Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:16]=[CH:15][O:14][CH:13]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][Mg+].[Br-].[NH4+].[Cl-].O>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[O:14]1[CH:15]=[CH:16][C:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:17])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:13]1
Reactant: Clc1ccc2c(-c3ccoc3)ccnc2c1
Reactant: C[Mg+]
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc2c(-c3ccoc3)ccnc2c1
Temperature: 30 °C

Procedure:
To a mixture of 7-chloro-4-(furan-3-yl)quinoline (30.2 g) and [1,3-bis(diphenylphosphino)propane]nickel (II) chloride (7.1 g) in Et2O (950 mL) was added MeMgBr (141 mL, 1.4M in 3:1 THF:toluene) at such a rate to maintain a temperature of 30° C. The mixture was refluxed for 30 min., cooled to 0° C. and saturated NH4Cl (200 mL) was added followed by H2O (100 mL). The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were washed with NH4OAc buffer, brine, dried (MgSO4) and concentrated. Chromatography (silica gel;EtOAc/hexane (3:7)) provided the title compound as a beige oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:14](=[O:19])[C:15]=2[C:16](O)=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:31])=O>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:14](=[O:19])[C:15]=2[C:16]([Cl:31])=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: Cn1c(-c2ccc(C(C)(C)C)cc2)c(C(=O)O)c(=O)n1-c1ccc(C#N)cc1
Product: Cn1c(-c2ccc(C(C)(C)C)cc2)c(C(=O)Cl)c(=O)n1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 12.1 g of 3-(4-t-butylphenyl)-1-(4-cyanophenyl)-4-hydroxycarbonyl-2-methyl-2H-pyrazol-5-one and 100 ml of thionyl chloride was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized in a liquid mixture of n-hexane-toluene to give 14.0 g of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:9]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:8][CH2:7][C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:9]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:8][CH2:7][C:6]1=[S:28]
Reactant: COC(=O)CN1C(=O)CN=C(c2c(F)cccc2F)c2cc(Cl)ccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CN1C(=S)CN=C(c2c(F)cccc2F)c2cc(Cl)ccc21

Procedure:
A mixture of 0.01 mole of 7-chloro-5-(2,6-difluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for about 24 hours. The reaction mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-chloro-5-(2,6-difluorophenyl)-2,3-dihydro-2-thioxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.ClC[C:35]1[C:36](C)=[N:37][O:38][C:39]=1[CH3:40]>ClCCl>[CH3:35][C:36]1[C:2]([CH2:1][O:4][C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=4[C:11]([NH2:15])=[N:12][C:13]=3[CH:14]=2)=[C:39]([CH3:40])[O:38][N:37]=1
Reactant: Cc1noc(C)c1CCl
Reactant: CCCc1nc2c(N)nc3cc(OC(C)=O)ccc3c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1nc2c(N)nc3cc(OCc4c(C)noc4C)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
A mixture of 4-amino-2-propylthiazolo[4,5-c]quinolin-7-ol acetate (318 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 4-(Chloromethyl)-3,5-dimethylisoxazole (160 mg, 1.1 mmol) was added dropwise over a period of 10 minutes. After 3 hours an additional equivalent of cesium carbonate was added in a single portion followed by the dropwise addition of an equivalent of 4-(chloromethyl)-3,5-dimethylisoxazole. After 1 additional hour the heat source was removed; the reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-5% methanol in dichloromethane for over 1000 mL and then with 5% methanol in dichloromethane over 400 mL. The resulting solid was recrystallized from acetonitrile to provide 156 mg of 7-[(3,5-dimethylisoxazol-4-yl)methoxy]-2-propylthiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 178.0-180.0° C. MS (ESI) m/z 369 (M+H)+; Anal. calcd for C19H20N4O2S: C, 61.94; H, 5.47; N, 15.21. Found C, 61.98; H, 5.25; N, 15.26.
Reaction SMILES: [H-].[Na+].C1COCC1.[CH2:8]([OH:12])[CH2:9][CH2:10][CH3:11].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)#[N:14]>O.CN(C=O)C>[CH2:8]([O:12][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCO
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCOCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of NaH (270 mg/66% in oil) and THF (20 mL) was added n-butanol (1.1 mL) at 0° C., which was stirred for 45 minutes at room temperature. The reaction mixture was cooled to 0° C., and a mixture of 4-cyanobenzyl bromide (1.5 g) and THF (10 mL) was added by drops thereto at the same temperature. The reaction mixture was stirred for 3 hours at room temperature, after which DMF (10 mL) was added to the reaction mixture, which was stirred for 4.5 hours at the same temperature. Water was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was washed with saturated brine, after which the solvent was evaporated from the organic layer under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:6) to obtain the titled compound (1.2 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15](I)[C:16]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)C.O>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:16]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Ic1cccc2c1C1CC2CN(Cc2ccccc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: c1ccc(CN2CC3CC(C2)c2c(-c4ccccc4)cccc23)cc1
Temperature: 90 °C
Yield: 55.3 %

