Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2=[CH:11][CH:12]=[CH:13][C:8]3=[C:9]2[N:3]([CH2:4][CH2:5][C:6](=[N:15]O)[C:7]3=[O:14])[C:2]1=[O:17]>ClCCl.CO.[B-](F)(F)(F)F.C1CC=CCCC=C1.C1CC=CCCC=C1.[Rh]>[NH2:15][C@H:6]1[C@H:7]([OH:14])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]3[NH:1][C:2](=[O:17])[N:3]([C:9]=23)[CH2:4][CH2:5]1
Reactant: O=C1C(=NO)CCn2c(=O)[nH]c3cccc1c32
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: C1=CCCC=CCC1
Solvent: ClCCl
Product: N[C@@H]1CCn2c(=O)[nH]c3cccc(c32)[C@H]1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A catalyst solution was prepared by dissolving (R,R)-(+)-2,2′-bis[(S)—(N,N-dimethylamino)(phenyl)methyl]-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene (52.6 mg; 0.05 mmol; identified above as Ligand Formula (A-1B)) and bis(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate (20.4 mg; 0.05 mmol; also known as “Rh(COD)2BF4”) in dichloromethane (1 ml) under argon, and then stirring the resulting mixture at room temperature for 10 min. In parallel, 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime (1.15 g, 5.0 mmol) was charged into a 100 mL autoclave and suspended in 40 mL of methanol. The autoclave was purged 3 times with H2 without stirring at 20 bar, and 3 times with stirring at 20 bar. Afterward, the catalyst solution, diluted with 4 ml of methanol, was charged into the autoclave. Hydrogen pressure (60 bar) was then applied, and the mixture was stirred at that pressure for 22 hr at 40° C. After cooling the mixture to room temperature and releasing the pressure, 2 g of Deloxan® THP II were added, and the resulting suspension was stirred at 55° C. for 10 min and filtered. The solvents were then removed to yield the product.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:11][CH2:12][C:13]1[O:17][CH:16]=[CH:15][CH:14]=1)[CH:8]1[O:10][CH2:9]1.C(N(CC)CC)C>CCOCC>[C:1]([O:6][CH2:9][CH:8]([OH:10])[CH2:7][O:11][CH2:12][C:13]1[O:17][CH:16]=[CH:15][CH:14]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: c1coc(COCC2CO2)c1
Reactant: C=C(C)C(=O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC(O)COCc1ccco1
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A mixture of methacrylic acid (10 g), furfuryl glycidyl ether (15 g) and triethylamine (0.3 g) was heated to 100° C. for 2 hours then to 105° C. for an additional 2 hours. GC analysis showed 96% conversion. The mixture was taken up into ether, washed with water, followed by saturated sodium bicarbonate, dried with MgSO4 filtered and rotary evaporated to provide 23.7 g of a faintly yellow oil (94.8%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[Cl:19].[CH3:20][N:21]1[C:25]([CH:26]=[O:27])=[CH:24][N:23]=[CH:22]1.[Li]CCCC.[NH4+].[Cl-]>C1COCC1>[Cl:12][C:7]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([Cl:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:26]([C:25]3[N:21]([CH3:20])[CH:22]=[N:23][CH:24]=3)[OH:27])[CH:3]=2)[N:8]=1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1-c1ccccc1
Reactant: Cn1cncc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a cloudy mixture of 6-bromo-2,4-dichloro-3-phenylquinoline (290.5 mg, 0.823 mmol, Intermediate 1: step c) and 1-methyl-1H-imidazole-5-carbaldehyde (90.6 mg, 0.823 mmol) in THF (8 mL) under nitrogen at −78° C. was added n-BuLi (1.6 M in hexane, 0.643 mL, 1.03 mmol) dropwise. The resulting solution was stirred at −78° C. for 3 hours, then was warmed to 0° C. for 15 minutes before addition of saturated aqueous NH4Cl to quench. The mixture was diluted with water and was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-6% MeOH-DCM) to afford the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[Mg].II.C(Br)C.[CH3:15][SiH:16]([CH3:18])Cl>O1CCCC1.C(OC)(C)(C)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SiH:16]([CH3:18])[CH3:15])=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cl)cc1
Reactant: C[SiH](C)Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C[SiH](C)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 69.8 %

Procedure:
About 9 kg of 1,4-dichlorobenzene (60 mol) were dissolved in 10.2 liters of tetrahydrofuran. About 1,440 g of magnesium turnings activated with iodine were introduced into a 50 liter stirred kettle. About 1.4 liters of tetrahydrofuran and 600 ml of 1,4-dichlorobenzene solution were then added, and the mixture was warmed to 50° C. The reaction was initiated by adding a few ml of ethyl bromide. The dichlorobenzene solution was added over a period of about 4 hours, the reaction temperature being kept between 60° and 63° C. When all the dichlorobenzene had been added, the reaction mixture was allowed to stand for 2.5 hours at 60° C. to complete the reaction. The reaction mixture was then cooled, diluted with 6 liters of tetrahydrofuran and transferred into a dropping funnel. The conversion was determined by weighing the unreacted magnesium. It was 88 percent by weight. Accordingly, 52.9 mol of dimethylchlorosilane in 12 liters of methyl tert-butyl ether were introduced into the 50 liter stirred kettle. The Grignard solution was added through the dropping funnel at a rate such that it was possible to keep the temperature at 30° C. with cooling. The reaction mixture was then stirred for an additional 30 minutes at room temperature. Sufficient water was added to the crystal slurry so that two homogeneous phases formed. The organic phase was separated off, and the aqueous phase was extracted once with methyl tert-butyl ether. The crude product was distilled in a water-pump vacuum. About 6,305 g of (4-chlorophenyl)dimethylsilane were obtained, which amounted to a yield of about 70 percent by weight, based on the amount of dichlorobenzene reacted.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: Nc1ccc(F)cc1
Product: O=C(Cc1cccc(O)c1)Nc1ccc(F)cc1
Yield: 88.6 %

Procedure:
The title compound was prepared as described in Example 44.A, using 3-hydroxyphenyl acetic acid (80 g, 0.52 mol) and 4-fluoroaniline (49.3 ml, 0.52 mol) to provide the title compound (113 g, 89% yield): ES−MS (m/z) 246 [M+H]+.
Reaction SMILES: [NH2:1][O:2]C1CCCCO1.[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][C:23]([CH:27]=[CH:28][C:29]([OH:31])=O)=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(O)(C(F)(F)F)=O>CN(C=O)C.CO>[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][C:23]([CH:27]=[CH:28][C:29]([NH:1][OH:2])=[O:31])=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)C=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(C=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
NH2OTHP (0.43 g, 3.67 mmol) was added to a solution of 8 (1.00 g, 3.05 mmol), PyBOP (1.69 g, 3.24 mmol), and triethylamine (1.02 ml, 7.33 mmol) in DMF (1.5 mL). The reaction mixture was stirred at room temperature for 3 h before it was quenched with water and extracted with EtOAc (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CH2Cl2:CH3OH=30:1:1% NH3(aq)) to give a white solid, which was treated with TFA (6.90 ml, 92.90 mmol) in the presence of CH3OH (140 mL). The reaction mixture was stirred overnight at room temperature. Then the mixture was concentrated under reduced pressure to give a white residue, which was recrystallized by CH3OH to afford Compound 3 (0.85 g) as a red solid. 1H NMR (500 MHz, CDCl3): δ6.42 (d, J=15.8 Hz, 1H), 6.75 (d, J=3.5 Hz, 1H), 7.49-7.54 (m, 3H), 7.59-7.62 (m, 1H), 7.61 (d, J=15.5 Hz, 1H), 7.68 (d, J=3.6 Hz, 1H), 7.72 (s, 1H), 7.93 (d, J=7.7 Hz, 2H), 7.98 (d, J=8.6 Hz, 1H). MS (EI) m/z: 327 (100%), 342 (M+, 3%). HRMS (EI) for C17H14N2O4S (M+): calcd, 342.0674. found, 342.0673.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([NH:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[S:8][CH:9]=1)[C:3]#[N:4].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].CCOCC>O>[C:25]([O:1][CH:2]([C:5]1[N:6]=[C:7]([NH:10][C:11]([O:13][CH2:14][C:15]([Cl:17])([Cl:18])[Cl:16])=[O:12])[S:8][CH:9]=1)[C:3]#[N:4])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC(O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: CC(=O)OC(C#N)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Reaction time: 1 h

Procedure:
To a solution of 1.10 g. of α-hydroxy-[2-(β,β,β-trichloroethoxycarbonyl)aminothiazol-4-yl]acetonitrile in 1 ml. of pyridine is added 2.5 ml. of acetic anhydride under ice-cooling and the mixture is stirred for 1 hour. To the mixture is added ether and water and the organic layer is washed with aq. NaHCO3 and further water in this order. Evaporation of ether gives α-acetoxy-[2-(β,β,β-trichloroethoxycarbonyl)aminothiazol-4-yl]acetonitrile. 1.3 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1=[O:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:23][C:24]1[CH:36]=[CH:35][C:27]2[CH:28]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[S:30][C:26]=2[CH:25]=1.