Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4]([NH:7][CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])(=[O:6])=[O:5])([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([S:4]([NH:7][CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CNS(=O)(=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC(C)S(=O)(=O)NCC(C)(C)C(=O)O

Procedure:
To a solution of methyl 3-amino-2,2-dimethylpropanoate (200 mg, 1.53 mmol) and Et3N (0.64 mL, 4.59 mmol) in 2 mL CH2Cl2 was added isopropylsulfonyl chloride (0.34 mL, 3.05 mmol). The reaction was stirred for 24 h, quenched by the addition of saturated aqueous NaHCO3, extracted with CHCl3, and chromatographed (1:1 hex:EtOAc) to provide methyl 3-[(isopropylsulfonyl)amino]-2,2-dimethylpropanoate (77 mg, 21%) as a solid. 1H NMR (400 MHz, CDCl3), 4.78 (t, 1H, J=6.6 Hz), 3.68 (s, 3H), 3.20-3.11 (m, 3H), 1.36 (d, 6H, J=6.9 Hz), 1.23 (s, 6H). Methyl 3-[(isopropylsulfonyl)amino]-2,2-dimethylpropanoate was hydrolyzed using aqueous NaOH to provide 3-[(isopropylsulfonyl)amino]-2,2-dimethylpropanoic acid, which was used without further purification.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[Cl:16].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[F:65][C:66]1[CH:72]=[C:71]([O:73][CH3:74])[CH:70]=[C:69]([F:75])[C:67]=1[NH2:68]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[NH:68][C:67]1[C:69]([F:75])=[CH:70][C:71]([O:73][CH3:74])=[CH:72][C:66]=1[F:65]
Reactant: Cc1nn(C)c(Br)c1-c1ccc(F)cc1Cl
Reactant: COc1cc(F)c(N)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cc(F)c(Nc2c(-c3ccc(F)cc3Cl)c(C)nn2C)c(F)c1

Procedure:
5-Bromo-4-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazole (i.e. the product of Step B) (0.20 g, 0.66 mmol), palladium(II) acetate (15 mg, 0.066 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (76 mg, 0.13 mmol) and powdered potassium carbonate (1.8 g, 13 mmol) were combined in anhydrous 1,4-dioxane (3 mL), and the mixture was sparged with a subsurface stream of N2 gas for 10 min. 2,6-Difluoro-4-methoxyaniline (0.22 g, 1.3 mmol) was added in one portion, and the reaction mixture was heated at reflux for 22 h. The reaction mixture was filtered through Celite® diatomaceous filter aid, and the filter pad was washed with ethyl acetate (20 mL). The filtrate was washed with water (10 mL) and brine (10 mL), dried over MgSO4, and concentrated to leave a semisolid residue. This residue was purified by column chromatography through 5 g of silica gel eluted with a gradient of hexanes/ethyl acetate (20:1 to 1:3) to give the title compound as a light-brown solid (48 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[CH3:26][C:27]1([CH3:36])[CH2:32][C:31](=[O:33])[CH2:30][C:29]([CH3:35])([CH3:34])[O:28]1>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:31]3([OH:33])[CH2:30][C:29]([CH3:34])([CH3:35])[O:28][C:27]([CH3:36])([CH3:26])[CH2:32]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CC1(C)CC(=O)CC(C)(C)O1
Product: CC1(C)CC=C(c2cc(C3(O)CC(C)(C)OC(C)(C)C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 2,2,6,6-tetramethyl tetrahydropyran-4-one (WO 2005012220). 1H-NMR (CD3OD; 400 MHz): δ 8.16 (d, 1H, J=8.4 Hz), 7.98 (s, 1H), 7.38 (dd, 1H, J=8.4, 2.0 Hz), 7.34 (d, 1H, J=2.0 Hz), 5.74 (br s, 1H), 2.32 (m, 2H), 2.08 (m, 2H), 1.87 (m, 4H), 1.56-1.58 (m, 8H), 1.56 (s, 6H), 1.21 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([OH:17])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:42][CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][C:45]1=[O:49].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][CH2:42][CH2:43][N:44]4[CH2:48][CH2:47][CH2:46][C:45]4=[O:49])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20]
Reactant: O=C1CCCN1CCO
Reactant: CCCc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1nc2cnc3cc(OCCN4CCCC4=O)ccc3c2n1CC(C)C
Temperature: 0 °C
Reaction time: 19 h
Yield: 65.7 %

