Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]2=[O:13].Cl.[N:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.C(O)(=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:22]([NH:21][C:18]1[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=1)[C:6]2=[O:13]
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Reactant: NNc1ccncc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)C(=O)N(Nc1ccncc1)C2=O
Yield: 33.9 %

Procedure:
A mixture of 5-methoxyisobenzofuran-1,3-dione (33.0 g), 4-pyridinylhydrazine hydrochloride (25.7 g) and glacial acetic acid (100 ml) was heated overnight, under reflux, under nitrogen, with stirring. Water (100 ml) was added, and the mixture was evaporated and dried in vacuo. The residue was triturated with acetone, the acetone decanted, and the residue was triturated with methanol to give 16.1 g of 5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione. To a mixture of lithium aluminum hydride (6.00 g) and dry tetrahydrofuran (150 ml) at ambient temperature, under nitrogen, 5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione hydrochloride (16.1 g) was added in portions, with stirring. The reaction mixture was stirred at room temperature, under nitrogen, 4 hrs, and sodium sulfate decahydrate was added in portions. The mixture was filtered through a bed of celite, the filter cake was washed thoroughly with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel, eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane:methanol:ammomium hydroxide. The appropriate fractions were collected and concentrated. The residue was crystallized from ethanol to give 5.8 (46%) of product, mp 166-167° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([NH2:19])[N:3]=1.OO.[C:22]([O:25]C(=O)C)(=[O:24])[CH3:23]>C(O)C>[NH2:19][C:4]1[N:3]([O:25][C:22](=[O:24])[CH3:23])[C:2](=[NH:1])[N:7]=[C:6]([O:8][S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(N)nc(N)n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: OO
Solvent: CCO
Product: CC(=O)On1c(N)cc(OS(=O)(=O)c2ccc(C)cc2)nc1=N
Temperature: 60 °C

Procedure:
2.8 g (0.001 mole) of 2,6-diamino-4-tosyloxypyrimidine are added to 70 ml of absolute ethanol. 5 ml of a 70% aqueous hydrogen peroxide solution are added to the obtained suspension at 40° C., then 3 ml of acetic anhydride are added dropwise. The suspension is homogenised by heating to 60° C., and the solution gets slowly opalescent while standing. Tracing the reaction by thin layer chromatography it will be found that the reaction has completed and the aimed compound is accompanied by some diacetyl compound. By filtering the reaction mixture 0.35 g of a solid material is separated. If the ethyl alcohol is distilled off and the residue is allowed to stand in a refrigerator, no product separation can be observed. Of decanting the water and dissolving the residue in ethanol a crystalline product is obtained. In this way 1.95 g (54%) of the aimed compound are obtained.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]([OH:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1CCNc2nc(Br)ccc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CCNc2nc(Br)ccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 7-bromo-1,2,3,4-tetrahydro-1,8-naphthyridin-4-ol (intermediate 73, 420 mg, 1.83 mmol) in DMF (5 ml) and treated with imidazole (374 mg, 5.50 mmol) and tert-butylchlorodiphenylsilane (0.565 ml, 2.20 mmol) and stirred at 25° C. for 16 h. The reaction mixture was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 30:70) and reverse phase chromatography (43 g C18 cartridge, 0.1% TFA in water/acetonitrile 90:10 to 0:100) to give the title compound as a white solid. (UPLC-MS 3) tR 1.61; ESI-MS 467.2, 469.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N+](C1C=CC(S(O[CH2:25][C@H:26]2[CH2:28][C:27]2([F:30])[F:29])(=O)=O)=CC=1)([O-])=O>>[F:29][C:27]1([F:30])[CH2:28][C@@H:26]1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Product: COC(=O)c1ccc(OC[C@H]2CC2(F)F)cc1

