Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[C:5]([CH3:27])[CH:6]=[C:7]([CH:19]([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1>ClCCCl.C(Cl)Cl.CO.O=[Mn]=O>[Cl:1][C:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[C:5]([CH3:27])[CH:6]=[C:7]([C:19]([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)=[O:20])[CH:8]=2)[N:3]=1
Reactant: Cc1cc(C(O)c2cncn2C)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Solvent: ClCCCl
Product: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Temperature: 70 °C

Procedure:
A suspension of crude (2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (801 mg, assume 1.46 mmol, Intermediate 48, step a) in DCE (15 mL) was stirred at 70° C. until a milky mixture resulted with no visible particulates. This was cooled to room temperature and treated with MnO2 (1.27 g, 14.5 mmol), and stirred under air (capped) at 70° C. for 35 hours. The reaction was diluted with 9:1 DCM/MeOH (10 mL) and Celite®, filtered on a bed of Celite®, and concentrated to provide an oil. This was flash chromatographed with a DCM to 100% EtOAc gradient to afford the title compound as a white foam.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42](O)=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=3)=[CH:6][CH:5]=1.ClC1N=C(OC2CC3N(C(=O)N(C)CCCCC=CC4C(C([NH:84][S:85]([CH:88]5[CH2:90][CH2:89]5)(=[O:87])=[O:86])=O)(NC3=O)C4)C2)C2C(C=1)=CC(OC)=CC=2>>[F:48][C:2]([F:47])([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42]([NH:84][S:85]([CH:88]6[CH2:90][CH2:89]6)(=[O:87])=[O:86])=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=3)=[CH:6][CH:5]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccc(OC(F)(F)F)cc3)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccc(OC(F)(F)F)cc3)cc2c1

Procedure:
The title product 58 was prepared from 17-(3-(4-trifluoromethoxyphenyl)-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.0416]octadec-7-ene-4-carboxylic acid (57) following the same procedures described for the preparation of N-[17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (43, Example 11): m/z=772 (M+H)+; 1H-NMR (CDC3): 10.63-10.57 (br s, 1H), 8.00 (d, J=8.5 Hz, 2H), 7.94 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.01 (dd, J=9.0 Hz, 2.4, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.79-6.72 (bs, 1H), 5.98-5.92 (m, 1H), 5.67 (dd, J=7.8 Hz, J=18.9 Hz, 1H), 5.09 (t, J=10.4 Hz, 1H), 4.71 (t, J=8.1 Hz, 1H), 4.03 (dd, J=11.0 Hz, 4.0, 1H), 3.85 (s, 3H), 3.64 (d, J=11.0 Hz, 1H), 3.61-3.53 (m, 1H), 3.15-3.03 (m, 1H), 2.93-2.82 (m, 1H), 2.77 (s, 3H), 2.54-2.38 (m, 3H), 2.25-2.08 (m, 1H), 2.04-1.87 (m, 2H), 1.66-0.86 (m, 9H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:4]=2[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH3:30])[C:25]([OH:29])=[C:26]([Cl:28])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(=O)(O)[O-].[Na+]>[Cl:28][C:26]1[CH:27]=[C:22]([Cl:21])[CH:23]=[C:24]([CH3:30])[C:25]=1[O:29][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:4]=2[N:3]=1
Reactant: Cc1cc(Cl)cc(Cl)c1O
Reactant: CCC(CC)c1ccc(C(=O)OC)c2nc(Cl)n(C)c12
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)c1ccc(C(=O)OC)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Temperature: 110 °C
Yield: 83.1 %

Procedure:
A mixture of methyl 2-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carboxylate (1.15 g, 3.90 mmol), 4,6-dichloro-o-cresol (2.07 g, 11.70 mmol), potassium carbonate (2.16 g, 15.60 mmol) and N,N-dimethylformamide (15 ml) was heated at 110° C. for 5 h. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on alumina with a 15% ethyl acetate/n-hexane to give 1.41 g (3.24 mmol, 83%) of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1)([CH3:18])[CH3:17].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:24]=[CH:25][C:20]([NH:19][CH:16]([CH3:17])[CH3:18])=[N:21][CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(NC(C)C)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)Nc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, N-isopropyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][C:15]([OH:17])=[O:16])[CH:3]=1.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][C:15]([O:17][CH2:23][CH3:24])=[O:16])[CH:3]=1
Reactant: O=C(O)Cc1cc(Cl)ccc1-c1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(Cl)ccc1-c1ccccc1

