Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([OH:22])=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH:16]=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:15]([CH:16]=[O:17])[C:14]=1[O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Cl)cc(OCCCOCc2ccccc2)c1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1cc(Cl)cc(OCCCOCc2ccccc2)c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
To a solution of 3-(3-benzyloxy-propoxy)-5-chloro-2-hydroxy-benzaldehyde (5.3 g, 16.6 mmol) and pyridine (3.4 mL, 41.5 mmol) in CH2Cl2 (70 mL) at 0° C. was added Tf2O (3.1 mL, 18.3 mmol) drop-wise over 5 minutes period and the reaction mixture was stirred for 3 h at room temperature. The solution was diluted with CH2Cl2 (100 mL), washed with water, brine, dried over Na2SO4, then concentrated under reduced pressure. The product was purified by silica gel column chromatography (2:1 hexanes-EtOAc mobile phase) generating the title compound (3.8 g, 8.5 mmol, 51%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.18 (s, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.37-7.29 (m, 6H), 4.52 (s, 2H), 4.23 (t, J=6.2 Hz, 2H), 3.69 (t, J=5.8 Hz, 2H), 2.16 (t, J=6.0 Hz, 2H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −73.23 (s).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][CH:10]=[CH2:11].N[C@H:13](C(O)=O)[CH2:14][C:15]1[CH:24]=[C:23]2[C:18](C=CC=C2)=[CH:17][CH:16]=1.C[N:29](C=O)C>CCOCC>[CH2:8]([NH:29][C@H:14]([C:15]1[CH:24]=[CH:23][CH:18]=[CH:17][CH:16]=1)[CH3:13])[CH2:9][CH:10]=[CH2:11]
Reactant: CN(C)C=O
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: C=CCCN[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a solution of S-(−)-1-phenyl ethylamine (15.75 g, 130 mmol) in 150 mL of DMF at 0° C. is added K2CO3 (53.9 g, 390 mmol) in small portions. After stirring at 0° C. for 10 min, 4-bromobutene (13.5 g, 100 mmol) is added dropwise and followed by Nal (58.5 g, 390 mmol) in small portions. The reaction mixture, a white suspension, is heated to 95° C. and stirred overnight/16 hrs. The solution is cooled to RT and diluted with 200 mL of ether, and washed with 3×100 ml of water. The organic layer is dried over Na2SO4 and concentrated. The crude product is purified by distillation (65˜70° C. under high vacuum) to yield a colorless liquid(13.5 g, 76.7%). (NMR and MS data confirmed, U-4117-28-23).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][S:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=2)([C:14]([NH:16][OH:17])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CO.O1CCOCC1>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][CH2:18][C:11]2([C:14]([NH:16][OH:17])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:21][CH:22]=1)[C:28]#[C:29][CH3:30]
Reactant: CC#CCOc1ccc(SCC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CC#CCOc1ccc(SCC2(C(=O)NO)CCNCC2)cc1
Reaction time: 1 h
Yield: 842.7 %

Procedure:
To a solution of 0.143 g (0.033 mmol) of tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl}methyl)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate in 5 mL of CH2Cl2 and 1 mL of MeOH was added 5 mL of 4M HCl in dioxane and stirred for 1 h. The reaction was concentrated in vacuo and the residue was triturated with ether and filtered to provide 0.093 g (76%) of the desired product as a pale orange solid. Electrospray Mass Spec: 335.3 (M+H)+
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[S:3].Cl.[O-:11][Mn](=O)(=O)=O.[K+].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>>[CH2:8]([O:7][C:5]([CH2:4][N:1]1[C:2](=[O:11])[S:3][N:19]([CH2:17][CH3:18])[C:20]1=[O:21])=[O:6])[CH3:9]
Reactant: CCN=C=O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCOC(=O)CN=C=S
Agent: Cl
Agent: [K+]
Product: CCOC(=O)Cn1c(=O)sn(CC)c1=O

Procedure:
Reagents: Ethyl isothiocyanatoacetate (0.8 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), ethyl isocyanate (0.51 ml, 6.5 mmol).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C>C1COCC1>[CH2:19]([O:18][C:16](=[O:17])[NH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)OCc2ccccc2)C1
Reaction time: 4 h
Yield: 77.2 %

Procedure:
A solution of (R)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (1.0 g, 5.0 mmol) and 50 mL THF was cooled in an ice bath. To this mixture was added benzyl chloroformate (0.77 mL, 5.5 mmol), followed by triethylamine (1.39 mL, 10 mmol). After removing the ice bath, the reaction was stirred for 4 h. The mixture was poured into ice water and extracted with EtOAc. The organic extracts were washed with water, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using EtOAc in hexanes (0-40%) gave benzyl((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (1.29 g, 77%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.10 (s, 2H), 4.87 (s, 1H), 3.52-2.95 (m, 6H), 2.41-2.35 (m, 1H), 2.10-1.79 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[C:32]2[C:31](=[O:33])[NH:30][C:29]([C:34]([O:36]CC)=O)=[N:28][C:27]=2[S:26][CH:25]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:82]2[CH:86]=[N:85][C:84]([O:87][CH2:88][CH2:89][O:90][C:91]3[CH:92]=[C:93]([CH2:97][NH2:98])[CH:94]=[CH:95][CH:96]=3)=[N:83]2)C=CC=CC=1>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[C:32]2[C:31](=[O:33])[NH:30][C:29]([C:34]([NH:98][CH2:97][C:93]3[CH:94]=[CH:95][CH:96]=[C:91]([O:90][CH2:89][CH2:88][O:87][C:84]4[N:85]=[CH:86][NH:82][N:83]=4)[CH:92]=3)=[O:36])=[N:28][C:27]=2[S:26][CH:25]=1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3ccccc3Cl)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3ccccc3Cl)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(2-chlorophenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 70 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (68.2 mg, 44%).
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([CH:10]=[C:11]([C:16]4[CH:17]=[C:18]([CH:26]5[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]5)[N:19]5[C:24]=4[C:23]([NH2:25])=[N:22][CH:21]=[N:20]5)[CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:32][N:33]([CH2:34][C:35]([N:28]1[CH2:29][CH2:30][CH2:31][CH:26]([C:18]2[N:19]3[C:24]([C:23]([NH2:25])=[N:22][CH:21]=[N:20]3)=[C:16]([C:11]3[CH:12]=[CH:13][C:14]4[C:9]([CH:10]=3)=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]=4)[CH:17]=2)[CH2:27]1)=[O:36])[CH3:38]
Reactant: Nc1ncnn2c(C3CCCNC3)cc(-c3ccc4cn(-c5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCCC(c2cc(-c3ccc4cn(-c5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
A mixture of 5-(2-phenyl-2H-indazol-6-yl)-7-piperidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (120 mg, 0.27 mmol), N,N-dimethylglycine (31 mg, 0.30 mmol), EDCl (62 mg, 0.32 mmol), HOBt (44 mg, 0.32 mmol), and N,N-diisopropylethylamine (187 μL, 1.08 mmol) in DMF (2 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 19 mg (16%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1 H), 8.10 (d, 2 H), 7.94 (d, 1 H), 7.85 (d, 1 H), 7.69 (s, 1 H), 7.53-7.63 (m, 2 H), 7.39-7.48 (m, 1 H), 722 (s, 1 H), 6.67-6.73 (m, 1 H), 3.98-4.57 (m, 2 H), 2.84-3.38 (m, 5 H), 2.58-2.81 (m, 1 H), 2.08-2.29 (m, 6 H), 1.68-1.91 (m, 2 H), 1.39-1.66 (m, 1 H); ES-MS m/z 495.15 [M+H]+, HPLC RT (min) 2.27.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[NH:19][N:20]=[CH:21][CH:22]=1.Cl>COCCO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:17]=[C:18]3[NH:19][N:20]=[CH:21][C:22]=23)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Reactant: Nc1ccn[nH]1
Agent: Cl
Solvent: COCCO
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Yield: 47.2 %

Procedure:
In a volumetric flask, 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (23.56 g, 109.4 mmol, obtained in reference example 1) and 2-methoxyethanol (150 mL) were introduced. A solution of 3-amino-2H-pyrazole (10.00 g, 120.3 mmol) in 2-methoxyethanol (170 mL) and 37% HCl (3.23 g, 32.8 mmol) were added under argon atmosphere. This was heated to reflux for 3 days. It was allowed to cool and concentrated. The solid obtained was dissolved in CHCl3 (400 mL) and MeOH (50 mL) and washed with 0.1 N HCl (300 mL) and 1 N NaOH (300 mL). The organic phase was dried over Na2SO4 and concentrated to dryness, to afford 9.93 g of the desired product in solid cream form (yield: 47%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].[C:11](OC)(=[O:14])[C:12]#[CH:13]>CO>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]2[C:3]=1[N:10]=[CH:13][CH:12]=[C:11]2[OH:14]
Reactant: C#CC(=O)OC
Reactant: COc1ccc(N)c(F)c1
Solvent: CO
Product: COc1cc(F)c2nccc(O)c2c1
Temperature: 50 °C
Yield: 32.2 %

Procedure:
2-Fluoro-4-methoxyphenylamine (3.80 g, 26.7 mmole) and methyl propiolate (2.37 ml, 0.267 mole) in methanol (100 ml) was stirred for 72 hours at room temperature, then heated at 50° C. for 24 hours. It was evaporated and the product purified by chromatography on silica gel (dichloromethane) to give a solid (1.66 g), a portion of which was recrystallised from dichloromethane-hexane. The unsaturated ester (0.96 g) in warm Dowtherm A (5 ml) was added over 3 minutes to refluxing Dowtherm A (15 ml), and after a further 20 minutes at reflux the mixture was cooled and poured into diethyl ether. The precipate was filtered to give the title compound (0.50 g, 61%). MS (ES) m/e 196 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[NH:8][C:7]=12.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl.[Pd](Cl)Cl>[C:13]1([C:11]([C:9]2[NH:8][C:7]3=[CH:2][N:3]=[CH:4][CH:5]=[C:6]3[CH:10]=2)=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1ccccc1)c1cc2ccnc(Cl)c2[nH]1
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Temperature: 60 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
(7-Chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanone (Example 29) (1.09 g, 4.25 mmol), palladium(II)chloride (15.4 mg, 3 mol %) and triethylamine (1.3 mL) were combined in N,N-dimethylformamide (25 mL). The reaction mixture was heated at 60° C. under an atmosphere of hydrogen for 8 h, then at room temperature for an additional 16 h. The reaction mixture was diluted with methylene chloride (25 mL) and filtered through a pad of diatomaceous earth. Evaporation of the solvents provided 1.3 g of crude orange solid. Purification by chromatography (SiO2; 0-10% methanol in methylene chloride, 1400 mL) afforded phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (196 mg, 0.893 mmol, 21%) as an off-white solid: mp 245-247° C.; 1H NMR (300 MHz, CD3OD) δ 7.18 (1H, s), 7.55-7.63 (2H, m), 7.65-7.77 (2H, m), 7.95-8.04 (2H, m), 8.17 (1H, d, J=5.7 Hz), 8.87 (1H, s); ESI MS m/z 223 [C14H10N2O+H]+; HPLC (Method A) >99% (AUC), tR=13.4 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[CH:13][N+:14]([O-:16])=[O:15])=[C:10]([CH:17]=[S:18](=[O:20])=[O:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(Cl)(Cl)Cl.[BH4-].[Na+]>CC(O)C>[Cl:1][C:2]1[C:11]([CH2:12][CH2:13][N+:14]([O-:16])=[O:15])=[C:10]([CH:17]=[S:18](=[O:20])=[O:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C=S(=O)=O)c(C=C[N+](=O)[O-])c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)c1ccc(C=S(=O)=O)c(CC[N+](=O)[O-])c1Cl

Procedure:
19.4 g (61 mmol) of methyl 2-chloro-3-(2-nitroethenyl)-4-sulfonylmethylbenzoate and 121 g of silica gel 60 are suspended in 180 ml of 2-propanol and 970 ml of chloroform and treated at room temperature with 3.5 g (94 mmol) of sodium borohydride. The reaction mixture is filtered, the filtrate is washed with dichloromethane/methanol 1:1 (v/v) and the organic phase is freed from the solvent under reduced pressure. Yield: 19.5 g; 1H NMR, δ [ppm], CDCl3; 3.2 (s), 3.9 (m), 4.0 (s), 4.7 (m), 7.8 (d), 8.1 (d).
