Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.Cl.Cl.[C@@H:25]12[NH:32][C@@H:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]([N:33]1[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[C:34]1[CH3:42])[CH2:26]2.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:42][C:34]1[N:33]([CH:27]2[CH2:28][C@H:29]3[N:32]([CH2:2][CH2:3][C:4]4([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]4)[C@H:25]([CH2:31][CH2:30]3)[CH2:26]2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(CC=O)(c2ccccc2)C1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of tert-butyl 2-(2-oxoethyl)-2-phenylmorpholine-4-carboxylate (226.1 mg, 0.74 mmol), 1-[(1R,5S)8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazole dihydrochloride (272.7 mg, 0.74 mmol) and diisopropylethylamine (0.27 mL, 1.48 mmol) in 3 mL CH2Cl2 was added sodium triacetoxyborohydride (235.4 mg, 1.11 mmol) and the reaction mixture was stirred for 2 h at room temperature. After evaporation, the residue was chromatographed (5% (2M NH3/MeOH) in CHCl3) to provide tert-butyl 2-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholine-4-carboxylate (329.9 mg, 84%) as an off-white foam: 1H NMR (400 MHz, CDCl3), δ 7.65 (m, 1H), 7.49-7.40 (br., 2H), 7.39-7.34 (m, 2H), 7.31 (m, 1H), 7.27 (m, 1H), 7.19-7.11 (m, 2H), 4.75-4.16 (m, 2H), 3.76-3.47 (m, 3H), 3.40-3.13 (m, 4H), 2.58 (s, 3H), 2.46-2.32 (m, 2H), 2.17-1.82 (m 8H), 1.63 (m, 2H), 1.53-1.40 (br., 9H); ESI-MS 531 (M+H), 553 (M+Na).
Reaction SMILES: [N:1]([C@H:4]1[C@H:8](O)[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+:2]=[N-:3].CCN(S(F)(F)[F:23])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[N:1]([C@H:4]1[C@H:8]([F:23])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)[C@H](N=[N+]=[N-])C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To the solution of (trans)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (120 g, 0.44 mol, 5/6 purity, containing DCM) in DCM (1.2 L) at −78° C. was added dropwise DAST (141 g, 0.88 mol) in DCM (200 mL). After addition, the mixture was stirred at −78° C. for 1 hr, then warmed to rt and stirred overnight. The reaction mixture was poured into sat. Na2CO3 (2 L) slowly then the DCM phase was washed with water (1 L), sat. NaCl and dried over Na2SO4. Concentrated and purified via flash chromatography (petroleum ether/EtOAc 20/1˜10/1) to give the title compound (48 g, 48% yield) as light yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH2:29][CH3:30]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:28]([CH2:29][CH3:30])[CH2:27][CH2:26][O:25][CH3:24])=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Reactant: CCNCCOC
Product: CCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)c(C)sc2c1)CCOC

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and N-(2-methoxy-ethyl)-ethylamine were converted to yield {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine as yellowish oil, MS: 476 (MH+,1Br).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:35])([F:36])[F:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-(4-trifluoromethyl-phenyl)-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H25F3NO5 [M+H]+: 467.
