Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C@@H:15]([CH3:25])[C:14]([N:9]2[C@@H:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12][O:11][C:10]2=[O:13])=[O:24])=[CH:21][CH:20]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COc1ccc(CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
A solution of (S)-4-benzyl-3-(2-(4-methoxyphenyl)acetyl)oxazolidin-2-one (1.00 g, 3.07 mmol) in dry THF (10 ml) was added to lithium diisopropyl amide (400 mg, 3.69 mmol, 0.1 M) at −78° C. The reaction mixture was stirred for 2 h. Iodomethane (2.00 g, 14.1 mmol) was added to the reaction mixture and warmed to −20° C. and stirred for another 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml) and extracted with ethyl acetate (3×25 ml). The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated. The crude compound was purified by column chromatography over silica gel (60-120 mesh) using ethyl acetate (10%) in petroleum ether as eluent to afford 350 mg (33.8%) of (S)-3-((R)-2-(4-methoxyphenyl)propanoyl)-4-benzyloxazolidin-2-one as light yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=[C:6]([CH:16]=O)[CH:5]=2)[CH2:3][CH2:2]1.[CH2:18]([NH:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)[CH3:19]>>[CH:1]1([C:4]2[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=[C:6]([CH2:16][N:31]3[CH2:30][CH2:29][N:28]([C:25]4[CH:24]=[CH:23][C:22]([C:21]([NH:20][CH2:18][CH3:19])=[O:34])=[CH:27][CH:26]=4)[CH2:33][CH2:32]3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CC1Oc2c(cc(C=O)cc2C2CC2)NC1=O
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Product: CCNC(=O)c1ccc(N2CCN(Cc3cc4c(c(C5CC5)c3)OC(C)C(=O)N4)CC2)cc1

