Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:18]([C:22](O)=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[NH2:55][CH:56]([CH2:61][C:62]([F:65])([F:64])[F:63])[C:57]([O:59][CH3:60])=[O:58]>CN(C=O)C.O>[F:63][C:62]([F:64])([F:65])[CH2:61][CH:56]([NH:55][C:22]([C:18]1[N:13]2[CH:14]=[C:15]([CH3:17])[CH:16]=[C:11]([O:10][CH2:9][C:4]3[C:3]([F:2])=[CH:8][CH:7]=[CH:6][N:5]=3)[C:12]2=[N:20][C:19]=1[CH3:21])=[O:23])[C:57]([O:59][CH3:60])=[O:58]
Reactant: Cc1cc(OCc2ncccc2F)c2nc(C)c(C(=O)O)n2c1
Reactant: COC(=O)C(N)CC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)C(CC(F)(F)F)NC(=O)c1c(C)nc2c(OCc3ncccc3F)cc(C)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg (0.71 mmol) of 8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid hydrochloride from Example 121A were initially charged in 4.1 ml of DMF, and 274 mg (0.85 mmol) of TBTU and 0.47 ml (4.26 mmol) of 4-methylmorpholine were added. 221 mg (1.07 mmol) of methyl 2-amino-4,4,4-trifluorobutanoate hydrochloride from Example 75A were then added, and the reaction mixture was stirred at RT overnight. About 32 ml of water were added to the mixture. The precipitated solid was filtered off, washed with water and dried under high vacuum. This gave 298 mg (68% of theory, purity 76%) of the target compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]3[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:21][C:16]2[C:15]([NH:14][CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: Nc1ccccc1NCC1CCN(c2ccncc2)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccccc2NCC2CCN(c3ccncc3)CC2)cc1
Reaction time: 17 h
Yield: 16.6 %

Procedure:
A solution of N1-[1-(4-pyridyl)piperidin-4-ylmethyl]-1,2-benzenediamine (212 mg, 0.75 mmol) and pyridine (4 mL) in chloroform (2 mL) at 0° C. was treated with a solution of 4-methoxybenzoyl chloride (128 mg, 0.75 mmol) in chloroform. The mixture was allowed to warm to roam temperature and stir for 17 h. The mixture was concentrated and the residue was dissolved in EtOAc. The organic layer was washed with 1 N NaOH (2×), water (3×), brine (1×), dried (K2CO3), and concentrated. The residue was purified by RPHPLC, yielding 52 mg (17%) of the title compound as a hydrochloride salt.
Reaction SMILES: [I-:1].[Na+].Cl[C:4]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:11]2[C:6](=[CH:7][C:8]([O:31][CH3:32])=[C:9]([O:29][CH3:30])[CH:10]=2)[N:5]=1.[CH2:33](C(C)=O)C>>[CH3:30][O:29][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:31][CH3:32])[N:5]=[C:4]([CH2:33][I:1])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]2[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: CCOC(=O)c1c(Cl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: [I-]
Reactant: CCC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1c(CI)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A mixture of sodium iodide (1.68 g) and methyl ethyl ketone (15 ml) was stirred at 80° C. for 1 hour. Then ethyl 2-chloro-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (2.0 g) was added, and the resulting mixture was stirred at the same temperature for 12 hours. The insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and the solvent was distilled off. The residual oil was subjected to column chromatography on silica gel. From the fraction eluted with chloroform/ethyl acetate (1:1, v/v), ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-iodomethylquinoline-3-carboxylate (1.4 9, 58%) was obtained and recrystallized from ethyl acetate/hexane.
Reaction SMILES: [CH3:1][C:2](=[CH2:14])[CH2:3][C:4]([O:10]CCC)(OCCC)[CH3:5].[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18]O.C1CCCCC1>C(O)=O>[CH3:5][C:4]([CH2:10][CH2:18][CH:17]=[C:16]([CH3:20])[CH3:15])=[CH:3][C:2](=[O:14])[CH3:1]
Reactant: CC(C)=CCO
Reactant: C=C(C)CC(C)(OCCC)OCCC
Solvent: C1CCCCC1
Solvent: O=CO
Product: CC(=O)C=C(C)CCC=C(C)C
Yield: 89 %

