Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH3:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:28]([N:36]2[CH2:48][CH2:47][C:46]3[N:45]4[C:40]([CH2:41][CH2:42][CH2:43][CH2:44]4)=[CH:39][C:38]=3[C:37]2=[O:49])=[N:29][CH:30]=[CH:31][C:32]=1B(O)O)(=[O:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].C(#N)C.O>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:36]2[CH2:48][CH2:47][C:46]3[N:45]4[C:40]([CH2:41][CH2:42][CH2:43][CH2:44]4)=[CH:39][C:38]=3[C:37]2=[O:49])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH3:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: CN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CN(C)C4)cn3)c(=O)n(C)c2)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Temperature: 100 °C
Yield: 37 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 5-bromo-1-methyl-3-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)pyridin-2(1H)-one 239c (140 mg, 0.40 mmol), 244c (230 mg, 0.60 mmol), Pd(dppf)Cl2 (20 mg, 0.020 mmol), K3PO4 (180 mg, 0.80 mmol), sodium acetate.3 water (120 mg, 0.80 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified on silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 244d as a yellow solid (90 mg, 43%). MS-ESI: [M+H]+ 608.3
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:11][C:10]=1[N:26]([S:32]([NH:35]C(OC(C)(C)C)=O)(=[O:34])=[O:33])[CH2:27][C:28]([O:30]C)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:35][S:32]([N:26]([C:10]1[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:27][C:28]([OH:30])=[O:29])(=[O:33])=[O:34]
Reactant: COC(=O)CN(c1ccc(OCC(=O)OCC[Si](C)(C)C)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCOC(=O)COc1ccc(N(CC(=O)O)S(N)(=O)=O)c(OCc2ccccc2)c1

Procedure:
A solution of methyl N-(2-(benzyloxy)-4-{2-oxo-2-[2-(trimethylsilyl)ethoxy]ethoxy}phenyl)-N-{[(tert-butoxycarbonyl)amino]sulfonyl}glycinate (1.15 g, 1.84 mmol) in 20 mL of TFA/methylene chloride (1:1) is stirred at RT for 30 min. The solvent is removed under reduced pressure and the residue is dissolved in methylene chloride and the solvent evaporated (4×) to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].IC.[H-].[Na+].[C:32](OCC)(=O)C>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH3:32])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.00 g) and iodomethane (0.87 mL) in N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.17 g), and the mixture was stirred at room temperature for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.95 g, 91%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH:15]=[O:16])[CH:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH:15]=[O:16])[CH:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(C=O)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(C=O)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.38 g (1.7 mmol) of methyl 3-tert-butyl-5-formylbenzoate [for the preparation, see, for example, WO 2008/089034-A2, intermediate K/step 1] were initially charged in 20 ml of water, 0.5 g of lithium hydroxide monohydrate were added and the mixture was stirred at RT for 1 h. The reaction solution was then adjusted to pH 2 with 1 M hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated on a rotary evaporator. This gave 0.31 g (87% of theory) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][CH2:4][C@H:3]1[NH:6][C:7]1[C:8]([CH3:27])=[N:9][C:10]2[C:15]([N:16]=1)=[C:14]([C:17]1[NH:25][C:24]3[CH2:23][CH2:22][NH:21][C:20](=[O:26])[C:19]=3[CH:18]=1)[CH:13]=[CH:12][CH:11]=2.CCN(C(C)C)C(C)C.[CH3:37][C:38](OC(C)=O)=[O:39]>C(Cl)Cl>[CH3:27][C:8]1[C:7]([NH:6][C@H:3]2[CH2:4][CH2:5][C@H:2]2[NH:1][C:38](=[O:39])[CH3:37])=[N:16][C:15]2[C:10]([N:9]=1)=[CH:11][CH:12]=[CH:13][C:14]=2[C:17]1[NH:25][C:24]2[CH2:23][CH2:22][NH:21][C:20](=[O:26])[C:19]=2[CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CC[C@@H]1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1CC[C@@H]1Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 51 %