Procedure:
A mixture composed of 900 mg (3.65 mmol) of (4-chlorobiphenyl-2-yl)acetic acid (J. Am. Chem. Soc. (1955), 77, 2325), 25 ml of absolute ethanol and 50 μl of concentrated sulfuric acid is refluxed for 8 hours. After cooling and concentrating under vacuum, the reaction medium is taken up in ether, washed with saturated NaHCO3 solution and then with water, and then dried over Na2SO4. After concentrating under vacuum, 1 g of a yellow oil is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[NH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][CH2:34]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:33]3[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][CH2:34]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: OCC1CCNCC1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCC(CO)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 4-piperidinemethanol. A yellow solid 101 was obtained (0.0299 g, 64%). 1H-NMR (CDCl3, 400 MHz) δ 1.41–1.50 (m, 2H), 1.86–1.94 (m, 1H), 1.97–2.03 (m, 2H), 3.27 (t, J=13.6 Hz, 2H), 3.57 (d, J=5.8 Hz, 2H), 3.83 (s, 3H), 4.38 (d, J=13.5 Hz, 2H), 6.93 (d, J=6.6 Hz, 1H), 6.97 (s, 1H), 7.01–7.07 (m, 3H), 7.46–7.52 (m, 3H), 7.84 (s, 1H), 8.24 (d, J=6.2 Hz, 1H); MS (APCI) m/z 475 (M+H)+.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:17])[CH2:8][O:9][Si](C(C)(C)C)(C)C)[C@H:4]([C:18]#[N:19])[CH2:3]1.O.C(O)(=O)C>O1CCCC1>[F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:17])[CH2:8][OH:9])[C@H:4]([C:18]#[N:19])[CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)N1C[C@@H](F)C[C@H]1C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CO
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 96.5 %

Procedure:
(2S,4S)-4-fluoro-1-[2-(tert-butyldimethylsilyloxy)acetyl]pyrrolidine-2-carbonitrile (5.50 g) was dissolved in tetrahydrofuran (37 mL). To this solution, water (37 mL) and acetic acid (115 mL) were sequentially added and the mixture was stirred at 50° C. for 7.5 hours and then at 70° C. for 9 hours. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting pale brown tar-like residue was triturated with diethyl ether. The resulting solid was collected by filtration and dried under reduced pressure to give (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile as a pale brown solid (3.19 g).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:48]=[CH:47][C:9]([O:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:24]([OH:39])[C:25]([N:27]2[CH2:38][CH2:37][CH2:36][C@H:28]2[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])=[O:13])=[CH:8][CH:7]=1)=[O:4].[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>>[O:52]1[CH2:53][CH2:54][N:49]([CH2:2][C:3]([NH:5][C:6]2[CH:48]=[CH:47][C:9]([O:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:24]([OH:39])[C:25]([N:27]3[CH2:38][CH2:37][CH2:36][C@H:28]3[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])=[O:13])=[CH:8][CH:7]=2)=[O:4])[CH2:50][CH2:51]1
Reactant: C1COCCN1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(NC(=O)CBr)cc1
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(NC(=O)CN2CCOCC2)cc1

Procedure:
Following a procedure similar to that described in Example 38, but using 100 mg (0.137 mmol) of 1-[(2S,3S)-3-[N2 -(4-bromoacetamidophenoxy)acetyl-L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide and 1 ml of morpholine, 70 mg of the title compound were obtained as a colorless powder, melting at 121°-127° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].[OH:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].N1C=CC=CC=1>ClCCCl.O.Cl[Cu]>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl[Cu]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: C=Cc1ccc(ON2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
To a stirred solution of 4-vinylphenylboronic acid (2 g, 13 mmol), 2-hydroxyisoindoline-1,3-dione (3.63 g, 24.53 mmol), and CuCl (1.214 g 12.26 mmol) in 1,2-dichloroethane (50 mL) was added pyridine (1.065 g, 13.48 mmol), and the resultant reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was diluted with H2O and extracted with CHCl3. The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 20% EtOAc in petroleum ether) afforded the title compound as a white solid (2 g, 63%): mp 129-131° C.; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=2.0 Hz, 2H), 7.82 (d, J=3.2 Hz, 2H), 7.38 (d, J=2.0 Hz, 2H), 7.14 (d, J=2.0 Hz, 2H), 6.70 (m, 1H), 5.83 (d, J=16.0 Hz, 1H), 5.22 (d, J=10.8 Hz, 1H); ESIMS m/z 266.12 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[C:12]([C:27]#[N:28])[CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C([O-])(O)=O.[Na+]>[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][N:18]=2)=[C:12]([CH:11]=1)[C:27]#[N:28]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)c(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(CCN)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92 %

