Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5]C(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].C(N(CC)CC)C.C(OC)(OC)(OC)CCC.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OC)(OC)(OC)CCC.O>[NH2:15][C:14]1[N:39]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:5]([CH2:6][CH2:1][CH3:11])=[N:12][C:13]=1[C:16]#[N:17]
Reactant: N#CC(N)C#N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)CN
Agent: CCCC(OC)(OC)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCc1nc(C#N)c(N)n1CC(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Aminomalononitrile p-toluenesulfonate (744.65 g, 2.94 mol), triethylamine (297.5 g, 2.94 mol), and trimethyl orthobutyrate (436 g, 2.94 mol) were combined in toluene (7.45 L) and the solution was heated at 60° C. for 2.5 hours. Additional trimethyl orthobutyrate (21 g) was added, and the reaction was allowed to cool over a period of 30 minutes, and triethylamine (297.5 g, 2.94 mol) was added. The solution was further cooled to about 3° C. over 30 minutes, and isobutylamine (215.03 g, 2.94 mol) was added over a period of 90 minutes. During the addition, the reaction temperature rose to 10° C. The reaction was warmed to room temperature slowly and stirred overnight. Deionized water (7.35 L) and sodium carbonate (735 g) were added over a period of 15 minutes while maintaining the temperature of the mixture at 20° C. with the addition of ice. The mixture was stirred for 15 minutes, and then the precipitate was isolated by filtration, washed sequentially with toluene (300 mL) and water (3 L), air-dried, and further dried under vacuum at 70° C. for 24 hours to provide 394.4 g (65%) of 5-amino-1-(2-methylpropyl)-2-propyl-1H-imidazole-4-carbonitrile as a beige solid, mp 134.5-136.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Br:10])[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])=[CH:6][C:3]=1[CH:4]=O.[CH3:22][NH:23][NH2:24]>C1COCC1>[Br:1][C:2]1[CH:9]=[C:8]([Br:10])[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])=[CH:6][C:3]=1[CH:4]=[N:24][NH:23][CH3:22]
Reactant: O=Cc1cc(Oc2ccc([N+](=O)[O-])cc2F)c(Br)cc1Br
Reactant: CNN
Solvent: C1CCOC1
Product: CNN=Cc1cc(Oc2ccc([N+](=O)[O-])cc2F)c(Br)cc1Br
Yield: 76.5 %

Procedure:
2,4-Dibromo-5-(2-fluoro-4-nitrophenoxy)benzaldehyde (13.0 g, 31.0 mmol) is refluxed with methylhydrazine (4.3 g, 93 mmol) in THF (130 mL) for 2 hours. The reaction is quenched with water (150 mL) and extracted with MTBE (2×150 mL). The organic layer is washed with saturated sodium chloride aqueous solution (2×150 mL), dried with anhydrous sodium sulfate, and concentrated to obtain a solid. The crude solid is recrystallized in EtOAc/hexane to obtain 1-(2,4-dibromo-5-(2-fluoro-4-nitrophenoxy)benzylidene)-2-methylhydrazine as a yellow solid (10.6 g, 76.7% yield). MS (m/z): 447.9 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[CH:5][CH:4]=[N:3]1.[Cl:13]Cl>C(O)(=O)C>[ClH:13].[Cl:13][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[NH:7][C:8]1[NH:9][CH2:10][CH2:11][N:12]=1
Reactant: ClCl
Reactant: Cn1nccc1NC1=NCCN1
Solvent: CC(=O)O
Product: Cl
Product: Cn1ncc(Cl)c1NC1=NCCN1

Procedure:
2(1-Methyl-5-pyrazolyl) amino-2-imidazoline (15.74 g.) was treated with 2.60 g. chlorine gas in 30 ml. acetic acid, while cooling in ice, by the method of Example VII to give 6.34 g. mp 254°-257°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:9]=2[C:10]#[N:11])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[N:27]=[C:28]=[O:29]>>[Cl:16][C:12]1[CH:13]=[CH:14][N:15]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28]([NH:27][C:20]3[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=3[O:18][CH3:17])=[O:29])=[CH:7][CH:6]=2)[C:9]=1[C:10]#[N:11]
Reactant: N#Cc1c(Cl)ccnc1-c1ccc(N)cc1
Reactant: COc1ccc(N=C=O)c(OC)c1
Product: COc1ccc(NC(=O)Nc2ccc(-c3nccc(Cl)c3C#N)cc2)c(OC)c1

