Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:14]2[CH:15]=[C:16]([C:32]([O:34]C)=[O:33])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[CH3:30])=[CH:20][C:19]3=[O:31])[CH3:13])[CH:7]=[C:8]([F:10])[CH:9]=1.C1COCC1.Cl>CO>[F:3][C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:14]2[CH:15]=[C:16]([C:32]([OH:34])=[O:33])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[CH3:30])=[CH:20][C:19]3=[O:31])[CH3:13])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COC(=O)c1cc(C(C)Nc2cc(F)cc(F)c2)c2oc(N3CCOC[C@@H]3C)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOC[C@@H]3C)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
2N NaOH (0.206 mL, 0.41 mmol) was added to a stirred suspension of methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-((S)-3-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (90 mg, 0.20 mmol) in MeOH (1 mL)/THF (1 mL) and cooled with an ice-water bath. The resulting suspension was stirred at RT for 2 hours. The reaction was incomplete thus the temperature was increased to 35° C. and stirred for an additional hour. The reaction mixture was cooled with an ice bath, the pH was adjusted to 2-3 with hydrochloric acid 1M and the volatiles were evaporated. The resulting precipitate was collected by filtration, dried, triturated with diethyl ether, collected by filtration and dried again under vacuum to give 8-(1-(3,5-difluorophenylamino)ethyl)-2-((S)-3-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (75 mg, 86%). Mass Spectrum: M+H+ 445.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:34])([F:33])[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[NH2:32].Cl>O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]2[C:25]([F:24])([F:33])[F:34])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: NC1CCCCC1C(F)(F)F
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc(NC2CCCCC2C(F)(F)F)c([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 101.3 %

Procedure:
To a solution of 0.92 g of 4-fluoro-3-nitro-benzoic acid methyl ester in 15 ml of abs. DMF was added 0.84 ml of DIPEA, followed by 0.85 g of 2-(trifluoromethyl)cyclohexylamine. After 16 h at rt, the mixture was poured into water, the pH was adjusted to 4 by the addition of 1 M aqueous hydrochloric acid, and the reaction mixture was extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over sodium sulphate and concentrated to yield 1.62 g (100%) of 3-Nitro-4-(2-trifluoromethyl-cyclohexylamino)-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][CH:32](O)[CH3:33]>O1CCCC1>[Cl:31][CH2:32][CH2:33][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Reactant: CC(O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(OCCCl)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of 2-methyl-3-nitro-phenol (3.0 g, 19.6 mmol), triphenylphosphine (7.2 g, 27.4 mmol), and chloroethanol (1.89 g, 23.5 mmol) in anhydrous tetrahydrofuran (70 mL) was slowly added a solution of diethylazidodicarboxylate (4.78 g, 27.4 mmol). After 1 h the reaction was complete and the solvent was removed and the residue dissolved in 1:1 ethyl acetate-hexanes (150 mL). After 30 min the solid triphenylphosphine oxide was filtered and the solvent again removed. The crude product was purified by chromatography (20% ethyl acetate-hexanes) to afford 4.2 g (100%) of a light yellow solid: mp 58°-59° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>N1C=CC=CC=1.[Cu-]=O>[N:1]1([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=Cc1ccc(F)cc1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1ccc(-n2cncn2)cc1