Procedure:
Entire reaction was performed under argon atmosphere using syringe septa technique. {2-[3-cyano-4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.425 mmol, 1 eq) was dissolved in dichloromethane (1.5 ml) and stirred at 0° C. for 5 min. TFA (2.213 mmol, 5 eq) was added and stirring was continued for 2 hours. Reaction mixture was diluted with 10 ml NaHCO3 (sat.) and extraction with DCM (3×20 ml) followed. Organic layers were combined and evaporated in vacuo to give 5-(2-amino-ethyl)-2-(5-trifluoromethyl-pyridin-2-yloxy)benzonitrile (0.391 mmol, yield=92%, purity=80%). [M+H]+=308.29 1H NMR (300 MHz, CDCl3) δ/ppm 2.79 (br. s., 2H), 2.94-3.07 (m, 2H), 7.21 (br. s., 2H), 7.49 (d, J=8.9 Hz, 1H), 7.54 (br. s., 1H), 7.90-8.05 (m, 1H), 8.38 (br. s., 1H)
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[C:7](C(=O)C(F)(F)F)=[CH:6][N:5]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[O:22][C:21]3=[O:34])=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+]>CO.C(#N)C>[O:35]=[S:2]1(=[O:1])[CH:3]=[CH:4][N:5]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[O:22][C:21]3=[O:34])=[CH:18][CH:19]=2)[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(N3C=C(C(=O)C(F)(F)F)S(=O)(=O)CC3)cc2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(N3C=CS(=O)(=O)CC3)cc2)C(=O)O1

Procedure:
The crude sulfone prepared in Step 6 (6.7 mmol) is suspended in 220 mL of MeOH-acetonitrile (2:1) and heated to reflux. Solid K2CO3 (3.4 g, 25 mmol) is then added, and the mixture stirred at reflux for 2 h. Upon cooling, the solution is filtered and the filtrate concentrated. The residue is dissolved in 50 mL of EtOAc—2.5% aq. NaHCO3 (1:1), the layers separated, and the aqueous phase extracted with more ethyl acetate. The combined organic layers are washed with brine and dried (MgSO4), filtered and concentrated. The resulting crude product is purified by column chromatography (0–2% MeOH—CH2Cl2) provided the title compound as a foam.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]1([CH2:16][C:17]([NH2:19])=[S:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)C>N1C=CC=CC=1>[CH2:16]([C:17]1[S:18][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1csc(Cc2ccccc2)n1
Yield: 45.6 %

