Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:3].C(=O)([O-])[O-].[K+].[K+].[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.O>CC(C)=O>[CH2:15]([CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:5][O:4][C:2]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)=[O:3])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCC(CCCCCC)COC(=O)Cl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCC(CCCCCC)COC(=O)n1cncn1
Reaction time: 16 h
Yield: 67.4 %

Procedure:
2-Hexyldecyl chloroformate (90 g) was added during 30 minutes to a stirred suspension of potassium carbonate (41 g), and 1,2,4-triazole (21 g) in acetone (350 ml). During addition the temperature of the reaction mixture rose from ambient (22°) to 40°. The mixture was stirred for 16 hours and then poured into water (750 ml) and extracted with toluene. The toluene solution was distilled giving 1-(2'-hexyldecyloxycarbonyl)-1,2,4-triazole (67.1 g), b.p. 165°-175° at 0.4 mm of mercury.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:3][C:4]([O:6]CC)=O.C(O)(=O)C(O)=O.C1(NN)CC1.C1(C2[N:33]([CH:34]([CH3:36])[CH3:35])[N:32]=[CH:31]C=2C=O)CC1>>[CH:34]1([N:33]2[C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[C:3]([CH:4]=[O:6])[CH:31]=[N:32]2)[CH2:36][CH2:35]1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Reactant: CCOC(=O)CC(=O)c1ccccn1
Agent: NNC1CC1
Agent: O=C(O)C(=O)O
Product: O=Cc1cnn(C2CC2)c1-c1ccccn1

Procedure:
1-Cyclopropyl-5-pyridin-2-yl-1H-pyrazole-4-carbaldehyde was prepared from ethyl 3-oxo-3-pyridin-2-yl-propionate and cyclopropyl hydrazine oxalate in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>C(O)C>[CH:15]1([NH:18][C:2]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]3[C:3]=2[NH:4][CH:5]=[N:6]3)[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: FC(F)(F)c1nc(Cl)c2[nH]cnc2n1
Solvent: CCO
Product: FC(F)(F)c1nc(NC2CC2)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 108 h
Yield: 62 %

Procedure:
A mixture of 12 g (54 mmol) of 6-chloro-2-trifluoromethylpurine, 30 g (540 mmol) of cyclopropylamine and 250 mL of ethanol was stirred at room temperature for 4.5 days leaving a white solid. The mixture was concentrated in vacuo to dryness, 215 mL of H2O was added and the mixture was stirred for 1 hour. The product was collected by filtration and after drying (vacuum oven, 50° C., 5 hours) 8.1 g of product was obtained, 62% yield. M.P. 260° C. (dec.); 1H NMR (CD3OD) δ 8.18 (s, 1H), 3.30 (bs, 1H), 0.904 (m, 2H), 0.67 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C@@H:3]([N:5]1[CH2:10][CH2:9][C@:8]([CH2:18][CH2:19][C:20](O)=[O:21])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:7][C:6]1=[O:23])[CH3:4].CC[N:28]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]([CH3:25])([CH3:24])[C@@H:3]([N:5]1[CH2:10][CH2:9][C@:8]([CH2:18][CH2:19][C:20]([NH2:28])=[O:21])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:7][C:6]1=[O:23])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: C[C@H](N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
3-((R)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid (50 mg, 0.144 mmol), EDCI (55 mg, 0.28 mmol), HOBt (38 mg, 0.28 mmol), and DIEA (90 mg, 0.07 mmol) were dissolved in CH2Cl2 (10 mL) under ice bath. The mixture was stirred under an NH3 atmosphere overnight. The reaction mixture was concentrated to give the crude product, which was purified by preparative TLC to give 3-((R)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide (15 mg, 30%). LC-MS Method 1 tR=2.027, min, m/z=351.1; 1H NMR (CDCl3) 0.73 (s, 9H), 1.12 (d, 3H), 1.89-1.98 (m, 1H), 2.01-2.12 (m, 1H), 2.22-2.38 (m, 3H), 2.48-2.52 (m, 1H), 2.71 (m, 1H), 3.18 (m, 1H), 4.46 (m, 1H), 5.29 (s, 1H), 5.53 (s, 1H), 7.07 (m, 2H), 7.29 (m, 2H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:16][C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:3][N:2]=1.N.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccnnc2)nc2ccccc12
Agent: N
Product: Clc1nc(-c2ccnnc2)nc2ccccc12
Temperature: 0 °C