Procedure:
A mixture of 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol (0.500 g, 1.76 mmol), triphenylphosphine (0.462 g, 1.76 mmol), and 1-(2-hydroxyethyl)pyrrolidin-2-one (0.200 mL, 1.77 mmol) in THF (17 mL) was cooled to 0° C. Diethyl azodicarboxylate (0.277 mL) was added dropwise, and the reaction mixture was allowed to warm to ambient temperature and stirred for 19 hours. Solid unreacted 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol (0.150 g, 0.42 mmol) was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 98:2 dichloromethane:methanol) to provide 0.456 g of 1-{2-[1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]ethyl}pyrrolidin-2-one an off-white, waxy solid.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)[CH3:2]>CO.[Pd]>[C:11]([O:10][C:8]([N:6]1[CH2:7][C@@H:3]([CH2:1][CH3:2])[CH2:4][C@H:5]1[C:15]([OH:17])=[O:16])=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC[C@H]1C[C@@H](C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of (2S,4S)-2-benzyl 1-tert-butyl 4-ethylpyrrolidine-1,2-dicarboxylate (18 g, 54.1 mmol), Pd/C (3.6 g) in MeOH (1 L) was hydrogenated at room temperature overnight. TLC showed that the reaction was completed. The mixture was filtered by Celite. The filtrate was concentrated to afford (2S,4S)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-2-carboxylic acid (10 g, 77%) as white solid. 1H NMR: 400 MHz CDCl3: δ 9.88 (br, 1H), 4.31-4.19 (m, 1H), 3.82-3.68 (m, 1H), 3.03-2.95 (m, 1H), 2.49-2.39 (m, 1H), 2.12-2.03 (m, 1H), 1.81-1.56 (m, 1H), 1.45 (d, J=8 Hz, 11H), 0.92 (t, J=6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:5](=[O:8])[NH:6][CH:7]=1.C([O:30][CH2:31][C:32]1[C:33]([N:47]2[N:56]=[CH:55][C:54]3[C:49](=[C:50]([F:61])[CH:51]=[C:52]([C:57]([CH3:60])([CH3:59])[CH3:58])[CH:53]=3)[C:48]2=[O:62])=[N:34][CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)(=O)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[C:57]([C:52]1[CH:53]=[C:54]2[C:49](=[C:50]([F:61])[CH:51]=1)[C:48](=[O:62])[N:47]([C:33]1[C:32]([CH2:31][OH:30])=[C:37]([C:2]3[CH:3]=[C:4]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([N:16]5[CH2:21][CH2:20][N:19]([CH:22]6[CH2:25][O:24][CH2:23]6)[CH2:18][C@@H:17]5[CH3:26])=[CH:12][N:11]=4)[C:5](=[O:8])[NH:6][CH:7]=3)[CH:36]=[CH:35][N:34]=1)[N:56]=[CH:55]2)([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Cl)c[nH]c2=O)nc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)c[nH]c2=O)nc1
Temperature: 120 °C
Yield: 18 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 138c (150 mg, 0.40 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (495.6 mg, 1.2 mmol), Pd2(dba)3 (36.6 mg, 0.040 mmol), P(cy)3(44.6 mg, 0.16 mmol), Cs2CO3 (391.2 mg, 1.2 mmol), dioxane (8 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 120° C. for 4 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 40:1 ethyl acetate/methanol and further purified by reverse-phase prep-HPLC to afford 138 (48 mg, 18%) as a yellow solid. MS-ESI: [M+H]+ 667.3. 1H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.55 (d, J=3.0 Hz, 1H), 8.44 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.87 (d, J=2.5 Hz, 1H), 7.79 (dd, J=1.0 Hz, 13.0 Hz, 1H), 7.54 (d, J=5.0 Hz, 1H), 7.39 (dd, J=2.5 Hz, 9.0 Hz, 1H), 7.26-7.23 (m, 2H), 4.97-4.95 (m, 1H), 4.58-4.54 (m, 2H), 4.48-4.46 (m, 1H), 4.43-4.41 (m, 1H), 4.38-4.37 (m, 2H), 3.69-3.68 (m, 1H), 3.41-3.39 (m, 1H), 3.11-3.09 (m, 1H), 2.97-2.93 (m, 1H), 2.56-2.54 (m, 1H), 2.35-2.32 (m, 2H), 2.21-2.17 (m, 1H), 1.40 (s, 9H), 0.94 (d, J=6.5 Hz, 3H),
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][NH:31][CH3:32])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:41][C:42]1[S:43][C:44]([Cl:50])=[CH:45][C:46]=1[C:47](Cl)=[O:48]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:33])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][N:31]([C:47]([C:46]1[CH:45]=[C:44]([Cl:50])[S:43][C:42]=1[Cl:41])=[O:48])[CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1CCC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN(C)C(=O)c2cc(Cl)sc2Cl)c1