Reaction SMILES: CC#N.[O:4]([C:11]1[CH:12]=[C:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[CH:20]=2)[CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:30][C:31]([F:36])([F:35])[CH:32]1[O:34][CH2:33]1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>C(OCC)C.CCO>[O:4]([C:11]1[CH:12]=[C:13]([N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[CH:20]=2)[CH2:33][CH:32]([OH:34])[C:31]([F:36])([F:35])[F:30])[CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccc(Oc2cccc(NCc3cccc(C4CCCO4)c3)c2)cc1
Reactant: FC(F)(F)C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCO
Solvent: CCOCC
Product: OC(CN(Cc1cccc(C2CCCO2)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Temperature: 40 °C
Reaction time: 18 h
Yield: 30.6 %

Procedure:
To a CH3CN (1 mL) solution of the amine (0.32 g, 0.93 mmol) from EX-608E was added 1,1,1-trifluoro-2,3-epoxypropane (0.24 mL, 2.8 mmol) and Yb(OTf)3 (0.115 g, 0.18 mmol). The cloudy solution was stirred in a sealed flask at 40° C. for 18 h. The cooled reaction mixture was diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.13 g (30%) of the desired 3-[(3-phenoxyphenyl)[[3-(tetrahydro-2-furanyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C26H26NO3F3.0.5 EtOH: C, 67.33; H, 6.04; N, 2.94. Found: C, 67.49; H, 6.08; N, 2.91. HRMS calcd. 458.1943 [M+H]+, found: 458.1937. 1H NMR (C6D6) δ0.45 (d, 1H), 1.43 (m, 3H), 1.79 (m, 1H), 1.99 (m, 1H), 3.24 (m, 1H), 3.43 (m, 1H), 3.76 (m, 2H), 4.24 (s, 2H), 4.60 (t, 1H), 6.35 (m, 1H), 6.43 (dd, 1H), 6.54 (dd, 1H), 6.8 (m, 2H), 6.9-7.0 (m, 7H), 7.15 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][CH:42]=1)[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[N:30]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:22]=[C:21]([NH:20][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=5)=[O:9])[CH:42]=[CH:41][CH:40]=4)=[N:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cn1nc(C(F)(F)F)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)cc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 77.5 %

Procedure:
Using 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (100 mg, 0.515 mmol), N,N-dimethylformamide (1 drop), oxalyl chloride (60 μL, 0.7 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (122.5 mg, 0.396 mmol), triethylamine (120 mg, 1.19 mmol) and tetrahydrofuran (15 mL) as starting materials and in the same manner as in Example 109, the title compound (149 mg, 78%) was obtained as a white powder.
Reaction SMILES: [CH3:1][NH2:2].NC1[C:5]([F:28])=[CH:6][C:7]([Cl:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1.[N:29]1C=CC=C[CH:30]=1>>[NH2:2][C:1]1[C:5]([F:28])=[CH:6][C:7]([Cl:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:29][CH3:30])[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(Cl)cc1F
Reactant: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3Cl)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution (100 mg) of methylamine and 1-(5-amino-2-chloro-4-fluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) were added to pyridine (2 ml), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, ethanol was added to the residue, and solids were collected by filtration to obtain the title compound (46 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)(=[O:5])=[O:4].C(O)(=O)C.Cl.[OH-].[Na+]>O.C(Cl)(Cl)Cl>[CH3:1][O:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])(=[O:4])=[O:5]
Reactant: COS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COS(=O)(=O)c1ccccc1N
Reaction time: 4 h

Procedure:
688 g of 2-nitrobenzenesulfonic acid methyl ester, 4.7 L of acetic acid, and 2.18 kg of SnCl.H2O are placed in a reaction container having a stirrer, a thermometer, and a nitrogen introducing pipe attached thereto, and cooled to a temperature of not more than 10° C. Hydrochloric acid gas is blown into the reaction mixture under stirring for 4 hours. Next, the reaction mixture is stirred at not more than 10° C. for 10 hours. 8.4 L of chloroform is added to the reaction mixture, and neutralized by a 20% NaOH aqueous solution while the temperature is kept at not more than 10° C. Further, 56 L of water is added, and the reaction mixture is separated. An aqueous phase is extracted by 4 L of chloroform, washed with a chloroform layer with 4 L of water twice, and separated. The separated product is dried by anhydrous magnesium sulfate, and filtered to obtain a chloroform solution of 2-aminobenzenesulfonic acid methyl ester. The obtained solution and 950 g of diethylaniline are placed in a reaction container having a stirrer, a thermometer, and a nitrogen introducing pipe attached thereto, and 287 g of acrylic acid chloride is dropped at a temperature of not more than 5° C. over 15 minutes. The temperature is kept at not more than 5° C., and the solution is stirred for 6 hours. 800 mL of concentrated hydrochloric acid and 12.8 L of water are added to the reaction mixture, and the reaction mixture is separated. An organic layer is washed with 6.4 L of 2% hydrochloric acid, 6.4 L of water, 6.4 L of a 3% sodium hydrogen carbonate aqueous solution, and 6.4 L of water in this order. The organic layer is dried with anhydrous magnesium sulfate, filtered, and dried under reduced pressure at 30° C. to obtain 796 g of crystals. The crystals are refined by column chromatography (5 kg of silica gel, mobile phase of hexane/ethyl acetate=2/1) to obtain 406 g of Monomer 6B represented by the formula (6B):
