Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N+:13]([O-:25])=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2ncc3cnccc32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: [O-][n+]1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine (0.920 g, 4.31 mmol) in dichloromethane (50 mL) was added 65% m-chloroperbenzoic acid (1.26 g, 4.75 mmol). After 2 hours, the mixture was diluted with EtOAc and water. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate, filter and concentrated to afford 1-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine 5-oxide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][NH2:31])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCCCN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and butane-1,4-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 8.01-7.95 (m, 1 H), 7.92-7.86 (m, 1 H), 7.83-7.76 (m, 1 H), 7.69-7.61 (m, 1 H), 7.61-7.54 (m, 1 H), 7.50-7.42 (m, 1 H), 7.39-7.31 (m, 1 H), 5.96 (s, 1 H), 5.20 (brs, 2 H), 3.63 (brs, 2 H), 3.47 (brs, 2 H), 3.37 (s, 2 H), 2.42 (s, 3 H), 2.27-2.24 (m, 4 H), 1.86 (d, J=3.28 Hz, 2 H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28].C(N(CC)CC)C.Cl>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4cccc(C(F)(F)F)c4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (1.00 g, 3.20 mmol) and 3-(trifluoromethyl)benzoyl chloride (0.67 g, 3.20 mmol) in N,N-dimethylformamide (25 mL), was added triethylamine (0.90 mL, 6.40 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (50 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (50 mL) and water (50 mL). The solids were dissolved in EtOAc (75 mL) and washed with water (75 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-trifluoromethyl-benzamide as an off-white solid (0.95 g, 66% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.69 min (98.71%); mp: 244-246° C.; 1H NMR (DMSO-d6) δ 1.94-2.06 (m, 1H), 2.27-2.46 (m, 1H), 2.53-2.68 (m, 1H), 2.80-3.04 (m, 1H), 4.32 (d, J=17.4 Hz, 1H), 4.45 (d, J=17.4 Hz, 1H), 4.63 (d, J=5.9 Hz, 2H), 5.11 (dd, J=5.0, 13.3 Hz, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.57 (s, 1H), 7.66-7.82 (m, 2H), 7.94 (d, J=7.7 Hz, 1H), 8.16-8.34 (m, 2H), 9.42 (t, J=5.8 Hz, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.50, 31.19, 42.90, 47.14, 51.59, 122.21, 122.99, 123.86 (q, J=3.6 Hz), 123.90 (q, J=270 Hz), 127.18, 127.94 (q, J=3.5 Hz), 129.2 (q, J=32 Hz), 129.71, 130.47, 131.44, 134.97, 142.42, 143.50, 164.79, 167.91, 170.98, 172.85. LCMS: MH=446; Anal Calcd for C22H18N3O4F3+0.6H2O: C, 57.92; H, 4.24; N, 9.21. Found: C, 57.87; H, 4.08; N, 9.16.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[C:31]=1[F:38]>CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]3[N:17]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[C:31]=4[F:38])[C@H:16]([C:18]([F:20])([F:21])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(CBr)c(F)c1F
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1ccc(F)c(F)c1F

Procedure:
The product is prepared according to the procedure described in Example 22, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 214 mg of caesium carbonate and 82 mg of 1-(bromomethyl)-2,3,4-trifluorobenzene in 2 ml of dimethylformamide. After purification by preparative HPLC/MS (Method C), 76 mg of (8S)-2-(morpholin-4-yl)-9-(2,3,4-trifluorobenzyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]1([NH:31][CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:31]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH3:32])(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCCCC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CN(C1CCCCC1)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (82 mg, 0.22 mmol), cyclohexyl(methyl)amine (50 mg, 0.44 mmol) and DMAP (54 mg, 0.44 mmol) in MeCN (4 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 58 mg (59% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.22-1.32 (m, 2 H), 1.33-1.44 (m, 4 H), 1.47-1.62 (m, 6 H), 1.65 (s, 9 H), 1.66-1.74 (m, 2 H), 2.27-2.44 (m, 1 H), 2.76 (s, 3 H), 3.29-3.38 (m, 2 H), 3.68-3.81 (m, 1 H), 3.87-3.97 (m, 2 H), 4.50 (d, J=7.42 Hz, 2 H), 7.89 (dd, J=8.79, 1.76 Hz, 1 H), 8.00 (d, J=8.79 Hz, 1 H), 8.12 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=448.0; Anal. Calcd for C24H37N3O3S+1.00 TFA+0.30 EtOAc+0.2H2O (591.70): C, 55.21; H, 6.95; N, 7.10. Found: C, 55.22; H, 6.85; N, 7.08.