Procedure:
40 g of ethyl bromopyruvate were progressively added to a mixture of 30.2 g of phenylthioacetamide, 120 ml of ethanol and 20 ml of pyridine and the mixture was refluxed for 16 hours. The mixture was evaporated to dryness under reduced pressure and the residue was added to a water-ether mixture. The mixture was stirred and the decanted aqueous phase was extracted with ether. The combined organic phases were evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 7-3 hexane-ethyl acetate mixture yielded 22.5 g of ethyl 2-benzyl-thiazole-4-carboxylate melting at 78°-79° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:10])=[N:6][O:7][C:8]=1[NH2:9].[CH2:11]([C:13]1[S:21][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[C:14]=1[S:22](Cl)(=[O:24])=[O:23])[CH3:12]>C1COCC1>[Cl:3][C:4]1[C:5]([CH3:10])=[N:6][O:7][C:8]=1[NH:9][S:22]([C:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:21][C:13]=1[CH2:11][CH3:12])(=[O:24])=[O:23]
Reactant: Cc1noc(N)c1Cl
Reactant: CCc1sc2ncccc2c1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1sc2ncccc2c1S(=O)(=O)Nc1onc(C)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a mixture of NaH (38 mg, 1.6 mmoles) in THF (5 ml) at ambient temperature was added 4-chloro-3-methyl-5-amino isoxazole (84 mg, 0.63 mmoles). The mixture was stirred 1 hr. at ambient temperature then cooled to 0° C. followed by the addition of 2-ethylthieno[2,3-b]pyridine-3-sulfonyl chloride (0.19 g, 0.73 mmoles) via cannula in THF (2 ml). The cooling bath was removed and the brown mixture was stirred 1 hr. at ambient temperature and then diluted with 3% NaOH (50 ml) and washed with CHCl3 (2×75 ml). The aqueous layer was acidified to pH 4 using concentrated HCl, upon which a precipitate formed. The aqueous phase was extracted with EtOAc (50 ml), and the organic layer was dried (MgSO4), filtered and concentrated to collect 0.23 g of a yellow oil. Recrystallization from EtOAc/hexanes provided 0.18 g (79%) of the title compound as a light yellow solid, m.p. 152-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][N:8]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][N:8]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of tert-butyl (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxylate, 1b, (2.1 g, 3.5 mmol) in CH2Cl2 (30 mL) was added trifluoroacetic acid (20 mL). After stirring the reaction mixture at room temperature for 75 min, the mixture was concentrated under vacuo. The crude residue was diluted with EtOAc and neutralized with 1N sodium hydroxide solution. The aqueous phase was separated and extracted again with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated under vacuo to afford the desired product (1c) as a light yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[OH:12])[CH2:2][CH3:3].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[CH2:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:2][CH3:3]
Reactant: CCCc1c(O)ccc(Cl)c1Cl
Reactant: O=C(O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCCC(=O)O)ccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
A solution of 3.09 g. of 2-propyl-3,4-dichlorophenol, 3.1 g. of 7-bromoheptanoic acid, 3.1 g. of potassium carbonate, and 2.0 g. of potassium iodide in 50 ml. of methyl ethyl ketone was heated at reflux overnight. The reaction mixture was cooled to room temperature and evaporated in vacuo. Ethyl acetate and water were added to the residue and the layers were separated. Fresh water was added to the organic layer, the pH was adjusted to 2.0 with acid, and the layers were separated. The organic layer was washed with a saturated sodium chloride solution, filtered through sodium sulfate, and evaporated to dryness to give 4.68 g. of the desired title product.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:63]=[CH:64][CH:65]=1)[CH2:23][N:24]1[C:32]2[C:27](=[N:28][C:29](Cl)=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][O:45][Si:46]([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:39]=1)=[O:35])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:66]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[NH:67][C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:63]=[CH:64][CH:65]=1)[CH2:23][N:24]1[C:32]2[C:27](=[N:28][C:29]([N:66]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[NH:67][C:68]([O:70][C:71]([CH3:72])([CH3:73])[CH3:74])=[O:69])=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][O:45][Si:46]([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:39]=1)=[O:35])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](OCc1cccc(COC(=O)c2cc3nc(Cl)ccc3n2Cc2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)c1)(c1ccccc1)c1ccccc1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(=O)OCc3cccc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c3)n2Cc2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)n1
Temperature: 110 °C

Procedure:
3-({[tert-Butyl(diphenyl)silyl]oxy}methyl)benzyl 1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)benzyl]-5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (2.18 g, 2.38 mmol, from Step 3) and di-tert-butyl hydrazine-1,2-dicarboxylate (0.71 g, 3.1 mmol, Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.22 g, 0.28 mmol, Aldrich) and Cs2CO3 (0.91 g, 2.8 mmol) were combined in toluene (27 mL) and the mixture was degassed by a stream of nitrogen bubbled through the solution for 10 minutes. The reaction vessel was sealed and heated at 110° C. for 3 hours. The reaction mixture was partitioned between water and ethyl acetate, the aqueous layer was extracted three times and the combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-25% EtOAc/hexanes. Yield: (1.31 g, 50%).
Reaction SMILES: [CH:1]1([C:7](=[O:19])[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:7]2[O:19][C:12]3[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:11]=3[C:9](=[O:10])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cccc(C(=O)CC(=O)C2CCCCC2)c1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc2c(=O)cc(C3CCCCC3)oc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Cyclohexyl-3-(2-hydroxy-3-methylphenyl)-1,3-propanedione (5.2 g) was dissolved in dichloromethane (50 ml). Trifluoroacetic acid (4 ml) was added to the solution and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate and then water and dried (MgSO4). The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (4:1)) to obtain the title compound as crystals. The crystals were recrystallized from ethyl acetate and hexane to obtain prisms (3.66 g), m.p. 108°-109° C., yield 75.6%.