Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH2:16]([C:18]1[N:19]=[N+:20]([O-:33])[C:21]2[C:30]([N:31]=1)=[CH:29][C:28]1[CH2:27][N:26]([CH3:32])[CH2:25][CH2:24][C:23]=1[CH:22]=2)[CH3:17].C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH2:16]([C:18]1[N:19]=[N+:20]([O-:33])[C:21]2[C:30]([N+:31]=1[O-:4])=[CH:29][C:28]1[CH2:27][N:26]([CH3:32])[CH2:25][CH2:24][C:23]=1[CH:22]=2)[CH3:17]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CCN(C)C3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CN(C)CC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 17.1 %

Procedure:
H2O2 (70%, 2.4 mL, ca. 25 mmol) was added dropwise to a stirred solution of TFAA (3.5 mL, 25 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 260 (590 mg, 2.4 mmol) and TFA (0.96 mL, 12.2 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4×150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give 1,4-dioxide 261 (107 mg, 17%) as a yellow solid: mp 124-128° C.; 1H NMR δ 8.23 (s, 1H, H-10), 8.18 (s, 1H, H-5), 3.83 (s, 2H, H-6), 3.15-3.24 (m, 4H, CH2, H-8), 2.78 (t, J=6.0 Hz, 2H, H-9), 2.51 (s, 3H, NCH3), 1.43 (t, J=7.5 Hz, 3H, CH3); 13C NMR δ 149.3, 145.5, 136.5, 135.3, 129.3, 120.5, 116.3, 58.1, 51.9, 45.8, 29.6, 23.9, 9.3; MS (APCI) m/z 261 (MH+, 100%). Anal. calcd for C13H16N4O2.¼CH2Cl2: C, 56.5; H, 5.9; N, 19.9. Found: C, 56.6; H, 5.9; N, 19.7%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([CH3:20])[C:11]=1[CH:21]([C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[C:27]([Cl:33])[N:26]=[C:25](Cl)[C:24]=1[Cl:35])[OH:22]>CO.[C].[Pd]>[CH3:8][O:9][C:10]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([CH3:20])[C:11]=1[CH:21]([C:23]1[C:24]([Cl:35])=[CH:25][N:26]=[C:27]([Cl:33])[C:28]=1[C:29]([F:30])([F:32])[F:31])[OH:22]
Reactant: COc1cc(C)c(C(O)c2c(Cl)c(Cl)nc(Cl)c2C(F)(F)F)c(OC)c1OC
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(C)c(C(O)c2c(Cl)cnc(Cl)c2C(F)(F)F)c(OC)c1OC
Reaction time: 14 h
Yield: 24 %

Procedure:
2.7 ml (19 mmol) of triethylamine and 0.9 g of 5% palladium carbon were added to a solution having (2,3,4-trimethoxy-6-methylphenyl)(2,3,6-trichloro-5-trifluoromethyl-4-pyridyl)methanol obtained in step (a) dissolved in 200 ml of methanol, followed by stirring under hydrogen atmosphere for 14 hours. The mixture was subjected to filtration, 30 ml of water was added thereto, and methanol was distilled off under reduced pressure. Extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 2.38 g (yield 24%) of (2,3,4-trimethoxy-6-methylphenyl)(2,5-dichloro-3-trifluoromethyl-4-pyridyl)methanol (m.p. 162-165° C.).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][CH2:19][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)(=O)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=1>>[O:23]=[S:22]1(=[O:24])[C:8]2[C:7]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:33]=3)=[N:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=S1(=O)CCCc2nc(-c3ccccc3)nc(OS(=O)(=O)C(F)(F)F)c21
Product: CCOC(=O)Cc1ccc(Nc2nc(-c3ccccc3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 77.1 %

Procedure:
Following general procedure G, 5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (1.0 g, 2.46 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.527 g, 2.94 mmol) to afford the desired product (0.83 g, 77%) as a light yellow solid. MW=437.51. 1H NMR (DMSO-d6, 500 MHz) δ 8.77 (s, 1H), 8.28-8.24 (m, 2H), 7.64-7.49 (m, 5H), 7.34 (d, J=8.5 Hz, 2H), 4.10 (q, J=7.0 Hz, 2H), 3.76-3.72 (m, 2H), 3.70 (s, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.43-2.35 (m, 2H), 1.20 (t, J=7.0 Hz, 3H); APCI MS m/z 438 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[OH:3][NH:4][C:5]([NH:17][CH3:18])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16].O(N)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.Cl.Cl.ON(CCSCC1NC=NC=1C)C(N)=NCCSCC1NC=NC=1C>>[ClH:1].[ClH:1].[CH3:18][NH:17][C:5]([NH:4][O:3][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16]
Reactant: CNC(=NCCSCc1[nH]cnc1C)NO
Reactant: NOc1ccccc1
Agent: Cc1nc[nH]c1CSCCN=C(N)N(O)CCSCc1[nH]cnc1C
Agent: Cl
Product: CNC(=NCCSCc1[nH]cnc1C)NOc1ccccc1