Reaction SMILES: C([O:8][C:9](=[O:46])[CH2:10][N:11]([C:19](=[O:45])[C@H:20]([CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:44])[NH2:43])[N:21]([N+:35]([O-])=O)[S:22]([C:25]1[CH:34]=[CH:33][C:32]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:26]=1)(=[O:24])=[O:23])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>C(O)C.[Pd]>[N:21]#[N:35].[CH:26]1[C:27]2[CH2:28][CH2:29][CH2:30][CH2:31][C:32]=2[CH:33]=[CH:34][C:25]=1[S:22]([NH:21][C@H:20]([C:19]([N:11]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:10][C:9]([OH:46])=[O:8])=[O:45])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:43])[NH2:44])(=[O:23])=[O:24]
Reactant: [H][H]
Reactant: N=C(N)NCCC[C@@H](C(=O)N(CC(=O)OCc1ccccc1)CC1CCCCC1)N([N+](=O)[O-])S(=O)(=O)c1ccc2c(c1)CCCC2
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: N#N
Product: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2c(c1)CCCC2)C(=O)N(CC(=O)O)CC1CCCCC1
Yield: 87 %

Procedure:
To a solution of 3.00 g of NG -nitro-N2 -(5,6,7,8-tetrahydro-2-naphthalenesulfonyl)-L-arginyl-N-cyclohexylmethylglycine benzyl ester in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion ® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 2.07 g (87%) of N2 -(5,6,7,8-tetrahydro-2-naphthalenesulfonyl)-L-arginyl-N-cyclohexylmethylglycine as a powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.CC(O)C.[OH-].[Na+].Cl[CH:21]([F:23])[F:22]>CCOCC.O>[F:22][CH:21]([F:23])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: CC(C)C(C#N)c1ccc(O)cc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)O
Product: CC(C)C(C#N)c1ccc(OC(F)F)cc1
Yield: 81.4 %

Procedure:
A mixture of 2-(4-hydroxyphenyl)-3-methylbutyronitrile (25.0 g; 0.1427 mol), 2-propanol (230 ml), and 25.8% aqueous sodium hydroxide (103 ml; 0.857 mol) is stirred in a pressure vessel and chlorodifluoromethane (36.4 g; 0.421 mol) is added over a period of 52 minutes with cooling to control the exotherm and to maintain the temperature of the reaction mixture below 52° C. The reaction mixture is then stirred for an additional 11/2 hours. Water (700 ml) and ether (300 ml) are then added to the reaction mixture and the two phase mixture is separated. The ether solution is washed twice with water (1000 ml+500 ml) and then with saturated brine (300 ml). It is then dried and evaporated under vacuum to yield 30.48 g (94.8%) of a clear, very slightly yellow liquid, shown to be 85.9% pure by gas-liquid chromatography. This corresponds to a yield of 81.4%.