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([NH:9][C:10](=[O:25])[CH2:11][NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:7][CH2:6][C@@H:5]([N:26]([CH:34]([CH3:36])[CH3:35])C(=O)OC(C)(C)C)[CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH2:2][C@@H:3]1[CH2:4][C@H:5]([NH:26][CH:34]([CH3:36])[CH3:35])[CH2:6][CH2:7][C@@H:8]1[NH:9][C:10](=[O:25])[CH2:11][NH:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1
Reactant: CC(C)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CO)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A solution of tert-butyl(1R,3R,4S)-3-(hydroxymethyl)-4-(2-(3-(trifluoromethyl)-benzamido)acetamido)cyclohexyl(isopropyl)carbamate (130 mg) in CH2Cl2 is treated with CF3COOH (7 ml) and stirred at room temperature for 2 hours. The solution was evaporated and the residue neutralized with 1 N NaOH and extracted into CH2Cl2. The extract was washed with water, brine, dried over Na2SO4, filtered and the solvent evaporated to give 100 mg of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ(TMS): 8.12 (s, 1 H), 8.03 (d, J=7.8 Hz, 1 H), 7.94 (bt, 1 H), 7.75 (d, J=7.8 Hz, 1 H), 7.57 (t, J=7.8 Hz,l H), 7.39 (bd, 1 H), 4.31 (m, 1 H), 4.26 (dd, J=5 Hz, J=16 Hz, 1 H), 4.13 (dd, J=5 Hz, J=16 Hz, 1 H), 3.42 (m, 1 H), 3.27 (m, 1 H), 3.05 (m, 1 H), 2.84 (m, 1 H), 1.92-1.60 (m, 8 H), 1.12 (d, J=6.3 Hz, 6 H). MS found: (M+H)+=416.38.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C@@H:7]([NH2:9])[CH3:8])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Br:19][C:20]1[C:21](Cl)=[N:22][C:23]([Cl:26])=[N:24][CH:25]=1>C(O)C.C(OCC)(=O)C>[Br:19][C:20]1[C:21]([NH:9][C@H:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH3:8])=[N:22][C:23]([Cl:26])=[N:24][CH:25]=1
Reactant: C[C@H](N)C1CCOCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Cl)ncc1Br)C1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
To a solution of (S)-1-(tetrahydro-2H-pyran-4-yl)ethanamine (1.0 g, 7.75 mmol) in ethanol (15 mL) was added N,N-diisopropylethylamine (3.0 g, 23.3 mmol) and 5-bromo-2,4-dichloropyrimidine (2.0 g, 8.53 mmol) at 25° C. under N2. The reaction was stirred at 25° C. for 18 hrs. The mixture was diluted with ethyl acetate and washed with water. The crude product was purified by column chromatography on silica gel eluted with petroleum ether: ethyl acetate=20:1 to give (S)-5-bromo-2-chloro-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)Pyrimidin-4-amine (1.5 g, 60.7%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[NH2:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: NC(CO)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(C(=O)NC(CO)CO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.2 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (93 mg, 0.221 mmol) obtained in Example 12 in methylene chloride (3 ml), 2-amino-1,3-propanediol (24 mg, 0.265 mmol), 1-hydroxybenzotriazole (30 mg, 0.221 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (51 mg, 0.265 mmol) and 4-methylmorpholine (29 μl, 0.265 mmol) were added, and the resulting mixture was stirred for 17 hours at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with a saturated solution of sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:20) was concentrated under reduced pressure. Ethylacetate-hexane was added to the resulting concentration residue, and the solid thus precipitated was collected by filtration, to obtain the title compound (81 mg, 0.164 mmol, 74%) as a white powder.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].[Br:19][C:20]1[CH:28]=[N:27][CH:26]=[C:25](F)[C:21]=1[C:22]([OH:24])=[O:23]>C1COCC1>[Br:19][C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[F:11])[C:21]=1[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1c(F)cncc1Br
Reactant: Nc1ccccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1c(Br)cncc1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
Lithium bis(trimethylsilyl)amide (54.6 mL, 1.0 M in THF, 54.6 mmol) was added to a solution of 2-fluoro aniline (3.5 mL, 36.4 mmol) in THF (100 mL) at −78° C. The resulting solution was for 1 h at −78° C. 3-Bromo-5-fluoro-isonicotinic acid (1) (4.0 g, 18.2 mmol) was added as a solid, and the reaction solution was stirred for 48 h at room temperature. The reaction solution was concentrated via rotary evaporation, diluted with satd. NaHCO3, and washed with EtOAc. The aqueous solution was acidified with concentrated HCl. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to afford the desired product (4.2 g, 74%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:3]1.[O-:19][CH2:20]C.[Na+].O>C(OCC)=O>[OH:19][CH:20]=[C:8]1[C:9](=[O:11])[C:10]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]=2[CH2:6][C:7]1([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1nn(C)c2c1CC(C)(C)CC2=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC=O
Product: CCOC(=O)c1nn(C)c2c1CC(C)(C)C(=CO)C2=O
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A solution of ethyl 1,5,5-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (1.00 g, 4 mmol) in anhydrous ethyl formate (10 mL) was treated with sodium ethoxide (0.54 g, 8 mmol) and refluxed for 3 hours. The mixture was cooled to room temperature and poured into cold water (40 mL). The aqueous layer was washed with diethyl ether (40 mL) to remove unreacted starting material, acidified with a 20% NaH2PO4 solution and extracted with ethyl acetate (50 mL×2). The organic extracts were collected, dried on Na2SO4 and evaporated to dryness to obtain the title compound (0.88 g, 78.8% yield) as a brown solid.