Procedure:
Prepared according to Example 50, using rac-2-(3-((cis-2-aminocyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Ex. 54, 120 mg, 0.331 mmol) and DIPEA (0.173 ml, 0.993 mmol, and Ac2O (0.034 ml, 0.364 mmol) in DCM (13.2 mL, and stirring at 25° C. for 2.5 h. Purification by column chromatography (silica gel) provided rac-N-(cis-2-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-quinoxalinyl)amino)cyclobutyl)acetamide (68.3 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91-11.99 (1H, m) 8.20-8.24 (1H, m) 7.88 (1H, d, J=1.00 Hz) 7.55-7.60 (1H, m) 7.49-7.53 (1H, m) 7.34 (1H, t, J=1.00 Hz) 7.30 (1H, s) 7.03 (1H, s) 4.48-4.59 (2H, m) 3.44-3.51 (2H, m) 2.84-3.02 (3H, m) 2.54 (3H, s) 2.25-2.35 (1H, m) 2.09-2.19 (1H, m) 1.91 (1H, s) 1.70 (1H, s) 1.58-1.67 (1H, m). m/z (ESI, +ve) 405.2 (M+H)+.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3]([O:5][CH3:6])=[O:4].[SH:25][CH2:26][CH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[S:25][CH2:26][CH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1
Reactant: SCCc1nnn[nH]1
Reactant: CCCCCCCCCCCCc1ccccc1C(Cl)C(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCc1ccccc1C(SCCc1nnn[nH]1)C(=O)OC
Reaction time: 18 h

Procedure:
A mixture of methyl 2-chloro-2-(2-dodecylphenyl)acetate (0.615 g, 1.75 mmol), 5-(2-mercaptoethyl)tetrazole (0.227 g, 1.75 mmol), and triethylamine (0.48 ml, 3.5 mmol) in 20 ml of methylene chloride was stirred 18 hours at 22° and the solvent was evaporated. The residue taken up in diethyl ether, washed with 1N hydrochloric acid, dried and the solvent removed. The residue was chromatographed over a silica gel column. Impurities were eluted with ethyl acetate/hexane (1:3), and the product was eluted with methanol/ethyl acetate (1:19). Evaporation of the solvents from these functions gave the desired product, 0.570 g (73%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>O1CCCC1>[O:1]([C:8]1[N:9]=[CH:10][C:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[O:17][N:16]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2ccccc2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccccc4)nc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 1.08 h
Yield: 96.5 %

Procedure:
To a solution of (2-phenoxy-pyridin-5-yl)-acetohydroximoyl chloride (59.1 mg, 225 μmol) described in Manufacturing Example 40-1-4 and 3-ethynyl-pyridin-2,6-diamine (20.0 mg, 150 μmol) described in Manufacturing Example 13-1-3 in tetrahydrofuran (1.3 mL) was added triethylamine (41.8 μL, 300 μmol) at room temperature, which was stirred for 65 minutes at 50° C. The reaction solution was allowed to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (52 mg, 97%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH:10]([CH2:28][CH3:29])[CH2:9]1)=O)(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[CH2:28]([CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:29]
Reactant: NCCc1ccc(O)cc1
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CCC1CNCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 130 was coupled with tyramine following procedure F. The product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.35 (s, 1H) 8.29 (d, 2H) 8. 7.81 (d, 1H) 7.68 (t, 1H) 7.49 (d, 1H) 7.2-7.2 (m, 3H) 6.68 (d, 2H) 4.8 (d, 1H) 4.17 (d, 1H) 3.85 (br s, 2H) 3.68 (d, 1H) 3.1-3.6 (m, 6H) 2.9 (t, 2H) 2.2 (m, 1H) 1.9 (m, 1H) 1.1 (t, 3H).
Reaction SMILES: [CH2:1]([C:8]1[NH:29][C:11]2=[N:12][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])[CH2:17]3)=[CH:14][CH:15]=[C:10]2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:30]1CCOCC1>[O-2].[Mn+4].[O-2]>[C:1]([C:8]1[NH:29][C:11]2=[N:12][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])[CH2:17]3)=[CH:14][CH:15]=[C:10]2[N:9]=1)(=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([C@@H]1CCCN(c2ccc3nc(Cc4ccccc4)[nH]c3n2)C1)N1CCCC1
Reactant: C1COCCO1
Agent: [Mn+4]
Agent: [O-2]
Product: O=C(c1ccccc1)c1nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2[nH]1
Temperature: 120 °C

