Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12])([O-:7])=[O:6].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26]>CN(C=O)C>[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[NH:17][C:18](=[O:26])[CH2:19]2)=[O:12])([O-:7])=[O:6]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: O=C1Cc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C1Cc2cc(C(=O)c3cccc([N+](=O)[O-])c3)ccc2N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 3 L, 3 necked round bottomed flask equipped with a mechanical stirrer, thermocouple and was charged with AlCl3 (256 g, 1.92 mol). The solids were cooled to 0° C. with an ice-H2O bath. DMF (42 ml) was added dropwise over a period of 35 min. The temperature was stirred at 0° C. for 2 h then was warmed to room temperature. The reaction mixture was treated with 3-Nitrobenzoyl chloride (37.3 g, 0.2 mol) and the resulting slurry was heated to 41° C. Subsequently, oxindole (25 g, 0.19 mol) was added over a period of 10 min. The reaction that ensued was exothermic and caused the internal reaction temperature to rise to 60° C. The reaction was heated at 90° C. for 3.5 h. Thin layer chromatographic analysis (Hexanes/ethylacetate 1:1) indicated completion of reaction. The reaction was cooled and ice-H2O (1.5 L) was added dropwise over a period of 1.5 h. The solids were filtered, washed with saturated NaHCO3(aq) (2×300 mL), H2O (300 mL) and Methyl-t-Butyl Ether (500 mL) to yield 5-(3-Nitro-benzoyl)-1,3-dihydro-indol-2-one in quantitative yield (53.63 g, 0.19 mol).
Reaction SMILES: O.O.[I-].[Li+].[Li+].[I-].C(C[C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:13][C:12]=1[NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(O)=O.Cl>N1C(C)=CC(C)=CC=1C.C(Cl)(Cl)Cl.O>[C:16]1([C:14]2[S:13][C:12]([NH:22][C:23](=[O:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:11][CH:15]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)Cc1cc(-c2ccccc2)sc1NC(=O)c1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(Nc1ccc(-c2ccccc2)s1)c1ccccc1
Yield: 53 %

Procedure:
Lithium iodide dihydrate (25.5 g, 0.168 mole) in collidine (50 ml) under nitrogen were stirred and refluxed until the LiI dissolved. The amido-ester of Example 52 (17 g, 0.053 mole) in warm collidine (400 ml) was added and the solution stirred and refluxed for 48 hours. The cooled solution was poured into a mixture of 5N. HCl (800 ml., 4 mole) and ice, extracted with chloroform, which was washed with saturated sodium hydrogen carbonate solution, dried (NA2SO4), and evaporated to leave a semisolid. This was heated in vacuo with water to remove residual collidine, stirred with saturated sodium hydrogen carbonate solution, the solid filtered, washed with water and dried to give the title compound (7.85 g) (m.p. 202°-203° C.).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14](OCC)=[O:15])[N:6]=1.CO.O.[NH2:26][NH2:27]>C1COCC1>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]([NH:26][NH2:27])=[O:15])[N:6]=1
Reactant: NN
Reactant: CCOC(=O)c1nc(Cc2ccccc2F)n2ccccc12
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NNC(=O)c1nc(Cc2ccccc2F)n2ccccc12
Temperature: 65 °C
Reaction time: 10 h