Procedure:
A mixture of 1,2,4-triazole (4.06 g, 58.7 mmol), potassium carbonate (9.05 g, 65.5 mmol), 4-fluorobenzaldehyde (6.3 ml, 58.7 mmol), and copper(I) oxide (0.26 g, 1.82 mmol) in pyridine (30 ml) is heated under nitrogen atmosphere at reflux overnight. After pyridine is distilled, the residue is diluted with chloroform, filtered, and washed with chloroform. The combined filtrate is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The crude material is purified by column chromatography on silica with hexane/ethyl acetate (1:2) to give 4-(1,2,4-triazol-1-yl)-benzaldehyde and with ethyl acetate/methanol (19:1) to give 4-(1,3,4-triazol-1-yl)-benzaldehyde.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:18]=[C:17]([O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][CH:26]([C:30]([NH:32][C:33]4[CH:34]=[C:35]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=4)[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:31])[CH2:27]3)=[CH:22][CH:21]=2)[CH:16]=[CH:15][N:14]=1.O>C(Cl)Cl>[CH:12]([C:13]1[CH:18]=[C:17]([O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][CH:26]([C:30]([NH:32][C:33]4[CH:34]=[C:35]([CH:45]=[C:46]([C:48]([F:51])([F:49])[F:50])[CH:47]=4)[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:31])[CH2:27]3)=[CH:22][CH:21]=2)[CH:16]=[CH:15][N:14]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(CO)c4)cc3C2)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(C=O)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution of oxalyl chloride (0.086 mL, 1.02 mmol) in DCM (4 mL) at −78° C., was added a solution of DMSO (0.109 mL, 1.53 mmol) in DCM (1 mL) dropwise. The reaction mixture was allowed to stir at −78° C. for 30 min, and then a solution of tert-butyl [3-{[(7-{[2-(hydroxymethyl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalen-2-yl)carbonyl]amino}-5-(trifluoromethyl)benzyl]carbamate (292 mg, 0.51 mmol) in DCM (1 mL) was added dropwise. After 45 min. the reaction was incomplete. In a separate flask, oxalyl chloride (0.086 mL, 1.02 mmol) and DCM (4 mL) were cooled to −78° C., and a solution of DMSO (0.109 mL, 1.53 mmol) in DCM (1.00 mL) was added dropwise. The solution was stirred at −78° C. for 15 min, and then transferred via cannula to the reaction mixture and allowed to stir for 1 h. TEA (0.712 mL, 5.11 mmol) was added and the mixture was allowed to warm to rt. Water was added and the layers were separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated to give tert-butyl [3-[({7-[(2-formylpyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)amino]-5-(trifluoromethyl)benzyl]carbamate (285 mg, 97.9%). LCMS: (FA) ES+ 570.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[N:14]=1>O>[O:23]([C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:9]([C:6]3[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:11])=[N:14]2)=[CH:19][CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Reactant: COc1ccc(C(=O)O)nn1
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccccc4)nc3n2)nn1
Yield: 70.6 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 6-methoxy-3-pyridazinecarboxylic acid (2.2 g), N,N'-carbonyldiimidazole (2.3 g) and 2-amino-7-phenoxy-1,8-naphthyridine (2.7 g). The product obtained by precipitation in water is purified by recrystallization in acetonitrile (300 cc). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-6-methoxy-3-pyridazinecarboxamide (3 g), m.p. 95° C., is thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([Br:17])=[C:15]([Br:18])[N:14]=[C:13]2Br)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C(Cl)Cl.C([Mg]Br)C.Cl.[CH2:28]([O:30]CC)C>CN(C)C=O>[Br:18][C:15]1[N:14]=[C:13]([CH:28]=[O:30])[N:12]([CH2:11][C:3]2[C:2]([Cl:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=2)[C:16]=1[Br:17]
Reactant: CCOCC
Reactant: Clc1cc2c(cc1Cn1c(Br)nc(Br)c1Br)OCO2
Agent: CC[Mg]Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1nc(Br)c(Br)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.33 h

Procedure:
20 g of the product obtained in Stage 1 above is introduced into 200 ml of anhydrous methylene chloride to which 500 ml of anhydrous ethyl ether is added. A 3M solution of ethyl magnesium bromide in ethyl ether is added and the whole is left under agitation for 20 minutes at ambient temperature. Then an excess (15 ml) of anhydrous dimethylformamide is added. After 2 hours at ambient temperature, hydrolysis is carried out with 200 ml of 1N hydrochloric acid followed by extraction 3 times with 300 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride then dried and evaporated to dryness. In this way 14.5 g of expected product is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=C(NC)[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].[N:26]1[CH:31]=CC=C[CH:27]=1.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:32]([N:33]([CH3:37])[C:34]([N:26]([CH3:31])[CH3:27])=[O:35])[CH:17]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: c1ccncc1
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC)c1)N2
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N(C)C(=O)N(C)C)c1)N2
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
To a solution of 3,3-dimethyl-2-(3-methylamino-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (338 mg, 1 mmol) in dichloromethane (5 mL) and pyridine (0.5 mL, 6 mmol) was added a solution of dimethylcarbamyl chloride (0.1 mL, 1.1 mmol) in dichloromethane (2 mL) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 12 h. Then the reaction mixture was extracted with dichloromethane (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-[3-(trimethyl-ureido)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (409 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C24H31N3O3 (M+H)+: 410.53, observed: 410.1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[Cl:8][C:9]([Cl:13])([Cl:12])[CH2:10]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:10][C:9]([Cl:13])([Cl:12])[Cl:8])=[O:6]
Reactant: O=C(O)CCCBr
Reactant: OCC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CCCBr)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.9 %