Procedure:
In an autoclave, a mixture of 120 parts of 4-methyl-2,2-di-n-propoxy-4-pentene, 50 parts of prenol and 170 parts of cyclohexane is heated with 3.4 parts of formic acid for 4 hours at 160°C. Fractional distillation gives 57.5 parts of 4,8-dimethyl-3,7-nonadien-2-one, equivalent to a yield of 89% and a conversion of 67% based on prenol.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14])=[C:2]=[O:3].[CH2:15]([CH:17]([NH:20][OH:21])[CH2:18][CH3:19])[CH3:16]>ClCCl>[OH:21][N:20]([CH:17]([CH2:18][CH3:19])[CH2:15][CH3:16])[C:2](=[O:3])[NH:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([N:20]([CH:17]([CH2:18][CH3:19])[CH2:15][CH3:16])[OH:21])=[O:14]
Reactant: O=C=NCCCCCCCCN=C=O
Reactant: CCC(CC)NO
Solvent: ClCCl
Product: CCC(CC)N(O)C(=O)NCCCCCCCCNC(=O)N(O)C(CC)CC
Yield: 91.9 %

Procedure:
The same general procedure as reported in Example 16 was followed. 1,8-Diisocyanatooctane (3.9 ml, 20 mmol), N-(1-ethylpropyl)hydroxylamine (4.3 g, 42 mmol), and dichloromethane (200 ml) were combined to provide 7.4 g of the desired product as a white powder: MP: 89.0-90.0° C. ; 1H NMR (500 MHz, DMSO): δ 8.65 (s, 2H), 6.71 (t, J=5.9 Hz, 2H), 3.78 (m, 2H), 3.01 (q, J=6.7 Hz, 4H), 1.49-1.21 (m, 20H), 0.79 (t, J=7.5 Hz, 12H); 13C NMR (125 MHz, DMSO): δ 161.2, 60.1, 39.3, 29.9, 28.9, 26.3, 24.5, 11.1; IR (KBr): 3444, 3128, 2962, 2933, 2856, 1628, 1537, 1473, 1358, 1319, 1271, 1165, 1140, 1105, 1070, 1039, 927, 839, 779, 748 cm-1 ; MS (FAB): m/e 403.3277 (403.3284 calc'd for C20H43N4O4, M+H), 300; Anal. calc'd for C20H42N4O4 : C, 59.67; H, 10.51; N, 13.92. Found: C, 59.71; H, 10.65; N, 13.92.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]1[O:31][C:41](=[O:42])[NH:33][N:32]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCc2ccccc2[C@H]1c1cc(Cl)ccc1OCc1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of (S)-1-(5-chloro-2-hydrazinocarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (137 mg, 0.29 mmol, 1.0 eq.) and NEt3 (82 μL, 0.59 mmol, 2.0 eq.) in THF (3 mL), 1,1′-carbonyldiimidazole (72 mg, 0.44 mmol, 1.5 eq.) was added. The reaction mixture was stirred at r.t. for 1 hour. The solvent was removed in vacuo. The residue, redissolved in DMF (2.4 mL), was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired product as a white foam.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: Nc1ccc(S(=O)(=O)c2ncccn2)cc1
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(S(=O)(=O)c2ncccn2)cc1)C(O)(C(F)F)C(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmoles) in dimethyl acetamide (10 ml) at -10° C. was added thionyl chloride (0.34 g, 2.84 mmoles) dropwise. The resulting solution was stirred at -10° C. for approximately 30 mins. 4-(2-pyrimidylsulfonyl)aniline (0.59 g, 2.5 mmoles) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and sodium bicarbonate solution was added to give a pH of 7-7.5. A dark colored precipitate was formed that was filtered, washed with water and dried. The crude material gas preabsorbed onto silica gel and chromatographed on silica gel eluting with 70-80% ethyl/acetate/hexane. Evaporation of product-containing fractions and crystallization from methylene chloride/methanol/hexane Eave the title compound (0.33 g, 34%) as a white solid; mp 209°-210° C. 1H-NMR (300 MHz, d6-DMSO):6.46(t, J=54.06 Hz, 2H, HCF2), 7.78 (t, J=4.8 Hz, 1H, ArH), 7.95-7.98(m, 3H, ArH, OH), 8.02-8.06(m, 2H, ArH), 9.01 (d, J=5.01 Hz, 2H, ArH), 10.58 (s, 1H, NH). MS(CI):394(M+1, 100%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Br:7][C:8]1[N:9]=[C:10]([C:29]#[C:30][Si](C)(C)C)[C:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12][CH:13]=1>CN(C=O)C.CCOC(C)=O.O>[Br:7][C:8]1[N:9]=[C:10]([C:29]#[CH:30])[C:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 94.1 %

