Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][C:12]=1[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O>[CH3:20][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:11]=1[N:10]1[CH:3]=[CH:7][CH:6]=[CH:5]1)[C:15]([NH2:17])=[O:16]
Reactant: COC1CCC(OC)O1
Reactant: Cc1cc(C(N)=O)ccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(N)=O)ccc1-n1cccc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 671.6 %

Procedure:
The 2,5-dimethoxy-tetrahydrofuran (106 g, 80 mmol) was added to the solution of 4-amino-3-methylbenzamide (100 g, 66.7 mmol) in AcOH (300 mL). The mixture was stirred at 80° C. for about 1.5 h and then cooled to room temperature. The solution of Na2CO3 was added dropwise at 0° C. and extracted with ethyl acetate for three times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and washed with petroleum ether. The resultant solid was filtrated and dried to afford 3-methyl-4-(1H-pyrrol-1-yl)benzamide as a pale solid (89.7 g, yield 67%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:14][CH:13]=1
Reactant: CSc1ccc(O)cc1
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(Oc2ccccc2C#N)cc1
Temperature: 100 °C
Yield: 99.1 %

Procedure:
2-Fluorobenzonitrile (15.7 mL, 149 mmol) and 4-(methylsulfanyl)phenol (25 g, 178 mmol) were dissolved in DMF (500 mL) and K2CO3 (61.8 g, 447 mmol) was then added. The mixture was heated at 100° C. for 16 h under a nitrogen atmosphere. After cooling to room temperature the mixture was evaporated to dryness and then partitioned between ether (1 L) and water (2 L). The organic layer was separated, washed with 2M NaOH (500 mL), 10% (aq) K2CO3 (500 mL), dried (MgSO4) and evaporated to give a light brown solid (35.62 g, 92%); δH (CDCl3, 400 MHz) 2.50 (3H, s), 6.82 (1H, d), 7.05 (2H, d), 7.15 (1H, t), 7.30 (2H, m), 7.43 (1H, t), 7.62 (1H, d); MS m/z (TS+) 259 (MNH4+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:27])[N:7]([C:14]1([F:26])[CH2:19][CH:18]([O:20]C(=O)C)[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13])([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:27])[N:7]([C:14]1([F:26])[CH2:19][CH:18]([OH:20])[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13])([O-:3])=[O:2]
Reactant: CC(=O)OC1CC(F)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1NC(=O)C(F)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)CC1O

