Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2([O:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22][CH2:21]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2].[H][H].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt](=O)=O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2([O:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:21][CH2:22][CH2:23]2)[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCC1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc3c(c2n1CC1(OCCS(C)(=O)=O)CCC1)CCCC3
Yield: 69.1 %

Procedure:
A mixture of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclobutyl}methyl)-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 26, 0.500 g, 1.16 mmol) and platinum(IV) oxide (0.5 g) in trifluoroacetic acid (5 mL) was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) hydrogen pressure for 1 day. The mixture was filtered through CELITE filter agent, which was washed afterwards with dichloromethane. The filtrate was concentrated under reduced pressure to afford an oil that was suspended in water (20 mL) and adjusted to pH 13 with 50% aqueous sodium hydroxide. A white solid formed that was isolated by filtration, washed with water, and recrystallized from acetonitrile. The crystals were isolated and dried under vacuum at 65° C. to afford 0.35 g of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclobutyl}methyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 186-188° C.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]C)=[O:16])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1>C1COCC1.CO>[Br:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1CCN(c2cccc(Br)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2cccc(Br)c2)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 83.9 %

Procedure:
1M NaOH aq. (2 mL) was added to a solution of methyl 1-(3-bromophenyl)pyrrolidine-3-carboxylate in THF-MeOH (1 mL-1 mL). After stirring the mixture at room temperature for 13 hours, the mixture was concentrated. The residue was diluted with 1M NaOH aq. and washed with ether. The aqueous layer was acidified with 1M HCl aq. and extracted with DCM (3×). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to afford desired product (293 mg, 83.9%) as yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Cl:12].[OH-].[Na+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[Cl:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]1[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: ClCCCCCBr
Reactant: c1c[nH]nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: ClCCCCCn1ccnn1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Triazole (0.41 ml), 1-bromo-5-chloropentane (1.0 ml), tetrabutylammonium iodide (10 mg), and a 3 M aqueous sodium hydroxide solution (1 ml) were dissolved in acetone (1.0 ml), and the solution was stirred at 50° C. for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography by development with chloroform to give an intermediate (1-(5-chloropentyl-1H-1,2,3-triazole, 390 mg).
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)CCCC.[F-].[OH:19][C:20]([CH3:50])([CH3:49])[CH2:21][C@@:22]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:27][C:26](=[O:28])[N:25]([C@H:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]#[C:38][Si](C)(C)C)=[CH:33][CH:32]=2)[CH3:30])[CH2:24][CH2:23]1>O1CCCC1>[C:37]([C:34]1[CH:33]=[CH:32][C:31]([C@@H:29]([N:25]2[CH2:24][CH2:23][C@:22]([CH2:21][C:20]([OH:19])([CH3:49])[CH3:50])([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:27][C:26]2=[O:28])[CH3:30])=[CH:36][CH:35]=1)#[CH:38]
Reactant: C[C@@H](c1ccc(C#C[Si](C)(C)C)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
nBu4NF (1 mol/L in tetrahydrofuran, 4.90 mL) was added to a solution of (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-trimethylsilylethynyl-phenyl)-ethyl]-[1,3]oxazinan-2-one (2.00 g) in tetrahydrofuran (20 mL) at room temperature. The solution was stirred for 1 h at room temperature and then concentrated under reduced pressure. Ethyl acetate was added to the residue and the resulting mixture was washed with water and brine. The organic phase was dried (MgSO4) and the solvent was evaporated to afford the title compound as an oil that solidified on standing. Yield: 1.60 g (95% of theory); LC-MS (Method 1): tR=3.64 min; Mass spectrum (ESI+): m/z=378 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([NH:16]C(=O)OCC1C=CC=CC=1)([CH2:4][CH2:5][S:6]([CH2:9][CH:10]([OH:15])[CH:11]([OH:14])[CH2:12][OH:13])(=[O:8])=[O:7])[CH3:3].[H][H]>CO.[Pd]>[NH2:16][C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][S:6]([CH2:9][CH:10]([OH:15])[CH:11]([OH:14])[CH2:12][OH:13])(=[O:8])=[O:7]
Reactant: [H][H]
Reactant: CC(C)(CCS(=O)(=O)CC(O)C(O)CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)CCS(=O)(=O)CC(O)C(O)CO
Reaction time: 3.5 h

