Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([CH3:48])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[C:12]([C:22]([NH:24][C:25]2([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41]([O:43]CCCC)=[O:42])[CH:37]=[CH:38][C:31]=5[N:30]=4)[CH2:28][CH2:27][CH2:26]2)=[O:23])[CH:11]=3)=[N:6][CH:7]=1.CO.[OH-].[Na+].C(O)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([CH3:48])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:14][CH:13]=[C:12]([C:22]([NH:24][C:25]2([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42])[CH:37]=[CH:38][C:31]=5[N:30]=4)[CH2:26][CH2:27][CH2:28]2)=[O:23])[CH:11]=3)=[N:6][CH:7]=1
Reactant: CCCCOC(=O)/C=C/c1ccc2nc(C3(NC(=O)c4ccc5c(C6CCCC6)c(-c6ncc(Br)cn6)n(C)c5c4)CCC3)n(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cn1c(C2(NC(=O)c3ccc4c(C5CCCC5)c(-c5ncc(Br)cn5)n(C)c4c3)CCC2)nc2ccc(/C=C/C(=O)O)cc21
Temperature: 66.5 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To the suspension of (E)-butyl 3-(2-(1-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido)cyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate VII (489.0 g, 91.9 Wt %, 633.3 mmol) in THF (1298 g) and MeOH (387 g) was added 50% NaOH (82.7 g, 949.9 mmol), followed by rinse with water (978 g). The mixture was stirred between 65-68° C. for about 1 h for complete hydrolysis. The resulting solution was cooled to 35° C., and filtered through an in-line filter (0.5 micron), and rinsed with a pre-mixed solution of water (978 g) and MeOH (387 g). The solution was heated to 60±4° C., and acetic acid (41.4 g, 689 mmol) was added over 1 h while the mixture was well agitated. The resulting suspension was stirred at 60±4° C. for 0.5 h. Another portion of acetic acid (41.4 g, 689 mmol) was charged in 0.5 h, and batch was stirred at 60±4° C. for additional 0.5 h. The batch was cooled to 26±4° C. over 1 h and held for 1 h. The batch was filtered, rinsed with a premixed solution of water (1956 g) and MeOH (773.6 g), dried at 50° C. under vacuum to give (E)-3-(2-(1-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido)cyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylic acid (1) (419.0 g, 95% yield) with ≧99.0 A % (240 nm) and 94.1 Wt % by HPLC.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:50]1[CH:49]=[C:48]3[C:44]([CH:45]=[CH:46][N:47]3[CH2:51][C:52]3[CH:57]=[CH:56][C:55]([CH2:58][CH3:59])=[CH:54][CH:53]=3)=[CH:43][C:42]=1[CH2:41][O:40]2)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[CH2:58]([C:55]1[CH:54]=[CH:53][C:52]([CH2:51][N:47]2[C:48]3[C:44](=[CH:43][C:42]4[CH2:41][O:40][C@@:10]5([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]5)[C:50]=4[CH:49]=3)[CH:45]=[CH:46]2)=[CH:57][CH:56]=1)[CH3:59]
Reactant: CCc1ccc(Cn2ccc3cc4c(cc32)[C@]2(OC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cn2ccc3cc4c(cc32)[C@]2(OC4)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 42.7 %

Procedure:
To a solution of (3′R,4′S,5′S,6′R,7S)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-1-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-spiro[furo[3,4,f]indole-7(5H),2′-[2H]pyran] (43 mg, 0.055 mmol) in methanol (1 mL) and THF (1 mL) was added with 10% palladium on carbon (41 mg). The resultant solution was stirred under a hydrogen atmosphere for 1 hour at room temperature, and the catalyst was then filtered off. Solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solution=dichloromethane:methanol (10:1)), to thereby obtain the titled compound (10 mg, 43%).
Reaction SMILES: [C:1]1([N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[N:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:12][CH:11]2[C:29]([OH:31])=O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:59]([N:66]([CH3:71])[CH2:67][CH2:68][NH:69][CH3:70])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH2:59]([N:66]([CH2:67][CH2:68][N:69]([CH3:70])[C:29]([C@@H:11]1[CH2:12][N:13]([C:16](=[O:28])[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH2:15][N:10]1[C:8](=[O:9])[N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:31])[CH3:71])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C(C(=O)O)C1
Reactant: CNCCN(C)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)[C@H](C(=O)N(C)CCN(C)Cc2ccccc2)C1
Yield: 77.6 %