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([S:31]([C:29]2[S:30][C:26]3[CH:25]=[C:24]([Cl:23])[CH:36]=[CH:35][C:27]=3[CH:28]=2)(=[O:33])=[O:32])[CH2:10][C:9]1=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: CC(C)(C)OC(=O)CN1CCNCC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of (2-oxo-piperazin-1-yl)acetic acid tert-butyl ester (1.22 g, 5.7 mmol) in 10 ml of methylene chloride is added triethylamine (1.2 mL, 8.55 mmol) and 6-chlorobenzothiophenesulfonyl chloride (1.52 g, 5.7 mmol). The reaction mixture is stirred overnight at ambient temperature. Flash column chromatography (50% ethyl acetate/hexane) affords 2.3 g (92%) of [4-(6-chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazine-1-yl]acetic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[C:20]([C:43]([F:46])([F:45])[F:44])=[N:21][N:22](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:23]=4)[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[C:20]([C:43]([F:45])([F:44])[F:46])=[N:21][NH:22][CH:23]=4)[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)cn1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccnc3ccc(-c4c[nH]nc4C(F)(F)F)cc23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A mixture of 210 mg 4-(6-methoxypyridin-3-yl)-6-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl) quinoline obtained in Example 1063 and 10 mL trifluoroacetic acid was stirred at room temperature for 1 hour. The trifluoroacetic acid was evaporated, and an aqueous saturated sodiumbicarbonate solution was added to the residue which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 110 mg of the title compound as a colorless solid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]1([N:11]2[C:15]([NH2:16])=[C:14]([C:17]#[N:18])[C:13]([CH2:19][CH3:20])=[N:12]2)[CH2:10][CH2:9][CH2:8][CH2:7]1>[OH-].[NH4+]>[CH:6]1([N:11]2[C:15]([NH2:16])=[C:14]([C:17]([NH2:18])=[O:2])[C:13]([CH2:19][CH3:20])=[N:12]2)[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=S(=O)(O)O
Reactant: CCc1nn(C2CCCC2)c(N)c1C#N
Agent: [NH4+]
Agent: [OH-]
Product: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To concentrated sulfuric acid (50 ml) cooled in an ice/sodium chloride bath was added in small portions 1-cyclopentyl-3-ethyl-4-cyano-5-amino-1H-pyrazole. The reaction mixture was warmed to room temperature and stirred for 24 hours. The reaction mixture was slowly added to a solution of concentrated ammonium hydroxide (150 ml) in ice-water (500 ml). A yellow precipitate formed which was collected by filtration, washed with water and dried at 90° C. for 60 hours in high vacuum to afford 3.47 g (85%) of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide, m.p. 167°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[O:13]1[C@@H:23]2[C@:14]31[C@@H:19]([CH2:20][CH2:21][CH2:22]2)[O:18][CH2:17][CH2:16][CH2:15]3.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@@H:23]2[CH2:22][CH2:21][CH2:20][C@@H:19]3[C@:14]2([OH:13])[CH2:15][CH2:16][CH2:17][O:18]3)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: C1C[C@@H]2O[C@@]23CCCO[C@@H]3C1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O[C@]12CCCO[C@@H]1CCC[C@H]2Nc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dissolved 55 uL 4-fluoroaniline in 1.3 mL CH2Cl2 then cooled to 0° C. and added 0.21 mL AlMe3 (2.0M in toluene). Warmed to RT, stirred for 30 minutes, then added 50 mg (1aS,4aR,8aS)-hexahydro-1aH,6H-oxireno[e]chromene (7-5) in 1.0 mL CH2Cl2. Stirred for two hours at RT, then sat. sodium potassium tartrate solution was added dropwise to the reaction, allowing gas evolution to cease between drops, until no further gas evolution was noted. The mixture was diluted with water, then extracted with CH2Cl2. The extract was dried over Na2SO4, filtered, concentrated, then purified on silica (0-40% EtOAc in hexanes) to yield the title compound. 1H NMR (500 MHz, CDCl3) δ=1.42-1.69 (m, 7H), 1.90-2.09 (m, 3H), 2.47 (s, 1H), 3.38-3.48 (m, 3H), 3.53 (s, broad, 1H), 3.92-3.95 (m, 1H), 6.54-6.59 (m, 2H), 6.84-7.26 (m, 2H) ppm. HRMS (ES) m/z M±H calc'd: 266.1551. found 266.1551.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=1)[CH2:6][NH2:7])[CH3:2].C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31].O>ClCCl>[Cl:14][C:13]1[C:8]([C:5](=[N:4][O:3][CH2:1][CH3:2])[CH2:6][NH:7][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=2[C:27]([F:26])([F:37])[F:38])=[N:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=1
Reactant: CCON=C(CN)c1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(C(F)(F)F)cc1Cl
Yield: 71.2 %

Procedure:
To a solution of 47 mg of 2-amino-1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanone-O-ethyloxime and 25 mg of triethylamine in 2 ml of dichloromethane, 31 mg of 2-(trifluoromethyl)benzoyl chloride was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 1 hour. After completion of the reaction, the reaction mixture was mixed with 2 ml of water and extracted with dichloromethane (2 ml×1), the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography (preparative medium pressure chromatograph: YFLC-Wprep manufactured by Yamazen Science, Inc.) using ethyl acetate-hexane (with a gradient of from 2:18 to 5:15) as the eluent to obtain 48 mg of the desired product as a colorless resinous substance.