Procedure:
2-(4-Aminophenyl)-4-chloronicotinonitrile is reacted with 2,4-dimethoxyphenyl isocyanate under conditions similar to those described in Example 27. 1-[4-(4-Chloro-3-cyanopyrid-2-yl)phenyl]-3-(2,4-dimethoxyphenyl)urea is obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH:19]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20]2)=[O:17])[C:5]2[O:10][CH:9]([CH2:11][CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[CH:15]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH+:18]([O-:35])[CH:19]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20]2)=[O:17])[C:5]2[O:10][CH:9]([CH2:11][CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: CCC1Oc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc2N(C)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCC1Oc2c(C(=O)[NH+]([O-])C3CN4CCC3CC4)cc(Cl)cc2N(C)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 2.6 g of 6-chloro-2-ethyl-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide in 100 ml of chloroform is added portionwise 1.9 g of metachloroperbenzoic acid under cooling and stirring. After 0.5 hour, ammonia gas is bubbled through the reaction solution under stirring and the precipitate is filtered off. The mother liquor is distilled off under reduced pressure followed by recrystallizing the residue from ethanol-isopropyl ether to give 6-chloro-2-ethyl-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4- benzoxazine-8-carboxamide N-oxide.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].[C:11](#[N:14])[CH:12]=[CH2:13].Cl>CCOCC>[C:11]([CH2:12][CH2:13][C:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)#[N:14]
Reactant: C=CC#N
Reactant: O=CC1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: N#CCCC1(C=O)CCCCC1
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a stirred solution of cyclohexanecarboxaldehyde (100 g.; 0.89 mole) and 50% potassium hydroxide solution (10.2 g.) is added, dropwise, acrylonitrile (50.4 g.; 0.95 mole) over the course of one hour, maintaining the reaction temperature between 50°-60° C. by occasional cooling. After all has been added, the mixture is stirred for an additional one hour until the exotherm ceases and then heated to 50°-60° C. for 30 minutes. The product is acidified with dilute hydrochloric acid, taken up into ether, washed with water, dried (MgSO4) and distilled to afford 38% of colorless 1-(2-cyanoethyl)-1-formylcyclohexane (55.4 g.), b.p. 142°-146° C./5 mm.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2.C(N(CC)CC)C.ClCCl>CN(C)C=O>[OH:19][C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc2c(O)c(N)cnc2c1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCC(=O)Nc1cnc2cc(OC)ccc2c1O
Temperature: 25 °C
Yield: 62.8 %

Procedure:
Butyryl chloride (0.63 mL, 6.1 mmol) was added dropwise to a solution containing 3-amino-7-methoxyquinolin-4-ol hydrochloride (1.0 g, 5.26 mmol), triethylamine (2.35 mL, 16.8 mmol), dichloromethane (30 mL) and N,N-dimethylformamide (10 mL). The reaction mixture was maintained at ambient temperature overnight. The N,N-dimethylformamide was removed under vacuum and the resulting solid was partitioned between dichloromethane (100 mL) and water (100 mL). The organic fraction was washed with water, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide 0.86 g of N-(4-hydroxy-7-methoxyquinolin-3-yl)butanamide as a tan solid.
Reaction SMILES: C1[CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.C([Li])CCC.C([C:22]1[C:30]2[C:29]([NH:31][NH2:32])=[N:28][CH:27]=[N:26][C:25]=2[N:24]([C@@H:33]2[O:39][C@H:38]([CH2:40][OH:41])[C@@H:36]([OH:37])[C@@:34]2([CH3:42])[OH:35])[CH:23]=1)=O>C(Cl)(Cl)Cl.O>[NH:31]([C:29]1[C:30]2[C:22]([CH:2]=[CH:3][O:4][CH3:5])=[CH:23][N:24]([C@@H:33]3[O:39][C@H:38]([CH2:40][OH:41])[C@@H:36]([OH:37])[C@@:34]3([CH3:42])[OH:35])[C:25]=2[N:26]=[CH:27][N:28]=1)[NH2:32]
Reactant: C1CCOC1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(C=O)c2c(NN)ncnc21
Agent: [Li]CCCC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC=Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@]2(C)O)c2ncnc(NN)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of THF at 0° C., diisopropyl ethyl amine (10 eq.), and n-butyl-lithium (10 eq.), is (Ph3P)ClCH2OCH3 (10 eq.). After stirring this mixture at room temperature for 1.5 hours, one cools to −78° C. and adds the compound from Step 2. After stirring at −78 C overnight one warms to room temperature, separates the reaction mixture between water and chloroform, extracts the aqueous layer two more times with chloroform, and combines the organic layers. They are dried over sodium sulfate, evaporated and purified via column chromatography to give the target compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[NH2:11][C:12]1[C:17]([O:18][C:19](=[S:23])[N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=[CH:14][N:13]=1.[CH:24]([O-])([O-])OCC>>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[C:5](=[CH:24][NH:11][C:12]2[C:17]([O:18][C:19](=[S:23])[N:20]([CH3:21])[CH3:22])=[CH:16][CH:15]=[CH:14][N:13]=2)[C:4](=[O:9])[O:3]1
Reactant: CCOC([O-])[O-]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CN(C)C(=S)Oc1cccnc1N
Product: CN(C)C(=S)Oc1cccnc1NC=C1C(=O)OC(C)(C)OC1=O