Procedure:
150 mg (0.50 mmol) of ethyl 3-(2-fluorobenzyl)imidazo[1,5-a]pyridine-1-carboxylate from example 7A are introduced into a mixture of 1 ml of methanol and 0.5 ml of THF, and 503 mg (10.1 mmol) of hydrazine hydrate are added. The mixture is heated firstly at 65° C. for 4 h and then at 90° C. for 10 h. It is then concentrated to dryness. The resulting crude product (157 mg, quantitative) is reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:22])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1[N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CO.O>[Cl:1][C:2]1[C:3](=[O:22])[NH:4][N:5]=[CH:6][C:7]=1[N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(c1ccccc1)c1cnn(C2CCCCO2)c(=O)c1Cl
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(c1ccccc1)c1cn[nH]c(=O)c1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
A solution of 4-chloro-5-(methyl-phenyl-amino)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (272.5 mg, 0.85 mmol) in methanol (1.7 mL, 0.5M) was treated with a 6N aqueous hydrochloric acid solution (0.71 mL). The reaction solution was heated to 110° C., where it stirred for 4 h and was then allowed to completely cool down to 25° C. where it stirred overnight. After this time, the reaction was then diluted with water. The resulting solids were collected by filtration, washed with water, and dried in vacuo to afford 4-chloro-5-(methyl-phenyl-amino)-2H-pyridazin-3-one (159.2 mg, 79%) as a yellow solid that was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[O:18])=[CH:15][C:14]=2[O:28][CH3:29])=[CH:5][CH:4]=1)#[N:2].[OH-:32].[Na+].Cl.[NH2:35]O>O.C(O)C>[NH2:2][C:1](=[N:35][OH:32])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([N:19]([CH:23]([CH3:24])[CH3:25])[CH:20]([CH3:21])[CH3:22])=[O:18])=[CH:15][C:14]=2[O:28][CH3:29])=[CH:30][CH:31]=1
Reactant: NO
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCOc1ccc(C#N)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCOc1ccc(C(N)=NO)cc1

Procedure:
A stirred solution of 4-[4-(4-cyanophenoxy)butoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide (500 mg, 1.18 mmol) in 2 mL of water and 8 mL of ethanol is treated with sodium hydroxide (57.7 mg, 1.34 mmol) and hydroxylamine hydrochloride (90 mg, 1.29 mmol). After refluxing overnight, the reaction is partitioned between dichloromethane and brine. The organic phase is dried over magnesium sulfate, and concentrated in vacuo. The resulting material is purified by chromatography on silica gel (15 g) with ethyl acetate as the eluent to afford 4- [4-[4-[amino(hydroxyimino)methyl]phenoxy]butoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide as colorless crystals, mp=63°-65° C.;
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[Si](C)(C)C.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:22](=[O:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: C[Si](C)(C)c1cc2ccccc2o1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Cc1ccc(Br)cc1)c1cc2ccccc2o1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 17.4 %