Reaction SMILES: [OH-].[Na+].BrBr.[OH:5][C@H:6]1[CH2:11][C@H:10]([CH3:12])[CH2:9][CH2:8][C@H:7]1[C:13](=[O:15])C.[O:16](Br)[Na].[O-]S([O-])=O.[Na+].[Na+].Cl>O.O1CCOCC1>[OH:5][C@H:6]1[CH2:11][C@H:10]([CH3:12])[CH2:9][CH2:8][C@H:7]1[C:13]([OH:15])=[O:16]
Reactant: CC(=O)[C@@H]1CC[C@@H](C)C[C@@H]1O
Reactant: [Na]OBr
Agent: BrBr
Agent: Cl
Agent: O=S([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CC[C@@H](C(=O)O)[C@@H](O)C1
Temperature: 12.5 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a ice-cold solution of NaOH (4.8 g, 119.2 mmol) in water (40 mL) and 1,4-dioxane (30 mL) was added bromine (1.5 mL, 29.57 mmol). To the resultant NaoBr yellow solution was added drop wise a solution (1R, 2S, 4R)-1-(2-Hydroxy-4-methyl-cyclohexyl)-ethanone (1.4 g, 8.962 mmol) in dioxane (130 mL) and water (35 mL). The resulting solution was stirred for 3 h at 10-15° C. The excess NaOBr solution was decomposed by adding a solution of Na2SO3 (1.1 g in 11 mL water), acidified with 10% HCl, extracted with DCM. The combined organic extract was washed with brine, dried and concentrated to give (1R, 2S, 4R)-2-hydroxy-4-methyl-cyclohexanecarboxylic acid (1.30 g, 92%). NMR 1H (CDCl3, 400 MHz): 4.34 ppm (s, 1H); 2.43-2.39 ppm (m, 1H); 1.96-1.76 ppm (m, 5H); 1.14-1.08 ppm (m, 1H); 1.02-0.93 ppm (m, 1H); 0.90 ppm (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](N)[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.C(O)(=[O:26])C>[OH-].[Na+]>[NH2:1][C:2]1[N:3]=[C:4]([OH:26])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(=O)O
Reactant: Nc1nc(N)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Temperature: 25 °C
Yield: 88 %

Procedure:
A suspension of 1.0 g of 2,4-diamino-6-[2-(4-carboxyphenyl)ethenyl]pyrido[2,3-d]pyrimidine in 30 mL of 1N aqueous sodium hydroxide was heated under reflux under nitrogen for 3 hours. The resulting homogenous orange solution was cooled to room temperature, acidified with 6 mL of glacial acetic acid, and the resulting yellow precipitate collected by filtration. The filter cake was washed successively with water, methanol, acetone and ether and was then dried under reduced pressure to give 0.88 g (88%) of the title compound, which can be alternatively named as either 6-[2-(4-carboxyphenyl)ethenyl]-5-deazapterin or 6-(4-carboxystyryl)-5-deazapterin, as a microcrystalline yellow powder, mp>250° C.; NMR (TFA-d1 delta 6.8, 7.25(AB q, 2H, J=12 Hz), 7.45, 8.2(AB q, 4H, J=9 Hz), 8.55(s, 1H), 8.85(s, 1H); IR (Nujol) 3500-2500(br), 1670, 1625, 1600 cm -1.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]2[O:17][C:18]1[C:19]([CH3:28])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.[I-].[Na+]>CN(C)C=O>[N:35]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:14]=2[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]3[O:17][C:18]2[C:19]([CH3:28])=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: c1c[nH]cn1
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCCn1ccnc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
N,N-Dimethylformamide (3 ml) was added to 6-(2-chloro-ethoxy)-7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (24 mg), potassium carbonate (25 mg), imidazole (12 mg), and sodium iodide (1.8 mg), and the mixture was stirred at 75° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (9.2 mg, yield 36%).