Procedure:
Using methyl 4-hydroxybenzoate and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Example 5, the title compound was obtained. 1H NMR (300 MHz, DMSO-d6) δ 1.41-1.61 (1H, m), 1.66-1.84 (1H, m), 2.13-2.38 (1H, m), 3.81 (3H, s), 3.99-4.14 (1H, m), 4.18-4.31 (1H, m), 7.00-7.15 (2H, m), 7.85-7.97 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])[CH2:15][CH2:14]2)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[C:28](Cl)(=[O:30])[CH3:29]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([NH:24][C:28](=[O:30])[CH3:29])[CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:18]2)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)ccc(F)c2n1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1cccc(CCN2CCN(c3ccc(F)c4nc(C)ccc34)CC2)c1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield according to the general procedure for the preparation of amides (Method B) starting from 3-{2-[4-(8-fluoro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline and acetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:16])[CH:10]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:26][CH:25]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a solution of ethyl 3-(4-methoxyphenyl)-3-oxopropionate (20 g, 84.6 mmol) in acetonitrile (200 ml) were added 4-trifluoromethylbenzyl bromide (20.2 g, 84.6 mmol) and potassium carbonate (23.4 g, 169 mmol) and the mixture was stirred at 60° C. for 2 hrs. The reaction solution was evaporated under reduced pressure, diluted with water (500 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) to give ethyl 3-(4-methoxyphenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (19.2 g, 56%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]1[NH:7][CH2:8][CH2:9][N:10]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:16]1([NH:22][C:23]([N:10]2[CH2:9][CH2:8][N:7]=[C:6]2[CH2:5][O:4][C:3]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:2]=2[CH3:1])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: Cc1cccc(OCC2=NCCN2C(=O)Nc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline (20.4 g; 1.0 moles) in methylene chloride (300 ml) was cooled to -65° C. and a solution of phenylisocyanate (11.9 g; 1.0 moles) in methylene chloride (300 ml) added dropwise during 30 minutes. The reaction mixture was then allowed to warm to ambient temperature and left to stand for 2 hours, when a precipitate had formed. The reaction mixture was evaporated under reduced pressure and the residue recrystallised from acetone to give 1-N-phenylcarbamoyl-2-(2,3-dimethylphenoxymethyl)-2-imidazoline, m.p. 150°-152° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][C:14]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[NH:19][C:18]2=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=[C:17]2[O:16][CH2:15]1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH3:13][C:14]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:19]2[C:2](=[O:4])[NH:24][C:20]3=[CH:21][CH:22]=[CH:23][C:17](=[C:18]23)[O:16][CH2:15]1
Reactant: CC1(c2ccccn2)COc2cccc(N)c2N1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reaction time: 1 h

Procedure:
Triphosgene (40 mg, 0.1 mmol) was added to the solution of 3-methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (90 mg, 0.4 mmol) in tetrahydrofuran (10 mL) and N,N-diisopropylethylamine (100 μL) at room temperature. The reaction was stirred for 1 h and was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as a semisolid (0.10 g. 90%). LCMS calculated for C15H14N3O2 (M+H)+: m/z=268.1. found: 268.0.
Reaction SMILES: [Cl:1]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[CH:13]([NH:15][C:16]1[S:17][CH:18]=[C:19]([C:21](=[N:27][O:28][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:20]=1)=[O:14].O>CN(C)C=O>[CH:13]([NH:15][C:16]1[S:17][C:18]([Cl:1])=[C:19]([C:21](=[N:27][O:28][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:20]=1)=[O:14]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: CCOC(=O)C(=NOC)c1csc(NC=O)n1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=NOC)c1nc(NC=O)sc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 224.7 %

Procedure:
Trichloroisocyanuric acid (6.7 g.) was added portionwise to a chilled solution of ethyl 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetate (syn isomer, 20.0 g.) in dry dimethylformamide (400 ml.) and stirred at room temperature for 2 hrs. The reaction mixture was poured into chilled water (2 l.), and the precipitates were collected by filtration, washed with water and dried to give ethyl 2-(2-formamido-5-chlorothiazol-4-yl)-2-methoxyiminoacetate (syn isomer, 18.9 g.).
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:14]=1[O:21][CH3:22])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[I-:23].[CH3:24][N+:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].C[O-].[Na+]>CO>[I-:23].[C@@H:2]1([O:1][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:31][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N+:25]=3[CH3:24])=[CH:15][C:14]=2[O:21][CH3:22])[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: COc1cc(C=O)ccc1O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: Cc1cccc[n+]1C
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C=Cc2cccc[n+]2C)ccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.5 %