Procedure:
A 100-mL round-bottom flask was charged with 2-(pyridazin-4-yl) quinazolin-4(3H)-one (30 mg) which was suspended in 3 mL of POCl3. The reaction mixture was heated to reflux for 1 h. The reaction mixture turned to a clear brown solution. After cooling, 50 mL of ice/water was carefully added. An aqueous ammonia solution (25% by weight in water) was added dropwise to the mixture with stirring until the pH of the mixture was adjusted to 7˜8. An internal temperature of 0° C. was maintained by the addition of ice. The mixture was warmed to room temperature and extracted with DCM (50 ml×3). The combined organic layers were washed with brine, dried over Na2SO4. After filtration and evaporation, 32 mg was obtained as a light brown solid. LCMS m/z=242.9 (M+1) (Method B) (retention time=1.65 min). The solid was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Cl:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1ccc(F)cc1Cl
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(F)cc2Cl)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Chloro-4-fluoro-benzoic acid. LC-MS (basic): tR=0.91 min; [M+H]+=484.0.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[C:44]1([CH2:50]C(Cl)=O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:50]([C:6]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:11]([CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]2)[CH2:10]1)=[O:5])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)Cc3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and phenylacetyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:6]([CH:18]=[CH2:19])[CH:5]=1)([O-])=O.[H][H]>C(O)C.O=[Pt]=O>[CH2:18]([C:6]1[CH:5]=[C:4]([CH:17]=[CH:16][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[NH2:1])[CH3:19]
Reactant: C=Cc1cc([N+](=O)[O-])ccc1OCc1ccccn1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CCc1cc(N)ccc1OCc1ccccn1
Yield: 82.9 %

Procedure:
A mixture of 2-[(4-nitro-2-vinylphenoxy)methyl]pyridine (1.06 g, 4.16 mmol) and PtO2 (123 mg) in ethanol (100 ml) was stirred under an atmosphere of hydrogen until completion of the reaction (the reaction being complete when 4 mole equivalents of hydrogen have been reacted). After filtration on celite, the solvent was evaporated and the residue purified on silica gel (2% methanol/CH2Cl2) to give 3-ethyl-4-(pyridin-2-ylmethoxy)aniline (787 mg, 83%); NMR Spectrum: 1.12 (t, 3H), 2.53 (q, 2H), 4.56 (br s, 2H), 5.01 (s, 2H), 6.33 (dd, 1H), 6.43 (d, 1H), 6.69 (d, 1H), 7.32 (dd, 1H), 7.5 (d, 1H), 7.84 (t, 1H), 8.55 (d, 1H); Mass Spectrum: 229 (MH+).
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].[F:24][C:25]([F:30])([F:29])[CH2:26][NH:27][NH2:28]>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:28][N:27]2[CH2:26][C:25]([F:30])([F:29])[F:24])=[CH:14][CH:15]=1
Reactant: NNCC(F)(F)F
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Oc1ccc(-c2nn(CC(F)(F)F)c3cc(O)ccc23)c(O)c1
Yield: 17.3 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.164 g, 2 mmol) and 2,2,2-trifluoroethylhydrazine (0.088 mL, 1.0 mmol) to give 0.028 g of product as a yellow solid
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].[C:14](O)(=[O:36])[CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[C:14]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])(=[O:36])[CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH3:35]
Reactant: COC(=O)/C=C/C(=O)NCCN
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)/C=C/C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
The HCl salt of (E)-methyl 4-(2-aminoethylamino)-4-oxobut-2-enoate (8.1 mmol) was takes up in 40 mL of CH3CN along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (DHA, 2.60 g, 8.1 mmol), HATU (3.4 g, 12.1 mmol) and DIEA (4.2 mL). The reselling reaction mixture was stirred at room temperature for 2 h and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 1.4 g of (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate. MS (EI) calcd for C29H42N2O4: 482.31; found 483 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:13][C:14](N)=[O:15]>>[Cl:12][C:8]1[CH:7]=[C:3]2[C:2](=[C:10]([Cl:11])[CH:9]=1)[NH:1][C:14](=[O:15])[NH:13][C:4]2=[O:5]
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Reactant: NC(N)=O
Product: O=c1[nH]c(=O)c2cc(Cl)cc(Cl)c2[nH]1