Reaction SMILES: [CH3:1][C:2](=[CH2:19])[C:3]([O:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15](=[O:18])[CH:16]=[CH2:17])=[O:10])=[O:4].[CH3:20][CH:21]1[CH2:23][NH:22]1>>[CH3:19][C:2](=[CH2:1])[C:3]([O:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15](=[O:18])[CH2:16][CH2:17][N:22]1[CH2:23][CH:21]1[CH3:20])=[O:10])=[O:4]
Reactant: C=CC(=O)OCCOC(=O)NCCOC(=O)C(=C)C
Reactant: CC1CN1
Product: C=C(C)C(=O)OCCNC(=O)OCCOC(=O)CCN1CC1C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
The product of Step 1 (2-({[2-(acryloyloxy)ethoxy]carbonyl}amino)ethyl 2-methylacrylate, 10.0 g, 37 mmol) was mixed with 2-methylaziridine (2.8 g, about 44 mmol, 90% pure, available from Aldrich) to cause a slight exotherm. The reaction mixture was allowed to stand at room temperature overnight. Excess 2-methylaziridine was removed at reduced pressure to leave the desired product (12.0 g) as a colorless liquid. NMR and IR spectral analyses confirmed the structure of the product.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12](=[O:27])[N:13]2[CH:17]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:16][CH:15]=[N:14]2)[CH2:8][C:9](O)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28]1([CH2:34][O:35][NH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN1CCOCC1.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:8][C:9](=[O:10])[NH:36][O:35][CH2:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:12]([N:13]2[C@H:17]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:16][CH:15]=[N:14]2)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NOCc1ccccc1
Reactant: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccccc1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-oxo-4-{5-[(phenylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoic acid (336 mg, 0.90 mmol) in dichloromethane (DCM) (10 ml) was added O-(phenylmethyl)hydroxylamine (167 mg, 1.36 mmol), 4-methylmorpholine (0.26 ml, 2.35 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (123 mg, 0.90 mmol), and EDC (208 mg, 1.09 mmol) at 0° C. The reaction was left to warm to room temperature and stirred overnight. The reaction was washed with water (15 mL) and NaHCO3 solution (15 mL×3), and then concentrated to give the crude product as a mixture of diastereomers, which was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-phenyl-4,5-dihydro-1H-pyrazole-5-carboxamide (110 mg, 25% yield). MS: 477 ([M+H]).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)O.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-:19].[Na+]>>[C:10]([O:17][C:7]1[CH:6]=[CH:5][CH:4]=[CH:2][C:1]=1[O:8][CH3:9])(=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccccc1O
Reactant: O=C(Cl)c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Product: COc1ccccc1OC(=O)c1ccccc1
Reaction time: 0.67 h

Procedure:
A stirred, ice-cold, aqueous solution of sodium hydroxide (250 mL; 15% w/v) is treated, dropwise, with guaiacol (22 mL), followed by benzoyl chloride (25.5 mL), and the mixture is stirred for a further period of 40 minutes. The resulting crystalline white solid is filtered off, washed with water, and dried, to give 2-methoxyphenyl benzoate (29.2 g), m.p. 59°-60° C. [Elemental analysis: C,73.3; H,5.2%; calculated: C,73.7; H,5.3%].