Procedure:
A solution of 3-{2-methylaminomethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid tert-butyl ester (37 mg, 0.083 mmol) in CH2Cl2 (5 mL) was treated with triethylamine (0.035 mL, 0.25 mmol) then 2,5-dichloro-thiophene-3-carbonyl chloride (0.054 mL, 0.25 mmol) and stirred at ambient temperature overnight. The mixture was diluted with EtOAc (25 mL) and washed with brine (3×10 mL). The organic layer was dried (Na2SO4) and concentrated to the title compound (50 mg, 96%). MS (ES) m/z 629, 631 [M+1].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH:12]1[CH2:17][NH:16][C:15](=[O:18])[CH2:14][CH2:13]1)=O)C.O.[OH-].[Na+]>C1COCC1>[OH:9][CH2:10][CH:12]1[CH2:17][NH:16][C:15](=[O:18])[CH2:14][CH2:13]1
Reactant: CCOC(=O)C1CCC(=O)NC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCC(CO)CN1
Reaction time: 1 h
Yield: 53 %

Procedure:
Solid lithium aluminum hydride (3.5 g) was added slowly to a solution of 15.0 g 5-ethoxycarbonyl-2-piperidone in 350 ml THF at -4° C. After stirring for 1 hour under a nitrogen atmosphere, the reaction was decomposed by dropwise addition of 3.5 ml water, 3.5 ml 5N NaOH and 10.5 ml water. The mixture was filtered and the granular precipitate washed with 100 ml THF. Evaporation of the combined filtrate and washings provided 6.0 g of the title compound: NS m/z 130 (M+ +1), 129 (M+), 128 (M+ -1) 101, 73, 56; 90-MHz 1H NMR (CDCl3) δ1.42-1.60 (m, 1H), 1.60-2.05 (m, 2H), 2.10-2.47 (m, 2H), 3.05 (t, J=9 Hz, 1H), 3.21-3.58 (m, 4H), 6.85 (s, 1H).
Reaction SMILES: BrC1N=C2C=CN(COCC[Si](C)(C)C)C2=NC=1.CN.[CH3:21][NH:22][C:23]1[N:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]2=[N:27][CH:28]=1.[CH:40]1([N:46]=[C:47]=[O:48])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CS(C)=O.ClCCCl>[CH:40]1([NH:46][C:47](=[O:48])[N:22]([CH3:21])[C:23]2[N:24]=[C:25]3[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]3=[N:27][CH:28]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CNc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Reactant: O=C=NC1CCCCC1
Agent: CN
Agent: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Product: CN(C(=O)NC1CCCCC1)c1cnc2c(ccn2COCC[Si](C)(C)C)n1
Temperature: 150 °C
Yield: 27 %

Procedure:
2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (0.328 g, 1.00 mmol) was dissolved in DMSO (2.5 mL). A solution of methylamine (33 wt % in EtOH, 2.5 mL, 20 mmol) was added and the resulting solution was heated at 150° C. in the sealed tube overnight, then cooled to RT. The reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to give a mixture of impure Methyl-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-amine, which was dissolved in 1,2-dichloroethane (3 mL). Cyclohexylisocyanate (0.38 mL, 3.00 mmol) was added and the reaction mixture was heated to reflux overnight, cooled to RT, concentrated, purified by SiO2 chromatography (12 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 0.110 g of 3-cyclohexyl-1-methyl-1-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a yellow solid (27% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=[O:21])([O-:12])=[O:11].C(N(CC)CC)C.O>C(OC(=O)C)(=O)C>[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[C:20]([OH:22])=[O:21])([O-:12])=[O:11]
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1ccc(Br)cc1)c1ccccc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
A solution of 4-bromobenzaldehyde (27.75 g, 0.150 mol), 2-nitrophenylacetic acid (27.18 g, 0.150 mol) and triethylamine (21.0 ml, 0.150 mol) in 150 ml of acetic anhydride was heated at 40° C. for 38 hours and then poured into 900 ml of water and stirred until the organic layer solidified. The solid was isolated by filtration and dried in vacuo to yield 48.3 g (92%) of the title compound as a tan solid which was sufficiently pure to use directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:15]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=1)=O.OC1C=CC(C2NC(=O)C3C(=CC(OC)=CC=3OC)N=2)=CC=1>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:15]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)cc3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCC(=O)O)cc3)nc2c1
Yield: 21 %