Procedure:
According to the procedure of Example 1, Step E above, 48 mg (0.094 sole) of 1-(N,N-diphenylcarbamoyl)-4-(N,N-di-n-pentylcarbamoyl)piperazine-2carboxylic acid, 14 mg (0.104 mmole) of HOBt, 25 mg (0.132 mmole) of EDAC, and 34 mg (0.19 mmole) of N-benzyl-N-methyl-N'-methylethylenediamine after purification by flash chromatography on 16 g of silica gel eluting with 400 mL of 100:4 CH2Cl2 :MeOH provided 49 mg (78%) of an oil.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:17])=[CH:12][CH:13]=2)[N:8]([CH3:18])[CH:7]=1)([OH:3])=[O:2].C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[C:1]([CH2:4][S:5]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:17])=[CH:12][CH:13]=2)[N:8]([CH3:18])[CH:7]=1)=[O:27])([OH:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1cc(SCC(=O)O)c(=O)c2ccc(F)cc21
Solvent: ClCCl
Product: Cn1cc(S(=O)CC(=O)O)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
To a stirred solution (a part remained undissolved) of crude 3-difluoromethylthio-7-fluoro-1-methyl-4-quinolone (4) (3.43 g, 13.23 mmol) in DCM (200 ml) at 0° C. was added ˜80% MCPBA (2.50 g, 11.59 mmol) in a few portions over a period of approximately 1 min. The stirred mixture was allowed to warm to room temperature and was stirred for 30 min. An additional amount of MCPBA (640 mg) was added in 5 portions in approximately 1 h intervals, and the progress of the oxidation was monitored by 1H NMR 30 min after each addition. The mixture was washed with 5% aqueous Na2CO3 (70 ml), the aqueous layer was extracted with DCM (2×200 ml), the combined extracts were dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel with DCM and then with hexane-ethyl acetate (gradient 2:1,1:1,1:2) to give 980 mg (20.7%; two steps) of the product. The product was further purified by recrystallization from absolute ethanol to give 620 mg (13.1%) of 3-difluoromethylsulfinyl-7-fluoro-1-methyl-4-quinolone (5) as off-white crystals. 1H NMR, CDCl3; δ=3.94 s, 3H, N—CH3; 7.050, 6.870, 6.866, 6.686 (4 lines, X part of ABX), 1H, CHF2; 7.21 dd, 1H, J=10.2 & 2.4 Hz, H at C8, 7.27 ddd, 1H, J=8.9, 7.9 & 2.2 Hz, H at C6; 7.99 s, 1H, H at C2; 8.44 dd, 1H, J=9.0 & 6.3 Hz, H at C5.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:10][CH2:9][C:8]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[N:7]1CC1C=CC=CC=1)(=[O:3])[CH3:2]>C(O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:4][CH2:5][CH:6]1[CH2:10][CH2:9][C:8]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])([CH2:11][O:12][Si:13]([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:14])[CH3:15])[NH:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CCC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)N1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)OCC1CCC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)N1
Temperature: 50 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
The mixture of [1-benzyl-5,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-yl]methyl acetate 81e (5.7 g, 10.94 mmol) and 20% palladium hydroxide on active carbon (1 g) in ethanol (150 mL) was stirred at 50° C. under 2.5 Mpa of H2 pressure for 16 hours. Then the catalyst was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford [5,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-yl]methyl acetate 81f (4.48 g, 95%) which was used for next step without further purification. MS: calc'd (MH+) 432, measured (MH+) 432.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(=O)=O.[CH2:30]([Sn](CCCC)(CCCC)C#CC)[CH2:31][CH2:32]C>>[CH2:21]([O:20][C:18]([NH:17][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[C:30]#[C:31][CH3:32])[C:13]([O:15][CH3:16])=[O:14])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(=O)OCc2ccccc2)c1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Product: CC#Cc1ccc(C(=O)OC)cc1NC(=O)OCc1ccccc1
Yield: 85.5 %