Reaction SMILES: [C:1]([C:3]1[C:7]([S:8]([C:10]([F:13])([F:12])[F:11])=[O:9])=[C:6]([N:14]=[CH:15]OCC)[N:5]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[N:4]=1)#[N:2].[BH4-].[Na+].C(O)(=[O:35])C>C(O)C>[C:1]([C:3]1[C:7]([S:8]([C:10]([F:12])([F:13])[F:11])(=[O:35])=[O:9])=[C:6]([NH:14][CH3:15])[N:5]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[N:4]=1)#[N:2]
Reactant: CCOC=Nc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNc1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 10 °C
Reaction time: 6.75 h
Yield: 22.5 %

Procedure:
A 50 L reactor was charged with 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylsulfinylpyrazole (1.645 g, 3.335 moles) and absolute ethanol (16 L) under nitrogen. The solution was cooled to 10° C., and sodium borohydride (266 g, 7.03 moles) was added slowly such that the temperature remained generally below 35° C. After 6.75 h, some additional sodium borohydride (25 g, 0.66 mole) was added and stirring was continued overnight. Acetic acid (1.3 L, 22.7 moles) was added to quench, followed by 16 L of water. The resulting precipitate was collected by filtration, washed with water, and air-dried. Recrystallization from methanol afforded 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfonylpyrazole (350 g) as an off-white solid (m.p. about 227° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][N:3]=1.S(Cl)([Cl:12])=O>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:12])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cl)nc1
Solvent: ClCCCl
Product: ClCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
On a water bath at 5°-20° C., a mixture of 70.3 g of 2-chloro-5-(hydroxymethyl)pyridine and 50 ml of 1,2-dichloroethane was added dropwise to a mixture of 87.4 g of thionyl chloride and 100 ml of 1,2-dichloroethane over a period of 30 minutes. The whole mixture was stirred at room temperature for 90 minutes and, then, under reflux for 4.5 hours. The reaction mixture was then concentrated and the residue was diluted with 200 ml of chloroform and 60 ml of water. Then, with stirring, 20 g of sodium hydrogen carbonate was added in small portions. Thereafter, the organic layer was separated, treated with activated carbon and concentrated to give 75.9 g of 2-chloro-5-(chloromethyl)pyridine as a yellow brown solid.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25](=O)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: O=Cc1ccncc1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1ccncc1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with isonicotinaldehyde (0.5 g, 4.7 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.093 g, 76%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:17])[C:5]=2[CH:4]=1.[N:18]([CH2:25][CH2:26][OH:27])([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21]>ClCCl>[Br-:1].[O:17]=[C:6]1[C:5]2[CH:4]=[C:3]([CH2:2][N+:18]([CH2:25][CH2:26][OH:27])([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: OCCN(CCO)CCO
Reactant: O=c1c2ccccc2sc2ccc(CBr)cc12
Solvent: ClCCl
Product: O=c1c2ccccc2sc2ccc(C[N+](CCO)(CCO)CCO)cc12
Product: [Br-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The intermediate (C122-2-2) (2-bromomethylthioxanthone) (1.0 part) was dissolved in dichloromethane (85 g), and triethanol amine [product of Wako Pure Chemical industries, Ltd.] (0.5 parts) was added dropwise to this solution (an exotherm was observed after the addition). The resulting mixture was stirred at room temperature (about 25° C.) for one hour, and the organic solvent was evaporated under reduced pressure. As a result, 2.2 g of white solids were obtained. The white solids were recrystallized in a tetrahydrofuran/dichloromethane mixed solution, and 1.0 part of an intermediate (C122-2-3) was obtained (as brown solids).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([S:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 7d (277 mg, 0.156 mmol) was reacted with the product from Example 9c (361 mg, 0.156 mmol) for 5 h by the procedure in Example 7g giving the title compound after purification of the crude product by HPLC with TFA as the trifluoroacetic acid salt (231 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.33 (s, 3 H) 2.77 (s, 3 H) 6.29 (d, J=6.99 Hz, 1 H) 6.73 (d, J=8.82 Hz, 2 H) 7.01 (d, J=7.72 Hz, 1 H) 7.19 (d, J=8.46 Hz, 2 H) 7.24 (s, 1 H) 7.27 (s, 1 H) 7.81 (d, J=8.82 Hz, 1 H) 8.44 (d, J=6.99 Hz, 1 H) 9.01 (d, J=8.82 Hz, 1 H) 9.91 (s, 1 H) 11.03 (s, 1 H) 14.38 (br. s, 1 H); MS (ESI+) m/z 374 (M+H)+.