Procedure:
A solution of 3-(4-nitro-1,3-dioxoisoindolin-2-yl)-3-fluoro-2,6-dioxo-5-acetoxypiperidine (1 g, 2.9 mmol) and p-toluenesulfonic acid (0.28 9, 1.5 mmol) in methanol (10 mL) is heated at reflux for 5 h. The solvent is removed in vacuo to give 4-nitro-2-(3-fluoro-5-hydroxy-2,6-dioxopiperid-3-yl)isoindoline-1,3-dione which is further purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH:27]=O>CO>[N:8]1([C:5]2[CH:6]=[CH:7][C:2](/[N:1]=[CH:27]/[C:26]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)=[C:3]([NH:13][C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ccc(N2CCCC2)cc1NC(=O)c1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CO
Product: COc1cc(/C=N/c2ccc(N3CCCC3)cc2NC(=O)c2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of N-(2-amino-5-(pyrrolidin-1-yl)phenyl)benzamide (2 mmol) and 3,4,5-trimethoxybenzaldehyde (3 mmol) in methanol was stirred at room temperature for 12 h. The suspension was filtered and the solid was washed with methanol to afford (E)-N-(5-(pyrrolidin-1-yl)-2-(3,4,5-trimethoxybenzylideneamino)phenyl)benzamide as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH:8]([C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=O)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[C:29]([O:48][NH2:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CC(C)N=C=NC(C)C>CN(C=O)C>[CH3:17][O:16][C:14](=[O:15])[CH:8]([CH2:9][CH2:10][C:11](=[O:13])[NH:49][O:48][C:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:18]
Reactant: COC(=O)C(CCC(=O)O)CC(=O)OC(C)(C)C
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)C(CCC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound of example 64 (1.10 g, 4.19 mmol) and HOBt (0.70 g, 5.03 mmol) in DMF (5 mL) were added O-trityl hydroxylamine (1.82 g, 6.28 mmol) and DIC (800 μL), respectively. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was partitioned between HCl (1N, excess) and ethyl acetate. The aqueous phase was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, saturated sodium bicarbonate, and brine. The solvent was evaporated following drying over sodium sulfate, and the crude was flashed with 20-30% ethyl acetate in hexanes. 1H-NMR(CDCl3, 400 MHz: 1.42(s, 9H); 1.58, 2.14, 2.47(3m, 7H); 3.69(s, 3H); 7.34(m, 15H); 7.88(d, broad, 1H).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[C:12]([NH:16][C:17]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[C:23]=2[Cl:30])[N:20]=[CH:19][CH:18]=1)(=[O:15])[CH2:13][CH3:14]>C(O)(=O)C>[N+:8]([C:18]1[CH:19]=[N:20][N:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[C:23]=2[Cl:30])[C:17]=1[NH:16][C:12](=[O:15])[CH2:13][CH3:14])([O-:11])=[O:9]
Reactant: CCC(=O)Nc1ccnn1-c1ccc(Cl)c(Cl)c1Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1ccc(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
2 ml (2.17 g/0.021 mol) of acetic anhydride and then 0.9 ml (1.3 g/0.02 mol) of 98% strength nitric acid are added in succession to 6.4 g (0.02 mol) of 5-propionamido-1-(2,3,4-trichlorophenyl)-pyrazole in 20 ml of glacial acetic acid at 10° C. When the addition is complete, the mixture is stirred for 16 hours at 25° C. To work up the mixture, it is evaporated down in vacuo, the residue is taken up in 20 ml of diethyl ether, the solution is washed three times with a total of 50 to 100 ml of concentrated sodium bicarbonate solution and twice with 50 ml of saturated sodium chloride solution, the solvent is removed in a vacuum from a water pump, and the solid residue is washed with a small amount of water and dried in a high vacuum at 30° C. to 40° C. 5.5 g (76% of theory) of 4-nitro-5-propionamido-1-(2,3,4-trichlorophenyl)-pyrazole of melting point 79°-81° C. are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=3[N:11]=[C:10]2[CH:20]([F:22])[F:21])[N:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=3[N:11]=[C:10]2[CH:20]([F:22])[F:21])[N:5]=1
Reactant: C1COCCN1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)cc(Cl)n1
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)cc(N2CCOCC2)n1
Yield: 89 %

Procedure:
Reaction of 1-(4,6-dichloro-2-pyrimidinyl)-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (International Publ. No. WO 2005/095389, the disclosure of which is incorporated herein by reference in its entirety) (50 mg, 0.145 mmol) with a ten-fold of excess morpholine in THF at room temperature gave 51 mg (89% yield) of 1-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole: mp (CH2Cl2/MeOH) 261-263° C.; 1H NMR (CDCl3) δ 7.90 (dd, J=8.4, 0.7 Hz, 1H), 7.47 (t, JHF=53.6 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 6.47 (s, 1H), 4.07 (s, 3H), 3.84 (m, 4H), 3.73 (m, 4H); Anal. Calcd. for C17H16ClF2N5O2: C, 51.6; H, 4.1; N, 17.7. Found: C, 51.7; H, 4.1; N, 17.9%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2([F:19])[CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:21][C:22]1([F:30])[CH2:26][NH:25][C@H:24]([C:27]([NH2:29])=[O:28])[CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][C:22]([F:30])([F:21])[CH2:23][C@H:24]3[C:27]([NH2:29])=[O:28])=[O:14])[CH:9]=[CH:8][C:7]=2[C:15]2([F:19])[CH2:18][CH2:17][CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Reactant: O=C(O)c1ccc(C2(F)CCC2)c(OCC2CC2)n1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1ccc(C2(F)CCC2)c(OCC2CC2)n1
Yield: 91 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid (Example 130 f, 20 mg, 49.8 μmol) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1, 11.1 mg, 59.7 μmol) to give the title compound (18 mg, 91%) as off-white solid, MS (EI): m/e=398.4 [MH+].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([NH2:13])=[O:12])[CH2:10][CH2:9]1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].F[B-](F)(F)F>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:17][Si:16]([C:14]#[C:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([NH2:13])=[O:12])[CH2:10][CH2:9]1)([CH3:19])[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: NC(=O)C1(c2ccccc2I)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccccc1C1(C(N)=O)CC1

