Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10](Cl)[N:9]=[C:8]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].[NH3:22]>>[NH2:22][C:10]1[N:9]=[C:8]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1cccc2c(Nc3ccccc3C)nc(Cl)nc12
Reactant: N
Product: COc1cccc2c(Nc3ccccc3C)nc(N)nc12
Yield: 31 %

Procedure:
8-Methoxy-4-(2-methylphenylamino)-2-chloroquinazoline (1.8 g, 0.006 mol) was dissolved in ethanolic ammonia and heated in a sealed vessel at 120° for 3 hours. After cooling, removal of excess solvent and chromatography (silica gel, 2% methanolic ammonia in chloroform) the 2 amino-4-(2-methylphenylamino)-8-methoxyquinazoline was isolated as crystals (0.52 g, 31%) from ethanol, m.p. 218°-220°.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.[OH:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([NH:23][CH3:24])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:24][NH:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=1[O:18][CH2:4][C@@H:2]1[CH2:3][O:1]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CNC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A mixture of (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (388.5 mg, 1.50 mmol), 2-hydroxy-N-methylbenzamide (226.5 mg, 1.50 mmol) and cesium carbonate (586 mg, 1.80 mmol) in dimethylformamide (6 mL) was kept on stirring at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulphate, Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-50% ethyl acetate in petroleum ether) to give the subtitled compound (284 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[C:32]1([CH:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39](O)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:39](=[O:40])[CH:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:2][CH2:3]1
Reactant: OCCC1CCNCC1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C(c1ccccc1)c1ccccc1)N1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
2-Piperidin-4-ylethanol (1.12 g; 8.65 mmol) was introduced into dimethylformamide (DMF, 10 ml). Then hydroxybenzotriazole (HOBT, 1.46 g, 9.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl, 1.83 g; 9.51 mmol) and diphenylacetic acid (2.02 g; 9.51 mmol) were added in this sequence. N,N-diisopropyl-ethylamine (DIEA; 1.67 ml; 9.51 mmol) was then added to the reaction mixture, which was stirred at RT for 16 h. The reaction solution was concentrated under reduced pressure. The residue was taken up in EA, and the organic solution was washed successively with saturated NaHCO3 solution, 2N HCl and saturated NaCl solution. The organic phase was separated off, dried over Na2SO4, filtered and concentrated. The 1-[4-(2-hydroxyethyl)piperidin-1-yl]-2,2-diphenylethanone (2.39 g; 8.11 mmol) obtained in this way was reacted further without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=1[F:39]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:32][C:31]=1[F:39]
Reactant: N#Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: COc1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)cc1F
Yield: 88.6 %

Procedure:
To a mixture of 2.4 g of 4-bromo-4'-cyanobiphenyl, 0.37 g of tetrakis(triphenylphosphine)palladium(0), 15.2 ml of a 2N aqueous sodium carbonate solution, and 19.4 ml of benzene, a solution which was prepared by dissolving 1.9 g of 4-methoxy-3-fluoro-benzene boronic acid synthesized in [1] above in 14.4 ml of ethanol was slowly added dropwise with stirring, and the solution was subjected to reflux for 8 hours. After the reflux was finished, the solution was cooled, and the crystals thus precipitated were separated by filtration and washed with water and methanol in turn, and dried to obtain 2.5 g of 4-methoxy-3-fluoro-4"-cyano-p-terphenyl.
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=2)[CH:9]=[N:8]1.C([O-])([O-])=O.[K+].[K+].[C:28](=S)=[S:29]>C(O)C.O>[CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:28]([SH:29])=[N:19][N:18]=3)[N:17]=2)[CH:9]=[N:8]1
Reactant: S=C=S
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(NN)nn2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(-c2ccc3nnc(S)n3n2)cn1
Temperature: 80 °C

Procedure:
To a solution of {6-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-pyridazin-3-yl}-hydrazine (490 mg, 1.6 mmol) in ethanol (6.5 mL) and water (1.8 mL) was added K2CO3 (359 mg, 2.6 mmol), followed by CS2 (0.212 mL, 3.5 mmol). The mixture was stirred and heated at 80° C. for 3 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated to 50% volume in vacuo and acidified to pH 1 with 1 N aqueous HCl. The resulting precipitate was collected, washed with water, and dried in vacuo to provide title compound as a dark red solid (quantitative yield): 1H NMR (DMSO-d6) δ 0.01 (9H, s), 0.90 (2H, t), 3.63 (2H, t), 5.56 (2H, s), 7.82 (1H, d), 8.24 (1H, d), 8.27 (1H, s), 8.80 (1H, s), 15.23 (1H, bs); MS (m/z) 349 [M+H]+.
Reaction SMILES: CC(C)(OC([NH:7][C@@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:10])=O)C.C(Cl)(Cl)[Cl:33].CO>Cl.C(O)(=O)C>[ClH:33].[NH2:7][C@@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1