Procedure:
Manganese (IV) oxide (2 g) was added to a solution of (R)-(1-(2-benzyl-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (200 mg, 0.51 mmol) in dioxane (30 mL). After heating at 120° C. for 48 h in a sealed tube, the mixture was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was concentrated in vacuo and the resulting residue was purified via preparative TLC to afford (R)-(1-(2-benzoyl-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (80 mg). MS (ES+APCI) (M+H) 404.1; LCMS retention time 2.855 min (Method G).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:32]=[CH:31][C:18]3[N:19]([CH3:30])[C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[N:21][C:17]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O.O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20]2[N:19]([CH3:30])[C:18]3[CH:31]=[CH:32][C:15]([O:14][C:12]4[CH:11]=[CH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:13]=4)=[CH:16][C:17]=3[N:21]=2)=[CH:24][CH:25]=1
Reactant: Cn1c(Nc2ccc(F)cc2)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1c(Nc2ccc(F)cc2)nc2cc(Oc3ccnc(C(=O)O)c3)ccc21

Procedure:
A stirring solution of 4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid tert-butyl ester in trifluoroacetic acid was treated with two drops of water at room temperature for 3-4 hours or when the reaction was determined to be complete by HPLC. The reaction was evaporated under reduced pressure and then ether was added to the residue, which was then sonicated for 30 minutes. Filtration and washing with ether yields the desired acid in quantitative yield. LCMS m/z 379.4 (MH+), tR=1.74 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([N:33]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[CH3:32])=[O:22])=[CH:17][C:9]1=2
Reactant: CNCc1ccccc1OC
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: COc1ccccc1CN(C)C(=O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with N-methyl-2-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=580.94 (M+H+); retention time=0.96 minutes.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=4)[CH:25]=3)[CH2:21][C:20](=[O:37])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C(F)(F)F)c(C)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (4-methyl-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M70) (0.32 g, 0.61 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off white solid (120 mg, 48%).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@:8]([CH3:24])([CH2:14][O:15]C(=O)C2C=CC=CC=2)[O:7][C@H:6]1[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][CH:28]=[N:29][C:30]=2[NH2:34])(=O)C>N>[CH3:24][C@:8]1([CH2:14][OH:15])[O:7][C@@H:6]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[C@H:5]([OH:4])[C@@H:9]1[OH:10]
Reactant: CC(=O)O[C@H]1[C@H](n2cnc3c(N)ncnc32)O[C@](C)(COC(=O)c2ccccc2)[C@H]1OC(C)=O
Agent: N
Product: C[C@]1(CO)O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Yield: 94.7 %

Procedure:
A solution of 20 (970 mg, 2.08 mmol) in methanolic ammonia (previously saturated at −10° C.) (50 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride (100 ml) and water (100 ml). The aqueous layer was washed with methylene chloride (2×100 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (10–30%) in ethyl acetate] to afford pure 21 (554 mg, 95%). Crystallization from methanol/ethyl acetate gave 21 as a white solid. Mp: 96–97 (dec.); 1H-NMR (DMSO-d6): δ 8.33 (s, 1H, H-2), 8.13 (s, 1H, H-8), 7.36 (brs, 2H, NH2), 5.84 (d, 1H, H-1′, J1′-2′=7.4 Hz), 5.69 (dd, 1H, OH-5′, J=4.2 Hz and J=7.8 Hz), 5.33 (d, 1H, OH-2′, J=6.6 Hz), 5.13 (d, 1H, OH-3′, J=4.4 Hz), 4.86 (m, 1H, H-2′), 4.04 (t, 1H, H-3′), 3.58–3.32 (m, 2H, H-5′ and H-5″), 1.15 (s, 3H, CH3); MS (matrix GT): FAB>0 m/z 563 (2M+H)+, 374 (M+G+H)+, 282 (M+H)+, 136 (B+2H)+, FAB<0 m/z 561 (2M−H)−, 280 (M−H)−, 134 (B)−.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[CH3:6][C:7]1[N:8]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=1>O1CCCC1>[CH3:2][C:1]([CH3:4])([CH3:3])[CH:12]([C:10]1[N:11]=[C:7]([CH3:6])[N:8]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:9]=1)[OH:13]
Reactant: Cc1nc(C=O)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1nc(C(O)C(C)(C)C)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyllithium (1.7 M in pentane) (1.7 mL, 2.8 mmol) was added slowly to an ambient temperature solution of 2-methyl-1-trityl-1H-imidazole-4-carboxaldehyde in tetrahydrofuran (10 mL) at 0° C. After stirring at ambient temperature for 2 h, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded 2,2-dimethyl-1-(2-methyl-1-trityl-1H-imidazol-4-yl)propan-1-ol.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[C:24]([C:32](O)=O)[N:23]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[N:25]=[C:24]([C:32]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=4)[N:14]=3)[N:23]=2)=[CH:20][CH:21]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)n2)cc1