Procedure:
(For a discussion, see: Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.) 10-Benzyl-3-iodo-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene (375.3 mg, 1.0 mmol), potassium acetate (785 mg, 8.0 mmol) and phenyl boronic acid (183 mg, 1.5 mmol) were combined in 10/1 ethanol/H2O (5 mL). The mixture was degassed (3 vacuum/N2 cycles), treated with tetrakis(triphenylphosphine)palladium(0) (57.5 mg, 0.05 mmol) and warmed to 90° C. for 18 h. The reaction was cooled, diluted with H2O and extracted with Et2O (3×50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), filtered and concentrated to provide an oil (180 mg, 55%). (TLC 4% ethyl acetate/hexanes Rf 0.18). GCMS m/e 325 (M)+.
Reaction SMILES: C1(C)C=CC(C2OC3C=CC=CC=3C=2)=CC=1.C(Cl)(=O)C1C=CC(OC)=CC=1.C[O:29][C:30]1[CH:53]=[CH:52][C:33]([C:34]([C:36]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[O:38][C:37]=2[C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)=[O:35])=[CH:32][CH:31]=1>>[OH:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([C:36]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[O:38][C:37]=2[C:45]2[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=2)=[O:35])=[CH:52][CH:53]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(C)cc3)oc3ccccc23)cc1
Agent: COc1ccc(C(=O)Cl)cc1
Agent: Cc1ccc(-c2cc3ccccc3o2)cc1
Product: Cc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(O)cc2)cc1

Procedure:
3-(4-Hydroxybenzoyl)-2-(4-tolyl)benzofuran is prepared by acylation of 2-(4-tolyl)benzofuran with p-anisoyl chloride followed by demethylation of the 3-(4-methoxybenzoyl)-2-(4-tolyl)benzofuran thus formed as described in the procedure of Example 5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.500 g, 2.67 mmol) in DCM (6.7 mL) was cooled to 0° C. and charged with triethylamine (0.45 mL, 3.20 mmol), methanesulfonyl chloride (0.23 mL, 2.90 mmol), and 4-dimethylaminopyridine (3.0 mg, 0.03 mmol) and stirred at rt for 6 h. The reaction mixture was partitioned between CHCl3 and sat. NaHCO3 and separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined organic fractions were washed with sat. NaHCO3 (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo resulting in the title compound as a pale yellow oil. This material was taken on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.47 (s, 9H), 2.06-2.39 (m, 2H), 3.05 (s, 3H), 3.38-3.82 (m, 4H), 5.27 (t, J=4.4 Hz, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)C1C=CC=CC=1.[C:17](=[O:28])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])OC(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(O)C.[Pd]>[C:17]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:28]
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of 1-benzyl-3,3-dimethylpiperidin-4-one (0.217 g, 1.00 mmol, 1.0 eq) in ethyl acetate-ethanol (1:1, 10 mL) was added palladium on carbon (approximately 0.100 g). The reaction was purged with nitrogen followed by hydrogen and stirred under an atmosphere of hydrogen for 1 hour. The reaction was purged with nitrogen and di-tert-butyl carbonate (0.327 g, 1.50 mmol, 1.5 eq) and sodium carbonate (0.212 g, 2.00 mmol, 2.0 eq) were added. The solution was stirred at room temperature for 1.5 hours and the reaction filtered through Celite®, eluting with EtOAc (4×20 mL). The filtrate was concentrated under reduced pressure. MPLC (15→50% EtOAc-hexane) yielded the title compound (0.206 g, 91%) as a white solid; 1H nmr (CDCl3) δ 3.69 (2H, dd, J 6.5, 6.0 Hz, pipH-6), 3.40 (2H, s, pipH-2), 2.46 (2H, t, J 6.5 Hz, pipH-5), 1.46 (9H, s, C(CH3)3), 1.08 (6H, s, 2×CH3); 13C nmr (CDCl3) δ 177.2, 154.7, 80.1, 54.9, 46.5, 43.4, 37.6, 28.3, 22.4; m/z 172 [M+H—C4H8]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: CN1CCC(N)CC1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Amino-3-Fluorobenzoic acid (Fluorochem; 1 g, 6.44 mmol), 4-Amino-1-methylpiperidine (Fluorochem; 811 mg, 7.09 mmol), HATU (2.70 g, 7.09 mmol), DIPEA (3.4 mL, 19.32 mmol) and DMF (15 mL) were combined and stirred for 18 hrs at room temperature. The solvent was evaporated and the resultant material dissolved in DCM (with a little MeOH to aid solubility) and chromatographed on silica eluting with a gradient of 0-10% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to give an orange solid which was dissolved in MeOH and added to a 50 g SCX-2 column pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated to yield the title compound as a beige solid. (1.72 g, 100%)
Reaction SMILES: [NH2:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:3]=1[C:4](N(OC)C)=[O:5].[CH2:16](OCC)C.Cl>C1COCC1.O>[NH2:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:3]=1[C:4](=[O:5])[CH3:16]
Reactant: CCOCC
Reactant: CON(C)C(=O)c1c(Cl)ccc(Cl)c1N
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1c(Cl)ccc(Cl)c1N
Yield: 27.7 %

