Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=O)[S:12][CH:13]=2)[N:4]([CH3:17])[N:3]=1.[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[C:6]([CH2:7][CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[O:16])[S:12][CH:13]=2)[N:4]([CH3:17])[N:3]=1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (120 mg, 0.44 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (171 mg, 0.44 mmol) [prepared according to Preparation 6] and n,n-diisopropylethylamine (0.39 ml, 2.22 mmol) in Dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (228 mg, 0.49 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (190 mg, 0.30 mmol, 68° A yield) as a white solid: LCMS (ES) m/e 601, 603 (M, M+2)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:26])=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH3:25])[C:17](=[O:24])[N:18]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]3=[CH:12][CH:11]=2)[CH:9]=1)(=O)[CH3:2].[NH:27]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.CO.[Ti](Cl)(Cl)(Cl)Cl>[CH3:22][C:20]([CH3:23])([CH3:21])[CH2:19][N:18]1[C:13]2[C:14](=[N:15][C:10]([C:8]3[CH:9]=[C:4]([C@H:1]([N:27]4[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]4)[CH3:2])[CH:5]=[CH:6][C:7]=3[CH3:26])=[CH:11][CH:12]=2)[N:16]([CH3:25])[C:17]1=[O:24]
Reactant: CC(=O)c1ccc(C)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Reactant: O=S1(=O)CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc([C@@H](C)N2CCS(=O)(=O)CC2)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a microwave vial was added 5-(5-acetyl-2-methylphenyl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (15-7) (30 mg, 0.085 mmol) and thiomorpholine 1,1-dioxide (17 mg, 0.13 mmol) were added under nitrogen and dissolved in toluene (0.43 ml). Titanium(IV) chloride (10 mg, 0.05 mmol) was added to the solution and the reaction was allow to stir at room temperature overnight. Sodium cyanoborohydride (8 mg, 0.12 mmol) was then added and allowed to stir for 1 hour. The reaction was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 1-(2,2-dimethylpropyl)-5-{5-[(1R)-1-(1,1-dioxidothiomorpholin-4-yl)ethyl]-2-methylphenyl}-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (36-1). HRMS (M+H)+: observed=471.2421, calculated=471.2424.
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[CH3:23][O:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27](OC)=O.[H-].[Na+]>CN(C=O)C>[OH:15][CH2:14][C@H:9]1[C@H:8]([C:7]2[C:6]([O:16][CH3:17])=[CH:5][C:4]([O:18][CH3:19])=[C:3]3[C:2]=2[O:1][C:27]([C:26]2[CH:31]=[CH:32][CH:33]=[CH:34][C:25]=2[O:24][CH3:23])=[CH:21][C:20]3=[O:22])[CH2:12][CH2:11][N:10]1[CH3:13]
Reactant: COC(=O)c1ccccc1OC
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(=O)c2c(OC)cc(OC)c([C@@H]3CCN(C)[C@H]3CO)c2o1

Procedure:
Compound of example 6 (0.7 g, 2.2 mmol) in dry DMF (10 mL) was reacted with methyl 2-methoxybenzoate (1.13 g, 6.8 mmol) in the presence of NaH (50%, 0.544 g, 11.3 mmol) as described in example 16 to obtain the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:33][CH2:32][N:24]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=3[CH:31]=[C:23]2[C:22]1=[O:34])(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:49]=[C:48]([CH2:50][O:51][CH3:52])[N:47]([CH3:53])[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[CH:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:49]=[C:48]([CH2:50][O:51][CH3:52])[N:47]([CH3:53])[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: COCc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Product: COCc1cc(Nc2cc(-c3cccc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nn1C
Yield: 71.9 %

Procedure:
Following Example 148b, 557 mg of 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a and 327 mg of 5-bromo-3-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one 176c were reacted to give 176d as a yellow solid (420 mg, 72%). LCMS: [M+H]+ 585