Procedure:
4-formyl-2-methoxyphenyl β-D-galactopyranoside (1c)(0.12 g, 0.38 mmol), 1,2-dimethylpyridinium iodide (0.12 g, 0.51 mmol) and methanolic sodium methoxide (1M, 0.38 ml, 0.38 mmol) in methanol (10 ml) was carefully heated until the reagents had completely dissolved, after which the reaction mixture was allowed to cool to room temperature. A yellow precipitate started to separate after about 2 h. The reaction mixture was left over-night (18 h), after which the precipitate was filtered off and washed well with methanol to give (17c)(0.11 g, 54%) as a fine yellow solid, m.p. 210°-230° C. (decomp.), [α]D -14° (c 1, DMSO).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:12][Mg]Cl>O1CCCC1>[OH:3][C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([CH3:12])[CH3:2]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C#N)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-acetylbenzonitrile (3.0 g, 20.0 mmol) in tetrahydrofuran at −78° C. was added drop-wise a solution of 3.0 M methyl magnesium chloride in tetrahydrofuran (7.6, 23.0 mmol). The reaction mixture was stirred at −78° C. for 3 hours and then quenched with methanol added drop-wise. The reaction mixture was thereafter poured into water (200 ml), acidified with oxalic acid added portion-wise, and then extracted with diethyl ether (2×200 ml). The organic extracts were combined, washed with water (1×40 ml), brine (1×40 ml), dried over magnesium sulfate (MgSO4), and then concentrated to give an oil. The oil product was purified using chromatography on silica gel, eluting with ethyl acetate/hexane (1:5), to give 1.4 g of 4-(1-Hydroxy-1-methyl-ethyl)-benzonitrile as a clear oil.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][CH:14]=[C:15]([C:23]3[NH:27][N:26]=[CH:25][CH:24]=3)[CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].CS(O[CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][CH:33]([N:27]2[C:23]([C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[C:11]3[N:21]([CH:22]=[C:9]([C:8]5[N:4]([CH:2]([CH3:1])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:10]=3)[CH2:20][CH2:19][O:18]4)=[CH:24][CH:25]=[N:26]2)[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccn[nH]3)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccnn3C3CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Temperature: 100 °C
Reaction time: 60 h
Yield: 6.6 %

Procedure:
A mixture of 4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-(1H-pyrazol-5-yl)-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (1.00 g, 2.77 mmol), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (1.95 g, 6.92 mmol), and K2CO3 (1.90 g, 13.8 mmol) in CH3CN (50.0 mL) was stirred at 100° C. for 60 hr. After removal of the solvents, the residue was treated with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and evaporated to afford the crude product, which was purified by reverse phase combiflash eluting with 0-50% gradient CH3CN in 0.5% NH4HCO3 and followed by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give tert-butyl-4-(5-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (100 mg, 7% yield) as pale yellow solid. LCMS (ESI) m/z: 545.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6): δ 8.54 (d, J=10.5 Hz, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.56 (s, 1H), 7.26, (dd, J=2.5 Hz, 10.5 Hz, 1H), 7.12 (s, 1H), 6.40 (s, 1H), 5.94-5.91 (m, 1H), 4.59-4.56 (m, 4H), 4.42 (s, 1H), 4.02-3.99 (m, 2H), 2.84-2.83 (m, 2H), 1.92-1.85 (m, 4H), 1.50 (s, 6H), 1.40 (s, 9H).
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21](Br)[CH:20]=2)[CH2:13][C:12]3([CH3:28])[CH3:27])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:20]=[C:21]([NH:29][C:30]4([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]4)[CH:22]=[C:23]([F:25])[CH:24]=2)[CH2:13][C:12]3([CH3:28])[CH3:27])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1(C(=O)O)CC1
Reactant: CC1(C)CC(c2cc(F)cc(Br)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cc(F)cc(NC3(C(=O)O)CC3)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A mixture solution of 2-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (150 mg, 0.32 mmol), copper(I) iodide (20 mg, 0.1 mmol), 1-amino-cyclopropanecarboxylic acid (135 mg, 1.3 mmol) and potassium carbonate (140 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(6-cyclobutylsulfamoyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-5-fluoro-phenylamino]-cyclopropanecarboxylic acid (73.2 mg, 47.0%) as a white solid: MS (ESI) M+1=488.1.
Reaction SMILES: Cl/[C:2](=[N:8]\[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(S[C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)C=C.C(N(CC)CC)C>O1CCOCC1>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:22]2=[N:26][CH:25]=[CH:24][N:23]2[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]1
Reactant: C=CCSc1ncc[nH]1
Reactant: CCOC(=O)/C(Cl)=N/NCc1ccccc1F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(Cc2ccccc2F)c2nccn12