Procedure:
Using 346A and N-ethyl-4-(piperazin-1-yl)benzamide 283 in the general procedure for reductive aminations, the title compound was obtained as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.60-0.70 (m, 2H) 0.88-0.94 (m, 2H) 1.09 (t, J=7.07 Hz, 3H) 1.43 (d, J=6.57 Hz, 3H) 2.04-2.12 (m, 1H) 2.41-2.49 (m, 4H) 3.17-3.29 (m, 6H) 3.36 (s, 2H) 4.64 (q, J=6.82 Hz, 1H) 6.41 (d, J=1.52 Hz, 1H) 6.69 (d, J=1.77 Hz, 1H) 6.92 (m, J=9.09 Hz, 2H) 7.71 (m, J=8.84 Hz, 2H) 8.17 (t, J=5.56 Hz, 1H) 10.55 (s, 1H). ESI-MS: m/z 449.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])[C:7]3[C:14]([C:15]([O:17]CC)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(O)(=O)C>[OH-].[Na+]>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (6 g, 18.75 mmol) in aqueous sodium hydroxide (206 mL, 0.2 N) was refluxed for 135 minutes. The mixture was cooled to room temperature and glacial acetic acid (30 mL) was added. The insoluble material was filtered and dried to give the title compound as a yellow solid (5.1 g, 94%, m.p. >400° C. dec.).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][OH:14])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.[H-].[Na+].Br[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[OH:14][CH2:13][CH2:12][C:8]1[C:9](=[O:11])[O:10][C:5]2[CH:4]=[C:3]([O:17][CH3:18])[C:2]([O:1][CH:22]([CH3:24])[CH3:23])=[CH:16][C:6]=2[C:7]=1[CH3:15]
Reactant: CC(C)Br
Reactant: COc1cc2oc(=O)c(CCO)c(C)c2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2oc(=O)c(CCO)c(C)c2cc1OC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
67 g (268 mmol) of 6-hydroxy-3-(2-hydroxyethyl)-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 41) is carefully added, using an ice bath for cooling, to 11.8 g (295 mmol) of sodium hydride (60% in white oil) in 300 ml of DMF. The mixture is stirred for 1 hour at room temperature, and then 49.5 g (402 mmol) of 2-bromopropane is added dropwise and the mixture is stirred for 24 hours at 60° C. under nitrogen. After adding a further 3.33 g (83 mmol) of sodium hydride and 52.4 g (426 mmol) of 2-bromopropane, the mixture is stirred for a further 24 hours at 60° C. The solution is evaporated, extracted with ethyl acetate, and the organic phase is washed with water, dried with Na2SO4 and re-evaporated. The product is purified by column chromatography over silica gel 60 (eluent: ethyl acetate). Yield 53.3 g (68%); m.p. 110°-112° C. (from acetone/PE).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25].[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33]>O1CCCC1>[C:32]([N:23]([C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:7][C:2]=1[Cl:1])[C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])(=[O:34])[CH3:33]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC(=O)N(C(C)=O)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-phenyl}-N′-propylurea 100 mg) was dissolved in anhydrous tetrahydrofuran (30 ml), and sodium hydride (60 wt %, 88 mg) was added to the solution. The mixture was stirred at room temperature for 15 min. Next, acetyl chloride (63 μl) was added to the reaction solution, and the mixture was stirred at room temperature for additional 2 hr. The solvent was removed by distillation under the reduced pressure, and water was added to the residue. The mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/acetone to give 27 mg (yield 26%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>O1CCCC1.O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH3:13]
Reactant: COCCCN
Reactant: CCOC(=O)CBr
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CNCCCOC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A solution containing 52 g of 3-methoxypropylamine in 100 ml of tetrahydrofuran is immersed in iced water and a solution containing 27 g of ethyl bromoacetate in 30 ml of tetrahydrofuran is added dropwise for 1 hour. The resultant is stirred at room temperature for 2 hours and the solvent and the excess 3-methoxypropylamine are evaporated under reduced pressure. The residue is purified by silica gel column chromatography (ethanol:dichloromethane=1:20) to obtain 19 g of the captioned compound in the form of colorless oil.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[C:15]4[C:14](=[O:25])[NH:13][C:12](=[O:26])[C:11]=4[C:10]=3[C:6]=2[CH:5]=[C:4]([OH:27])[CH:3]=1.[CH2:28](C([Sn])=C(CCCC)CCCC)[CH2:29]CC>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[C:15]2[C:14](=[O:25])[NH:13][C:12](=[O:26])[C:11]=2[C:10]2[C:6]3[CH:5]=[C:4]([OH:27])[CH:3]=[C:2]([CH:28]=[CH2:29])[C:7]=3[O:8][C:9]=2[CH:17]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1oc3c(Br)cc(O)cc3c21
Product: C=Cc1cc(O)cc2c1oc1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Yield: 79 %

Procedure:
Reaction of (862) prepared as described in example 443 with tributylvinyltin using the procedure described in example 309 gave (863) (79%). 1H NMR δ [(CD3)2SO] 9.80 (s, 1H), 8.04 (d, J=2.7 Hz, 1H), 7.91 (s, 1H), 7.56 (d, J=8 Hz, 1H), 7.45 (m, 3H), 7.2 (d, J=2.5 Hz, 1H), 6.96 (dd, J=18,1 Hz, 1H), 6.25 (d, J=18 Hz, 1H), 5.52 (d, J=11 Hz, 1H). MH−:390,388.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([CH2:15][OH:16])[CH:14]=[C:10]3[C:9](=[O:17])[NH:8][CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.C1COCC1>O=[Mn]=O.C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([CH:15]=[O:16])[CH:14]=[C:10]3[C:9](=[O:17])[NH:8][CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: O=C1NC(c2ccccc2)c2cc(Cl)ccc2-n2nc(CO)cc21
Agent: O=[Mn]=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)NC2=O

