (4-fluorophenyl)acetyl chloride: 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.34–7.19 (m, 8H) 7.11 (m, 1H), 6.98 (m, 3H), 5.75 (t, 1H, J=6.8 Hz) 3.61 (s, 2H), 2.92 (d, 2H, J=8.1 Hz), 2.48 (m, 2H) 2.31 (m, 2H), 1.99–1.84 (m, 4H), 1.84–1.67 (m, 5H) 1.55–1.35 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 531.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].I[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[N:24]=2)[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[N:24]=2)[N:21]=1
Reactant: Nc1cccc(O)c1
Reactant: CCC(=O)Nc1cn2nc(I)ccc2n1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a solution of 3-aminophenol (331 mg, 3.0 mol) in N,N-dimethylformamide (8.0 mL) was added potassium tert-butoxide (355 mg, 3.16 mmol), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)propaneamide (0.80 g, 2.53 mmol) and potassium carbonate (175 mg, 1.27 mmol), and the mixture was stirred at 140° C. for 16 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) and precipitated from hexane/ethyl acetate to give the title compound (420 mg, 56%) as a white powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]12[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=[C:12]1[C:11]1[C:6](=[CH:7][C:8]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:9]([Cl:19])[C:10]=1[Cl:18])[CH2:5]2.C(=O)(O)[O-].[Na+:29]>O>[Cl:1][CH2:2][CH2:3][C:4]12[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=[C:12]1[C:11]1[C:6](=[CH:7][C:8]([O:20][CH2:21][C:22]([O-:24])=[O:23])=[C:9]([Cl:19])[C:10]=1[Cl:18])[CH2:5]2.[Na+:29]
Reactant: O=C(O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCCl)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C([O-])COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCCl)C2

Procedure:
{[9a-(2-Chloroethyl)-5,6-dichloro-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-7-yl]oxy}acetic acid (500 mg) is dissolved by stirring and warming with 0.25N sodium bicarbonate solution (5.4 ml). The solution is diluted to 10 ml and sterilized by filtration. All the water that is used in the preparation is pyrogen-free. The concentration of the active agent in the final solution is 5%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH3:20])[CH:3]=1.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:24][CH3:23])[C:12]=2[O:19][CH3:20])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: COc1c(C=O)cccc1Oc1cc(Br)ccc1C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(Br)ccc2C#N)c1OC
Yield: 69.3 %

Procedure:
4-Bromo-2-(3-formyl-2-methoxyphenoxy)benzonitrile (0.55 g, 1.7 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (120 mg, 1.9 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (40 mL) for 17 h. The solvent was removed in vacuo. The residue was treated with. 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.20 g, 1.7 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-bromo-2-(2-methoxy-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (546 mg, 71%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25].Cl>CN(C=O)C.O>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][CH:24]=[CH2:23])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(O)c2[nH]c(=O)ccc12
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(OC(C)=O)c2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 Grams of 5-acetoxy-8-hydroxy-2(1H)-quinolinone was dissolved in 100 ml of DMF, to this solution was added 14 g of potassium carbonate and 9 ml of allyl bromide, stirred at room temperature for 8 hours. Under ice-cooling and stirring conditions, the reaction mixture was acidified by adding hydrochloric acid, this mixture was diluted by adding 200 ml of water. The mixture was extracted with 500 ml of ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate, then concentrated to dryness under reduced pressure. The residue thus obtained was recrystallized from a mixed solvent of ethyl acetate-n-hexane, there was obtained 9.8 g of 5-acetoxy-8-allyloxy-2(1H)-quinolinone as pale yellow needle-like crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH:3]=[O:4].BrBr.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][C:2]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:5])[CH:3]=[O:4]
Reactant: CC(C)C=O
Reactant: C1CCNC1
Agent: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methylpropanal (5.6 mL, 61.8 mmol) in DCM (75 mL) cooled with an ice bath was added bromine (3.2 mL, 61.8 mmol) dropwise. After 1 hr, the solution was evaporated, stirred in DCM (8 ml) at room temperature and pyrrolidine (0.94 mL, 11.26 mmol) was added. After stirring 4 h, the mixture was diluted with brine and the layers separated. The organic layer was washed with 1M HCl and then the aqueous layer was basified with KOH to pH=10-11. This was then extracted with DCM and the organic layers were combined, dried (MgSO4), filtered and concentrated to isolate 2-methyl-2-pyrrolidin-1-yl-propanal oil as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[C:7]2[C:19]3[N:18]4[CH:20]=[CH:21][N:22]=[C:17]4[C:16](=[O:23])[NH:15][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[N:3]=[CH:2]1.CN(C)C=O>[Pd].C(O)(=O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[C:19]3[N:18]4[CH:20]=[CH:21][N:22]=[C:17]4[C:16](=[O:23])[NH:15][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[N:3]=[CH:2]1
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3c[nH]cn3)c2n2ccnc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1c[nH]cn1)c1ccccc1-2
Yield: 14.4 %