Procedure:
Ethyl (2Z)-chloro[(2-fluorobenzyl)hydrazono]acetate (750 mg, 2.90 mmol) from example 2A, 2-allylthio-1H-imidazole [U.S. Pat. No. 3,574,593; Chem. Abstr. 75, 49078] (1.20 g, 7.25 mmol) and triethylamine (293 mg, 2.90 mmol) are dissolved in dioxane (10 ml) and heated under reflux for 4 h. This is followed by dilution with water and extraction with ethyl acetate. The organic phase is dried over sodium sulfate, and the crude product is purified by chromatography on silica gel (eluent: dichloromethane/methanol 50:1). 410 mg (41% of theory) of the desired product are obtained with 84% purity.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH2:13][CH2:14][C:15](OC)=[O:16])=[CH:10][CH:11]=2)[N:6]([CH3:19])[C:5]1=[O:20].CC(C[AlH]CC(C)C)C.C1COCC1.CCCCCCC>C1COCC1>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:10][CH:11]=2)[N:6]([CH3:19])[C:5]1=[O:20]
Reactant: COC(=O)CCc1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCO)nc21
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 37-1 (0.45 g, 1.40 mmol) in THF (8 mL) chilled to −78° C. was added DIBAL 1.0M in THF heptane (4.22 mL, 4.22 mmol) dropwise. The resulting mixture was stirred at −78° C. for 3 hr, then quench with slow addition of Rochelle's salt solution (3 mL). The resulting mixture was allowed to warm to room temperature, diluted with water and extracted with ethyl acetate. The organic phase was concentrated and flash column separation using a 20-100% ethyl acetate/hexane gradient gave 37-2. (0.22 g, 55%). LRMS (ES) (M+H)+: observed=278.1, calculated=278.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[OH:12])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([CH3:23])[N:17]=1>[OH-].[Na+].O.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[OH:12])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[O:8][C:20]1[N:21]=[C:16]([Cl:15])[N:17]=[C:18]([CH3:23])[N:19]=1
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: COc1cc(C(C)(C)O)cc(Br)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)(C)O)cc(Br)c1Oc1nc(C)nc(Cl)n1
Reaction time: 1 h

Procedure:
3-bromo-4-hydroxy-5-methoxy-a,a-dimethylbenzenemethanol (1.16 g) was dissolved in 10% NaOH (1.78 g) and 5 mL of water. The solvent was stripped under reduced pressure. The salt was taken up in 50 mL acetonitrile and cooled to 0°-5° C. 2,4-dichloro-6-methyl-1,3,5-triazine (0.61 g) was added and the mixture was stirred at 0°-5° C. for 1 hour. The solvent was removed under reduced pressure and the residue was extracted with methylene chloride. The extracts were combined and stripped under reduced pressure to yield 3-bromo-4-[[4-chloro-6-methyl-1,3,5-triazin-2-yl]oxy]-5-methoxy-a,a-dimethylbenzenemethanol.
Reaction SMILES: C=O.[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([N:9]=[CH:10][C:11]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C:26]4[CH:27]=[CH:28][C:29]5[S:34][CH2:33][C:32](=[O:35])[NH:31][C:30]=5[CH:36]=4)[CH2:20][CH2:19]3)=[N:12]2)=[CH:7][CH:6]=1.[C:37](O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl.CO>[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([N:9]=[CH:10][C:11]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([N:24]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]5[S:34][CH2:33][C:32](=[O:35])[NH:31][C:30]=5[CH:36]=4)[CH3:37])[CH2:20][CH2:19]3)=[N:12]2)=[CH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: COc1ccc2ncc(OCCN3CCC(NCc4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: COc1ccc2ncc(OCCN3CCC(N(C)Cc4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 22.3 %

Procedure:
Paraformaldehyde (29 mg, 0.10 mmol, 1.0 eq) is added at room temperature to a stirred solution of 6-({1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamino}-methyl)-4H-benzo[1,4]thiazin-3-one (50 mg, 0.10 mmol, 1.0 eq) in 1,2-dichloroethane (2 mL) and methanol (0.5 mL), followed by acetic acid (7 μL, 0.12 mmol, 1.3 eq) and sodium cyanoborohydride (9 mg, 0.12 mmol, 1.3 eq). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×5 mL) and a saturated sodium hydrogen carbonate aqueous solution (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-[({1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-methyl-amino)-methyl]-4H-benzo[1,4]thiazin-3-one as a light brown viscous oil (11 mg, 21% yield).
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH2:14](Cl)Cl.CO.[Si](C=[N+]=[N-])(C)(C)C>CCCCCC.[OH-].[Na+].C(Cl)Cl>[CH3:14][O:10][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:13][CH:12]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred suspension of 4-sulfamoyl-benzoic acid (25.0 g, 0.124 mol) in 4:1 CH2Cl2/MeOH at rt was added 1.0 M TMSCHN2 in hexane (175 mL), and the reaction mixture was allowed to stir for 2 h. The mixture was diluted with 1N NaOH (100 mL) and CH2Cl2 (150 mL), and the layers were separated. The organic layer was dried over Na2SO4, then filtered, and the solvent was removed under reduced pressure to afford the desired ester (25.2 g, 95%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6): 8.14 (d, J=8.1 Hz, 2H), 7.96 (d, J=8.1 Hz, 2H), 7.58 (s, 2H), 3.90 (s, 3H).