Procedure:
Prepared according to general method C from 2-amino-3,5-dichlorobenzoic acid (3.0 g) and urea (8.8 g). Yield: 3.20 g (95%) of a solid. Although it contained a small amount of an impurity it was used in the next step without further purification. 1H-NMR (DMSO-δ6) δ (ppm) 10.13 (br s, 1H), 7.58 (d, J=2.5 Hz, 1H), 7.50 (d, J=2.6 Hz, 1H).
Reaction SMILES: [CH2:1]1[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]([NH2:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>C(O)(C)C>[CH2:17]([NH:18][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:19][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1CO1
Reactant: NCCCCCCCCCCN
Solvent: CC(C)O
Product: CCCCC(O)CNCCCCCCCCCCNCC(O)CCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-hexene oxide (34.8 g.) and 1,10-decanediamine (30 g.) and recrystallization of the resulting product from isopropyl alcohol gave N,N'-(1,10-decylene)-bis[2-hydroxyhexylamine] (I: R = CH3 (CH2)3, R' = H, X = (CH2)10, Z = H) (8.9 g., m.p. 127.0°-137.0° C.).
Reaction SMILES: [Br-].[N+:2]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[H-].[Na+].[CH2:33]([O:40][C:41]1[C:46]([C:47]2[CH:48]=[C:49]([C:57]([CH3:60])([CH3:59])[CH3:58])[C:50]([O:55][CH3:56])=[C:51]([CH:54]=2)[CH:52]=O)=[CH:45][CH:44]=[C:43]([CH3:61])[N:42]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([O:40][C:41]1[C:46]([C:47]2[CH:54]=[C:51]([CH:52]=[CH:9][C:8]3[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:30][CH:29]=3)[C:50]([O:55][CH3:56])=[C:49]([C:57]([CH3:59])([CH3:58])[CH3:60])[CH:48]=2)=[CH:45][CH:44]=[C:43]([CH3:61])[N:42]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COc1c(C=O)cc(-c2ccc(C)nc2OCc2ccccc2)cc1C(C)(C)C
Reactant: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C=Cc2ccc([N+](=O)[O-])cc2)cc(-c2ccc(C)nc2OCc2ccccc2)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
step 4—To a solution of 4-nitro-benzyltriphenylphosphonium bromide (829 mg, 1.734 mmol) in DMF (5 mL) at 0° C. was added NaH (60% in oil dispersion, 133 mg, 3.32 mmol). The reaction was stirred for 30 min at 0° C. and followed by addition of a solution of 66 (215 mg, 0.553 mmol) in DMF (5 mL). The resulting mixture was gradually warmed to RT and stirred overnight. The reaction was quenched with 1N aqueous HCl solution (6 mL) then diluted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (0 to 4% EtOAc) to afford 180 mg (64%) of 2-benzyloxy-3-{3-tert-butyl-4-methoxy-5-[2-(4-nitro-phenyl)-vinyl]-phenyl}-6-methyl-pyridine (68) as an orange oil.
Reaction SMILES: CN(C)S([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([C:19]#[N:20])=[CH:13][C:12]=3[C:11]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])=[N:10][C:9]=2[CH:8]=[N:7]1)(=O)=O.C(O)(C(F)(F)F)=O.N>C(Cl)Cl.O>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:28])[C:21]=1[C:11]1[C:12]2[CH:13]=[C:14]([C:19]#[N:20])[CH:15]=[CH:16][C:17]=2[C:18]2[NH:6][N:7]=[CH:8][C:9]=2[N:10]=1
Reactant: CN(C)S(=O)(=O)n1ncc2nc(-c3c(F)cccc3F)c3cc(C#N)ccc3c21
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1cn[nH]c12
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A 250 ml round-bottomed flask is charged with 4 g of a mixture of the regioisomers of 7-cyano-5-(2,6-difluorophenyl)pyrazolo[4,3-c]isoquinoline-1-sulphonic acid dimethylamide in 160 ml of DCM. After cooling to 0° C. using an ice bath, 108 ml of TFA are added and the mixture is stirred at RT for 6 h. The mixture is concentrated under RP and the solid obtained is taken up in 600 ml of water, and 50 ml of 0.75 M ammonia solution are added. The aqueous phase is extracted with 3 times 150 ml of AcOEt. The organic extracts are combined, washed with saturated NaCl solution and then dried over MgSO4. Concentration of the AcOEt under RP gives 2.6 g of 5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile (beige solid). MS (E/I): m/z=306 (M+); 1H NMR: 7.38 (t, J=8.0 Hz, 2H); 7.72 (m, 1H); 8.24 (broad s, 1H); 8.34 (dd, J=1.5 and 8.5 Hz, 1H); 8.59 (s, 1H); 8.70 (d, J=8.5 Hz, 1H); 14.5 (very broad m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O-:12])=[O:11].[Na+].[C:14]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CN(C)P(N(C)C)(N(C)C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O:12][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=1)=[O:11]
Reactant: O=C([O-])C1=C(Cl)CC2CC(=O)N12
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(COC(=O)C2=C(Cl)CC3CC(=O)N23)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of sodium 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (20 mg), p-(t-butyl)benzyl bromide (34 mg), and anhydrous hexamethylphosphoramide (0.4 ml) is stirred under a nitrogen atmosphere at room temperature for 2.5 hrs. The mixture is diluted with toluene (5 ml), washed with water (5×2 ml) and brine, dried with MgSO4, filtered, and concentrated in vacuo. Chromatography of the residue on a silica gel plate yields p-(t-butyl)benzyl 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][CH:7]=1.NCCCCN.C([Li])CCC.[Cl:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23].[Cl-].[NH4+]>CCOCC.CCCCCC>[Cl:20][C:21]([F:28])([F:27])[C:22]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1)=[O:23]
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: Clc1cccc(Br)c1
Agent: NCCCCN
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(c1cccc(Cl)c1)C(F)(F)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of 25 g of 3-bromochlorobenzene in 100 ml ether was added to a solution of 15.1 g of tetramethylenediamine, 52.4 ml of a 2.5M solution of n-butyllithium in hexane and 75 ml ether at -78° C. under nitrogen. After 1 hour, a solution of 31.0 g of ethyl chlorodifluoroacetate in 150 ml ether was added. After warming to room temperature, the reaction was poured into excess ammonium chloride solution and extracted with ether. The extracts were dried (Na2SO4) and evaporated. The residue was distilled (0.1 mm Hg) to give 14.7 g of an oil which was used directly.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][CH2:6][CH2:7][C:8]#[N:9])#[N:2].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C(#N)C>[CH2:10]([N:5]([CH2:6][CH2:7][C:8]#[N:9])[CH2:4][CH2:3][C:1]#[N:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CCCNCCC#N
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#CCCN(CCC#N)Cc1ccccc1
Yield: 81.3 %