Procedure:
Reaction of the isothiourea dihydrochloride produced by Example 1 (i) with phenoxyamine by the procedure of Example 1 (ii) gave the title product.
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][CH:20]([C:23]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](=[O:36])[C:26]2=[CH:37][CH:38]=[CH:39][N:25]2[N:24]=1)[CH2:21][CH3:22].[C:40]1(=O)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>ClCCCl>[CH2:29]([N:28]1[C:27](=[O:36])[C:26]2=[CH:37][CH:38]=[CH:39][N:25]2[N:24]=[C:23]1[CH:20]([NH:19][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:21][CH3:22])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCC(N)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
Acetic acid (65 μl, 0.95 mmol) and sodium triacetoxyborohydride (200 mg, 0.95 mmol) were added to a solution of 2-(1-amino-propyl)-3-benzyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 26, 180 mg, 0.64 mmol) and cyclohexanone (62 mg, 0.64 mmol) in 1,2-dichloroethane (5 mL). The mixture was stirred for 4 h at room temperature concentrated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated, dried (MgSO4) and concentrated to give the title compound (211 mg, 91%) as a white solid: 1H NMR (DMSO-d6) δ 0.69–1.19 (m, 10H), 1.38–1.89 (m, 6H), 1.99 (m, 1H), 3.63 (m, 1H), 4.82 (m, 1H), 5.80 (m, 1H), 6.55 (s, 1H), 7.06 (s, 1), 7.15 (m, 2H), 7.22–7.35 (m, 4H).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C[Mg]Br.CCOCC.[F:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][N:28]=1)[C:20](N(OC)C)=[O:21]>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)=[O:21])[CH:26]=[CH:27][N:28]=1
Reactant: CON(C)C(=O)c1ccnc(F)c1
Reactant: Cn1cncc1Br
Agent: C[Mg]Br
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1cncc1C(=O)c1ccnc(F)c1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-1-methyl-1H-imidazole (0.964 g, 5.99 mmol) in CH2Cl2 (6 mL) at room temperature was added 3.0 Methylmagnesium bromide in Et2O (2.0 mL, 6.00 mmol) dropwise. The mixture changed to a white suspension briefly then to clear yellow. After 15 min stirring, the mixture was cooled to 4° C. A solution of 2-fluoro-N-methoxy-N-methylisonicotinamide (1.05 g, 5.70 mmol, Intermediate 13, step a) in CH2Cl2 (6 mL) was introduced via cannula and some hard solid formed. The cooling bath was removed, and the mixture was stirred for 2 days. NH4Cl (aqueous) was added, the organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was diluted with small amount of CH2Cl2. The undissolved solid was filtered, washed with Et2O, and dried under vacuum to provide the title compound as a white solid. The filtrate was concentrated and purified by flash column chromatography (40 g silica gel column, 100% EtOAc) to give more title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(N(CC)CC)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1
Reactant: ClCCN1CCCCC1
Reactant: Cc1cc2oc(=O)c3c(c2cc1C)CCNC3
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc2oc(=O)c3c(c2cc1C)CCN(CCN1CCCCC1)C3
Yield: 80.2 %

Procedure:
In the same way as described in example 3, 4.2g of 1,2,3,4-tetrahydro-8,9-dimethyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one, 4.05g of N-chloroethylpiperidine hydrochloride and 4.4g of triethylamine gave 5.0g of crude base. Crystallization from actronitrile gave analytical material, m.p. 142°-5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N[C@@H](Cc2ccccc2)C(=O)O)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (5.0 g) in dimethyl sulfoxide (100 mL) were added phenylalanine (6.37 g) and cesium carbonate (13.6 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted 3 times with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 9.67 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cc2)CC1
Temperature: 70 °C
Yield: 39.8 %