Procedure:
2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid was synthesized from 2-amino-4,6-dimethoxy-benzamide and (4-formyl phenoxy)acetic acid, using the method described for 2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one. 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid (135 mg, 21%) was isolated as an off-white solid. Selected data: MS (m/z): 357.04; MP 287-290° C.
Reaction SMILES: [F:1][C:2]1[C:26]([O:27]C)=[CH:25][C:5]2[N:6]=[C:7]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.C(S)(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[C:26]([OH:27])=[CH:25][C:5]2[N:6]=[C:7]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1F)Nc1sc3ccccc3c1C(N1CCN(C)CC1)=N2
Agent: CC(S)S
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN1CCN(C2=Nc3cc(O)c(F)cc3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 62 and using 8-fluoro-9-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine, dichloromethane, ethanedithiol and aluminium chloride, 8-fluoro-9-hydroxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:3]=1[CH2:4][N:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:6].C(=O)([O-])[O-].[K+].[K+].O.[NH2:24][C:25]1[N:34]=[C:33]([C:35]([N:37]2[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[C:32]2[C:27](=[CH:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[N:26]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:24][C:25]1[N:34]=[C:33]([C:35]([N:37]2[CH2:38][C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:45]2)=[O:36])[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:2]3[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:3]=3[CH2:4][N:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:6])[CH:31]=2)[N:26]=1
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Reactant: CN(Cc1cc(F)c(F)cc1Br)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CN(Cc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1)C(C)(C)C
Temperature: 120 °C

Procedure:
171 mg of (2-bromo-4,5-difluorobenzyl)-tert-butylmethylamine, 124 mg of potassium carbonate, 9 μl of water and 22 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are added to a solution of 150 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 4 ml of ethanol under argon. The mixture is heated at 120° C. for 30 min; the hot mixture is filtered through kieselguhr, and the filtrate is evaporated. and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[O:6]([CH2:13][CH:14]([OH:16])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[O:6]([CH2:13][CH:14]([O:16][S:1](=[O:4])(=[O:3])[NH2:2])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NS(=O)(=O)Cl
Reactant: CC(O)COc1ccccc1
Product: CC(COc1ccccc1)OS(N)(=O)=O

Procedure:
The title compound was prepared by procedures of Example 22 from sulfamoyl chloride and 3-phenoxy-2-propanol through the partitioning and final evaporation to give an oil as residue. The oil was purified by chromatography using a 4.5 cm×100 cm glass column packed with 500 g of silica gel and methylene chloride as eluting agent. Fractions containing the title compound were combined and the solvent was evaporated under reduced pressure to give a 37% yield of an oil which solidified on standing, mp 57°-60° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([Cl:20])[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.Cl>[Fe].C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([Cl:20])[CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccc(Br)cc2)cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)c2ccc(Br)cc2)cc1Cl

Procedure:
Iron powder (2.5 g) was added to a stirred mixture of 4-(4-bromophenylsulphonyl)-2-chloro-nitrobenzene (Method 13) (0.6 g), water (2 ml), concentrated hydrochloric acid (0.5 ml) and ethanol (10 ml). The mixture was heated under reflux for 1 hour then evaporated to near dryness and partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (3×15 ml) and the organic extracts were combined and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-25% ethyl acetate/hexane followed by trituration with ether to give the title compounde (0.11 g) as a solid. NMR: 6.42 (s, 2H), 6.82 (d, 1H), 7.5 (d, 1H), 7.8 (m, 5H); MS: 346 (M−H)−.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]([CH:26]([F:37])[C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[C:11]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=3)[C:10]1=2)(C(C)(C)C)(C)C.CO.O1CCCC1>Cl>[CH:21]1([C:13]2[C:12]([CH:26]([F:37])[C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[C:11]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=3)[C:10]3[CH:9]([OH:8])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]=3[N:14]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O[Si](C)(C)C(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
190 mg of 5-(tert-butyldimethylsilanyloxy)-2-cyclopentyl-4-(3,4-difluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7dimethyl-5,6,7,8-tetra-hydroquinoline, in a mixture of 1.6 ml of 5 N hydrochloric acid, 2.3 ml of methanol and 1.5 ml of tetrahydrofuran, were stirred at RT for 1 hour and then at 40° C.-45° C. for 2 hours. Some of the compound precipitated out as a by-product. This gives 80 mg of m.p. 206-207° C. The mother liquor is admixed with saturated aqueous sodium bicarbonate solution and with ethyl acetate. The organic phase is once more washed with saturated aqueous sodium bicarbonate solution and then dried. The solvent is distilled off under reduced pressure and the residue is then purified over a silica gel column. Crystallization with heptane gives 40 mg of the base of m.p. 149-150° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1OC
Product: COc1ccc(CNc2nc(-n3cncn3)nc3scc(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][C:19]#[N:20])[CH3:15]>CN(C=O)C>[C:19]([C:18]1([C:17]([O:16][CH2:14][CH3:15])=[O:21])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)#[N:20]
Reactant: CCOC(=O)CC#N
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C#N)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (30.4 g, 0.220 mol) and 1,5-dibromopentane (13.6 mL, 0.100 mol) were sequentially added to a solution of ethylcyanoacetate (10.6 mL, 0.100 mol) in DMF (100 mL), and the reaction was stirred overnight at ambient temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic fraction was separated, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide ethyl 1-cyanocyclohexanecarboxylate.