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([O:24][CH2:25][CH:26]([F:28])[F:27])[CH:23]=[C:18]3[N:17]([CH2:29][CH3:30])[C:16]2=[O:31])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[F:28][CH:26]([F:27])[CH2:25][O:24][C:22]1[CH:23]=[C:18]2[N:17]([CH2:29][CH3:30])[C:16](=[O:31])[N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:19]2=[N:20][CH:21]=1
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(OCC(F)F)cc21
Agent: [Pd]
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(OCC(F)F)cc21
Reaction time: 8 h

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-6-(2,2-difluoroethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) and 10% Pd—C (37.5 mg) in EtOH (10 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 6-(2,2-difluoroethoxy)-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a colorless solid. To a solution of this product and 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (153 mg) in DMF (5 mL) was added sodium hydride (34.1 mg) at 100° C., and the mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was quenched with water at room temperature and extracted with AcOEt. The organic layer was separated, washed with sat. NaHCO3 aq. and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 15%-50% AcOEt in hexane) to give 6-(2,2-difluoroethoxy)-1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (264 mg) as a colorless solid. The solid was crystallized from AcOEt-hexane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([NH:8]C(=O)C(F)(F)F)[CH:7]=1.[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21]([CH2:25][C:26]2[CH:27]=[C:28]([O:42][CH2:43][CH3:44])[C:29](I)=[C:30]([O:32][S:33]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])=[O:34])[CH:31]=2)=[CH:20][N:19]=1>>[NH2:8][C:6]1[CH:7]=[C:2]([C:29]2[C:28]([O:42][CH2:43][CH3:44])=[CH:27][C:26]([CH2:25][C:21]3[C:22]([NH2:24])=[N:23][C:18]([NH2:17])=[N:19][CH:20]=3)=[CH:31][C:30]=2[O:32][S:33]([CH2:36][C:37]([CH3:38])([CH3:40])[CH3:39])(=[O:34])=[O:35])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16]
Reactant: COc1ccc(Br)cc1NC(=O)C(F)(F)F
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)(C)C)c1I
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)(C)C)c1-c1ccc(OC)c(N)c1
Yield: 27 %

Procedure:
Starting from 197 mg (0.66 mmol) N-(5-bromo-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide and 173 mg (0.33 mmol) 2,2-dimethyl-propane-1-sulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester, 46 mg of the title compound are obtained as a brownish solid after two chromatography operations.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([C:23]([NH2:25])=[O:24])[O:20][C:19]2=[O:26])[CH:5]=[C:6]([F:17])[C:7]=1[C:8]1([CH3:16])[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]1.[CH3:27]N>CO>[CH3:27][NH:25][C:23]([C@@H:21]1[O:20][C:19](=[O:26])[N:18]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([C:8]3([CH3:16])[CH2:9][N:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:11]3)=[C:6]([F:17])[CH:5]=2)[CH2:22]1)=[O:24]
Reactant: COC(=O)N1CC(C)(c2c(F)cc(N3C[C@H](C(N)=O)OC3=O)cc2F)C1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2cc(F)c(C3(C)CN(C(=O)OC)C3)c(F)c2)C(=O)O1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
A suspension of methyl (5R)-3-[3,5-difluoro-4-(1-methoxycarbonyl-3-methylazetidin-3-yl]-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 57, Step 4, 500 mg, 1.30 mmol) in MeOH (10 mL) is heated at 50° C. to achieve full dissolution, then cooled to 0° C. and treated with methylamine (15 mL, 2.0 M in MeOH). The reaction mixture is stirred for 20 min at 0° C. and then concentrated under reduced pressure. Trituration (Et2O) affords the title compound as a white solid in 90% yield; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, 1 H), 7.35 (d, 2 H), 5.09 (dd, 1 H), 4.26 (m, 2 H), 4.25 (t, 1 H), 4.02 (dd, 1 H), 3.86 (d, 2 H), 3.56 (s, 3 H), 2.66 (d, 3 H), 1.56 (s, 3H); hMS (ESI) calcd for C17H19F2N3O5+H1 384.1371, found 384.1360; [α]25D=−35 (c 0.90, DMSO).