Procedure:
A solution of benzyl 2-methyl-4-(2,3,4-trihydroxybutylsulfonyl)butan-2-ylcarbamate (172.1 mg, 0.4418 mmol) in methanol (5 ml) was purged with nitrogen and palladium on carbon (10%, 40 mg) was added. The suspension was put under a blanket of hydrogen (1.3 atmospheres) and stirred for 3.5 hours. The suspension was filtered through a 0.45 um PTFE filter and concentrated in vacuo to afford the title compound which was used without further purification. LRMS (ESI/APCI) m/z 256 [M+H]+
Reaction SMILES: [CH2:1]([NH:3][NH2:4])[CH3:2].[F:5][C:6]([F:17])([F:16])[C:7](=O)[CH:8]([CH3:14])[C:9](OCC)=[O:10].Cl>C(O)C>[CH2:1]([N:3]1[C:9]([OH:10])=[C:8]([CH3:14])[C:7]([C:6]([F:17])([F:16])[F:5])=[N:4]1)[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Reactant: CCNN
Agent: Cl
Solvent: CCO
Product: CCn1nc(C(F)(F)F)c(C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution of 1.2 g (20.0 mmol) of ethylhydrazine in 20 ml of ethanol was added dropwise under stirring 4.4 g (20.0 mmol) of ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate under ice-cooling so that the temperature in the reaction system did not exceed 10° C. After the dropwise addition, the whole was stirred at room temperature for 30 minutes. Then, 1 ml of concentrated hydrochloric acid was added into the reaction solution, followed by 2 days of stirring under refluxing. After the completion of the reaction was confirmed, the solvent was removed by evaporation under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was washed with n-hexane to obtain 2.8 g (yield: 71.8%) of 1-ethyl-5-hydroxy-4-methyl-3-trifluoromethyl-1H-pyrazole as white crystals (melting point: 150 to 152° C.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:47]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[NH:50][CH2:49][CH2:48]2.Br[C:57]1[CH:58]=[CH:59][C:60]2[C:64]3[CH:65]=[CH:66][C:67](Br)=[CH:68][C:63]=3[S:62](=[O:71])(=[O:70])[C:61]=2[CH:72]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:70]=[S:62]1(=[O:71])[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=2[C:60]2[CH:59]=[CH:58][C:57]([N:50]3[CH:51]4[CH2:54][CH2:55][N:47]([CH2:53][CH2:52]4)[CH2:48][CH2:49]3)=[CH:72][C:61]1=2
Reactant: C1CN2CCC(CC2)N1
Reactant: O=S1(=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=S1(=O)c2ccccc2-c2ccc(N3CCN4CCC3CC4)cc21
Temperature: 90 °C
Yield: 36.1 %

Procedure:
A catalyst solution was prepared by mixing tris(dibenzylideneacetone)dipalladium (Pd2(dba)3; 15 mg, 0.016 mmol; Alfa) and racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 21 mg, 0.033 mmol; Strem) in toluene (1 mL) and heating the mixture to 90° C. for 15 min. The solution was cooled, and then added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (105 mg, 0.83 mmol; see J. Med. Chem. 1993, 36, 2311) and 3,7-dibromodibenzothiophene-5,5-dioxide (0.60 g, 1.60 mmol; see J. Med. Chem. 1978, 21, 1084), in toluene (3 mL). Cs2CO3 (1.04 g, 3.2 mmol; Aldrich) was then added, and the reaction mixture was flushed with nitrogen and heated to 80-85° C. overnight. After cooling to room temperature, the mixture was filtered through diatomaceous earth and purified by chromatography (35 g silica gel, 1-10% gradient of NH4OH-MeOH (1:10) in CH2Cl2) to afford the title compound (102 mg, 0.30 mmol, 36% yield): MS (DCI/NH3) m/z 341 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH2:28])[N:9]=1.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:44]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:46])=[O:45])[N:9]=1
Reactant: Nc1ccccc1Cn1nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(Cc2ccccc2)c1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=c1n(Cc2ccccc2NS(=O)(=O)c2ccccc2)nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1Cc1ccccc1