Procedure:
A solution of 1-(2-iodophenyl)cyclopropanecarboxamide (I11) (1.53 g, 85.3 mmol), ethynyltrimethylsilane (1.05 mL, 7.46 mmol), PdCl2(PPh3)2 (0.037 g, 0.053 mmol), t-Bu3PH.BF4 (0.031 g, 0.11 mmol) and copper(I) iodide (0.020 g, 0.11 mmol) in DMF (10 mL) was stirred under a nitrogen atmosphere at 50° C. for 26 hours. The volatiles were evaporated in vacuo and the resulting black residue was purified using silica gel column chromatography (CombiFlash Rf, 24 g SiO2 Cartridge, 5-20% EtOAc in cyclohexane) to give the title compound I12 as a dark yellow amorphous solid (1.09 g, 79%); 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=7.1 Hz, 1H), 7.26-7.50 (m, 3H), 5.26 (brs, 2H), 1.72 (dq, J=4.1 Hz, 2H) 1.16 (dq, J=3.9 Hz, 2H), 0.26 (s, 9H). LCMS-B: rt 7.446 min; m/z 258 [M+H]+.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].[C:12](Br)(=[O:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1)=[O:2]
Reactant: CC(=O)Br
Reactant: O=CNCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(CCNC=O)cc1

Procedure:
This was prepared in an identical manner to the compound described in Description 10 using N-formyl-2-phenylethanamine (95 g), acetylbromide (128 ml), aluminium chloride (288 g) in 1,2-dichloroethane (900 ml). 25 g of the crude produce was chromatographed on Kieselgel 60 (1 Kg). Elution with 1% methanol-chloroform gave the title compound as an oil (18 g). τ(CDCl3) 7.42 (3H, s), 7.1 (2H, t, J=7 Hz), 6.5 (2H, m), 3.45 (1H, broad), 2.7 (2H, d, J=8 Hz) 2.1 (2H, d, J=8 Hz), 1.9 (1H, s).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[CH3:23][O:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[O:24][CH3:23])=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COc1ccccc1N
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Product: COc1ccccc1NC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Yield: 31 %

Procedure:
4-Hydroxy-N-(2-methoxyphenyl)-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-methyoxy-aniline. Yield: 31% of theory; m.p. 198°-200° C (from ethylene chloride/petroleum ether).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:8]=[C:9]2[N:13]([CH:14]=1)[N:12]=[C:11]([CH2:15][O:16][CH3:17])[S:10]2.CN(C)[CH:20]=[O:21]>>[Cl:6][C:7]1[N:8]=[C:9]2[N:13]([C:14]=1[CH:20]=[O:21])[N:12]=[C:11]([CH2:15][O:16][CH3:17])[S:10]2
Reactant: COCc1nn2cc(Cl)nc2s1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1nn2c(C=O)c(Cl)nc2s1
Temperature: 0 °C
Yield: 79 %

Procedure:
Phosphorus oxychloride (2.75 ml, 3 eq) is added very slowly to dimethyl formamide (5 ml) cooled at 0° C. The temperature rises to 50° C. The reaction mixture is heated at 60° C., then 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole a15 (2 g, 9.82 mmol, 1 eq) is added portionwise for 2.5 h. The reaction mixture is poured on an ice/water mixture. The precipitate is filtered and washed with water. The residue is dried overnight at 40° C. under reduced pressure to afford 1.8 g of 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde a16 as a solid.
Reaction SMILES: [CH:1]1[C:5]2[C:6](Cl)=[N:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[NH2:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18].Cl>C(O)(C)(C)C.CO>[CH3:20][O:19][C:17]([C:13]1[S:14][CH:15]=[CH:16][C:12]=1[NH:11][C:6]1[C:5]2[CH:1]=[CH:2][NH:3][C:4]=2[N:9]=[CH:8][N:7]=1)=[O:18]
Reactant: COC(=O)c1sccc1N
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CO
Solvent: CC(C)(C)O
Product: COC(=O)c1sccc1Nc1ncnc2[nH]ccc12
Yield: 67.2 %