Procedure:
The process is performed as in Example 3 but starting with 1.1 g of 10-(4-imidazolylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 250 ml of dimethylformamide, 5 ml of acetic acid and 0.1 g of 10% palladium-on-charcoal. After evaporation of the solvents, the crude product is purified by chromatography on a column of silica (100 g partially deactivated with 3% water), eluting with a mixture of chloroform, methanol and 28% aqueous ammonia (24/6/1 by volume). A pale yellow solid is obtained which is triturated with 20 ml of water, filtered, washed with 20 ml of ethyl ether and dried at 80° C. under vacuum (2 mmHg; 0.26 kPa) to give 0.16 g of 10-(4-imidazolylmethyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one in the form of an off-white solid melting above 260° C. (Analysis, % calculated C: 67.32, H: 4.32, N: 23.09, O: 5.27, % found C: 67.7, H: 4.2, N: 22.6).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH:24]=[CH:23][CH:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:28][CH:29]1[CH2:31][CH2:30]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH:24]=[CH:23][CH:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:28][CH:29]3[CH2:31][CH2:30]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1C1C=CCN1C(=O)c1c(Cl)cccc1-2
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1C1C=CCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 0.5 h

Procedure:
2.0 g (5.4 mmol) of tert.butyl 8-chloro-11,13a-dihydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 0.5 g (2.1 mmol) of tetraethyl orthotitanate and 25 ml of hydroxymethyl-cyclopropane are stirred at 130° for 23 hours, portions each of about 2 ml of solvent being distilled off in vacuo three times. The mixture is subsequently evaporated in vacuo, the residue is treated with water and chloroform, stirred for 30 minutes, filtered over siliceous earth and the organic phase is separated. The aqueous phase is extracted twice with chloroform, the organic extracts are washed once with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate/n-hexane, there is obtained cyclopropylmethyl 8-chloro-11,13a-dihydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 189°-190°.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:35])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][C:21]=1[Cl:34])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:36]=[O+][O-].CSC>ClCCl.CO>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:35])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:22][C:21]=1[Cl:34])[CH2:16][CH:17]=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H](Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: CSC
Solvent: ClCCl
Product: O=CC[C@@H](Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C

Procedure:
Dissolve (R)-4-Benzyl-3-[(S)-2-(3,5-dichloro-4′-fluoro-biphenyl-4-ylmethyl)-pent-4-enoyl]-oxazolidin-2-one (1.95 mmoles; 1.00 g) in dichloromethane (10 ml) and methanol (1 mL). Cool the mixture to −78° C. in a dry ice acetone bath and add ozone subsurface to the reaction with an exotherm to −71° C. The reaction turns blue, and then sweep with nitrogen to a clear color. Add dimethyl sulfide (2 mL; 27.20 mmoles) dropwise at −78° C. Warm the solution to ambient temperature and then test with KI starch paper (test is negative). Remove the solvents under vacuum, extract with MTBE, wash with pH=7 buffer, water, and brine. Concentrate the organics under vacuum to give a white non-crystalline solid (0.81 g). LCMS (M+1=515.39).
Reaction SMILES: [CH3:1][C:2]([O:6][CH2:7][CH:8]1[CH2:10][O:9]1)([CH3:5])[CH2:3][OH:4].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[CH3:1][C:2]1([CH3:5])[CH2:3][O:4][CH:8]([CH2:10][OH:9])[CH2:7][O:6]1
Reactant: CC(C)(CO)OCC1CO1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)COC(CO)CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.2 %