Reaction SMILES: [CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:17][CH2:18][CH3:19])[C:9](=[O:20])[CH:8]([NH:21]C(OCC3C=CC=CC=3)=O)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br.CCOCC>C(O)(=O)C>[NH2:21][CH:8]1[N:7]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][CH3:19])[C:9]1=[O:20]
Reactant: CCCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCC2)c2ccccc21
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCN1C(=O)C(N)N=C(C2CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To 5-cyclopentyl-1,3-dihydro-1-propyl-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (507 mg, 1.21 mmol) was added 45% hydrobromic acid in acetic acid (1 ml) and the mixture stirred at room temperature for 2 h. Anhydrous ether (10 ml) was then added and the mixture was stirred for 1.5 h before removing the solvent by pipette. The resulting solid was washed with more ether, filtered off and washed again with ether, before partitioning between dichloromethane (30 ml) and 2N sodium hydroxide solution (30 ml). The aqueous layer was re-extracted with more dichloromethane (2×30 ml), the organic extracts combined, dried (Na2SO4) and evaporated to leave the title compound (333 mg, 96%) as a colourless oil. 1H NMR (360 MHz, CDCl3) δ 0.81 (3H, t, J=7.4 Hz), 1.25-1.94 (9H, m); 2.16 (1H, m), 3.29 (1H, m), 3.56 (1H, m), 4.28 (1H, s), 4.30 (1H, m), 7.24 (1H, t, J=7.3 Hz), 7.31 (1H, d, J=7.9 Hz), 7.46 (1H, t of d, J=7.8 and 1.5 Hz), 7.53 (1H, dd, J=7.8 and 1.4 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH2:26]([NH2:28])[CH3:27]>CO>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:28][CH2:26][CH3:27])[S:8]1(=[O:25])=[O:24]
Reactant: CCN
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1c(F)cccc1F
Solvent: CO
Product: CCNCCOCCN1c2ccccc2N(c2c(F)cccc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with 30-40% ethylamine in methanol to give 2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}-N-ethylethanamine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.67 g, 67%). HRMS: calcd for C18H21F2N3O3S+H+, 398.13444; found (ESI, [M+H]+Obs'd), 398.1341.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]=[O:28])=[CH:21][CH:20]=1)[S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8].[CH3:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][N:36]2[CH2:37][CH2:38][CH:33]([CH3:32])[CH2:34][CH2:35]2)=[CH:23][CH:24]=1)[S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8].[OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:23][CH:24]=1)[S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8]
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(CCC=O)cc2)c(C)c1
Reactant: CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(CCCN3CCC(C)CC3)cc2)c(C)c1
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(CCCO)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(3-hydroxy-benzyl)-2,4,6-trimethyl-N-[4-(3-oxo-propyl)-phenyl]-benzenesulfonamide (0.040 g, 0.09 mmol) in 2 mL methylene chloride was added 4-methylpiperidine (0.015 g, 0.15 mmol) and NaB(OAc)3H (0.047 g, 0.22 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the aqueous solution was washed with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (10% methanol/methylene chloride) followed by further medium-pressure chromatography (40% ethyl acetate/hexanes) afforded a mixture comprising 0.008 g of N-(3-hydroxy-benzyl)-2,4,6-trimethyl-N-{4-[3-(4-methyl-piperidin-1-yl)-propyl]-phenyl}-benzenesulfonamide and 0.017 g of N-(3-hydroxy-benzyl)-N-[4-(3-hydroxy-propyl)phenyl]-2,4,6-trimethyl-benzenesulfonamide. MS 440.2 (M+1)+
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17][C:16]=2[CH:24]2[CH2:26][CH2:25]2)[CH:12]=[CH:13][CH:14]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:59][C:60]([CH3:67])([C:62]1[S:63][CH:64]=[CH:65][N:66]=1)[NH2:61]>CN(C=O)C>[CH3:59][C:60]([NH:61][C:21]([C:19]1[CH:18]=[N:17][C:16]([CH:24]2[CH2:26][CH2:25]2)=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[N:20]=1)=[O:23])([C:62]1[S:63][CH:64]=[CH:65][N:66]=1)[CH3:67]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1cnc(C2CC2)c(-c2cccc(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1cnc(C2CC2)c(-c2cccc(Cl)c2)n1)c1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