Reaction SMILES: [NH2:1][C:2]1[C:13]([NH2:14])=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[C:4]([Cl:15])[CH:3]=1.[Cl:16][C:17]([Cl:23])([Cl:22])[C:18](=N)OC>C(O)(=O)C>[Cl:15][C:4]1[C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:12][C:13]2[N:14]=[C:18]([C:17]([Cl:23])([Cl:22])[Cl:16])[NH:1][C:2]=2[CH:3]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1cc(Cl)c(C(=O)NC2CC2)cc1N
Solvent: CC(=O)O
Product: O=C(NC1CC1)c1cc2nc(C(Cl)(Cl)Cl)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,5-diamino-2-chloro-N-cyclopropylbenzamide (4.1 g, 18.2 mmol) in glacial acetic acid (50 ml) was added, at 0° C., methyl 2,2,2-trichloroacetimidate (2.21 ml, 18.2 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The 6-chloro-N-cyclopropyl-2-(trichloromethyl)-1H-benzimidazole-5-carboxamide was used for Stage 4 directly without purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH3:16][S-:17].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:16][S:17][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: C[S-]
Reactant: O=[N+]([O-])c1sc(-c2cccnc2)nc1Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSc1nc(-c2cccnc2)sc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a solution of 4-chloro-5-nitro-2-(pyridin-3-yl)thiazole (500 mg, 2.07 mmol) in 1,4-dioxane (2 mL) was added in one portion solid sodium thiomethoxide (145 mg, 2.07 mmol). The orange-red mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. This solid was purified by silica gel chromatography (ethyl acetate/hexanes) to give 4-(methylthio)-5-nitro-2-(pyridin-3-yl)thiazole (358 mg, 68%): 1H NMR (300 MHz, CDCl3) δ 9.21 (d, J=5.4 Hz, 1H), 8.79 (dd, J=4.8, 1.8 Hz, 1H), 8.24 (dt, J=7.8, 2.1 Hz, 1H), 7.46 (ddd, J=8.1, 4.8, 0.9 Hz, 1H), 2.81 (s, 3H); EIMS m/z 253.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]([OH:50])[CH2:48]Br)=[CH:43][C:42]=1[NH:51][CH:52]=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:48][C@@H:47]([C:44]2[CH:45]=[CH:46][C:41]([O:40][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[C:42]([NH:51][CH:52]=[O:53])[CH:43]=2)[OH:50])=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCc1ccc(OCCNCc2ccccc2)cc1)OCc1ccccc1
Reactant: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=CNc1cc([C@@H](O)CN(CCOc2ccc(CCCCNC(=O)OCc3ccccc3)cc2)Cc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.6 %

Procedure:
Benzylamine 16 (619 mg, 1.43 mmol) was added to a suspension of bromoalcohol 5 (500 mg, 1.43 mmol) and K2CO3 (495 mg, 3.58 mmol) methanol (10 mL) and tetrahydrofuran (5 mL). The suspension was stirred at ambient temperature for 15 h, then heated to 55° C. for 75 h. The solid was vacuum filtered and the filtrate was concentrated under vacuum. The resulting oil was subjected to column chromatography eluting with 5-50% ethyl acetate in hexanes to afford the desired product 17 (508 mg, 5%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 1.45-1.62 (m, 4H), 2.54 (t, 2H), 2.65-2.71 (m, 1H), 3.14-3.23 (m, 3H), 3.58-3.74 (m, 1H), 3.88-4.09 (m, 3H), 4.71 (br, 2H), 5.04-5.21 (m, 4H), 6.79-7.25 (m, 6H), 7.34-7.52 (m, 16H), 7.65-7.87 (m, 1H), 8.32-8.49 (m, 1H); m/z, (ESI) 702 [C43H47N3O6+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([O-:30])=O)[CH2:27][CH2:26]1)=[O:24].[Li+].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[F:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[CH:66][CH:65]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([NH:68][C:67]2[CH:69]=[CH:70][C:64]([F:63])=[CH:65][CH:66]=2)=[O:30])[CH2:27][CH2:26]1)=[O:24]