Procedure:
A solution of the phenylmethyl ester product from part (a) (13.65 g., 32 mmole) in 1.5N hydrogen chloride gas in acetic acid solution (90 ml.) is stirred for 90 minutes at room temperature, and then the solvent is evaporated in vacuo. The residue is triturated in ether and the resulting white precipitate is collected to give 11.45 g. of crude product as a powdery white solid; m.p. 169°-175°. TLC (silica gel; chloroform:methanol:acetic acid, 6:1:1) Rf =0.52. One recrystallization from acetonitrile gives an analytical sample of 3-[[(S)-2-amino-1-oxo-3-phenylpropyl]amino]propanoic acid, phenylmethyl ester, hydrochloride as white needles; m.p. 170.5°-175°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH3:17][NH:18][CH3:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:18]([CH3:19])[CH3:17])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CNC
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 81 %

Procedure:
According to general procedure A, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and dimethylamine (10 mL, 33% in ethanol) were stirred in sealed tube for 16 hours. 4-Bromo-N,N-dimethyl-2-trifluoromethoxy-benzenesulfonamide (0.29 g, 81%) was provided after purification. Mp. 55-58° C. MS (ESI) m/z 348.14.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c(O)c2cccnc21
Temperature: 100 °C
Yield: 34.9 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added methanesulfonyl chloride (0.0064 g, 0.0043 mL, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 38 minutes. The reaction was diluted with ethyl acetate (40 mL), washed with 1 N hydrochloric acid, water, and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid, which was purified by chromatography on silica gel eluting with 99:1 dichloromethane:methanol to give the title compound (8.3 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.62 Hz, 6 H) 1.57 (m, 2 H) 1.70 (m, 1 H) 3.10 (s, 3 H) 4.49 (m, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.58 (dd, J=8.82, 2.57 Hz, 1 H) 7.64 (d, J=2.21 Hz, 1 H) 7.75 (d, J=8.82 Hz, 1 H) 8.56 (dd, J=8.09, 1.84 Hz, 1 H) 8.89 (dd, J=4.60, 1.65 Hz, 1 H) 10.29 (s, 1 H) 14.17 (s, 1 H). MS (ESI−) m/z 504 (M−H)−.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C1CCCCC1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH3:7]
Reactant: CC1CCCC1
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: CCCC(C)C

Procedure:
A hexanes stream, conventionally produced in petroleum refining, comprising normal hexane, isohexanes, methylcyclopentane, and cyclohexane is isomerized to produce primarily cyclohexane and to recover normal hexane by first fractionating the hexanes stream in a first fractionation step in a manner and under conditions to produce a normal hexane-isohexane rich overhead stream and a methylcyclopentane-cyclohexane rich bottoms stream, the bottoms stream is isomerized in the presence of an isomerization catalyst and under conditions sufficient to maximize the conversion of methylcyclopentane to cyclohexane, the overhead from the first fractionation step and the effluent from the isomerization step is then fractionated in at least one stage of a second fractionation step in a manner and under conditions to produce separate streams, comprising isohexanes, normal hexane, cyclohexane, and unreacted methylcyclopentane and the methylcyclopentane is recycled to the isomerization step and/or the first fractionation step. Since an original hexane stream usually contains benzene, it is preferred that the original hexane stream be hydrogenated to convert the benzene to cyclohexane prior to passing the feed to the first fractionation step.
Reaction SMILES: [C:1]([C@:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].S(OC)(O[CH3:22])(=O)=O.[OH-].[Na+].[OH-].[NH4+]>CC(C)=O>[C:1]([C@:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([O:15][CH3:22])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2]
Reactant: C#C[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: COS(=O)(=O)OC
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C#C[C@]1(C)CCc2c(C)c(OC)c(C)c(C)c2O1
Yield: 47 %

Procedure:
A solution of (S)-(+)-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol (354 mg, 1.54 mmol) in acetone (9 mL) was treated with dimethyl sulfate (0.8 mL), and 50% NaOH (1.2 mL) for 2 h at 25° C. with stirring. Ammonium hydroxide solution (1.0N, 50 mL) was added, and it was extracted with ether (3×50 mL). The extracts were combined, washed with 1.0N HCl, water, and dried over MgSO4. It was filtered and concentrated in vacuo to give 400 mg of solid, which or crystallization from ether-hexane (1:12) afforded 141 mg (47%) of (S)-(+)-2-ethynyl-3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran as white prisms: mp 94°-97° C., [α]D25 +53.86°, (C 0.4233, CHCl3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][CH:10]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([O-:27])=[O:26].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][CH:10]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=2)=[CH:30][CH:29]=1)([O-:27])=[O:26]
Reactant: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 85 °C
Yield: 75.2 %