Reaction SMILES: [N:1]([C:4]1[N:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)=[N+]=[N-].Cl.[OH-].[Na+]>CO.CCOC(C)=O>[N:9]1[C:10]2[CH:11]=[CH:12][N:13]=[C:4]([NH2:1])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=Nc1nccc2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nccc2ncccc12
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 69.2 %

Procedure:
To a suspension of 5-azido-1,6-naphthyridine (3.4 g, 19.9 mmol) in methanol (40 mL) was added hydrochloric acid (30 mL). Stannous chloride dihydrate (22.5 g, 99.5 mmol) was added. The mixture was stirred at 75° C. for 3.5 h. A yellow precipitate formed. The mixture was filtered to give a yellow solid. The solid was suspended in EtOAc (200 mL). Sodium hydroxide (saturated aqueous solution) was added to adjust pH to 9. A white precipitate formed. The mixture was filtered and the filtrate was extracted with EtOAc (200 mL×6). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give 2.0 g of the crude product as a yellow solid. MS (ESI): m/z 146 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1>>[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2,2-dimethylpropionyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (64% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 8.01, 6.98, 3.86-3.73, 3.57, 1.57-1.48, 0.79-0.70, 0.52-0.45, 0.16-0.12. MS (ES+) m/z 360.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:3][CH2:4][CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>CS(C)=O.O>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:6]([CH2:5][CH2:4][CH2:3][C:2]([F:21])([F:1])[C:17]([F:18])([F:19])[F:20])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: ClCCCCCBr
Reactant: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(CCCCCCl)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
Diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate (3 g, 9.37 mmol) was dissolved in dimethyl sulfoxide (20 ml), and sodium hydride (60%, 525 mg, 13.11 mmol) was added to the resulting solution followed by stirring for 1 hour at room temperature. 5-Bromo-1-chloropentane (7.4 ml, 56.2 mmol) was added to the reaction mixture, followed by stirring for 1.5 hours at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/hexane=1/4) to give diethyl 2-(5-chloropentyl)-2-(4,4,5,5,5-pentafluoropentyl)malonate (3.3 g, Yield 83%) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.[C:14]([O:18][C:19](ON=C(C1C=CC=CC=1)C#N)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCOCC1>[C:14]([O:18][C:19]([NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: NCc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 7.76 g (38.5 mmol) of 4-aminomethylphenylacetic acid hydrochloride, 10.42 g (42.3 mmol) of 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile and 13.33 ml (96.2 mmol) of triethylamine in 60 ml of 50% aqueous dioxane was stirred for 2.5 hours at ambient temperature. The solvent was removed, 25 ml of water and 50 ml of ethyl acetate were added and the layers were separated. The aqueous phase was extracted with ethyl acetate then stirred with ethyl acetate and acidified to pH 1-1.5 with 3 N hydrochloric acid. The mixture was then extracted three times with ethyl acetate and the combined extracts were washed with water, dried (MgSO4) and evaporated to give 4-(N-t-butoxycarbonylaminomethyl)phenylacetic acid, m.p. 108°-110°.