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.16 g, 0.75 mmol) and 4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.15 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.038 g, 16%). MS (ISN) 480.1 [(M−H)−]; mp 289.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:14]([CH2:28][CH2:29][CH3:30])[C:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25](I)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:16])[CH2:12][CH3:13]>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[CH2:28]([N:14]([CH2:11][CH2:12][CH3:13])[C:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:16])[CH2:29][CH3:30]
Reactant: c1cscn1
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2nccs2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a −78° C. solution of thiazole (1.2 g) in THF (25 mL) was added n-butyl lithium (1.6 M in hexanes, 10 mL). The mixture was stirred for 30 min and then allowed to warm to 0° C. in an ice/water bath. Zinc chloride (1M in ethyl ether, 40 mL) was added and the mixture was stirred for 1 h, at which time methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (5.1 g) in THF (20 mL) was added, followed by Pd(PPh3)4 (palladium tetrakis triphenylphosphine) (0.68 g). The mixture was then heated at 80° C. for 2 h, at which time it was allowed to cool and partitioned between ethyl acetate and water. The organic layers were washed with brine, dried (magnesium sulfate), and concentrated. The residue was chromatographed on silica gel using ethyl acetate/heptane (50/50) to give 4.5 g of methyl 3-[(dipropylamino)carbonyl]-5-(1,3-thiazol-2-yl)benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.BrC1C=CC(CC(Cl)=O)=CC=1.[OH-].[Na+].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:36][CH2:37][NH2:38]>C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:38][CH2:37][CH2:36][C:35]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:33]([O:32][CH3:31])[CH:34]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: COc1ccc(CCN)cc1OC
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)Cc1ccc(Br)cc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)Cc2ccc(Br)cc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The intermediate 2-(4-bromo-phenyl)-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-acetamide (31) was prepared as follows: A solution of 4-bromo-phenylacetic acid (10.06 g, 46.8 mmol) and oxalyl chloride (101.9 g, 0.8 mol) in 400 mL of benzene was refluxed for 6 h. The solution was evaporated with benzene 3 times and dried in vacuum. A solution of 4-bromo-phenylacetic acid chloride (1.1 mol. equiv.) in CH2Cl2 was added to a mixture of 300 mL of 1N NaOH and solution of 3,4-di-methoxy-phenethylamine (6.55 g, 36.1 mmol) in 300 mL of CH2Cl2. The reaction mixture was stirred overnight at room temperature. Another portion of acid chloride (0.1 eq.) in 20 mL of CH2Cl2 was added and stirred for 1 h. Organic phase was separated, washed with 1N HCl, 1N NaOH, water, dried over Na2SO4, filtered and evaporated. A residue was crystallized from EtOAc-hexanes mixture. Yield is 11.54 g (84.5%).
Reaction SMILES: [Br-].[CH3:2][PH+](C)C.[NH2-].[Na+].[CH:8]([C:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=2[S:13][C:12]=1[CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:30]([CH3:40])[CH:29]=1)=O)([CH3:10])[CH3:9].[Cl-].[NH4+]>C1COCC1>[CH:8]([C:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]([F:22])([F:23])[F:21])=[CH:19][C:14]=2[S:13][C:12]=1[CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:30]([CH3:40])[CH:29]=1)=[CH2:2])([CH3:10])[CH3:9]
Reactant: C[PH+](C)C
Reactant: COC(=O)CCc1ccc(C(=O)CCc2sc3cc(C(F)(F)F)ccc3c2C(C)C)cc1C
Agent: [Br-]
Agent: [Cl-]
Agent: [NH2-]
Solvent: C1CCOC1
Product: C=C(CCc1sc2cc(C(F)(F)F)ccc2c1C(C)C)c1ccc(CCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a suspension of trimethylphosphonium bromide (84 mg, 0.24 mmol) in THF (4 mL) was added sodium amide (12 mg, 0.31 mmol) under N2 atmosphere. The mixture was stirred for 30 minutes at room temperature, to which was added a solution of methyl 3-[4-[3-[3-isopropyl-6-(trifluoromethyl)benzothiophen-2-yl]propionyl]-2-methylphenyl]propionate [Example 12 (7)] (75 mg, 0.16 mmol) in THF (1 mL). The mixture was stirred for 22 hours at room temperature, treated with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1), to give the titled compound as a pale yellow oil (27 mg, yield 36%).