Procedure:
A suspension of 6-chloro-7-deazapurine (750 mg; 4.88 mmol), methyl 3-amino-2-thiophenecarboxylate (1.15 g; 7.33 mmol) and concentrated hydrochloric acid (410 μL; 4.9 mmol) in tert-butanol (15 mL) was microwaved at 75° C. for 3 h. The reaction mixture was diluted with methanol (15 mL) and filtered. The aqua solid was washed with methanol and dried under vacuo to afford the hydrochloric salt of 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester (900 mg, 59%) as a green-gray solid (HPLC: 99%, RT: 6.50 min). 1H NMR (DMSO-d6) 12.47 (br s, 1H), 10.68 (br s, 1H), 8.44 (s, 1H), 8.08 (br s, 1H), 8.02 (d, J=5.5 Hz, 1H), 7.47 (dd, J=3.3, 2.2 Hz, 1H), 6.66 (br s, 1H), 3.83 (s, 3H); MS (m/z) 275 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]#[N:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:42][C:43]1[CH:56]=[CH:55][C:46]([O:47][C:48]2[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=2)=[CH:45][CH:44]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:15](=[O:17])[NH:52][C:51]2[CH:50]=[CH:49][C:48]([O:47][C:46]3[CH:55]=[CH:56][C:43]([F:42])=[CH:44][CH:45]=3)=[CH:54][CH:53]=2)[CH2:10]1)#[N:14]
Reactant: CC(C)(C)OC(=O)N1C[C@H](C#N)C[C@H]1C(=O)O
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](C#N)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Step (a) A flask was charged with (2S,4R)-1-(tert-butoxycarbonyl)-4-cyanopyrrolidine-2-carboxylic acid (1.0 g, 4.16 mmol), HATU (1.74 g, 4.58 mmol), 4-(4-fluorophenoxy)aniline (0.844 g, 4.16 mmol), DIEA (4.8 mL, 27 mmol) and DMF (10 mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then quenched with saturated sodium bicarbonate (aq., 20 mL). The mixture was extracted with ethyl acetate (60 mL) and the extract was washed with deionized water (30 mL), and then brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,4R)-tert-butyl 4-cyano-2-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidine-1-carboxylate. The crude mixture was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[CH:12][NH:13][C:14]2[CH:25]=[CH:24][C:17]([CH2:18]OS(C)(=O)=O)=[CH:16][CH:15]=2)[C:4](=[O:26])[NH:3]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C)C=O>[N:27]1([CH2:18][C:17]2[CH:24]=[CH:25][C:14]([NH:13][CH:12]=[C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2](=[O:1])[NH:3][C:4]3=[O:26])=[CH:15][CH:16]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)OCc1ccc(NC=C2C(=O)NC(=O)c3ccccc32)cc1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2C1=CNc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.8 %

