Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C1N=C[N:17](C(N2C=NC=C2)=O)C=1.Cl.[NH2:28][CH2:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=[O:39])[N:34]([C:40]1([CH3:48])[CH2:45][CH2:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])[C:33]2=[O:49].CCOC(C)=O>CN(C)C=O>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:28][CH2:29][C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[C:35](=[O:39])[N:34]([C:40]2([CH3:48])[CH2:45][CH2:44][C:43](=[O:46])[NH:42][C:41]2=[O:47])[C:33]3=[O:49])=[O:12])=[CH:13][CH:14]=1)(=[O:4])=[O:5])[CH3:2].[CH3:1][S:3][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[N:17][CH:7]=1
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cc1
Product: CSc1ccc(C(=O)O)nc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
A stirred mixture of 4-ethylsulfonylbenzoic acid (0.43 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc/hexanes, gradient). The product fractions were combined and concentrated to give 5-methylsulfanyl-pyridine-2-carboxylic acid 4-ethanesulfonyl-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.31 g, 32% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.40 min (98.51%); mp: 178-180° C.; 1H NMR (DMSO-d6) δ 1.10 (t, J=7.2, 7.4 Hz, 3H), 1.89 (s, 3H), 2.00-2.15 (m, 1H), 2.54-2.77 (m, 3H), 3.35 (q, J=7.4 Hz, 2H), 4.66 (d, J=5.9 Hz, 2H), 7.73-7.86 (m, 3H), 7.97-8.07 (m, 2H), 8.07-8.21 (m, 2H), 9.48 (t, J=5.9 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 7.06, 21.00, 28.57, 29.09, 42.75, 49.04, 58.78, 121.70, 123.22, 128.02, 128.29, 129.71, 131.41, 133.47, 138.51, 140.85, 146.97, 165.21, 167.72, 167.85, 172.13, 172.19; LCMS: MH=498; Anal Calcd for C24H23N3O7S+0.15 CH2Cl2: C, 56.85; H, 4.60; N, 8.23. Found: C, 57.11; H, 4.87; N, 7.85.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[SH:38].O>CN(C=O)C>[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[S:38][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reactant: Sc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc(Cl)cc3Cl)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a stirred solution of 4-chloro-3-nitro-cinnamide (275 mg, 0.814 mmol) from Example 32A in 1.0 mL of DMF was added potassium carbonate (169 mg, 1.22 mmol), followed by the dropwise addition of 2,4-dichlorothiophenol (146 mg, 0.815 mmol). The mixture was then stirred at room temperature for 60 minutes. Completion of the reaction was indicated by the TLC. Water was then added to precipitate the product. Filtration, washing with cold water, and drying in a vacuum oven afforded 350 mg (0.728 mmol, 89%) of the titled compound as light yellow solid. 1H NMR (d6 -DMSO, 300 MHz) δ 2.05 (s, 3H), 3.42-3.50 (br m, 4H), 3.50-3.64 (br m, 2H), 3.64-3.79 (br m, 2H), 6.83 (d, J=8.7 Hz, 1H), 7.44 (d, J=15.3 Hz, 1H), 7.55 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.7, 8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 497, 499, 501. Analysis calculated for C21H19N3O4Cl2S1.0.82H2O: C, 50.94; H, 4.20; N, 8.49. Found: C, 50.91; H, 4.21; N, 8.69.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][CH:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)=[CH:19][CH:18]=1)[CH3:15]>C(OCC)(=O)C>[CH3:13][CH:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)=[CH:19][CH:18]=1)[CH3:15]
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)C)cc2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OC(C)C)cc2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.9 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-[4-(1-methylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.57 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.39 g, 61%).
Reaction SMILES: [NH2:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([Cl:17])=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4])[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: CC(C)[C@@H](N)C(N)=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@@H](Nc1nc(Cl)ncc1Cl)C(N)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.4 %

Procedure:
A mixture of (R)-2-amino-3-methyl-butyramide (50 mg), 2,4,5-trichloropyrimidine (67 mg) and K2CO3 (116 mg) in DMF (3 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with DCM and washed with brine three times. The organic layer was dried with sodium sulfate and concentrated. The residue was purified by silica gel chromatography to provide 60 mg of (R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methyl-butyramide: 1H NMR (300 MHz, CDCl3) 8.2 (s, 1H), 6.2 (bs, 1H), 5.8 (bs, 1H), 5.6 (bs, 1H), 4.6 (dd, 1H), 2.4 (m, 1H), 1.2 (d, 6H). MS (m/e) 263 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[C:15]=2[C:16](=[O:27])[C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]([CH3:26])[CH:18]=2)=[CH:7][CH:6]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>>[CH2:32]([N:34]([CH2:35][CH3:36])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[C:15]=2[C:16](=[O:27])[C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]([CH3:26])[CH:18]=2)=[CH:7][CH:6]=1)[CH3:33]
Reactant: CCNCC
Reactant: COc1c(C)cc(C(=O)c2c(-c3ccc(OCCBr)cc3)oc3ccccc23)cc1C
Product: CCN(CC)CCOc1ccc(-c2oc3ccccc3c2C(=O)c2cc(C)c(OC)c(C)c2)cc1