Procedure:
A solution of 5.85 g. (17 mmol) of the end product of Example 14 in 600 ml. dry THF was mixed with 24 g. of activated MnO2 and heated to reflux for 17 hours. The mixture was cooled, filtered and the collected solids washed thoroughly with THF. The combined filtrate and washings were concentrated in vacuo. Recrystallization of this crude product from THF/hexane yielded the desired end product. An analytical sample was prepared by an additional recrystallization from THF/hexane and was obtained as colorless plates: mp 276°-278°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18])[CH2:6][O:7][CH3:8].[I-].[CH3:23][N:24]1[C:32]2[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:34][N+](C)(C)C)=[CH:25]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:19])([CH3:20])[CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:34][CH:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[N:24]([CH3:23])[CH2:25]2)[C:10]1=[O:18])[CH2:6][O:7][CH3:8]
Reactant: COCC(n1c(=O)[nH]c2ccccc21)C(C)(C)C(=O)OC
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC(n1c(=O)n(CC2CN(C)c3cccc(C)c32)c2ccccc21)C(C)(C)C(=O)OC
Temperature: 100 °C
Reaction time: 4 h
Yield: 23.6 %

Procedure:
To a mixture of 4-methoxy-2,2-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butyric acid methyl ester (137 mg, 0.47 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (225 mg, 0.65 mmol) in DMF (2.5 mL) was added K2CO3 (200 mg, 1.45 mmol). The mixture was stirred at 100° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 50% EtOAc in Hexane as the eluent to afford the desired 3-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-4-methoxy-2,2-dimethyl-butyric acid methyl ester (50 mg, 24%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([N:21](S(C)(=O)=O)[S:22]([CH3:25])(=[O:24])=[O:23])[CH:15]=2)=[N:6][N:7]([CH3:13])[C:8]=1[O:9][CH:10]([F:12])[F:11]>O.CO>[Cl:3][C:4]1[C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])[CH:15]=2)=[N:6][N:7]([CH3:13])[C:8]=1[O:9][CH:10]([F:11])[F:12]
Reactant: Cn1nc(-c2ccc(Cl)c(N(S(C)(=O)=O)S(C)(=O)=O)c2)c(Cl)c1OC(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nc(-c2ccc(Cl)c(NS(C)(=O)=O)c2)c(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
0.3 g (4.7 mmol) of potassium hydroxide (dissolved in a little water) was added to a solution of 0.9 g (2.3 mmol) of 4-chloro-3-(4-chloro-3-[di-(methylsulfonyl)-amino]-phenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 30 ml of methanol. The mixture was stirred at room temperature for 18 hours and then concentrated. The residue was taken up in 1N hydrochloric acid and then extracted with ethyl acetate. Drying of the organic phase with magnesium sulfate followed by concentration gave 0.7 g of the target product.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]12([C:18]([NH:20][NH2:21])=[O:19])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:21][NH:20][C:18]([C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:19])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NNC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)NNC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Valeryl chloride (E) (0.981 mL, 8.1 mmol) was added dropwise to a solution of adamantane-1-carbohydrazide (F) (1.5 g, 7.72 mmol) and triethylamine (1.18 mL, 8.49 mmol) in methylene chloride (30 mL) at room temperature, and the mixture stirred at room temperature for 3.5 h. A solution of 10% NaHCO3 (15 mL) was added and the mixture stirred rapidly for 1.5 h. The mixture was extracted with methylene chloride (3×) and the combined extracts washed with water, dried (MgSO4) and concentrated in vacuo to give N′-pentanoyladamantane-1-carbohydrazide (G). 1H NMR (CDCl3): δ 0.94 (t, 3H); 1.38 (m, 2H); 1.75 (m, 8H); 1.93 (d, 6H); 2.08 (s, 3H); 2.29 (t, 2H); 8.47 (d, 1H); 8.7 (d, 1H).
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)=[CH:5][S:4][CH:3]=1.[C:13](C1C(Br)=CSC=1)(=[O:15])[CH3:14]>>[C:13]([C:2]1[C:6]([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)=[CH:5][S:4][CH:3]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1cscc1Br
Reactant: Brc1cscc1C1=CCCCC1
Product: CC(=O)c1cscc1C1=CCCCC1
Yield: 31 %