Procedure:
Methyl 3-benzyloxycarbonylamino-4-(1-propynyl)benzoate (1.34 g) was prepared from 2-benzyloxycarbonylamino-4-methoxycarbonylphenyl trifluoromethanesulfonate (2.1 g) and tributyl(1-propynyl)stannane (2.49 g) in a similar manner to that of Preparation 1 (2).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[CH:13]=2)O1.[Cl:24][C:25]1[O:35][C:28]2=[C:29]([NH2:34])[N:30]=[CH:31][C:32](I)=[C:27]2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[NH2:34][C:29]1[N:30]=[CH:31][C:32]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:15][CH2:16][N:17]([C:20](=[O:22])[CH3:21])[CH2:18][CH2:19]3)[CH:13]=2)=[C:27]2[CH:26]=[C:25]([Cl:24])[O:35][C:28]=12
Reactant: Nc1ncc(I)c2cc(Cl)oc12
Reactant: CC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Temperature: 100 °C
Yield: 86.6 %

Procedure:
A solution of 1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (422 mg, 1.32 mmol) and 2-chloro-4-iodo-furo[2,3-c]pyridin-7-ylamine (354 mg, 1.20 mmol) in 1,4-dioxane (8.06 mL) and H2O (2 mL) was charged with potassium carbonate (250 mg, 0.0018 mol) and (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride (9 mg, 0.01 mmol) under an atmosphere of nitrogen. The mixture was heated in a microwave at 100° C. for 40 min. The reaction mixture was dissolved in EtOAc and then washed with brine (2×). The aqueous layer was back-extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to a solid. The product was then purified by flash chromatography (0 to 5% 7 N NH3/MeOH:EtOAc) to afford 374 mg (86%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 8.05 (s, 1 H), 7.89 (s, 1 H), 7.83 (s, 1 H), 7.05 (s, 1 H), 4.67 (dd, J=13.52, 1.89 Hz, 1 H), 4.50 (tt, J=11.46, 4.20 Hz, 1 H), 4.08 (d, J=13.89 Hz, 1 H), 3.32-3.37 (m, 1 H), 2.79-2.91 (m, 1 H), 1.91-2.24 (m, 7 H). MS (ESI): 362.11 [M+H]+; HPLC tR=0.88 min (TOF: polar—3 min).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].[CH3:21][CH:22]([CH2:24][CH2:25][CH2:26][C@H:27]([C@@H:29]1[C@:46]2([CH3:47])[C@H:32]([C@H:33]3[C@H:43]([CH2:44][CH2:45]2)[C@:41]2([CH3:42])[C:36]([CH2:37][C@@H:38]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]I)[CH2:39][CH2:40]2)=[CH:35][CH2:34]3)[CH2:31][CH2:30]1)[CH3:28])[CH3:23].C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[S:7][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][O:48][C@H:38]1[CH2:39][CH2:40][C@@:41]2([CH3:42])[C:36](=[CH:35][CH2:34][C@@H:33]3[C@@H:43]2[CH2:44][CH2:45][C@@:46]2([CH3:47])[C@H:32]3[CH2:31][CH2:30][C@@H:29]2[C@H:27]([CH3:28])[CH2:26][CH2:25][CH2:24][CH:22]([CH3:23])[CH3:21])[CH2:37]1)(=[O:3])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](S)[C@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)[C@H]1OC(C)=O
Yield: 61 %