Procedure:
Benzofuran-2-yl-trimethyl-silane (3.4 g, 17.86 mmol) was dissolved in methylene chloride (40 mL) and cool to −78° C. 4-Bromophenyl-acetyl chloride (19.65 mmol, 1.1 equiv.) was added at this temperature. Under vigorous stirring, a solution of TiCl4 (23 mL, 1M, 23.2 mmol, 1.3 equiv.) in CH2Cl2 was added dropwise and stirring continued for 20 min. Then the reaction was quenched with H2O (100 mL), cooling bath was removed and the mixture was allowed to warm up to room temperature. It was then diluted with H2O (100 mL) and extracted with CH2Cl2 (3×). Organic layers were combined, washed with brine, dried over MgSO4, solvent evaporated. Crude product thus obtained was subject to column purification. (silica gel, 10% EtOAC/Hexane). 980 mg of 1-Benzofuran-2-yl-2-(4-bromo-phenyl)-ethanone was obtained in 17% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1)[N:8]=[CH:7]2
Reactant: Clc1ncc2cccc(Br)c2n1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O[C@H]1CC[C@H](Nc2ncc3cccc(Br)c3n2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 8-bromo-2-chloroquinazoline (7.3 g, 30 mmol) in acetonitrile (150 mL) was added trans-4-aminocyclohexanol (6.9 g, 60 mmol) to form a suspension. DBU (9.1 g, 60 mmol) was added. The reaction mixture was stirred at 45° C. overnight. A light yellow suspension was formed. The solvent was removed under reduced pressure, and the residue was taken into DCM (100 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4 and purified by chromatography (eluting with DCM) to give the title compound as a light yellow solid (3.36 g, 35%). 1HNMR (DMSO-d6, 400 MHz): δ 9.10 (s, 1H), 8.02 (dd, J=1.2, 7.6 Hz, 1H), 7.81 (dd, J=1.2, 7.6 Hz, 1H), 7.62-7.60 (m, 1H), 7.12 (dd, J=7.6, 7.6 Hz, 1H), 4.62-4.60 (m, 1H), 3.85-3.82 (m, 1H), 2.05-2.02 (m, 2H), 1.89-1.86 (m, 2H), 1.36-1.26 (m, 4H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:15]([O:17]C)=[O:16])=[C:8]([C:11]([O:13]C)=O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+].S(=O)(=O)(O)O>CC(C)=O.C(OC(=O)C)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]3[C:15](=[O:16])[O:17][C:11](=[O:13])[C:8]=3[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2cccnc2cc1C(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: O=C1OC(=O)c2cc3ncccc3cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
A mixture of dimethyl 6,7-quinolinedicarboxylate (3.00 g, 12.2 mmol), methanol and 10% aqueous sodium hydroxide (25 mL, 62.5 mmol) is stirred overnight at room temperature, cooled, acidified to pH 4-5 with concentrated sulfuric acid, diluted with acetone and filtered. The filtrate is concentrated in vacuo to give a tan solid, which is suspended in acetic anhydride (100 mL), stirred overnight at 56° C. and cooled. The solvent is removed in vacuo to afford the title product as a tan solid (1.20 g, 49.4%) identified by 1HNMR and IR spectral analyses.
Reaction SMILES: CC[O:3][CH2:4][CH2:5][OH:6].[Cl:7][CH2:8][CH2:9][S:10](Cl)=[O:11]>CCOCC>[Cl:7][CH2:8][CH2:9][S:10]([O:6][CH2:5][CH2:4][O:3][S:10]([CH2:9][CH2:8][Cl:7])=[O:11])=[O:11]
Reactant: CCOCCO
Reactant: O=S(Cl)CCCl
Solvent: CCOCC
Product: O=S(CCCl)OCCOS(=O)CCCl
Temperature: 25 °C

Procedure:
Ethyl glycol (6.2) was added dropwise under a nitrogen atmosphere to a stirred solution of 2-chloroethanesulfinyl chloride (14.7 w), prepared as in Example I, in dry ether (40 v). During the addition period the temperature of the reaction was controlled at -20° by external cooling. Upon completion of the addition, the reaction mixture was warmed to ambient temperature and the solvent was removed by distillation in a vacuum. Examination of the residue by gas-liquid chromatography revealed more than one major component. The residue was then redissolved in dry ether (200 v) and further treated with 2-chloroethanesulfinyl chloride (14.7 w) as above. Using the same procedure as above an oily residue was obtained which after purification in a wiped film molecular still yielded a colorless liquid, 2-(chloroethanesulfinyloxy)ethyl 2-chloroethanesulfinate (8.5 w) boiling at 110-115° under reduced pressure (1 × 10-4 torr).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][O:24][NH:25][CH3:26].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([C:19](=[O:21])[N:25]([O:24][CH3:23])[CH3:26])[CH2:17][CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
A 1 L flask was charged with 25.02 g (85.9 mmol) trans-4-(benzyloxycarbonylamino-methyl)-cyclohexanecarboxylic acid, 9,21 g (94.5 mmol) O,N-dimethylhydroxyl amine HCl, 41.8 g (94.5 mmol) BOP, 750 mL methylene chloride and 75 mL diisopropylethyl amine. The reaction mixture was then stirred under nitrogen overnight. The solution was then washed with water, 5% citric acid (2×300 mL), saturated sodium bicarbonate (2×300 mL), brine (1×300 mL) and dried over Na2SO4 and concentrated to an oil. The oil was chromatographed on silica gel eluted with 50% ethyl acetate/50% hexanes to give 27.2 g of a clear oil that solidified on standing.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:4]=1)#[N:2].C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N.O1CCOCC1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([NH2:37])=[O:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH:33]([CH3:34])[CH3:35])(=[O:32])=[O:31])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2S(=O)(=O)C(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=C(C(N)=O)C(c2ccc(C#N)cc2S(=O)(=O)C(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h