Reactant: Nc1ccc(F)cc1
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)C4(C(=O)[O-])CC4)cc3F)ccn2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of Example B5 (9.91 g, 23.58 mmol) in DMF (80 mL), under an atmosphere of argon, were added TBTU (11.36 g, 35.4 mmol), DIPEA (20.59 ml, 118 mmol) and 4-fluoroaniline (3.93 g, 35.4 mmol). The reaction mixture was stirred at RT overnight. An additional portion of TBTU (7.5 g, 17.8 mmol) was added and stirring was continued. After 2 h, an additional portion of TBTU (3.5 g, 8.33 mmol) was added and stirring was continued for 2 h. The solvent was removed under high vacuum and the residue was dissolved in EtOAc (700 mL) and washed with sat. aq. NaHCO3 (2×200 mL) and brine (50 mL), dried (MgSO4), concentrated to dryness and purified by silica gel chromatography (MeOH-DCM) to provide N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (7.2 g, 59% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 9.76 (s, 1H), 8.39 (d, J=5.6 Hz, 1H), 8.28 (s, 1H), 8.13 (dd, J=12.1, 7.1 Hz, 1H), 7.99 (s, 1H), 7.62-7.53 (m, 3H), 7.27 (d, J=2.6 Hz, 1H), 7.22-7.15 (m, 2H), 6.71 (dd, J=5.6, 2.4 Hz, 1H), 3.86 (s, 3H), 1.69-1.56 (m, 4H); MS (ESI): m/z 508.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[CH2:15]([CH:17](CC)C(O)=O)[CH3:16].C(C(CC)C(O)=O)C.C(=O)CC=O>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[CH:16][CH:15]=[CH:17][N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CCC(CC)C(=O)O
Agent: O=CCC=O
Solvent: CC(=O)O
Product: c1ccc(CSc2nc3ncccn3n2)cc1
Temperature: 25 °C
Yield: 17.2 %

Procedure:
A solution of 2.0 g (9.6 mmol) of 3-amino-5-benzylthio-1,2,4-triazole and 2.3 ml (9.6 mmol) of malonaldehyde bis(diethylacetate) in 20 ml of glacial acetic acid was heated at reflux for 17 hours. After cooling to room temperature, the solvent was removed by evaporation at reduced pressure. The brown solid residue was recrystallized from isopropyl alcohol to afford 0.4 g (17%) of the desired product as a light brown crystalline solid, m.p. 104°-106° C. IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1>N.CO>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)ccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)ccc32)[C@H](O)[C@@H]1O

Procedure:
A solution of 0.226.g (0.508 mmole) of 72 in 10 mL of NH3 /MeOH was stirred in a pressure bottle at room temperature for 5 hr. The reaction mixture was evaporated and coevaporatad with MeOH (3×) to give a solid. This solid was recrystallized from MeOH to give 0.136 g (76%, based on C12H12Cl2N2O4MeOH) of 73 as white crystals. MP 102°-150° C. (melted over a large range of temperature). MS (Cl) m/e 319.0242 (37%, MH+ =319.0252). 1H NMR (OMSO-d6): d 8.08 (d, 1, 7-H, J7-6 =9.0 Hz), 7.73 (d, 1, 4-H, J4-6 =2.0 Hz), 7.30 (dd, 1, 6-H), 5.89 (d, 1, 1'-H, J1-2 =8.0 Hz), 5.51 (d, 1, 2'-OH, J2'-2'OH =6-5 Hz), 5.29 (d, 1, 3'-OH J3'-3'OH=4.5 Hz),5.26 (t, 1, 5'-OH, J5'-5'OH =5-0 Hz), 4.45 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.12 (m, 1, 3'-H, J3'-4' =2.0 Hz), 3.99 (m, 1, 4'-H, J4'-5' =J4'-5' =3.5 Hz), 3.69 (m, 2, 5'-H and 5'-H, J5'-5' =12.0 Hz). 13C NMR (DMSO-d6) d 142.36 (C3a), 141.40 (C2), 131.88 (C7a), 127.49 (C5), 123.32 (C6), 118.40 (C4), 114.51 (C7), 89.07 (C1'), 86.23 (C4'), 71.49 (C2'), 69.75 (C3'), 61.23 (C5').