Reaction SMILES: [C:1]([C:3]1[C:12]([F:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:14])[CH:4]=1)#[N:2].[NH2:15][OH:16]>CO>[NH2:2][C:1](=[N:15][OH:16])[C:3]1[C:12]([F:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:14])[CH:4]=1
Reactant: NO
Reactant: COC(=O)c1cc(F)c(C#N)cc1F
Solvent: CO
Product: COC(=O)c1cc(F)c(C(N)=NO)cc1F
Temperature: 25 °C
Yield: 98.6 %

Procedure:
Methyl 4-cyano-2,5-difluorobenzoate (265 mg; 1.34 mmol; 1 eq.) was dissolved in MeOH. Hydroxylamine (0.40 mL; 6.72 mmol; 5 eq.) was added and the mixture was stirred at RT. After one night, the reaction was complete and the solvents were evaporated, affording the title product as a white solid (304 mg; 98%). LC/MS (Method A): 229.0 (M−H)−; 231.0 (M+H)+. HPLC (Method A) Rt 1.08 min (Purity: 98.7%)
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[C:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:22]=2)[N:17]=1)([CH3:15])=[CH2:14]>CS(C)=O.C1COCC1>[CH3:14][C:13]1([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:22]=3)[N:17]=2)[CH2:7][CH2:15]1
Reactant: CC(C)(C)[O-]
Reactant: C=C(C)c1ccc2cc(C(=O)OC)ccc2n1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(C3(C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a stirred suspension of trimethylsulfoxonium iodide (435 mg, 2.06 mmol) in dimethylsulfoxide (3 ml) and THF (2 ml) was added potassium tert-butoxide (231 mg, 2.06 mmol) in one portion at ambient temperature. After 30 min. at the same temperature, to this (colorless solution) was added a solution of methyl 2-isopropenylquinoline-6-carboxylate (312 mg, 1.37 mmol) in THF (3 ml) at room temperature. The mixture was stirred at room temperature for 40 min then 1 hour at 60° C. The mixture was quenched with water and diluted with ethyl acetate-toluene (8:1) (90 ml). The organic solution was separated and washed with water (×2), brine, dried over sodium sulfate and concentrated in vacuo to crude product. The crude product was purified by column chromatography on silica gel (250 g) with hexane-ethyl acetate (10:1) to furnish the title compound (225 mg, 68%) as a white solid. 1H NMR (270 MHz, CDCl3) δ 0.91-0.98 (2H, m), 1.38-1.45 (2H, m), 1.64 (3H, s), 3.98 (3H, s), 7.42-7.48 (1H, m), 7.97-8.27 (3H, m), 8.50-8.55 (1H, m). MS (ESI): m/z 242.15 [M+H]+.
Reaction SMILES: Br.[C:2]([CH2:4][C:5]1[C:13]2[C:8]([N:9]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24]C)=[O:17])[CH:10]=[C:11]([F:14])[CH:12]=2)=[N:7][C:6]=1[CH3:26])#[N:3].B(Br)(Br)Br>C(Cl)Cl>[C:2]([CH2:4][C:5]1[C:13]2[C:8]([N:9]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])=[O:17])[CH:10]=[C:11]([F:14])[CH:12]=2)=[N:7][C:6]=1[CH3:26])#[N:3]
Reactant: COc1ccccc1C(=O)Cn1cc(F)cc2c(CC#N)c(C)nc1-2
Agent: Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nc2n(CC(=O)c3ccccc3O)cc(F)cc-2c1CC#N

Procedure:
A mixture of 3-cyanomethyl-5-fluoro-2-methyl-7-(2-methoxyphenacyl)pyrrolo[2,3-b]pyridine hydrobromide (25 mg, 0.06 mmol), methylene chloride (2 ml), and BBr3 in methylene chloride (1M; 0.4 ml) under argon was refluxed for 8 h. The red gum was digested in a methylene chloride aqueous sodium bicarbonate mixture. The organic phase was dried over anhydrous Na2SO4, filtered, and evaporated to give a yellow crystalline product. Yield 19 mg (98%).