Procedure:
Prepared by the method analogous to that described for Example 12 using the compound of Example 3 and benzenesulfonyl chloride. The title compound was isolated as a white solid (70%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[C:7]([C:9](=[O:23])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:14][CH:13]=2)[CH:8]=1.C1C=CC2[N:39]([OH:40])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[C:7]([C:9](=[O:23])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH:39][OH:40])=[O:21])=[CH:14][CH:13]=2)[CH:8]=1
Reactant: On1nnc2ccccc21
Reactant: CN1CCN(c2ccc(Cl)cc2C(=O)/C=C/c2ccc(/C=C/C(=O)O)cc2)CC1
Agent: Cl
Agent: NOC1CCCCO1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCN(c2ccc(Cl)cc2C(=O)/C=C/c2ccc(/C=C/C(=O)NO)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
A mixture of (E)-3-(4-{(E)-3-[5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride (250 mg, 0.56 mmol), HOBT (139 mg, 1.03 mmol), EDC (196 mg, 1.03 mmol), TEA (0.568 ml, 4.08 mmol) and NH2OTHP (89 mg, 0.765 mmol) in DCM (5 ml) was stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between water and AcOEt. The phases were separated and the aqueous layer was brought to basic conditions with NH4OH and extracted with DCM. The collected organic extract were dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.1) and the resulting product was dissolved in DCM and treated with HCl/Et2O for 2.5 h. The precipitate was filtered and triturated with isopropanol and di-isopropylether to give 61 mg of (E)-3-(4-{(E)-3-[5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-N-hydroxy-acrylamide hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I[CH2:15][C:16](=[O:38])[C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C:31](=[CH:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH:27]=[CH:28]2)[CH2:23][CH2:22]3)[CH2:19][C@H:18]1[CH3:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16](=[O:38])[C@@H:17]3[C@:34]4([CH3:35])[C@H:20]([C@H:21]5[C:31](=[CH:32][CH2:33]4)[C@:29]4([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH:27]=[CH:28]4)[CH2:23][CH2:22]5)[CH2:19][C@H:18]3[CH3:37])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CI
Reactant: Clc1cccc(N2CCNCC2)c1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cccc(Cl)c2)CC1

Procedure:
Following the general procedure of EXAMPLES 1-6A, 7, 8, 11-19, 83, 126 and 139 and making non-critical variations but starting with 4-(3-chlorophenyl)piperazine (PREPARATION A-57) and 21-iodo-16αmethylpregna-1,4,9(11)-triene-3,20-dione (PREPARATION S-22), the title compound is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:9]=1)[NH2:6])[CH3:2].N1C(C)=CC=CC=1C.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>O1CCCC1.C(OCC)(=O)C.Cl>[C:28]1([O:27][C:25](=[O:26])[NH:6][C:5]2[CH:7]=[C:8]([C:10]3[N:14]([CH3:15])[N:13]=[N:12][N:11]=3)[CH:9]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1cc(N)cc(-c2nnnn2C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)aniline (3.83 g, 19 mmol) in tetrahydrofuran was treated with 2,6-lutidine (2.17 mL, 19 mmol) and cooled to 0° C. A solution of phenyl chloroformate (2.36 mL, 19 mmol) in tetrahydrofuran was added dropwise. The mixture was stirred for 1 hour, then was diluted with ethyl acetate and 0.1 N aqueous hydrochloric acid. The separated organic phase was washed twice with 0.1 N aqueous hydrochloric acid, then with saturated aqueous sodium chloride. The solution was dried over magnesium sulfate and concentrated under vacuum to provide a tan solid (6.00 g, quantitative). 1H NMR (300 MHz, CDCl3) δ7.86 (s, 1H), 7.5-7.3 (m, 5H), 7.3-7.1 (m, 3H), 4.17 (s, 3H), 2.71 (q, J=7 Hz, 2H), 1.27 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([O:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([F:14])([F:13])[F:12])[C:5]([O:7]C)=[O:6].[I-].[Li+].Cl>N1C=CC=CC=1>[CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([O:9][CH:10]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:11]([F:13])([F:14])[F:12])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(CC(C)C)OC(c1ccccc1)C(F)(F)F
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)CC(OC(c1ccccc1)C(F)(F)F)C(=O)O
Temperature: 140 °C