6-(3-Chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid triethylamine salt (1:1) (Example 3a, 0.077 g, 205 μmol) was suspended in DMF (770 μL). TBTU (78.9 mg, 246 mmol), DIEA (106 mg, 136 μl) and α,α-dimethyl-2-thiazolemethanamine hydrochloride (43.9 mg, 246 μmol) were added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate and water; the organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 5% to 50% ethyl acetate in n-heptane) to give the desired product (48 mg, 59%) as white solid; LC-MS (UV peak area, ESI) 94%, 399.1042 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21](OC)=[O:22])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][OH:22])=[CH:15][CH:14]=3)=[O:9])=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc2nnc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(CO)cc2c1O
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To a suspension of methyl 3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-cinnolinecarboxylate (0.48 g, 1.29 mmol) in 40 mL THF is added lithium aluminum hydride (2.60 mL, 2.60 mmol) dropwise. The reaction turns a dark green color. After 1 h, the reaction is quenched carefully with water, 15% NaOH, and water again. The reaction is filtered to remove aluminum salts. The filtrate is concentrated and the resulting residue is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1 L), 0.5% MeOH/CH2Cl2 (1 L), 1% MeOH/CH2Cl2 (1 L), 2% MeOH/CH2Cl2 (1 L), 3% MeOH/CH2Cl2 (1 L), 4% MeOH/CH2Cl2 (1 L), 5% MeOH/CH2Cl2 (2 L), 5.5% MeOH/CH2Cl2 (2L)) affords the desired product (0.23 g, 0.67 mmol, 52%). Physical characteristics are as follows: m.p. 296-298° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.12, 8.14, 7.84, 7.74, 7.41, 5.50, 4.66, 4.56; IR (drift) 2922, 2873, 1647, 1602, 1555, 1490, 1358, 1183, 1022, 930, 919, 836, 808, 722, 684 cm−1; MS (FAB) m/z 344 (MH+), 346, 344, 287, 229, 153, 133, 125, 121, 107, 103; HRMS (FAB) calcd for C17H14ClN3O3+H1 344.0802, found 344.0805.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>CCCCCC.CCOC(C)=O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:6]2[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:17][CH:16]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: COc1ccc(B(O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(N)cc(C(F)(F)F)c2)cc1

Procedure:
The title compound is prepared as described in Example 13 but using 3-amino-5-bromobenzotrifluoride (RYAN SCIENTIFIC) and 4-methoxyphenylboronic acid (Aldrich). Title compound: ES-MS: 266.0 [M-H]−; single peak at tR=4.61 min (System 1); Rf=0.20 (Hexane/EtOAc, 3:1).
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:15]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C@@H:27]2[N:31]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])[C:30](=[O:43])[CH2:29][CH2:28]2)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>O1CCCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2]>[C:15]([C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:26]\[C@@H:27]2[N:31]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])[C:30](=[O:43])[CH2:29][CH2:28]2)=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2C#Cc2ccc(C(C)(C)C)cc2)c(OC)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/[C@H]1CCC(=O)N1Cc1ccc(OC)cc1OC)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Bis(tricyclohexylphosphine)palladium(II) dichloride (230 mg) and tributyltin chloride (1.0 mL) were sequentially added to a solution of (5R)-5-[(4-tert-butylphenyl)ethynyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (1.24 g) in tetrahydrofuran (15 mL) in a nitrogen gas stream, and the mixture was stirred at room temperature for two hours. The reaction solution was filtered through celite, and then the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to give the title compound as a colorless powder (2.16 g, 96%).
Reaction SMILES: [C:1]([OH:4])(=O)C.[CH2:5]([N:7](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:32]=1[CH2:33][NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1C=CC=CC=1.O>[CH3:29][O:30][C:31]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:32]=1[CH2:33][N:34]([C:1]([NH:7][CH3:5])=[O:4])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)O
Reactant: COc1ccc(OC)c(CNc2ccccc2Oc2ccccc2)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CNC(=O)N(Cc1cc(OC)ccc1OC)c1ccccc1Oc1ccccc1

Procedure:
To a solution of 3.43 ml of acetic acid and 8.36 ml of triethylamine in 90 ml of benzene was added 12.9 ml of diphenylphosphoryl azide, followed by reflux under heating for 2 hours. To the reaction solution was added 2.01 g of N-(2,5-dimethoxybenzyl)-2-phenoxyaniline synthesized in the same manner as in Example 2(1), followed by reflux under heating for 6 hours. The reaction mixture was poured into water, and the organic phase was separated, washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:2) and recrystallized from diethyl ether to give 1.20 g of N-(2,5-dimethoxybenzyl)-N-(N-methylaminocarbonyl)-2-phenoxyaniline.