Procedure:
Ethyl 4-(4-bromophenyl)-4-oxo-2-(2-phenylethyl)butanoate (4.32 g, 11.1 mmol) and 4-nitrophenylboronic acid (2.22, 13.3 mmol) was added to a dry flask under argon. Toluene (100 mL), dioxane (25 mL), saturated aqueous sodium carbonate (30 mL), and [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloro palladium(II) (1:1 complex with dichloromethane, 453 mg, 0.55 mmol) were added and the mixture was thoroughly degassed. The resulting mixture was then heated at 85° C. for 16 h before it was cooled to rt. Water was added and the mixture was extracted twice with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage flash 75, 5:1 ethyl acetate/hexane) to afford ethyl 4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (3.6 g, 75%). HPLC ret. time 3.99 min, 1H NMR (300 MHz, CDCl3) δ 1.29 (t, 3H), 1.85-2.08 (m, 2H), 2.71 (t, 2H), 3.05-3.20 (m, 2H), 3.45-3.52 (m, 1H), 4.20 (q, 2H), 7.18-7.31 (m, 5H), 7.72 (d, 2H), 7.78 (d, 2H), 8.05 (d, 2H), 8.33 (d, 2H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([OH:10])[CH:5]=[CH:6][CH:7]=2)[O:2]1.CN1CCOCC1.[C:18](OCC1C=CC=CC=1)(=[O:21])[C:19]#[CH:20]>C1COCC1>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][CH:6]=[C:5]3[C:4]=2[O:10][CH2:20][CH2:19][C:18]3=[O:21])[O:9]1
Reactant: Oc1cccc2c1OCO2
Reactant: C#CC(=O)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C1CCOc2c1ccc1c2OCO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-methylenedioxyphenol (27 g) and N-methyl morpholine (19.6 g) in THF (100 ml) was added benzyl propiolate (38 g) over a period of 30 minutes with cooling. After the addition was complete the reaction was stirred at room temperature for 1.5 hours followed by concentration. The residue was taken up into Et2O (500 ml), washed with 10% HCl (2×100 ml), dried over MgSO4. filtered and concentrated. This material was subjected to hydrogenation with 10%Pd/C in methanol at 4 atm. The reaction was filtered and concentrated. The resulting saturated acid was dissolved into methanesulfonic acid (350 ml) and stirred for 24 hours. The reaction was poured onto ice and extracted with CH2Cl2. The organic layer was washed with saturated Na2CO3, dried over MgSO4, filtered and concentrated to provide the desired material.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:1][C:2]1[C:3]([CH2:25][NH:26][CH3:27])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccnc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cc(OC)ccn2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (94 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 65 mg, 79%).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:33])[NH:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:20]3[N:29]=[C:30]([CH3:32])[CH:31]=[C:19]3[N:18]=2)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([O:6]C)=[O:5].[OH-].[Li+]>CO>[CH3:8][C:2]([C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:33])[NH:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:20]3[N:29]=[C:30]([CH3:32])[CH:31]=[C:19]3[N:18]=2)=[CH:13][CH:14]=1)([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(C)(C)c1ccc(C(=O)Nc2cc(-c3ccccc3)n3nc(C)cc3n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CC(=O)O)cc3)cc(-c3ccccc3)n2n1
Reaction time: 2.5 h
Yield: 34 %