Reaction SMILES: [C:1]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].S([O-])([O-])(=O)=O.[Mg+2]>O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)OC12CC3CC(C1)CC(OS(C)(=O)=O)(C3)C2
Temperature: 0 °C

Procedure:
A stirrer and a dropping funnel were equipped with a 3 L-glass reactor. Then, 222.3 g (1.0 mol) of Adamantate HA (manufactured by Idemitsu Kosan Co., Ltd.: 3-hydroxy-1-adamantyl acrylate), 151.8 g (1.5 mol) of dried triethylamine, and 2,000 mL of dried toluene were added into the glass reactor, and were stirred at 0° C. in an ice bath. Subsequently, 137.5 g (1.2 mol) of methanesulfonyl chloride was added thereto, and was stirred for 5 minutes. As a result of conducting gas chromatography-mass spectrography analysis, it was confirmed that the peak of the adamantate HA was completely disappeared. Subsequently, 100 mL of water was added into it, thereby unreacted methanesulfonyl chloride was deactivated. The reaction solution thus obtained was transferred to a 4 L-separating funnel, 800 mL of water was further added, and then the reaction solution was sufficiently stirred. After leaving at rest, the aqueous layer was removed. To remove the triethylamine, 500 mL of 0.5 N hydrochloric acid was added, and stirred. After leaving at rest, the aqueous layer was removed. Furthermore, an organic layer was washed using an aqueous saturated sodium hydrogen carbonate and an aqueous saturated sodium chloride. This organic layer was transferred to a conical flask, and 12.0 g (0.1 mol) of anhydrous magnesium sulfate was added. The magnesium sulfate was removed by filtration after being dried. Then, the toluene was distilled away from the filtrate by evaporation. As a result of conducting GC analysis, it was confirmed that compound 1 (chemical formula shown below) having purity of 95.4% was obtained (yield 301.6 g).
Reaction SMILES: C([O:3][C:4](=[S:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([S:13]C(=O)C)[CH2:10][CH2:11][CH3:12])C.[OH-].[K+]>CO.O>[SH:13][CH:9]([CH2:10][CH2:11][CH3:12])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[S:17]
Reactant: CCCC(CCCCC(=S)OCC)SC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(S)CCCCC(O)=S

Procedure:
11.9 grams (40.7 mmoles) of 6-acetylthio-8-methylthiooctanoic acid ethyl ester (XI) were added to a solution of 7.5 grams (133.7 mmoles) of potassium hydroxide in 100 ml of methanol and 5 ml of water and the mixture heated at reflux for 10 hours under a cover of nitrogen. After a further 10 hours at room temperature the solvent was removed in a vacuum, the residue taken up on 100 ml of 3N hydrochloric acid and extracted three times, each time with 100 ml of ethyl acetate. After drying the combined extracts with magnesium sulfate the solvent was removed in a vacuum. The short path distillation of the residue gave 7.1 grams (78% of theory) of 6-mercapto-8-methylthiooctanoic acidas a pale yellow oil having a boiling point of 150° C. to 170° C. at 0.5 mbar.
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[CH:11](Cl)([CH3:13])[CH3:12].[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: CC(C)Cl
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)P(C(C)(C)C)C(C)(C)C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride, 0.05 g (0.001 mol (corresponding to 1% by mol)) of copper(I) chloride and 30 ml of tetrahydrofuran were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 4.7 g (0.060 mol) of isopropyl chloride and 1.7 g (0.072 mol) of metallic magnesium in 50 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at the same temperature for 3 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 20 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent and a low-boiling component were distilled off under reduced pressure to obtain 8.2 g (purity: 95.0%) of the aimed di-tert-butylisopropylphosphine as an oily substance. The yield was 92.7%.