Procedure:
Prepared from 3-bromo-4-cyclohex-1-enyl-thiophene (See MacDowell; Jeffries J. Org. Chem., 1970, 35, 871-875 incorporated herein by reference), in 31% yield analogous to the procedure for the preparation of 4-acetyl-3-bromo-thiophene. 1H NMR (300 MHz, CDCl3) δ7.90(d, 1H, J=2.7 Hz), 6.97 (d, 1H, J=2.7 Hz), 5.66 (q, 1H, J=1.8 Hz), 2.49 (s, 3H), 2.15-2.19 (m, 4H), 1.64-1.79 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pt]=O.C(O)(=O)C>[C:1]([CH:5]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ncc2ccccc2c1-c1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)(C)C1NCc2ccccc2C1c1ccccc1

Procedure:
A mixture of 28.5 g. (0.11 mole) of 3-tert.butyl-4-phenyl isoquinoline, 2.85 g. platinum oxide and 300 ml. of acetic acid is hydrogenated at room temperature and 50 psi until two equivalents of hydrogen are absorbed. The catalyst is filtered off and the acetic acid is evaporated in vacuo. The residue is dissolved in ether, washed with 50% sodium hydroxide, water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue is crystallized from petroleum ether to give 3-tert.butyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline; m.p. 79°-81° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([CH2:18][C:19](=O)[CH3:20])[C:15]([CH3:17])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:20][C:19]1[N:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[C:15]([CH3:17])=[CH:14][CH:18]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 77.3 %

Procedure:
A mixture of 4-nitrobenzenesulfonamide (30.3 g, 0.15 mol), acetonylacetone (34.2 g, 0.30 mol) and 4-toluenesulfonic acid (3.0 g, catalyst) in 200 mL of toluene was heated at reflux under nitrogen using a Dean-Stark trap for 18 hours. The reaction was cooled and filtered through silica gel (700 g), eluting with mixtures of ethyl acetate and hexane. Removal of solvent in vacuo gave a crude brown solid. The crude product in ethyl acetate was treated with activated charcoal, and recrystallized from ethyl acetate and hexane to afford 4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]nitrobenzene (32.5 g, 77%) as a light yellow solid: mp (DSC): 101–103° C. Anal. Calc'd. for C12H12N2O4S: C, 51.42; H, 4.32; N, 9.99; S, 11.44. Found: C, 51.62; H, 4.18; N, 9.96; S, 11.31.
Reaction SMILES: CO[C:3](=[O:25])[C:4]([OH:24])=[CH:5][C:6](=[O:23])[N:7]([O:16][CH2:17][C:18](=[O:22])[N:19]([CH3:21])[CH3:20])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:34][N:35](C)[C:36](C1CN(C)C(=O)C=1O)=O>>[CH3:21][N:19]([CH3:20])[C:18]([CH2:17][O:16][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[C:6]([C:5]1[CH2:34][N:35]([CH3:36])[C:3](=[O:25])[C:4]=1[OH:24])=[O:23])=[O:22]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)OCC(=O)N(C)C
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CN(C)C(=O)CON(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 25 %

Procedure:
3-[Dimethylcarbamoylmethoxy-(4-fluorobenzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 72-B) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (25% yield); mp 147–149° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.79 (3H, s, NCH3), 2.96 (3H, s, NCH3), 3.11 (3H, s, NCH3), 4.25 (2H, s, CH2), 4.51 (2H, s, CH2), 4.96 (2H, s, CH2), 7.06 (2H, m, aromatics), 7.38 (2H, m, aromatics), 11.54 (1H, broad s, OH). HRMS (ES+) calculated for C17H21FN3O5, [M+H]+: 366.146524. found: 366.146176.
Reaction SMILES: O.NN.O[N:5]1C2C=CC=CC=2N=[N:6]1.Cl.C(N=C=NCCCN(C)C)C.[CH2:26]([O:33][C:34]([NH:36][C@H:37]1[CH2:45][O:44][C@H:40]([C:41](O)=[O:42])[CH2:39][CH2:38]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[NH:5]([C:41]([C@H:40]1[O:44][CH2:45][C@H:37]([NH:36][C:34](=[O:35])[O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:38][CH2:39]1)=[O:42])[NH2:6]
Reactant: O=C(N[C@@H]1CC[C@@H](C(=O)O)OC1)OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: NNC(=O)[C@@H]1CC[C@@H](NC(=O)OCc2ccccc2)CO1
Reaction time: 18 h
Yield: 86.1 %