Procedure:
Reaction of 2-[4'-(2-bromoethoxy)phenyl]-3-(3',5'-dimethyl-4-methoxybenzoyl)benzofuran with diethylamine as described in Example 11 gave the title compound.
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O.Cl.[CH:27]1[CH:32]=[CH:31][CH:30]=[CH:29]C=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=[C:29]1[CH2:30][CH2:31][CH2:32][C:27]1=[O:9]
Reactant: c1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C1=C(N2CCOCC2)CCC1
Agent: Cl
Product: COc1cc(C=C2CCCC2=O)cc(OC)c1OC
Temperature: 30 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 0.20 mol of 3,4,5-trimethoxybenzaldehyde and 200 mL benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C. and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield a light yellow flaky crystal product with a yield of 80.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=2[CH:10]=[C:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.Cl.[C:27]([NH2:30])(=[NH:29])[CH3:28].C(N(CC)CC)C.C(OCC)(=O)C>C(O)CCC>[ClH:1].[CH3:28][C:27]1[NH:30][CH:10]([C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[O:7][CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([CH3:19])[N:29]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)C(=Cc1ccccc1OCc1ccc(Cl)cc1)C(C)=O
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)N=C(C)NC1c1ccccc1OCc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 40.4 %

Procedure:
A mixture of ethyl 2-[2-(4-chlorobenzyloxy)-benzylidene]acetoacetate (10 g), acetamidine hydrochloride (3.16 g), and triethylamine (4.23 g) in n-butanol (100 ml) was refluxed for 3.5 hours. The reaction mixture, added ethyl acetate (100 ml), was washed with water (100 ml) and 5% hydrochloric acid (100 ml) successively. The solvent was evaporated and the residual crystalline was stirred with ethyl acetate (50 ml) for 1 hour. The crystals were collected by filtration dried in vacuo to afford ethyl 2,4-dimethyl-6-[2-(4-chlorobenzyloxy)phenyl]-1,6-dihydro-5-pyrimidinecarboxylate hydrochloride (2.45 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][S:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([N:14]=[CH:15][N:16]=2)[N:13]=1.[C:17]1([CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:37](=[O:40])([O-:39])[O-].[K+].[K+]>CN(C)C=O>[C:23]([OH:4])(=[O:24])/[CH:31]=[CH:36]/[C:37]([OH:39])=[O:40].[C:31]1([CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][S:7][C:8]3[CH:9]=[CH:10][C:11]4[N:12]([N:14]=[CH:15][N:16]=4)[N:13]=3)[CH2:27][CH2:26]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: BrCCOCCSc1ccc2ncnn2n1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)/C=C/C(=O)O
Product: c1ccc(C(OC2CCN(CCOCCSc3ccc4ncnn4n3)CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 121.7 %

Procedure:
1.35 g of 6-[2-(2-bromoethoxy)ethylthio][1,2,4]triazolo[1,5-b]pyridazine and 1.19 g of 4-(diphenylmethoxy)piperidine were dissolved in 15 ml of N,N-dimethylformamide, 740 mg of potassium carbonate was added, followed by stirring at room temperature for 17 hours. Ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol (10:1). The desired fraction was collected; the residue was dissolved in 10 ml of ethanol; 360 mg of fumaric acid was added, followed by concentration. Ethyl ether was added to the residue; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 1.64 g of the title compound.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:26]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH3:27].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:29]3[CH:30]=[CH:31][N:32]=[C:28]3[CH2:26][CH3:27])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: CCc1ncc[nH]1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2OC)o1
Temperature: 125 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxylphenoxy)propyl]oxazole (1.00 g), 2-ethylimidazole (960 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (5 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml), and the resulting precipitate was filtered, air-dried and recrystallized from acetone-isopropyl ether to give 4-(4-chlorophenyl)-2-(2-ethyl-1-imidazolyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole as pale yellow prisms (618 mg, 53%). Melting point 78-79° C.
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][C@@H:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH:19]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=O)=O.[NH:35]1[CH:39]=[N:38][CH:37]=[N:36]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C@H:9]1[CH2:8][C@@H:7]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[C@@H:6]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[C@@H:11]([CH3:12])[CH2:10]1.[NH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C@@H:9]1[CH2:8][C@H:7]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[C@H:6]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[C@H:11]([CH3:12])[CH2:10]1
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](c2ccncc2N)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1n1cncn1
Product: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1cncn1
Yield: 19 %
Yield: 19 %

Procedure:
A solution of (+/−)-(1R,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate (1.0 equiv.), 1H-1,2,4-triazole (3.0 equiv.) and Cs2CO3 (3.0 equiv.) in DMF (0.15 M) was stirred at 80° C. for 5 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by RP HPLC, followed by free basing by partitioning between an equal volume of EtOAc and Na2CO3, separating, washing with NaCl(sat.), drying over MgSO4, filtering, concentrating. Purification was completed via SFC (20% MeOH, 100 mL/min, AD column) to yield tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)cyclohexylcarbamate (19% yield, 99% ee) and tert-butyl (1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)cyclohexylcarbamate (19% yield, 99% ee). LC/MS (m/z)=373.3 (MH+), Rt=0.54 min.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)O)[CH2:3][CH2:2]1.[BrH:11]>>[Br:11][CH2:3][CH2:2]/[CH:1]=[CH:4]/[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: Br
Reactant: OC(c1cccs1)C1CC1
Product: BrCC/C=C/c1cccs1
Reaction time: 2 h
Yield: 94 %