Procedure:
In a 50 ml pear flask was added methyl 3-methyl-3-(4-(2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-ylcarbamoyl)phenyl)butanoate (30 mg, 0.068 mmol) in methanol (2 ml) to give a tan solution. To this mixture at room temperature, lithium hydroxide (2N solution) (2 ml, 4.0 mmol) was added. The reaction progress was carefully monitored by HPLC because hydrolysis was a significant competing side reaction. After 2.5 h, most of the starting material has been consumed. The reaction mixture was acidified to pH ˜3 with 2N HCl. The resulting suspension was partitioned between brine and ethyl acetate, and the aqueous layer was extracted one more time with ethyl acetate. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by preparatory HPLC (55-80% MeCN/H2O gradient+0.01% TFA). Lyophilization of the collected fractions gave the titled product (9.9 mg, 34% yield). 1H NMR (DMSO-d6) δ: 11.91 (s, 2H), 11.20 (s, 2H), 8.04-8.08 (m, 3H), 8.02 (d, J=8.8 Hz, 3H), 7.96 (s, 2H), 7.60-7.66 (m, 5H), 7.54 (d, J=8.8 Hz, 2H), 6.40 (s, 1H), 2.66 (s, 2H), 2.40 (s, 3H), 1.41 (s, 6H); ESI-MS: m/z 429.3 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[N:14][CH:15]=[CH:16][C:6]=2[O:5]1.[C:17]([OH:22])(=[O:21])[C:18]([OH:20])=[O:19].[CH3:23][NH:24][CH3:25]>C(O)(C)C.O>[OH2:5].[C:17]([OH:22])(=[O:21])[C:18]([OH:20])=[O:19].[CH3:23][N:24]([CH3:25])[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[N:14][CH:15]=[CH:16][C:6]=2[O:5]1
Reactant: CN1CC(CCCl)Oc2ccncc2C1=O
Reactant: CNC
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: CN(C)CCC1CN(C)C(=O)c2cnccc2O1
Reaction time: 72 h

Procedure:
A solution of 5 g (0.02 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepin-5(4H)-one, in 25 ml of dimethylamine was placed in a sealed vessel and stirred for 72 hr. The vessel was opened and the excess dimethylamine allowed to evaporate. The residue was dissolved in chloroform and the solvent was stripped off in vacuo to remove excess dimethylamine. The residue was partitioned between dilute sodium hydroxide and ethyl acetate. The ethyl acetate solution was concentrated and the residue was treated with 3 g (0.033 mole) of oxalic acid in 50 ml of isopropyl alcohol and enough water to dissolve the salt while boiling. The resulting crystals were recrystallized from the same solvent. Yield of product was 5.3 g (60%), m.p. 179°-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1>ClCCl.N1C=CC=CC=1.ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]([CH2:7][CH:8]([O:9][CH3:10])[O:11][CH3:12])[S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1ccc(F)c(Cl)c1)OC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(CN(Cc1ccc(F)c(Cl)c1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 65 %

Procedure:
147.0 g (3-Chloro-4-fluoro-benzyl)-(2,2-dimethoxy-ethyl)-amine (1, crude product) were dissolved in 540 ml of dichloromethane/pyridine (8:1). At 0° C. a solution of 145.8 g (1.04 mol) p-toluenesulfonylchloride in 200 ml of dichloromethane was added. After 5 h at room temperature additional 20 ml of pyridine, 29.16 g (0.15 mol) p-toluene-sulfonylchloride and a catalytic amount of DMAP were added. The solution was stirred at room temperature for 7 h and then refluxed for additional 4 h. Again 29.16 g (0.15 mol) p-toluene-sulfonylchloride and a catalytic amount of DMAP were added and the mixture was stirred overnight. For workup, the solution was washed twice with 2 N HCl and twice with saturated NaHCO3-solution. The organic layer was dried with MgSO4 and evaporated. Final silicagel chromatography (heptane/ethyl acetate 4:1) gave 155 g of the title compound as a yellow oil. Rt=1.80 min (Method B). Detected mass: 370.2 (M-OMe−).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:12])[CH:13]=[CH:1][C:2]2[CH:9]=[CH:8][C:5]([CH3:6])=[CH:4][CH:3]=2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=CC(=O)C=Cc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
4-Methylbenzaldehyde (1aa, 1.50 ml, 12.7 mmol) and acetone (19, 0.47 ml, 6.4 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.52 g, 13.0 mmol) and water (10 ml) was added and the mixture stirred for 1 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to give 1.30 g (78%) of a yellow solid: mp 174-176° C. [expected mp 171-172° C.]; 1H NMR: δ 2.37 (s, 6H), 7.02 (d, 2H, J=15.9 Hz), 7.20 (d, 4H, J=8.0 Hz), 7.50 (d, 4H, J=7.9 Hz), 7.70 (d, 2H, J=15.9 Hz); 13C NMR: δ 21.6, 124.6, 128.3, 129.6, 132.1, 140.8, 143.0, 188.9.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30](F)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])[CH:19]=[CH:20][C:21]=1[F:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CN1CCNCC1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)c(Cl)c2)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2ccc(F)c(Cl)c2)CC1
Yield: 85.3 %

Procedure:
Using General Method 4, the reaction of N-methylpiperazine (0.12 mL, 1 mmol), triethylamine (0.14 mL, 1 mmol), and 1-(3-chloro-4-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example D-1, 0.14 g, 0.32 mmol) provided 0.14 g of the title compound as a solid.