Procedure:
The reaction was carried out under argon. (rac)-4-{4-Cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (1000 mg, 1.97 mmol) and HATU (3 eq., 2248 mg, 5.9 mmol) were initially charged in dry DMF (25 ml) at 0° C., and a 0.5 M solution of ammonia in dioxane (3 eq., 11.8 ml, 5.9 mmol) and DIEA (3 eq., 764 mg, 5.9 mmol) were added after brief stirring (20 min). The mixture was stirred at RT for 6 h (HPLC control) and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). The title compound was obtained as a solid (750 mg, 75% of theory).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]([O:10][C:11](=O)[CH3:12])(=O)C.C(O)(=[O:16])C>>[CH3:1][O:2][CH2:3][C:4]([O:6][C:12](=[O:16])[CH2:11][O:10][CH3:7])=[O:5]
Reactant: CC(=O)O
Reactant: COCC(=O)O
Reactant: CC(=O)OC(C)=O
Product: COCC(=O)OC(=O)COC
Yield: 71 %

Procedure:
A mixture of methoxyacetic acid (360 g, 4 mol) and acetic anhydride (409 g, 4 mol) was heated with stirring in a 2 L 3-neck flask equipped with a bubble-plate distillation column and a fraction cutter. A mixture of acetic acid and acetic acid anhydride was distilled at atmospheric pressure until the internal temperature reached 164° C. The pressure was reduced and the product was collected at 65°-71° C. at 0.2 mmHg to give 229 g (71%) of pure title compound. A total of 34.8 kg of methoxyacetic acid was processed to give 26.1 kg (83%) of the anhydride (I).
Reaction SMILES: [CH:1]1([NH:7][N:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]=[CH:12][C:11]=3[N:10]=[C:9]2[CH2:21][O:22][CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.C(Cl)(Cl)Cl.CO>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH:1]1([NH:7][N:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N+:13]([O-:33])=[CH:12][C:11]=3[N:10]=[C:9]2[CH2:21][O:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOCc1nc2cnc3ccccc3c2n1NC1CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
N-Cyclohexyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-amine (0.51 g, 1.57 mmol) was placed in a 200 mL round bottom flask, purged with N2 and dissolved in dichloromethane (25 mL). MCPBA (0.484 g, 1.96 mmol, 77% max) was added over a S min period. The reaction was stirred at room temperature under N2. After 2 h, analysis by thin layer chromatography (TLC) (SiO2, 95:5 chloroform:methanol) showed complete conversion. The solution was diluted with dichloromethane (15 mL) and 2% sodium carbonate solution (15 mL). The mixture was transferred to a separatory funnel, and the phases were separated. The organic portion was washed sequentially with 2% sodium carbonate solution (15 mL), water (15 mL) and brine (15 mL), dried (Na2SO4), filtered and then concentrated to yield 0.431 g of N-cyclohexyl-2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-amine as a tan foam.
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: O=S1(=O)CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
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: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH3:32][C:33]1[C:34](B(O)O)=[N:35][CH:36]=[CH:37][CH:38]=1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[C:33]([CH3:32])=[CH:38][CH:37]=[CH:36][N:35]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cc1cccnc1B(O)O
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cc1cccnc1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@H](F)CO2)cs1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-methylpyridin-2-yl)boronic acid gave 231. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.53 (dd, J=4.7, 1.5 Hz, 1H), 8.47 (s, 1H), 7.91-7.83 (m, 1H), 7.81 (s, 1H), 7.45 (dd, J=7.7, 4.6 Hz, 1H), 4.84 (dd, J=10.7, 3.6 Hz, 1H), 4.53-4.30 (m, 1H), 4.25-3.94 (m, 2H), 3.79 (s, 3H), 3.29-3.12 (m, 1H), 2.85 (s, 3H), 2.51 (s, 1H), 2.13-2.02 (m, 1H), 1.94-1.79 (m, 1H), 1.76-1.62 (m, 4H). LCMS (ES+) m/z 431 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:12])[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](O)([C:15](F)(F)F)=[O:14].[C:20]([O:24][C:25](=[O:31])NCC(=O)N)([CH3:23])([CH3:22])[CH3:21].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9](=[O:12])[CH2:10][NH:11][C:13](=[O:14])[CH2:15][C:25]([O:24][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC(N)=O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CC(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 72.6 %