Procedure:
Sodium carbonate (918.5 μL of 2 M, 1.837 mmol) was added to a solution of tert-butyl N-[5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (720 mg, 1.531 mmol) in DMF (2 mL) and the resulting solution heated at 90° C. for 20 minutes. The reaction mixture was allowed to cool to RT and diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organics washed with water, dried (MgSO4) and concentrated in vacuo to give the product as a yellow solid (574 mg, 94% Yield). 1H NMR (400.0 MHz, DMSO) d 1.43 (18H, s), 3.53 (1H, s), 8.55 (1H, s); MS (ES+) 400.03
Reaction SMILES: [N+](C1C=CC(COC(NCCOC(C=CS[C:21]2[CH2:27][C@H:26]3[N:23]([C:24](=[O:31])[C@H:25]3[C@@H:28]([OH:30])[CH3:29])[C:22]=2[C:32]([O:34]CC2C=CC([N+]([O-])=O)=CC=2)=[O:33])=O)=O)=CC=1)([O-])=O.[H][H]>O1CCOCC1.P([O-])([O-])([O-])=O.[Pd]>[OH:30][C@H:28]([CH:25]1[C:24](=[O:31])[N:23]2[CH:26]1[CH2:27][CH:21]=[C:22]2[C:32]([OH:34])=[O:33])[CH3:29]
Reactant: [H][H]
Reactant: C[C@H](O)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC=CC(=O)OCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: C[C@H](O)C1C(=O)N2C(C(=O)O)=CCC12

Procedure:
The ester (e29) (150 mg) was dissolved in a mixture of dioxan (10 ml) and 0.05 M pH7 phosphate buffer (4.5 ml), and the solution was shaken with 5% palladium on charcoal (200 mg) in an atmosphere of hydrogen for 2 hours. The mixture was filtered over Celite, washed with water (20 ml), and the solution was then concentrated in vacuo to a volume of ca. 20 ml. The solution was washed with ethyl acetate (4×25 ml), and was then freeze-dried to afford (5R,6R)-3-[2-(Z)-2-aminoethoxycarbonyl)ethenylthio]-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (e30) as a solid; λmax. (H2O) 325 nm., σmax. (KBr) 1750, 1690 and 1565-1610 (br) cm-1. (The product contained ca. 5% of the corresponding E-isomer).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H].[ClH:24]>C(O)C.O.[Pd]>[ClH:24].[ClH:24].[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CCN2CCc3ccccc3C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(CCN2CCc3ccccc3C2)cc1

Procedure:
To a solution of the product of step (a) (11.0 g, 39.0 mmol) in 95% ethanol (150 ml), concentrated hydrochloric acid (7.5 ml) and water (50 ml) was added 10% Pd/C (1.0 g). The mixture was hydrogenated at 50 psig for 2.5 hours, until the theoretical amount of hydrogen was taken up. The catalyst was filtered and the filtrate concentrated to a solid residue. This was digested in absolute ethanol (75 ml), cooled, filtered and air dried; yield 11.4 g (90%) of the dihydrochloride salt.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.[CH2:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][CH:32]=[CH2:33]>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:33][CH2:32][CH2:31][CH2:30][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:29])[CH2:17]1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=CCCc1ccccc1
Product: O=C1CN(c2ccc(CCCCc3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and but-3-enyl-benzene analogous to Example 51: (M−1)−=359.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[C:4]([O:13][CH3:14])[CH:3]=1.[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[CH2:8]2)=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: O=C1CCC1
Reactant: COc1cc(Br)ccc1OC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(Br)ccc1OC1CN(C2CCC2)C1
Reaction time: 8 h
Yield: 56.6 %