Procedure:
To a suspension of methyl 4methyl-2-(2,2,2-trifluoro-1-phenylethoxy)pentanoate from example 69 step 3 (0.63 mmol, 241 mg) in pyridine (7 mL), lithium iodide (1.26 mmol, 168 mg) was added and the mixture was heated at 140° C. for 24 h. The mixture was cooled to r.t. HCl 10% (20 mL) was added and HCl 12 N was added until pH 1. The mixture was extracted with ethyl acetate (50 mL) 3×. The combined extracts were dried over anhydrous MgSO4 and concentrated. The crude title acid was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([CH3:38])=[C:35](Br)[CH:36]=4)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([CH3:38])=[C:35]([C:8]5[CH:9]=[CH:10][CH:11]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:15])[CH3:1])[CH:7]=5)[CH:36]=4)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: CN(C)S(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1cccc(S(=O)(=O)N(C)C)c1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(3-(N,N-dimethylsulfamoyl)phenyl)-6-methylpyridin-3-yl)cyclopropanecarboxamide was prepared from 3-(N,N-dimethylsulfamoyl)phenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:36][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[C:14]=3[C:13]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:8][CH:7]=1.N#N.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[O:36][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[C:14]=3[C:13]=2[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:10][CH:11]=1
Reactant: COCCOc1ccc(-c2oc3ncnc(NCCN4CCN(C(=O)OC(C)(C)C)CC4)c3c2-c2ccccc2)cc1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1ccc(-c2oc3ncnc(NCCN4CCNCC4)c3c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl 4-(2-(6-(4-(2-methoxyethoxy)phenyl)-5-phenylfuro[2,3-d]pyrimidin-4-ylamino)ethyl)piperazine-1-carboxylate 35 (Prepared in a manner analogous to Steps 1-2 of Example 7; 60 mg, 0.104 mmol) was dissolved in CH2Cl2 (1.5 mL). After purging with N2, TFA (0.37 mL, 4.8 mmol) was added and the mixture was allowed to stir at RT for 4 h. The reaction mixture was concentrated to remove TFA then taken up in CH2Cl2 and washed with saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated. Preparative TLC (SiO2, 20% MeOH in CH2Cl2) afforded the title compound 36. Mass for C27H31N5O3 found: 474 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:25]>CO.C(O)(=O)C.[Pd]>[ClH:25].[C:15]1(=[O:24])[N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]12
Reactant: O=C1c2ccccc2C(=O)N1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1C1CCNCC1