Procedure:
A mixture of 6.0 g of 2,2-dimethyl-1,3-dioxane-4,6dione and 30 ml of ethyl orthoformate is refluxed on an oil bath for 2 hours, mixed with 8.0 g of 2-amino-3-dimethylthiocarbamoyloxypyridine and again refluxed for 2 hours under stirring. After cooling, the precipitated crystal is filtered and washed with ether to give 6.4 g of 2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidenemethyl)amino-3-dimethylthiocarbamoyloxypyridine. The product is recrystallized from ethyl acetate.
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][C:5]1[CH:35]=[CH:34][C:8]([O:9][CH:10]2[CH2:13][N:12]([C:14]([CH3:33])([CH3:32])[CH2:15][CH2:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]#[N:19])[CH2:11]2)=[CH:7][CH:6]=1>CC(O)(CC)CC>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]2[CH2:11][N:12]([C:14]([CH3:32])([CH3:33])[CH2:15][CH2:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:18]([NH2:19])=[O:1])[CH2:13]2)=[CH:34][CH:35]=1
Reactant: COc1ccc(OC2CN(C(C)(C)CCC(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Reactant: [OH-]
Agent: CCC(C)(O)CC
Agent: [K+]
Product: COc1ccc(OC2CN(C(C)(C)CCC(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
Potassium hydroxide (135 mg, 2.41 mmol) was added to a solution of the product of example 105(53 mg, 0.12 mmol) in 3-methyl-3-pentanol (5 mL) and the mixture was heated under reflux for 18 hours. The reaction mixture was then cooled to room temperature, concentrated in vacuo and the residue was partitioned between ethyl acetate (20 mL) and water (5 mL). The aqueous layer was separated, extracted with ethyl acetate (2×20 mL) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo to give a colourless oil in 96% yield, 53 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:12][CH:13]([CH3:15])[CH3:14])[O:10][CH3:11].C([Li])CCC.[CH3:21][Si:22](Cl)([CH3:24])[CH3:23].[CH3:26][Si:27]([CH3:53])([CH3:52])[O:28][CH:29]1[CH:34]([O:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:33]([O:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:32]([CH2:45][O:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[O:31][C:30]1=[O:51]>CCCCCC.C(N(CC)CC)C>[CH3:21][Si:22]([CH3:24])([CH3:23])[O:51][C:30]1([C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=2[CH:9]([O:12][CH:13]([CH3:15])[CH3:14])[O:10][CH3:11])[CH:29]([O:28][Si:27]([CH3:26])([CH3:52])[CH3:53])[CH:34]([O:35][Si:36]([CH3:37])([CH3:38])[CH3:39])[CH:33]([O:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:32]([CH2:45][O:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[O:31]1
Reactant: COC(OC(C)C)c1ccc(Br)cc1Br
Reactant: C[Si](C)(C)Cl
Reactant: C[Si](C)(C)OCC1OC(=O)C(O[Si](C)(C)C)C(O[Si](C)(C)C)C1O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(OC(C)C)c1ccc(Br)cc1C1(O[Si](C)(C)C)OC(CO[Si](C)(C)C)C(O[Si](C)(C)C)C(O[Si](C)(C)C)C1O[Si](C)(C)C