Procedure:
Hydrazine monohydrate (0.23 ml, 3.86 mmol), 1-hydroxybenzotriazole (434 mg, 3.21 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (740 mg, 3.86 mmol) were added to an N,N-dimethylformamide (16 ml) solution of the compound (898 mg, 3.21 mmol) obtained in Step 3 above at room temperature and the resulting mixture was stirred for 18 hours. The reaction mixture was subjected to extraction with chloroform:methanol [10:1 (v/v)] and the organic layer was washed with saturated sodium bicarbonate solution and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography [dichloromethane:methanol=49:1→13:1 (v/v)] to give 811 mg (86%) of the title compound as a colorless solid.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.CN(C)P(=O)(N(C)C)N(C)C.[CH3:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].Cl>O>[CH2:6]([O:5][C:1](=[O:8])[CH2:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:7]
Reactant: CC(=O)C(C)(C)C
Reactant: CCOC(=O)OCC
Agent: Cl
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)CC(=O)C(C)(C)C
Temperature: 45 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
250 g of potassium-tert.-butylate were suspended in a solution of 480 cc of diethyl carbonate and 100 cc of hexamethyl phosphoric acid triamide, followed by the gradual dropwise addition of 100 g pinacolone at 45° C/normal pressure. On completion of the addition, the mixture was stirred for 1 hour at 45° C and, after cooling, alcohol, water and finally hydrochloric acid carefully added one after the other to the reaction mixture. The reaction mixture was then treated and purified in the same way as described in 1 above. The yield was 67% of pivaloyl acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[S:30])[CH:25]=[CH:26][CH:27]=1>C(OCC)(=O)C>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([NH:1][C:29]([NH:28][C:24]3[CH:23]=[C:22]([CH3:21])[CH:27]=[CH:26][CH:25]=3)=[S:30])[CH:3]=2)[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1cccc(N=C=S)c1
Reactant: COc1ccc(C(=O)Nc2ccc(C)c(C)c2)cc1N
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccc(C)c(C)c2)cc1NC(=S)Nc1cccc(C)c1
Yield: 52.4 %

Procedure:
A solution of 3-amino-N-(3,4-dimethylphenyl)-4-methoxy-benzamide from Example 6 (0.541 g, 2.00 mmol) and 3-methylphenyl isothiocyanate (0.28 mL, 2.07 mmol) in ethyl acetate (35 mL) was boiled until nearly all the solvent had evaporated. Filtration after 2 days at room temperature afforded the product (0.44 g) in two crops; m.p. 155-160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[CH3:12].[H][H]>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:6]=[CH:7][CH:8]=1)[NH2:9]
Reactant: COc1cccc([N+](=O)[O-])c1C
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: COc1cccc(N)c1C

Procedure:
200 gm (1.19 mols) of 2-methoxy-6-nitro-toluene were hydrogenated in 2.5 liters of ethanol in the presence of 25 gm of Raney nickel at 100 bar until the absorption of the calculated amount of hydrogen. The reaction mixture was filtered and evaporated in vacuo. After distillation 158.3 gm (97% of theory) of 3-methoxy-2-methylaniline were obtained.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:26][CH2:27][F:28])[C:10]1=[O:29])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[F:28][CH2:27][CH2:26][N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:29]
Reactant: [H][H]
Reactant: O=c1c2cc(F)c(N3CCCC3)cc2n(CCF)c(=O)n1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(CCF)c(=O)n1O
Yield: 128.5 %

Procedure:
Twenty percent Pd/C (25 mg) was added to a solution of 3-benzyloxy-1-(2-fluoroethyl)-6-fluoro-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example E-4, 0.17 g, 0.4 mmol) in 50 mL of THF, this was shaken under 50 PSI of hydrogen for 14.5 hours. The mixture was filtered and concentrated to afford 0.16 g of a solid, which was triturated with ether and dried to give 0.07 g of the title compound as a solid, mp 228-230° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(Cl)c1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(3-chloro-phenyl)-1-methyl-propyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.