Procedure:
2-Amino-3,6-dichloro-N-methoxy-N-methyl-benzamide (2491 mg, 10 mmol) were dissolved in THF (100 ml). At −78° C. under nitrogen 1.6 M methyllithium solution in diethylether (25.0 ml, 40 mmol) were added dropwise and the reaction was allowed to reach room temperature and was stirred over night. The reaction was cooled in an icebath and 2N aqueous hydrogen chloride solution (30 ml) were added and the reaction was stirred for 30 min (r.t.). The reaction was diluted with water and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (CH2Cl2) to yield the product as an orange oil (565 mg, 28%).
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](=[O:29])SC2C=CC=CN=2)=[CH:3]1.[C:30]([NH2:34])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([NH:34][C:21]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C:4](=[CH:3][C:2](=[O:1])[CH2:19][CH2:18]1)[CH2:5][CH2:6]3)=[O:29])([CH3:33])([CH3:32])[CH3:31]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Following a procedure similar to that described in Example 2(b), but using 9.77 g of S-2-pyridyl 3-oxo-4-androstene-17β-thiocarboxylate [prepared as described in Example 2(a)] and 14 ml of t-butylamine, 8.9 g of the title compound were obtained.
Reaction SMILES: C1C2C(COC(=O)N[C@H](C([N:25]3[C:29]4=[N:30][CH:31]=[C:32](Br)[CH:33]=[C:28]4[C:27]([C@@H:35]([C:37]4[C:42]([Cl:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=4[Cl:45])[CH3:36])=[CH:26]3)=O)CC(C)C)C3C(=CC=CC=3)C=2C=CC=1.Cl.CC1(C)C(C)(C)OB([C:56]2[CH:57]=[N:58][N:59]([CH:61]3[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]3)[CH:60]=2)O1.ClC1C=CC=C(Cl)C=1C(C1C2C(=NC=C(C3C=NN(C4CCNCC4)C=3)C=2)NC=1)C>>[Cl:45][C:38]1[C:39]([F:44])=[CH:40][CH:41]=[C:42]([Cl:43])[C:37]=1[C@H:35]([C:27]1[C:28]2[C:29](=[N:30][CH:31]=[C:32]([C:56]3[CH:57]=[N:58][N:59]([CH:61]4[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]4)[CH:60]=3)[CH:33]=2)[NH:25][CH:26]=1)[CH3:36]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)n1cc([C@H](C)c2c(Cl)ccc(F)c2Cl)c2cc(Br)cnc21
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Agent: CC(c1c(Cl)cccc1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Agent: Cl
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12

Procedure:
((S)-1-{5-Bromo-3[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]-pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methylbutyl)carbamic acid 9H-fluoren-9-ylmethyl ester was treated with 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyrazol-1-yl]piperidine hydrochloride according to typical Suzuki coupling procedure described for synthesis of 3-[1-(2,6-Dichlorophenyl)ethyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine in example 1, to give the title compound. 1H NMR (400 MHz, DMSO-d6): δ=1.70-1.80 (m, 2H), 1.83 (d, J=7.1 Hz, 3H), 1.94 (dd, J=11.6, 2.0 Hz, 2H), 2.08 (br s, 1H), 2.57 (td, J=12.3, 2.3 Hz, 2H), 3.03 (ddd, J=12.6, 2.9, 2.7 Hz, 2H), 4.17 (tt, J=11.6, 4.1 Hz, 1H), 5.16 (q, J=7.2 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.36-7.44 (m, 2H), 7.48-7.65 (m, 1H), 7.56 (d, J=0.5 Hz, 1H), 8.03 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 11.51 (d, J=1.8 Hz, 1H). MS (ES+): m/z 458.07/460.05 (100/70) [MH+]. HPLC: tR=2.53 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:46]([OH:48])=[O:47])[NH:17][C:18](=[O:45])[CH2:19][CH2:20][C@H:21]([C@@H:23]2[C@:40]3([CH3:41])[C@H:26]([C@H:27]4[C@H:37]([CH2:38][C@@H:39]3[OH:42])[C@:35]3([CH3:36])[C@@H:30]([CH2:31][C@H:32]([OH:43])[CH2:33][CH2:34]3)[CH2:29][C@H:28]4[OH:44])[CH2:25][CH2:24]2)[CH3:22])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:50]1(C)C=CC(S(O)(=O)=O)=CC=1.CCN(CC)CC>CO>[CH3:50][O:47][C:46](=[O:48])[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:10])[NH:17][C:18](=[O:45])[CH2:19][CH2:20][C@H:21]([C@@H:23]1[C@:40]2([CH3:41])[C@H:26]([C@H:27]3[C@H:37]([CH2:38][C@@H:39]2[OH:42])[C@:35]2([CH3:36])[C@@H:30]([CH2:31][C@H:32]([OH:43])[CH2:33][CH2:34]2)[CH2:29][C@H:28]3[OH:44])[CH2:25][CH2:24]1)[CH3:22]
Reactant: C[C@H](CCC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 429.3 %