Procedure:
According to the procedure of Example 1, Step 3, 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene was treated with n-butyllithium in hexane, 3,4,5-tris(trimethylsilyloxy)-6-trimethylsilyloxymethyl-tetrahydropyran-2-one, triethylamine, and trimethylsilyl chloride. The reaction mixture was subjected to workup procedure, and the resulting residue was purified by HPLC (column; Inertsil ODS-3, 20 mm I.D.×250 mm; acetonitrile, 30 mL/min) to give the titled compound as two isolated diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C[N:14](C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl>[F:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([NH2:14])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)/C=C/c1ccc(F)cc1
Reaction time: 3 h

Procedure:
4-fluorocinnamic acid (25 g) was suspended in dichloromethane (300 ml); under ice cooling and stirring, DMF (0.5 ml) and then oxalyl chloride (15.36 ml) were added drop by drop; the same temperature was kept for 3 hours and gradually returned to room temperature. Under reduced pressure, the solvent was distilled off; the residue was dissolved in ethyl acetate (100 ml). This solution was added drop by drop to an ice-cooled mixed solution of 25% aqueous ammonia (250 ml) and ethyl acetate (52.5 ml). The reaction mixture was extracted with ethyl acetate (400 ml×2) and washed with saturated saline, after which it was dried over anhydrous magnesium sulfate. Under reduced pressure, the solvent was distilled off; the precipitated crystal was collected by filtration and dried to yield (E)-3-(4-fluorophenyl)-2-propenamide (24.4 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[N:10]([CH2:19][CH:20]=O)[C:9](=[O:22])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][N:34]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO.C(O)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[N:10]([CH2:19][CH2:20][N:45]3[CH2:46][CH2:47][CH:42]([N:34]([CH2:33][C:31]4[CH:30]=[CH:29][C:28]5[O:23][CH2:24][CH2:25][O:26][C:27]=5[CH:32]=4)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:38])[CH3:39])[CH2:43][CH2:44]3)[C:9](=[O:22])[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: COc1ccc2c(C(=O)NC3CC3)cc(=O)n(CC=O)c2c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2c(C(=O)NC3CC3)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
To 1.0 mL of methanol solution containing 0.13 g of N-cyclopropyl-7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxamide, 0.16 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 25 μL of acetic acid were added at room temperature and stirred at the same temperature for 1.5 hours. To the reaction mixture, 42 mg of sodium cyanoborohydride was added and stirred at the same temperature for 2 hours. Further, 42 mg of sodium cyanoborohydride was added and stirred at the same temperature for 2 hours and 15 min. 76 μL of acetic acid was added and stirred at the same temperature for 2 hours. To the mixture, aqueous saturated sodium hydrogen carbonate solution was added under ice-cooling to be adjusted to pH 8.7, 5.0 mL of methanol and 15 mL of chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [gradient elution of chloroform:methanol=100:0-70:30], to give 0.13 g of tert-butyl (1-(2-(4-((cyclopropylamino)carbonyl)-7-methoxy-2-oxoquinolin-1-(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate as a white foam.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[C:10](O)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[C:10]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCCC(CC)CO
Reactant: O=C(O)c1ccccc1
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CCCCC(CC)COC(=O)c1ccccc1

Procedure:
Using a method similar to the procedure carried out in Example 1, 12 mol of 2-ethylhexanol were reacted with 8 mol of benzoic acid and tetrabutyl titanate. Distillation gave 2-ethylhexyl benzoate with purity of 99.7% determined by gas chromatography.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[C:16]([NH2:22])[N:15]=2)=[N:6]1.Cl[C:28]([O:30][CH3:31])=[O:29]>C(O)(C)C>[NH2:22][C:16]1[C:17]([NH:21][C:28](=[O:29])[O:30][CH3:31])=[C:18]([NH2:20])[N:19]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])[N:6]=2)[N:15]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N
Reactant: COC(=O)Cl
Solvent: CC(C)O
Product: COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 35 °C
Yield: 90.8 %