Procedure:
A stirred solution of 4-bromobutyric acid (3.34 g, 20.0 mmol) in toluene (50 ml) was added 2,2,2-trichloroethanol (14.94 g, 0.10 mol) and p-toluenesulfonic acid monohydrate (7.60 g, 40.0 mmol) and refluxed with a Dean-Stark trap attached for 6 h. Water was removed continuously. The reaction mixture was cooled to room temperature and concentrated in vacuo. The mixture was added CH2Cl2 (75 ml) and washed with H2O (3×25 ml). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to leave an oil. The residue was distilled to leave the title compound as a colourless oil (4.77 g, 79.9%) (bp 100° C. at 0.5 mmHg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8].[C-:16]#[N:17].[K+].ClCCl>C(O)C>[C:16]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])#[N:17]
Reactant: [C-]#N
Reactant: CCOC(=O)CNC(=O)CCCCCBr
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CNC(=O)CCCCCC#N
Yield: 99 %

Procedure:
23.73 g (84.7·10-3 mol) of N-(6-bromohexanoyl)-glycine, ethyl ester are dissolved in 200 ml of ethanol, and 6.5 g (0.1 mol) of powdered potassium cyanide are added. The reaction mixture is brought to the reflux point and stirred under reflux for 15 hours. After concentration of the mixture under reduced pressure, the residue is taken up with dichloromethane and the organic phase is washed with aqueous sodium chloride solution. The organic phase is dried and concentrated under reduced pressure to give 19 g of the expected product (yield=99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[C:10](Cl)(Cl)[CH:11]([OH:13])O.S([O-])([O-])(=O)=O.[Na+].[Na+].Cl.[NH2:24][OH:25].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:11](=[O:13])[CH:10]=[N:24][OH:25])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Nc1ccc(F)cc1
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NO)Nc1ccc(F)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a slurry of 4-fluoro-phenylamine (5 g, 45.0 mmol) in water (150 mL), was added chloral hydrate (11.28 g, 67.56 mmol), sodium sulphate (31.97 g, 225.2 mmol), hydroxylamine hydrochloride (6.21, 90.0 mmol), conc. HCl (5 mL) and the reaction mixture was heated to 85° C. It was stirred for another 2 h at the same temperature. After completion of the reaction, a solid separated out. The reaction mixture was cooled to room temperature and filtered, washed with water (2-3 times) and dried to obtain the title compound as off white solid.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:8][C:9]([CH:11]([C:14]2[C:23]([F:24])=[C:22]([F:25])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:26])[C:15]=2[F:27])[CH2:12]O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.Cl>C(Cl)Cl.O>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]([C:11]([C:14]2[C:15]([F:27])=[C:16]([F:26])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:22]([F:25])[C:23]=2[F:24])=[CH2:12])=[O:10])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1c(F)c(F)c(C(CO)C(=O)OC(c2ccccc2)c2ccccc2)c(F)c1F
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)c(F)c(C(=O)OC)c(F)c1F
Reaction time: 1 h
Yield: 98.1 %