Procedure:
Benzyl-2-aminoacetate, TFA salt (13; 1.72 g, 5.12 mmol) and carbamoylmethyl-carbamic acid tert-butyl ester (8a; 1.13 g, 6.19 mmol) were dissolved in 40 mL dichloromethane with stirring at 0° C., followed by addition of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC; 1.33 g, 7.0 mmol) and triethylamine (1.0 mL, 7.2 mmol), and the reaction was replaced under room temperature with continuous stirring for 6 h. After the reaction was completed, dichloromethane was removed by concentration under reduced pressure. The obtained solid was dissolved in ethyl acetate (50 mL), and then the organic phase was washed by H2O, 5% citric acid, H2O, saturated NaHCO3 and saturated NaCl solution separately, and dried over MgSO4 and concentrated under reduced pressure to remove ethyl acetate to obtain colorless oil-like 14 (1.15 g; 72.6%). 1H-NMR (200 MHz) (CDCl3) δ: 7.28-7.33 (m, 5H, ArH), 6.89 (br, s, 1H, CONHCH2), 5.36 (br, s, 1H, NHBOC), 5.13 (s, 2H, CO2CH2Ph), 4.04 (d, 2H, CH2CO2CH2Ph), 3.81 (d, 2H, CH2NHBOC), 1.40 [s, 9H, CO2C(CH3)3].
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([C:6]3[CH:18]=[CH:17][O:16][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H][H]>O1CCOCC1.C(O)(=O)C.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([C:6]3[CH2:18][CH2:17][O:16][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc2c1ncc1occc12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(N)ccc2c3c(cnc12)OCC3
Reaction time: 24 h
Yield: 58.5 %

Procedure:
A solution of methyl 7-aminofuro[2,3-c]quinoline-6-carboxylate (Intermediate 24, 1.13 g) in a mixture of dioxane (5 mL) and acetic acid (5 mL) was treated under an atmosphere of nitrogen with palladium hydroxide on carbon (10%, 0.1 g). The nitrogen was replaced by hydrogen and the mixture was stirred under an atmosphere of hydrogen for 24 hours. The mixture was diluted with ethyl acetate and filtered through Celite and the filtrate was washed with 1M aqueous sodium hydroxide solution, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of methanol and ethyl acetate with a gradient of 0-10%. The isolated product was triturated with a mixture of ether and cyclohexane and the solid was collected by filtration to give methyl 7-amino-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylate (0.666 g) as a yellow solid.
Reaction SMILES: [CH2:1]([P:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)[O:4]CC)[CH3:2].C(Cl)(=O)C([Cl:17])=O>C1C=CC=CC=1>[CH2:1]([P:3]([Cl:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOP(=O)(CC)c1ccccc1
Solvent: c1ccccc1
Product: CCP(=O)(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl ethylphenylphosphinate (2 g, 10 mmol) in benzene (200 mL) is added oxalyl chloride (1.3 mL, 15 mmol). The mixture is stirred for 3 hours at room temperature. The volatiles are removed on a rotary evaporater and the product is dried under vacuum for 12 hours to give ethylphenylphosphinic chloride as an oil.