Procedure:
In a reaction vessel, 1.50 kg of the compound of the formula (VI) were initially charged in 14.25 l of isopropanol, and the mixture was heated with stirring to 35° C. 531 g of methyl chloroformate were, at a steady rate, metered in over a period of 30 min, rinsing with 750 ml of isopropanol, and the mixture was stirred at 35° C. for 16 h. The mixture was then heated to 50° C. and 3.85 l of methanol and 606 g of triethylamine were metered in with stirring at 50° C., rinsing with 450 ml of methanol. The mixture was then stirred at 50° C. for 1 h, cooled to RT and stirred at RT for 1 h. The suspended solid was filtered off with suction, washed twice with in each case 3.0 l of isopropanol/methanol (4:1) and once with 3.0 l of isopropanol and sucked dry. The moist product was dried at 50° C. for 1 h and then at 100° C. for 22 h in a vacuum drying cabinet. The weight of the product obtained was 1.793 kg or 103.3% of theory. The product of the formula (VI) contained 6.45% of isopropanol virtually unremovable by drying (partially, an isopropanol solvate was present), and the analytical content was 87.9% by weight (HPLC). Based on this content, the yield was 90.8% of theory.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4].[C:42]1([CH3:52])[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1.C(N(CC)CC)C.O>C1COCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][S:48]([C:45]3[CH:46]=[CH:47][C:42]([CH3:52])=[CH:43][CH:44]=3)(=[O:50])=[O:49])[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:36])[CH3:37])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCO)c2)c2cccnc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCOS(=O)(=O)c3ccc(C)cc3)c2)c2cccnc21
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a solution of N-[1-butyl-4-{3-(2-hydroxyethoxy)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (2.02 g, 3.63 mmol) in THF (20 ml) were added p-toluenesulfonyl chloride (0.69 g, 3.63 mmol) and triethylamine (0.40 g, 3.99 mmol), and the mixture was stirred at 40°-50° C. for 8 hours. The mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (1.40 g, 1.97 mmol).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[CH2:21]([N:23](CC)CC)C.ClC(OCC(C)C)=O.[N+](=C)=[N-]>C1COCC1.CCOCC>[NH:23]=[CH:21][C:8](=[O:10])[CH2:7][N:6]1[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:2]1=[O:1]
Reactant: CCN(CC)CC
Reactant: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Agent: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: N=CC(=O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Temperature: -10 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (144 mg, 0.535 mmol, described in Intermediate 16) in THF (5 mL) at −10° C. was added triethylamine (0.097 mL, 0.695 mmol), followed by isobutyl chloroformate (0.090 mL, 0.695 mmol) and the resulting mixture was stirred at −10° C. for 3 h. A cold solution of diazomethane (ca. 1.0 mmol) in Et2O (3 mL) was added, and stirring was continued for 16 h, allowing the mixture to warm slowly to ambient temperature. The mixture was cooled to −10° C. and a cold solution of diazomethane (ca. 1.5 mmol) in Et2O (5 mL) was added, and the resulting mixture was allowed to warm to ambient temperature and stirred for 3 h. The solvent was removed in vacuo and the residue was partitioned between Et2O (20 mL) and saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted further with Et2O (2×10 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with MeOH to give a pale solid. This solid was further purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=266 (M−N).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:4][C:3]1(OC)[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=O)=O)=[CH:7][CH:6]=1.C1(COCC(O)=O)CC1>C(OC)(C)(C)C>[CH3:1][CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11][CH3:14])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC1(c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Agent: O=C(O)COCC1CC1
Solvent: COC(C)(C)C
Product: CSc1ccc(C(=O)C(C)C)cc1

Procedure:
A solution of raw 3,3-dimethyl-2-methoxy-2-(4′-methylsulphonylphenyl)oxirane (3.6 g, 14.1 mmol) and 2-(cyclopropylmethoxy)acetic acid (2.17 g, 16.7 mmol, 1.2 equiv) in anhydrous tert-butylmethylether (10 ml) is stirred at room temperature for 2 days. The reaction mixture is then concentrated in order to supply a yellow solid (5.24 g) containing 65% p/p of [2-methyl-1-(4′-methylsulphonylphenyl)-1-oxo-prop-2-yl] 2-(cyclopropylmethyoxy)acetate. The concatenated yield from the 2-methyl-1-(4′-methylthiophenyl)propan-1-one is 46% pure/pure.