Procedure:
In 175 ml of methylene chloride was dissolved 35.0 g of methyl 4-(1-diphenylmethoxycarbonyl-2-hydroxyethyl)-2,3,5,6-tetrafluorobenzoate. To the solution was added 7.9 g of methanesulfonyl chloride with ice-cooling. Into the mixture was dropped 16.8 g of triethylamine in 10 minutes. The resulting mixture was stirred at the same temperature for 1 hour, and 200 ml of water was added to the reaction mixture. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 33.0 g (yield: 97.9%) of methyl 4-(1-diphenylmethoxycarbonylvinyl)-2,3,5,6-tetrafluorobenzoate.
Reaction SMILES: C(OC(N1CCC(C([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[H-].[Na+].[CH2:46]([O:48][C:49](=[O:61])[C:50](Br)([CH2:56][CH:57]1[CH2:59][CH2:58]1)[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]>CN(C=O)C>[CH2:46]([O:48][C:49](=[O:61])[C:50]([CH2:56][CH:57]1[CH2:59][CH2:58]1)([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)C(Br)(CC1CC1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CC1)(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 187.2 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (100 mg, 0.307 mmol) in DMF (2 mL) was added sodium hydride (12.3 mg, 60% in oil, 0.307 mmol). The mixture was stirred at RT for 15 min, then 2-bromo-2-cyclopropylmethylmalonic acid diethyl ester (135 mg, 0.46 mmol) was added. The reaction mixture was stirred at RT for 1 h, and then at 70° C. for 6 h. The reaction was repeated with 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (400 mg, 1.23 mmol), DMF (8 mL), sodium hydride (49.2 mg, 1.23 mmol) and 2-bromo-2-cyclopropylmethylmalonic acid diethyl ester (540 mg, 1.84 mmol). The cooled reaction mixtures were combined and partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% MeOH in DCM) affording the title compound (0.309 g, 37%). LCMS (Method B): RT 3.77 min [M+H]+ 538.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.C[C:24]1[C:25]([CH2:30][NH2:31])=[N:26][CH:27]=[CH:28][CH:29]=1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:31][CH2:30][C:25]2[CH:24]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Cc1cccnc1CN
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccn2)cc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester and C-(3-methyl-pyridin-2-yl)-methylamine in DME. ES-MS m/e (%): 306 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:7]=1[CH3:14])[CH3:2].C([Mg]Cl)(C)C.C([Li])(C)(C)C.CN(C)[CH:28]=[O:29]>O1CCCC1.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH:28]=[O:29])=[CH:8][C:7]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)Nc1c(C)cc(Br)cc1C
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1c(C)cc(C=O)cc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To (4-bromo-2,6-dimethyl-phenyl)-carbamic acid ethyl ester (1t, 1.0 g) dissolved in dry tetrahydrofuran (25 mL) under argon was added isopropylmagnesium chloride (2 M in tetrahydrofuran, 1.9 mL) over 5 minutes and then stirred for 30 minutes. The reaction mixture was cooled to −78° C. and tert-butyllithium (1.7 M in heptane, 4.5 mL) was added dropwise while keeping the internal temperature below −65° C. The temperature of the reaction was raised to −10° C. after complete addition, and then cooled to −78° C. again followed by addition of N,N-dimethylformamide (0.6 mL). The reaction was stirred for 30 minutes at −78° C., 30 minutes at 25° C. and then poured onto crushed ice mixed with acetic acid (25 mL). The mixture was stirred for 30 minutes, extracted with ethyl acetate (3×100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was subjected to flash chromatography to furnish 0.60 g (73% yield) of the title compound as a white solid. LC-MS (m/z) 222 (MH+); tR=2.14, (UV, ELSD) 86%, 99%. 1H NMR (500 MHz, CDCl3): 1.30 (t, 3H), 2.34 (s, 6H), 4.21 (q, 2H), 6.28 (b, 1H), 7.59 (s, 2H), 9.92 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[CH2:14][O:13][CH2:12][CH2:11][C:9]=2[N:10]=1)[CH3:4].[F:16][C:17]1[CH:34]=[CH:33][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=O)[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]([N:2]([CH3:1])[CH:3]([C:5]3[NH:6][C:7](=[O:15])[C:8]4[CH2:14][O:13][CH2:12][CH2:11][C:9]=4[N:10]=3)[CH3:4])=[O:32])[CH2:27][CH2:28]2)=[O:22])=[CH:33][CH:34]=1
Reactant: CNC(C)c1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: CC(c1nc2c(c(=O)[nH]1)COCC2)N(C)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 24.8 %

Procedure:
The title compound (170 mg) was prepared according to the general procedure of Example 1 from 2-(1-(methylamino)ethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (320 mg, 1.5 mmol) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (450 mg, 1.7 mmol). 1H NMR (400 MHz, CDC3) δ 12.88 (br. s., 1H), 7.97 (dd, J=8.8, 5.3 Hz, 2H), 7.05-7.21 (m, 2H), 4.48-4.70 (m, 2H), 3.95 (t, J=5.5 Hz, 2H), 3.68 (d, J=12.5 Hz, 1H), 3.39 (br. s., 1H), 3.16-3.36 (m, 1H), 3.07-3.16 (m, 1H), 2.83-3.07 (m, 3H), 2.62-2.77 (m, 5H), 2.56 (t, J=9.8 Hz, 1H), 2.27-2.47 (m, 1H), 1.97-2.27 (m, 2H), 1.76-1.94 (m, 1H), 1.46-1.69 (m, 3H). HRMS calculated for C24H23FN4O4 457.2251. found (ESI, [M+H]+), 457.2257. Retention time=1.83 min.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16](O)[CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[N:14][CH:15]=1)[CH3:9].[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>ClCCl.O>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]([S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[N:14][CH:15]=1)[CH3:9]
Reactant: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(C(COc2ccc(C=O)cc2)S(=O)(=O)c2ccc(C)cc2)nc1
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
0.44 g (0.0044 mol) triethyl amine was added to a solution of 1 g (0.0036 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde and 0.7 g (0.0036 mol) tosyl chloride dissolved in 25 mL dichloromethane at 0-5° C. Reaction mixture was stirred at 0-5° C. for 4 hr. Progress of the reaction was monitored by TLC and after completion of reaction, substantial work-up in excess water yielded the desired product. Yield of the product was 1 g (70%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]2[C:23](=O)[O:22][C:20](=[O:21])[C:19]2=[CH:25][CH:26]=1>>[CH3:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:25][CH:26]=1)[C:20](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:23]2=[O:22]
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Product: CCOC(=O)C(CN1C(=O)c2ccc(C)cc2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.38 g, 40%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.60 g, 3.25 mmol) and 4-methylphthalic anhydride (0.79 g, 4.87 mmol), and the obtained product was identified with the following NMR data.