Procedure:
4-(4-Bromo-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.171 g, 0.5 mmol), Na2CO3 (0.16 g, 1.5 mmol), 4-fluoro phenyl boronic acid (0.21 g, 1.5 mmol) and (PPh3)2PdCl2 (0.035 g, 0.05 mmol) were mixed in a mixture of THF/H2O (4:1, 7.5 mL) and heated at 70° C. overnight. After cooling to rt, the reaction mixture was partitioned between 50 mL ethyl acetate and 25 mL sat. NaCl solution. The separated organic layer washed with brine (10 mL), dried (MgSO4) and concentrated. The crude was purified with prep TLC (15% ethyl acetate in hexanes) to give a solid (0.071 g). M+H 356.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24]3([CH3:35])[O:28][C:27]4=[N:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][N:26]4[CH2:25]3)[C:15]2=[O:36])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:35][C:24]1([CH2:23][N:16]2[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15]2=[O:36])[O:28][C:27]2=[N:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][N:26]2[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)n(CC3(C)Cn4cc([N+](=O)[O-])nc4O3)c3ccccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(Cn2c(=O)n(C3CCNCC3)c3ccccc32)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A mixture of 1-(1-tert-butoxycarbonyl-piperidin-4-yl)-3-(2-methyl-6-nitro-2,3-dihydroimidazo-[2,1-b]oxazol-2-ylmethyl)-1,3-dihydrobenzimidazol-2-one prepared in Example 567 (371 mg, 0.74 mmol), trifluoroacetic acid (1 ml) and methylene chloride (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue, a saturated sodium hydrogencarbonate solution, and the precipitates were filtered off. The precipitates were washed with water several times to afford 1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-(3-piperidin-4-yl)-1,3-dihydrobenzimidazol-2-one (255 mg, yield 86%) as a light yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[F:11][C:12]([F:21])([F:20])[C:13](=O)[C:14]([O:16]CC)=[O:15]>CCO.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[NH:9][C:14](=[O:15])[C:13]([C:12]([F:21])([F:20])[F:11])=[N:10]2.[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([N:9]=[C:13]([C:12]([F:11])([F:20])[F:21])[C:14](=[O:16])[NH:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: CCOC(=O)C(=O)C(F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c(=O)c(C(F)(F)F)nc2c1
Product: COc1ccc2nc(C(F)(F)F)c(=O)[nH]c2c1
Temperature: 25 °C
Yield: 17 %
Yield: 42 %

Procedure:
A mixture of 4-methoxybenzene-1,2-diamine (2.00 g, 14.5 mmol) and ethyl trifluoropyruvate (2.47 g, 14.5 mmol) in absolute EtOH (30 mL) was refluxed overnight. The mixture was cooled to room temperature and diluted with EtOAc (300 mL), washed with water (100 mL×2), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 6-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one (1.50 g, yield 42%) as solid (also obtained 7-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one (600 mg, yield 17%)).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:8][O:9][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:1][CH2:2]1
Reactant: O=Cc1ccccc1
Reactant: CC(CO)(CO)C(=O)O
Product: CC1(C(=O)O)COC(c2ccccc2)OC1

Procedure:
Synthesis of benzylidene protected 2,2-bis(hydroxymethyl)-propanoic acid, that is the acetal of benzaldehyde and 2,2-bis(hydroxymethyl)propanoic acid, yielding 5-methyl-2-phenyl-1,3-dioxane-5-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=O.[CH3:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17](Cl)=O.C(=O)([O-])[O-].[K+].[K+].[Br:26][C:27]1[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[N:31][CH:32]=1>CN(C)C=O.CCOCC>[Br:26][C:27]1[CH:28]=[C:29]2[NH:34][C:5]([C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([O:1][CH2:17][C:13]4[N:12]([CH3:11])[CH:16]=[CH:15][N:14]=4)[CH:3]=3)=[N:33][C:30]2=[N:31][CH:32]=1
Reactant: Cn1ccnc1C(=O)Cl
Reactant: Nc1cc(Br)cnc1N
Reactant: O=C(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cn1ccnc1COc1cccc(-c2nc3ncc(Br)cc3[nH]2)c1