Procedure:
Dissolve 3-(4-bromo-2-methoxy-phenoxy)-azetidine (1.84 g, 7.13 mmol) in dichloroethane (80 mL). Add cyclobutanone (1.86 mL, 25 mmol), sodium triacetoxyborohydride (3.02 g, 14.3 mmol) and acetic acid (0.82 mL, 14.3 mmol). Stir the mixture overnight, then add saturated sodium bicarbonate and extract three times using dichloromethane. Dry the combined organic portions over sodium sulfate, filter, and concentrate. Purify by silica gel chromatography using a 0-3% gradient of methanol/dichloromethane to give 1.26 g (56%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.CC([O-])=[O:27].[K+]>CC(O)=O.O>[F:22][C:21]([F:24])([F:23])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[N:3][C:2]([OH:27])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)[O-]
Reactant: FC(F)(F)c1ccccc1OC1CCN(c2ccc(Cl)nn2)CC1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Reaction time: 3 h

Procedure:
A solution of 3-chloro-6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine (100 mg, 0.28 mmol) and KOAc (55 mg, 0.56 mmol) in AcOH/H2O (1:1, 2 mL) was heated at 150° C. After 3 h, the solvent was evaporated and the mixture diluted with water (2 mL), extracted with (3×2 mL) EtOAc and dried over Na2SO4. Evaporation of the solvent followed by purification Combiflash chromatography (SiO2, eluant 5% MeOH/EtOAc) afforded the desired product. 1H NMR (500 MHz, acetone-d6): δ 1.86-1.93 (m, 2H), 2.10-2.14 (m, 2H), 3.33-3.39 (m, 2H), 3.54-3.60 (m, 2H), 4.88-4.90 (m, 1H), 6.77 (d, 1H), 7.10 (t, 1H), 7.34 (d, 1H), 7.49 (d, 1H), 7.59-7.65 (m, 2H). MS (+ESI) m/z 340 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23](O)[CH3:24]>>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:23][CH3:24])=[O:9]
Reactant: CCO
Reactant: Nc1cnccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccncc1N
Temperature: 25 °C

Procedure:
A suspension of 3-aminopyridine-4-carboxylic acid (2.00 g, 14.5 mmol), prepared by the method of Crum and Fuchsman, J. Het. Chem. 3, 252 (1966), in ethanol (~4 g) was treated with 4.0 g of sulfuric acid and warmed on a steam bath for 4 hours. After cooling to ambient temperature, water (~40 mL) and solid sodium carbonate were added to basify the solution which was then extracted with chloroform (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained was flash chromatographed on silica gel eluting with 2:1 hexane/ethyl acetate to afford the title compound. 1H NMR (CDCl3, 300 MHz) δ 1.41 (t, J=7 Hz, 3H), 4.37 (q, J=7 Hz, 2H), 7.60 (d, J=6 Hz, 1H), 7.93 (d, J=6 Hz, 1H), 8.19 (s, 1H). MS (DCI/NH3) m/e 167 (M+H)+, 184 (M+H+NH3)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[CH2:23][C:24]([OH:26])=[O:25])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[Cl:27][C:28]1[CH:29]=[N+:30]([O-:53])[CH:31]=[C:32]([Cl:52])[C:33]=1[CH2:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:46])[F:45])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][C:28]1[CH:29]=[N+:30]([O-:53])[CH:31]=[C:32]([Cl:52])[C:33]=1[CH2:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:46])[F:45])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)[O:25][C:24](=[O:26])[CH2:23][N:18]1[C:19]2[C:15](=[C:14]([N:9]([CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[S:10]([CH3:13])(=[O:12])=[O:11])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1cccc2c1ccn2CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)c1cccc2c1ccn2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 10.3 %