Procedure:
16.0 Grams of 1-benzyl-4-phthalimido-piperidine were dissolved in 200 milliliters of 50% methanol/acetic acid and 25 milliliters of ethereal hydrogen chloride, and were hydrogenated at 60° C. and 60 psi in the presence of 2.0 grams of 10% palladium-on-charcoal catalyst. After 4 hours the reaction mixture was filtered while still hot and addition of ether gave 8.7 grams of 4-phthalimido-piperidine mono-hydrochloride. Melting point: 300° C. with decomposition.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[CH:18]=[CH:19][S:20][C:16]=3[C:15]3[CH:14]=[CH:13][C:12]([C:21]#[N:22])=[CH:11][C:10]=3[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:23]O.[OH-].[Na+].O>CN1C(=O)CCC1>[C:1]1([NH:7][C:8]2[C:17]3[CH:18]=[CH:19][S:20][C:16]=3[C:15]3[CH:14]=[CH:13][C:12]([C:21]([NH2:22])=[O:23])=[CH:11][C:10]=3[N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
4-(phenylamino)thieno[3,2-c]quinoline-7-carbonitrile (34 mg, 0.113 mmol) was dissolved in NMP (0.3 ml). 30% aqueous H2O2 (0.2 ml) was added followed by addition of 6N NaOH (50 ul). The mixture was stirred at 50° C. for 2 hours. An extra amount of 30% aqueous H2O2 (0.3 ml) and 6N NaOH (100 ul) were added and a 70% conversion was achieved after 30 min. Water was added and the solid filtered and dried. The material was further reacted under the same conditions in order to achieve a complete transformation. 4-(phenylamino)thieno[3,2-c]quinoline-7-carboxamide was isolated as solid (30 mg, 83% yield). LCMS (ES): 95% pure, m/z 320 [M+1]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]4[CH:32]=[C:31]([N+:33]([O-])=O)[C:30]([C:36]5[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH:41]=5)=[CH:29][C:28]=4[O:43][CH3:44])[N:20]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]4[CH:32]=[C:31]([NH2:33])[C:30]([C:36]5[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH:41]=5)=[CH:29][C:28]=4[O:43][CH3:44])[N:20]=3)=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)n1
Reaction time: 0.08 h
Yield: 140.2 %

Procedure:
A mixture of 4-[1-(benzenesulfonyl)indol-3-yl]-5-chloro-N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]pyrimidin-2-amine (Intermediate 9, 349 mg, 0.47 mmol), iron (157 mg, 2.82 mmol) and NH4Cl (17.60 mg, 0.33 mmol) in ethanol (9 mL) and water (3 mL) was heated at reflux for 1.5 h. The mixture was cooled and concentrated in vacuo. CH2Cl2 (20 mL) and CH3OH (2 mL) were then added and the mixture was stirred for 5 minutes and then filtered. The organic solution was washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (396 mg, 140%) as a green foam which was used without further purification. m/z: ES+ MH+ 601.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[CH3:21][C:22]1[N:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[N:23][C:22]([CH3:21])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: Cc1cnc(C(=O)O)cn1
Product: Cc1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OC(C)(C)C3(F)F)c2)cn1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-methyl-pyrazine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=408.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][C:21](C)(C)[CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:4][N:3]=1.[K+].[Br-]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C=Cc2cnc(N)c(C#N)c2)cc1
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1ccc(C=Cc2cnc(N)c(C#N)c2)cc1

Procedure:
By substituting an equivalent amount of 3-cyano-2-(4-nitrophenylthio)-5-[2-(4-tert-butoxycarbonylphenyl)ethenyl]pyridine in the foregoing procedure there is obtained 2-amino-3-cyano-5-[2-(4-tert-butoxycarbonylphenyl)ethenyl]pyridine, which can be alternatively named as 2-amino-3-cyano-5-(4-t-butoxycarbonylstyryl)pyridine; yield 1.14 g (84%) of light yellow crystals, mp 190°-195° C.; NMR (Me2SO-d6) delta 1.57(s, 9H), 6.57-6.60(m, 2H), 7.00(br, 2H), 7.35(d, 2H, J=8.1 Hz), 7.65(d, 1H, J=2.7 Hz), 7.84(d, 2H, J=2.7 Hz), 7.84(d, 2H, J=8.1 Hz), 8.00(d, 1H, J=2.7 Hz); IR (KBr) 3460, 3360, 2215, 1707, 1623, 1480, 1300, 1287, 1158 cm-1.