Procedure:
To a suspension of crude methanesulfonic acid 4-[(1,3-dioxo-2,3-dihydro-1H-isoquinolin-4-ylidenemethyl)-amino]-benzyl ester (72 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL) is added pyrrolidine (21 μL, 0.25 mmol). The reaction mixture is shaken at ambient temperature for 16 hours. The reaction mixture is diluted to 2 mL with N,N-dimethylformamide and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield the title compound (3.0 mg).
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:24])([F:23])[C:9]1[C:10]([S:15]([NH:18][C:19](=[O:22])OC)(=[O:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH3:25][C:26]1[CH2:30][CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:28][N:27]=1>N1C=CC=CC=1>[F:23][C:8]([F:7])([F:24])[C:9]1[C:10]([S:15]([NH:18][C:19]([N:28]2[CH:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:30][C:26]([CH3:25])=[N:27]2)=[O:22])(=[O:16])=[O:17])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1=NNC(c2ccccc2)C1
Reactant: COC(=O)NS(=O)(=O)c1ncccc1C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC1=NN(C(=O)NS(=O)(=O)c2ncccc2C(F)(F)F)C(c2ccccc2)C1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A dry dioxane (10 ml) solution containing methyl N-(3-trifluoromethylpyridine-2-sulfonyl)carbamate (0.43 g, 1.5 mmol), 3-methyl-5-phenyl-2-pyrazoline (0.48 g, 3.0 mmol) and pyridine (0.45 g) was refluxed under heating and stirring for one hour. After cooling the mixture, the solvent was distilled off under reduced pressure, and the residue was stirred together with ethyl ether. Precipitated crystals were collected by filtration and then thoroughly washed with ethyl ether, and the crystals were suspended in 20 ml of water. Then, the pH was adjusted to a level of from 1 to 2 with concentrated hydrochloric acid, and the suspension was stirred at room temperature for 5 minutes. Crystals were collected by filtration, thoroughly washed with water and then with ethyl ether and dried to obtain 0.51 g of desired 1-(3-trifluoromethylpyridine-2-sulfonylcarbamoyl)-3-methyl-5-phenyl-2-pyrazoline. Melting point: 185°-187° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=[O:39])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:29]([C:31]4[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=4)[C:34]#[N:35])[CH2:28][C:27](=[O:39])[NH:22][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1)[CH3:21]
Reactant: CCc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)cc1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(-c2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)cc1

Procedure:
Prepared from (3-amino-4′-ethyl-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G8) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige solid (67 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[N:11][N:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:17][CH:18]=1.C1C(=O)N([Br:32])C(=O)C1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Br:32][C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:9]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][CH:18]=2)=[N:10][N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Brc1ccccc1-n1cnnc1-c1ccc(-c2ccccc2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1ccccc1-n1c(Br)nnc1-c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 69 %

Procedure:
5-[4-(2-Bromophenyl)-4H-1,2,4-triazol-3-yl]-2-phenylpyridine prepared in the Production Example 2 was dissolved in a mixture solvent of carbon tetrachloride (100 ml) and acetic acid (100 ml), followed by addition of n-bromosuccinimide (5.90 g), and refluxed under heating for 3 hours. After the reaction solution was cooled to ambient temperature, the solution was concentrated-under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and extracted with chloroform. Subsequently, the organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1), to afford the entitled compound as yellow solid (6.96 g, 69%). The physico-chemical values are as follows.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N+:13]([C:16]1[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:21][C:19]1[O:20][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: O=[N+]([O-])c1ccc(C=NNC(=S)NC2CC3C=CC2C3)o1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 5-nitro-2-furaldehyde (59 μL, 0.56 mmol) similar to Example 3 and isolated as a dark yellow solid (4 mg, 2%). 1H NMR (CDCl3): 10.02 (s, 1H), 7.74 (s, 1H), 7.50 (d, J=7.2 Hz, 1H), 7.39 (d, J=3.9 Hz, 1H), 6.88 (d, J=3.9, 1H), 6.26-6.14 (m, 2H), 4.26-4.22 (m, 1H), 3.07 (s, 1H), 2.99 (s, 1H), 1.94-1.87 (m, 1H), 1.68 (d, J=9.3 Hz, 1H), 1.51 (d, J=9.0 Hz, 1H), 1.48-1.42 (m, 1H).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][OH:26]>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([N:20]3[CH2:24][CH2:23][CH2:22][C@@H:21]3[CH2:25][OH:26])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OC[C@H]1CCCN1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CS(C)=O
Product: OC[C@H]1CCCN1c1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C

Procedure:
250 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 400 ml (4 equivalents) of (R)-(−)-2-pyrrolidinemethanol, and the mixture is then heated at 120° C. for approximately 5 hours. The mixture is allowed to return to ambient temperature. The DMSO is concentrated to dryness and the dry product is taken up in CH2Cl2, then partial drying is carried out. 258 mg of expected product are obtained.