Procedure:
A mixture of 50.0 g (0.406 mol) of bis(2-cyanoethyl)amine, 51.45 g (0.406 mol) of benzyl chloride, 1.0 g (6.7 mmol) of sodium iodide, 22.05 g (0.208 mol) of sodium carbonate and 150 mL of acetonitrile was stirred mechanically and heated at reflux under nitrogen for 5 h. The cooled reaction mixture was filtered and the solids were washed with acetonitrile (3×50 mL). The combined filtrates were concentrated by rotary evaporation. A solution of the residue in 100 mL of CH2Cl2 was washed with saturated aqueous Na2S2O3 (2×20 mL) and saturated aqueous NaCl (2×50 mL). The combined aqueous layers were extracted with CH2Cl2 (3×30 mL). The combined CH2CO2 solutions were dried over MgSO4, filtered and concentrated by rotary evaporation. The residual solvent was removed under vacuum (0.5 mm), yielding 70.4 g (89%) of product as a light yellow oil. 1H NMR (CDCl3/TMS) δ 7.34 (m, 5 H), 3.70 (s, 2 H), 2.88 (t, J=6.8 Hz, 4 H), 2.44 (t, J=6.8 Hz, 4 H). 13C NMR (CDCl3) δ137.5, 128.3, 127.4, 118.4, 57.7, 49.1, 16.4. IR (film, cm−1) 3070 (w), 3050 (m), 3020 (s), 2930 (s), 2830 (s), 2240 (s), 1595 (m), 1575 (w), 1485 (s), 1445 (s), 1415 (s), 1360 (br), 1250 (br), :1125 (s), 1070 (s), 1020 (s), 960 (s), 730 (s), 690 (s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:3][CH2:2]1.Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>>[CH2:49]([O:48][C:46](=[O:47])[CH2:45][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:42])([CH3:41])[CH3:43])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:5][CH2:6]1)[CH3:50]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCNCC1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN1CCC(NC(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 146, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carboxylic acid piperidin-4-yl amide (example 206) was reacted with ethyl bromoacetate (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O4 [(M+H)+] 708.3078, observed 708.3074.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[N:5]=[CH:4][C:3]=1[C:15]([O:17]C)=[O:16].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH3:1][C:2]1[N:6]([CH:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1cnn(C(C)c2ccccc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)cnn1C(C)c1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 66.5 %