Procedure:
2,3,4-Tri-O-acetyl-1-thio-β-L-fucopyranose (10 mmol) is treated with 6-(5-cholesten-3β-yloxy)hexyl iodide (10 mmol) in dichloromethane (30 ml) containing triethylamine (10 mmol). The reaction takes place in 1 day at room temperature under nitrogen. The resulting solution is washed with distilled water (20 ml) and dried with anhydrous sodium sulfate. The filtered solution is concentrated to form a syrup which is put on a silica gel column and eluted with chloroform followed by 1.0% ethanol in chloroform. The fractions containing the title compound, as determined by thin layer chromatography, are pooled and evaporated to give the title compound in 61% yield [α]D -4° (c 1.5, chloroform).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[Cl:35][C:36]1[CH:41]=CC(CCl)=[CH:38][CH:37]=1.Cl>>[ClH:35].[Cl:35][C:36]1[CH:41]=[CH:25][C:24]([CH2:23][S:22][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:14]([NH:15][C:16]3[S:17][CH:18]=[C:19]([CH3:21])[N:20]=3)=[N:13][CH:12]=2)=[CH:38][CH:37]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Cc1csc(Nc2ncc(SCc3ccc(Cl)cc3)cc2OCc2ccccc2)n1
Yield: 137.2 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 1-chloro-4-(chloromethyl)benzene (27 mg, 0.17 mmol) were reacted according to the method of Example 43 to afford 5-(4-chlorobenzylthio)-3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (57.2 mg, 69.2% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 10.85 (bs, 1H), 7.79 (d, 1H), 7.57 (m, 2H), 7.53 (d, 1H), 7.45-7.34 (m, 3H), 7.30 (m, 2H), 7.18 (m, 2H), 6.78 (s, 1H), 5.29 (s, 2H), 4.17 (s, 2H), 2.29 (d, 3H); Mass spectrum (apci) m/z=238.0 (100), 454.0 (75), 362.9 (60).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28](C)(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: N
Product: CC(C)(O)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 459, substituting 2-(4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 600 mg, 60%). mp 163-164° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.05 (s, 6H), 1.73 (t, J=6 Hz, 2H), 4.30 (s, 1H), 4.52 (t, J=6 Hz, 2H), 7.37 (t, J=9 Hz, 1H), 7.47 (s, 2H), 7.65 (dd, J=9 Hz, J=3 Hz, 2H), 8.83 (d, J=9 Hz, 2H), 8.95 (d, J=9 Hz, 2H), 8.18 (s, 1H); MS (DCI/NH3) m/z 448 (M+H)+. Anal. calcd. for C21H22FN3O5S: C, 56.36; H, 4.95; N, 9.39. Found: C, 55.96; H, 4.89; N, 9.09.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([N:8]2[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CCOCC.Cl.C(Cl)(Cl)Cl.CO>C1COCC1>[ClH:1].[Cl:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([N:8]2[C:12]([CH2:13][NH2:14])=[CH:11][C:10]([C:15]([F:17])([F:18])[F:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1C#N
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1CN
Temperature: 0 °C
Yield: 6 %

Procedure:
To a stirred solution of 1-(3-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonitrile (2.03 g, 6.74 mmol, 1.0 eq) in THF (20 mL) was added BH3-DMS (0.512 g, 6.74 mmol, 1.0 eq) at 0° C. and heated to reflux for 3 h. The reaction mixture was cooled to 0° C. and quenched with 1N HCl and basified with 1N solution of NaOH to a pH of ˜10 and extracted with ethyl acetate (100 mL×2), dried (Na2SO4), the solvent evaporated to get a pale yellow oil. The oil was treated with ether and HCl to get (1-(3-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (0.20, 6% yield over 3 steps) as an off white solid (TLC system: CHCl3/MeOH (9:1), Rf 0.5).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=O.C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>ClCCl>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([Cl:14])=[O:10]
Reactant: O=C(O)C1CC2C=CC1C2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-norbornene-2-carboxylic acid (Aldrich, mixture of endo and exo, 1.25 g, 9.05 mmol) in dichloromethane (50 mL) was treated with oxalyl chloride (0.99 mL, 11.31 mmol) and a catalytic amount of N,N-dimethylformamide (100 μL). The reaction mixture was stirred at ambient temperature for 2 hours and then solvent and excess oxalyl chloride were removed under reduced pressure to yield the title compound which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)CN)#[N:2].C(#N)C.[C:14](=[O:17])([O-])[OH:15].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>[Ru]=O.O>[C:1]([C:3]1[CH:10]=[C:9]([CH:8]=[CH:5][CH:4]=1)[C:14]([OH:15])=[O:17])#[N:2]
Reactant: N#Cc1cccc(CN)c1
Reactant: O=C([O-])O
Agent: O=[Ru]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1cccc(C(=O)O)c1
Temperature: 80 °C
Yield: 55.8 %