Procedure:
A solution of N6 -(phenylmethoxy)carbonyl-N2 -[(3α,5β,7α,12α)-3,7,12-trihydroxy-24-oxocholan-24-yl]-L-lysine 27.5 g) in MeOH (600 ml), kept at room temperature and under nitrogen atmosphere, was added to p-toluenesulfonic acid monohydrate (1.56 g; 8.2 mmol). After 20 h the reaction mixture was added to Et3N (0.832 g; 8.2 mmol). The mixture was evaporated under reduced pressure and the resulting crude was purified by flash chromatography to obtain the desired product (24.1 g; 35.2 mmol).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:21]([NH:23][CH3:24])=[O:22]>>[CH3:27][CH:26]([CH3:28])[CH2:25][C@H:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:21](=[O:22])[NH:23][CH3:24]
Reactant: CNC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and (2S)-2-amino-N,4-dimethyl-pentanamide monohydrochloride (CAN 99145-71-8) as starting materials, and isolated (67 mg, 87%) as off-white solid; LC-MS (UV peak area, ESI) 100%, 361.2232 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]3[S:23][CH:24]=[C:25]([CH:27]4[CH2:30][CH2:29][CH2:28]4)[N:26]=3)[CH:15]=2)=[O:12])=[C:6]([O:31][CH3:32])[CH:5]=1.O1CCCC1.O.[OH-].[Li+]>CO>[CH:27]1([C:25]2[N:26]=[C:22](/[CH:21]=[CH:20]/[C:16]3[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:33])=[O:2])=[CH:5][C:6]=4[O:31][CH3:32])[CH:19]=[CH:18][CH:17]=3)[S:23][CH:24]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1ccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1CC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1

Procedure:
A solution of 0.57 g of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]-3-methoxybenzoic acid methyl ester, 25 ml of tetrahydrofuran, 8 ml of methanol and 0.28 g of lithium hydroxide monohydrate was stored at 25° C. for 20 hr. The solvents were removed by rotary evaporation and the residual materials solubilized in 50 ml of water. Acetic acid was added and the precipitate of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]-3-methoxybenzoic acid was isolated by filtration, m.p. 242°-243° C. after trituration with hot acetonitrile.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH2:19]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[CH2:19]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]2[C:10]3[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:17])[CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC1CCNCC1
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(OC)cc32)CC1
Yield: 40.9 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.636 g, 1.77 mmol) and 4-butylpiperidine (0.226 g, 1.6 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF38) (0.245 g, 27%). 1H NMR (CDCl3) δ 6.89 (d, J=8.8 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.50 (dd, J=2.8, J=8.8 Hz, 1H), 4.54 (q, J=32.4, J=14.8, 2H), 3.94-3.90 (m, 2H), 3.77 (s, 3H), 2.90 (d, J=11.2 Hz, 1H), 2.72 (d, J=10.8 Hz, 1H), 2.25-2.10 (m, 3H), 1.93 (t, J=11.2 Hz, 1H), 1.80 (t, J=11.2 Hz, 1H), 1.61 (d, J=10.8 Hz, 2H), 1.31-1.19 (m, 9H), 0.90-0.86 (m, 6H); 13C NMR (CDCl3) δ 165.3, 155.5, 139.7, 129.8, 117.2, 107.1, 103.3, 68.0, 64.2, 55.9, 55.7, 54.5, 45.5, 36.5, 36.0, 32.9, 32.5, 29.2, 29.2, 23.1, 16.9, 14.3.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[C:18]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1cncc(-c2cccc(C(F)(F)F)c2)c1

Procedure:
10.0 g (46.3 mmol) of methyl 5-bromonicotinate and 10.6 g (55.5 mmol) of 3-trifluoromethylphenylboronic acid were reacted according to the General Method 1A. Yield: 11.9 g (91% of theory)