Procedure:
A mixture of methyl 5-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylate (80 mg, 0.32 mmol), lithium hydroxide monohydrate (57.1 mg, 1.36 mmol), tetrahydrofuran (5 mL), methanol (1 mL) and water (1 mL) was stirred at 20° C. for 4 hours. The mixture was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 5-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylic acid as a white solid (49 mg, 62%). 1H NMR (300 MHz, d6-DMSO): δ 12.16 (s, 1H), 8.26 (s, 1H), 7.37-7.25 (m, 5H), 5.55 (q, J=7.2 Hz, 1H), 2.30 (s, 3H), 1.78 (d, J=6.9 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.[OH-].[Na+]>O1CCOCC1>[O:15]1[CH2:14][CH:13]1[CH2:11][O:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2nsnc12
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: c1cc(OCC2CO2)c2nsnc2c1
Yield: 69 %

Procedure:
7.6 g (50 mM) 4-hydroxy-2,1,3-benzthiadiazole were dissolved in 100 ml. dioxan and mixed with 50 ml. epichlorohydrin and 55 ml. 1 N aqueous sodium hydroxide solution and the reaction mixture stirred for 4-5 hours at 55°-60° C. When the reaction was finished, the reaction mixture was diluted with 300 ml. water and extracted with chloroform. The dried chloroform solution was evaporated and the residue was chromatographed on a silica gel column (elution agent: chloroform). The residue obtained after evaporation of the elution fractions crystallized upon treatment with diisopropyl ether. There were obtained 7.2 g (69% of theory) 4-(2,3-epoxypropyloxy)-2,1,3-benzthiadiazole, which had a melting point of 65°-67° C.