Procedure:
A mixture containing m-cyanobenzylamine (13.2 g), acetonitrile (80 g), sodium hydrogencarbonate (76 g), water (500 g), sodium persulfate (95 g), and ruthenium oxide (0.25 g) was stirred for reaction at 80° C. over ten hours. After the precipitated solid was removed through filtration, the pH of the filtrate was adjusted to four through addition of sulfuric acid. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 8.2 g of m-cyanobenzoic acid (yield 56%, based on m-cyanobenzylamine). The m-cyanobenzoic acid obtained had a purity of 94%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([Si](C)(C)C)[S:5][CH:6]=1.[Li]CCCC.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[C:19]([O:25][CH3:26])[CH:18]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]([C:6]2[S:5][CH:4]=[N:3][CH:2]=2)[OH:22])=[C:19]([O:25][CH3:26])[CH:18]=1
Reactant: COc1cc(Cl)ccc1C=O
Reactant: C[Si](C)(C)c1nc(Br)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1C(O)c1cncs1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A solution of 4-bromo-2-trimethylsilanyl-thiazole (1.0 g, 4.23 mmol) in THF (8 mL) was cooled to −78° C. n-BuLi (1.68 mL, 2.5M in hexanes, 4.65 mmol) was added dropwise and the resulting solution was stirred at −78° C. for 30 minutes. A solution of 4-chloro-2-methoxy-benzaldehyde in THF (2 mL) was added to the reaction, followed by 30 minutes of stirring at −78° C. The reaction was then allowed to warm slowly to room temperature. 3M HCl (10 mL) was added and the reaction was stirred for 16 hours. The solution was then neutralized with Na2CO3 solution and partitioned between ethyl acetate and water. The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was then purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 204 mg (19%) of the title compound. MS (ESI) m/e 256 (M+H)+, 1H NMR (DMSO-d6, 300 MHz): □ 8.92 (s, 1H), 7.61 (s, 1H), 7.51 (d, J=7.80 Hz, 1H), 7.03-7.07 (m, 2H), 6.30 (d, J=4.75 Hz, 1H), 6.19 (d, J=4.41 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[C:20]=3[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>[Pd].C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(CC(=O)N2CCc3c2ccnc3Cl)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CC(=O)N2CCc3cnccc32)CCN1C(=O)OC(C)(C)C
Reaction time: 5 h
Yield: 51.3 %

Procedure:
10% Pd/C (62 mg, 0.06 mmol) and (R)-4-[2-(4-chloro-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (232 mg, 0.6 mmol) were mixed with THF (5.82 mL) and triethylamine (1.22 mL, 0.87 mmol) was added. The reaction was hydrogenated at 1 bar for 5 h at ambient temperature then filtered under vacuum and the solvent evaporated in vacuo. The residue was dissolved in MeOH and loaded onto SCX column eluting with MeOH then 2 M ammonia in MeOH to release the amine and concentrated, to give the title compound (111 mg, 53%) as a yellow oil, 1H NMR (Me-d3-OD): 8.35 (1H, s), 8.31 (1H, d), 8.05 (1H, s), 4.33 (2H, t), 4.28-4.17 (1H, m), 3.83 (1H, d), 3.28 (2H, d), 3.24-3.08 (1H, m), 3.00-2.79 (3H, m), 2.36 (1H, dd), 2.26-2.12 (1H, m), 1.48 (9H, s), 1.31 (3H, d).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]([CH2:26][CH3:27])[C:6]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[CH3:25])(=[O:17])=[O:16])=[N:9]1)=[O:7])[CH3:4].O>CO>[CH2:26]([N:5]([CH2:3][CH3:4])[C:6]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[CH3:25])(=[O:17])=[O:16])=[N:9]1)=[O:7])[CH3:27]
Reactant: CCN(CC)C(=O)n1cc(C=O)c(S(=O)(=O)c2cccc(Cl)c2C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CC)C(=O)n1cc(CO)c(S(=O)(=O)c2cccc(Cl)c2C)n1
Reaction time: 0.5 h

Procedure:
11 mg of sodium borohydride were added at 0° C. to a solution of 112 mg of 1-(diethylcarbamoyl)-3-(2-methyl-3-chlorophenylsulfonyl)-4-formylpyrazole [prepared as described in Example 9(3)] in 3.5 ml of methanol, and the resulting mixture was stirred for 30 minutes. At the end of this time, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, eluted with a 5:1 by volume mixture of hexane and ethyl acetate, to afford 114 mg (a quantitative yield) of the title compound as an oil.