Procedure:
3-Hydroxybenzoic acid was reacted with N-methyl-2-imidazoylchloride in the presence of potassium carbonate in dimethylformamide to produce the ether adduct as shown. Subsequent reactions as described previously with 5-bromo-2,3-diaminopyridine followed by microwave reaction gave the final product. 1H NMR (400 MHz, CDCl3) δ ppm 8.37 (s, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.35 (m, 3H), 6.95 (m, 1H), 6.87 (m, 1H), 6.73 (m, 1H), 5.30 (s, 2H), 2.25 (s, 3H); Calc'd for C17H14BrN5O; m/z (M+2H+)=385; found 385.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH2:30].[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH:30][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NCCc1ccccc1F
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCc2ccccc2F)nc1
Yield: 33.9 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), 2-(2-fluorophenyl)ethylamine (501 mg, 3.60 mmol), Ti(iPrO)4 (1.70 g, 6.00 mmol), TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH3CN (377 mg, 6.00 mmol) gives the title compound (398 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)[CH:7]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCCO3)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)OCCO3)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-(3-{[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester of Step A and benzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.84 (m, 2H), 7.60-7.49 (m, 3H), 7.14 (m, 1H), 7.04 (d, 1H), 6.89 (d, 1H), 6.78 (s, 1H), 6.69 (d, 1H), 6.51 (m, 2H), 4.29 (s, 2H), 4.20 (m, 6H), 3.67 (s, 3H), 2.81 (t, 2H), 2.51 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:33]([NH:35][C:36]2[CH:37]=[C:38]([S:54]([OH:57])(=[O:56])=[O:55])[CH:39]=[C:40]3[C:45]=2[C:44]([S:46]([OH:49])(=[O:48])=[O:47])=[CH:43][C:42]([S:50]([OH:53])(=[O:52])=[O:51])=[CH:41]3)=[O:34])[CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([S:29]([OH:32])(=[O:31])=[O:30])[CH:14]=[C:15]3[C:20]=2[C:19]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:18][C:17]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:16]3)=[O:9])[CH:7]=1.[F:58][S:59]([C:62]1[CH:63]=[C:64]([N:68]=[C:69]=[O:70])[CH:65]=[CH:66][CH:67]=1)(=[O:61])=[O:60]>O>[F:58][S:59]([C:62]1[CH:63]=[C:64]([NH:68][C:69](=[O:70])[NH:1][C:2]2[CH:3]=[C:4]([C:33]([NH:35][C:36]3[CH:37]=[C:38]([S:54]([OH:57])(=[O:56])=[O:55])[CH:39]=[C:40]4[C:45]=3[C:44]([S:46]([OH:49])(=[O:47])=[O:48])=[CH:43][C:42]([S:50]([OH:53])(=[O:52])=[O:51])=[CH:41]4)=[O:34])[CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:12]=[C:13]([S:29]([OH:32])(=[O:30])=[O:31])[CH:14]=[C:15]4[C:20]=3[C:19]([S:21]([OH:24])(=[O:22])=[O:23])=[CH:18][C:17]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:16]4)=[O:9])[CH:7]=2)[CH:65]=[CH:66][CH:67]=1)(=[O:61])=[O:60]
Reactant: Nc1cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c1
Reactant: O=C=Nc1cccc(S(=O)(=O)F)c1
Solvent: O
Product: O=C(Nc1cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c1)Nc1cccc(S(=O)(=O)F)c1
Temperature: 95 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 3.0 g of 8,8'-[(5-amino-m-phenylene)bis(carbonylimino)]di-1,3,6-naphthalenetrisulfonic acid, hexasodium salt in 45 ml of water is added 3.0 g of m-fluorosulfonylphenylisocyanate. Stirring is continued for 6 hours at room temperature, the resulting mixture is heated to about 95° C and is filtered through diatomaceous earth. The filter pad is washed with 40 ml of hot water and the filtrate is diluted with 500 ml of anhydrous ethanol while heating in a steam bath. The solution is filtered after standing at room temperature for 72 hours and the precipitate is washed with absolute ethanol followed by ether to give 8,8'-{{5-{3-[m-(fluorosulfonyl)phenyl]ureido}-1,3-phenylene}bis(carbonylimino)}di-1,3,6-naphthalenetrisulfonic acid, hexasodium salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:26])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH3:24])[CH2:12][O:11][C@@H:10]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C@@H:9]1[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:26])[C@@H:15]([NH:25][C:34](=[O:36])[CH3:35])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH3:24])[CH2:12][O:11][C@@H:10]([O:27][CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])[C@@H:9]1[CH3:33])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccccc1C[C@H](N)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccccc1C[C@H](NC(C)=O)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Yield: 53.3 %

Procedure:
Dissolve the diastereomeric mixture of amines from the previous reaction which contains (2R,3S,5R)-5-[(1S,2S)-2-amino-3-(2-ethylphenyl)-1-hydroxypropyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (418 mg, 0.9 mmol) in dry dichloromethane (7 mL) under a nitrogen atmosphere and add acetic anhydride (90 μL, 0.95 mmol) and triethylamine (150 μL, 1.1 mmol). After 4 hours quench with methanol, concentrate and purify (silica gel chromatography) to give a mixture of amide diastereomers containing the title compound (243 mg). Purify the resulting mixture by HPLC, eluting with 65:35 acetonitrile:water with 8 μM hydrochloric acid, to give the title compound as a single diastereomer (47 mg, 10% overall).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2].[CH2:35]([NH2:37])[CH3:36].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20]([NH:37][CH2:35][CH3:36])(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)Cl)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNS(=O)(=O)c1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, abs. THF (3 ml) was stirred with molecular sieve (4 Å, 30 mg) for 30 min. (7R)-6-Cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride (63%, 50 mg, 62 μmol), ethylamine (2 M solution in THF; 94 μl, 0.19 mmol, 3 eq.) and triethylamine (9 μl, 62 μmol, 1 eq.) were added, and the mixture was stirred at RT for 12 h. The reaction solution was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (29.9 mg, 93% of theory).