Procedure:
2-Methyl-2-(oxiran-2-ylmethoxy)propan-1-ol (870 mg, 5.95 mmol) and 10-CSA (207 mg, 15%) were dissolved in DCM (70 mL) and stirred at ambient temperature for 24 hr. More 10-CSA (100 mg) was added and the solution was stirred overnight. Saturated NaHCO3 solution was added. The two layers were separated and the aqueous layer was extracted twice with DCM. The organic layers were combined, dried over Na2SO4 and concentrated to give the product as a colorless oil (750 mg, 86%). 1H NMR (400 MHz, CDCl3) δ ppm 3.69-3.74 (1H, m), 3.52-3.64 (5H, m), 3.43 (1H, dd, J=11.6, 0.8 Hz), 2.57 (1H, br s), 1.32 (3H, s), 1.13 (3H, s).
Reaction SMILES: C1C2C(=CC=CC=2)[C@H](N)[C@@H]1O.[Br:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19](/[C:23](=[N:25]/[S@@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])/[CH3:24])=[N:20]2)=[CH:15][CH:14]=1.CC(C)([O-])C.[K+]>CC(O)C.C([C@@H]1NC(=O)[C@H](C)[C@H](OCC(F)(F)F)CCC=CC2=CC(=CC=C2)[C@@H](C)NC(=O)[C@H]2NN(CCC2)C(=O)[C@H](C)NC1=O)(C)C>[Br:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([C@H:23]([NH:25][S@@:26]([C:28]([CH3:29])([CH3:31])[CH3:30])=[O:27])[CH3:24])=[N:20]2)=[CH:15][CH:14]=1
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1ccc2ccc(Br)cc2n1
Agent: CC(C)(C)[O-]
Agent: CC(C)[C@@H]1NC(=O)[C@H](C)[C@H](OCC(F)(F)F)CC/C=C/c2cccc(c2)[C@@H](C)NC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](C)NC1=O
Agent: CC(C)[C@@H]1NC(=O)[C@H](C)[C@H](OCC(F)(F)F)CCC=Cc2cccc(c2)[C@@H](C)NC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](C)NC1=O
Solvent: CC(C)O
Product: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc2ccc(Br)cc2n1
Temperature: 90 °C
Yield: 63.6 %

Procedure:
A mixture of (1S,2R)-(−)-cis-1-amino-2-indanol (19 mg, 0.13 mmol), [Ru (p-cymen) Cl2]2 (39 mg, 0.064 mmol) and powdered 4 Å Molecular Sieves (0.7 g) was suspended in anhydrous 2-propanol (3 mL) and stirred under nitrogen. The suspension was heated at 90° C. for 30 minutes. The reaction mixture was cooled to 40° C. and a solution of (R)-2-methyl-propane-2-sulfinic acid [1-(7-bromo-quinolin-2-yl)-eth-(E)-ylidene]-amide (448 mg, 1.27 mmol) in 2-propanol (9 mL) was added followed by a solution of potassium tert-butoxide (36 mg, 0.32 mmol) in 2-propanol (3 mL). The reaction mixture was stirred for 2 hours at 40° C. and then allowed to cool. The mixture was poured directly onto a silica gel cartridge and eluted with ethyl acetate. After concentration the residue was further purified by silica gel chromatography using a gradient of iso-hexane/ethyl acetate 1:1 to 0:1 to give the title compound (287 mg, 64%) as a brown gum. 1H NMR (300 MHz, CDCl3) δ 1.33 (s, 9H), 1.60 (d, J=6.7 Hz, 3H), 4.80 (m, 1H), 5.42 (br d, J=4.2 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.62 (dd, J=8.5, 1.2 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.25 (s, 1H). LCMS (m/z) 354.9/356.8 [M+H], Tr 2.49 min
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[S:26]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][NH:27]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[N:3][C:2]([N:27]5[CH2:28][CH2:29][CH2:30][S:26]5(=[O:32])=[O:31])=[CH:7][N:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Reactant: O=S1(=O)CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3CCCS3(=O)=O)cn2)CC1
Yield: 66.1 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 243 and isothiazolidine 1,1-dioxide (54 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (109 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([NH:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=1.Cl.[N:23]([O-])=[O:24].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([N:18]([CH3:19])[N:23]=[O:24])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=1
Reactant: CNc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N(C)N=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.9 g. of 2,4-diamino-5-[3,5-dimethoxy-4-(methylamino)-benzyl]-pyrimidine in 40 ml. of 1N hydrochloric acid was treated dropwise with a solution of 830 mg. of sodium nitrite in 10 ml. of water with stirring and ice-cooling. The mixture was stirred for 3 hours at room temperature and then sodium carbonate was added to obtain an alkaline reaction. The precipitate was removed by filtration with suction, washed with water and recrystallized from methanol, whereby there was obtained 2,4-diamino-5-[3,5-dimethoxy-4-(methyl-nitrosoamino)-benzyl]-pyrimidine having a melting point of 249°-250° C.