Procedure:
To a solution of 2-(4-(N-(2-morpholinoethyl)methylsulfonamido)-1H-indol-1-yl)acetic acid (100 mg, 0.262 mmol) in DCM (5 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (110 mg, 0.262 mmol), EDC (151 mg, 0.786 mmol) and DMAP (64.1 mg, 0.524 mmol) were added, and the mixture was reacted overnight at room temperature. The solvent was evaporated and the residue was partitioned between 1N HCl (10 ml) and EtOAc; the aqueous phase was extracted with EtOAc, the combined organic layers were dried over sodium sulfate and the solvent was removed under vacuum. Three flash chromatographic column on silica gel (DCM/MeOH 97/3) were required to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(N-(2-morpholinoethyl)methylsulfonamido)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (21.4 mg, 0.027 mmol, 10.4% yield, MS/ESI+ 783.19 [MH]+, [αD]=+14.1, c=0.2 DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.50 (s, 2H), 7.34 (d, 1H), 7.07-7.21 (m, 5H), 6.90 (dd, 1H), 7.06 (t, 1H), 6.55 (d, 1H), 6.02 (dd, 1H), 5.25 (d, 1H), 5.10 (d, 1H), 3.91 (d, 2H), 3.80 (t, 2H), 3.46-3.54 (m, 4H), 3.41 (dd, 1H), 3.21 (dd, 1H), 3.09 (s, 3H), 2.32 (dd, 2H), 2.23-2.31 (m, 4H), 1.07-1.36 (m, 1H), 0.54-0.65 (m, 2H), 0.29-0.47 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[O:11].[CH2:12]([Mg]Br)[CH3:13]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:11])[CH2:12][CH3:13]
Reactant: CC[Mg]Br
Reactant: O=Cc1nc2ccccc2s1
Solvent: C1CCOC1
Product: CCC(O)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,3-benzothiazole-2-carbaldehyde (0.96 g, 5.88 mmol) in THF (15.0 mL) was added ethylmagnesium bromide (1.0 M solution in THF, 12.0 mL, 12.0 mmol, 2 eq), slowly over 15 minutes (an exotherm was observed). The resulting dark red solution was stirred at room temperature for 55 minutes, then quenched with saturated aqueous ammonium chloride solution (4 mL). The mixture was then concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-70% EtOAc in hexanes gradient) provided the title compound as a red oil.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:32])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:31])[C@H:17]([CH2:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](=[O:23])[OH:22])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:40]1([S:46](Cl)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:32])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:31])[C@H:17]([CH2:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](=[O:22])[OH:23])[NH:18][S:46]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:48])=[O:47])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@@H](CC(Cc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C(Cc1ccccc1)C[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 92.4 %

Procedure:
γ-Benzyl-L-glutamyl-L-proline benzylester hydrochloride (2.30 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mole) was added thereto at -30 ° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise thereto. The solution was stirred for 1 hour at less than 0° C., and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The solution was washed with 55 aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice), and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give N-benzenesulfonyl-γ-benzyl-L-glutamyl-L-proline benzylester (yield: 2.61 g, 92.4%)
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CC[N:27](C(C)C)C(C)C.[CH2:34]([CH:36]1[CH2:40][CH2:39][N:38](N)[CH:37]1[CH3:42])[CH3:35]>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][CH:36]([CH2:34][CH3:35])[C:37]4([CH3:42])[NH2:27])=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: CCC1CCN(N)C1C
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CCN(C(C)C)C(C)C
Product: CCC1CCN(c2ccc3c(C(=O)NC[C@@]4(O)CCC[C@@H](C)C4)c(Cl)ccc3n2)C1(C)N

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-ethyl-methyl-amino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 3H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 3H), 0.83 (d, 3H). m/z: 460 [M+H]