Procedure:
225 g (1.46 mol) of cyclopropyl-2-thienylcarbinol were added dropwise to 972 ml of 48% strength hydrobromic acid at from 5° to 10° C. in the course of 1 hour. After 2 hours at room temperature, the organic phase was separated off and the aqueous solution was extracted with three times 300 ml of dichloromethane. The combined organic phases were washed neutral with dilute sodium hydroxide solution and water, dried over magnesium sulfate and evaporated under reduced pressure. 322 g (94% corrected) of crude bromide were obtained (GC: 92%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1C=[CH:12][C:13]2[N:19]([CH3:20])[C:18](=[O:21])[CH:17]([CH3:22])[N:16]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:14]=2[CH:30]=1.[CH2:31]([Cl:33])Cl>C(=O)([O-])[O-].[Na+].[Na+]>[NH2:9][C:10]1[C:31]([Cl:33])=[CH:12][C:13]2[N:19]([CH3:20])[C:18](=[O:21])[CH:17]([CH3:22])[N:16]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:14]=2[C:30]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ClCCl
Reactant: CC1N=C(c2ccccc2Cl)c2cc(N)ccc2N(C)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1N=C(c2ccccc2Cl)c2c(cc(Cl)c(N)c2Cl)N(C)C1=O
Reaction time: 65 h

Procedure:
26.8 g (0.2 mol) of N-chlorosuccinimide are added to a solution, stirred at room temperature, of 30 g (0.095 mol) of rac-7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one in 500 ml of methylene chloride and the mixture is stirred for 65 hours. The mixture is subsequently diluted with 400 ml of methylene chloride, 500 ml of 2 N sodium carbonate solution are added thereto, the phases are separated and the organic phase is washed with water. After drying and removal of the solvent in vacuo, the residue is chromatographed on 1 kg of silica gel using chloroform for the elution. From methylene chloride/cyclohexane there is obtained rac-7-amino-6,8-dichloro-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one of melting point 186°-187° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([NH:9][C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](O)=O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH:1]([N:4]1[C:8]2=[N:9][C:10]3[C:11]([C:12]([Cl:21])=[C:7]2[CH:6]=[N:5]1)=[CH:15][CH:16]=[CH:17][CH:18]=3)([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)n1nccc1Nc1ccccc1C(=O)O
Product: CC(C)n1ncc2c(Cl)c3ccccc3nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
A mixture of N-(1-isopropylpyrazol-5-yl)anthranilic acid (52 g, 0.212 mol) and POCl3 (436 ml, 4.68 mol) was refluxed for 3 hours, then was stirred at room temperature overnight. The excess POCl3 was removed by distillation and then the residue was poured into ice/water. The mixture was neutralized with 35% NaOH and then extracted with CH2Cl2. The CH2Cl2 layer was separated and washed with water, then brine and then was dried over MgSO4, filtered and evaporated. The residue was dissolved in CH2Cl2 and then was purified by column chromatography on silca gel eluting with CH2Cl2 to afford 21.3 g (40.9%) of 1-isopropyl-4-chloro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][C:22]([OH:24])=O)[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C([Cl:37])(=O)OCC.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>C1COCC1>[ClH:37].[ClH:37].[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][C:22]([N:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)=[O:24])[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)Cl
Reactant: O=C(O)Cc1csc(Nc2ncccc2OCc2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(C(=O)Cc2csc(Nc3ncccc3OCc3ccccc3)n2)CC1
Product: Cl
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A 100 mL round-bottomed flask was charged with 2-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)acetic acid (prepared according to Example 24; 0.050 g, 0.1465 mmol) and THF (30 mL) and cooled to −5° C. Triethylamine (0.03112 g, 0.3076 mmol) and ethyl carbonochloridate (0.07002 mL, 0.7323 mmol) were added successively, and the reaction mixture was stirred at −5° C. for 30 minutes. 1-Methylpiperazine (0.07335 g, 0.7323 mmol) was added, and the reaction mixture was stirred at −5° C. for 30 minutes and then at room temperature for 1 hour. The reaction mixture was washed with water, the organic layer was separated, dried and concentrated, and the residue was purified first by silica gel chromatography and then by reverse phase chromatography to give the title compound as the free base. The free base was dissolved in dichloromethane, and 2M HCl in ether was added. The mixture was concentrated to provide 2-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)-1-(4-methylpiperazin-1-yl)ethanone dihydrochloride (0.024 g, 33.01% yield). 1H NMR (DMSO-d6) δ 10.35 (bs, 1H), 10.11 (bs, 1H), 7.89 (dd, 1H), 7.57 (m, 2H), 7.42 (m, 3H), 7.35 (m, 1H), 6.95 (m, 1H), 6.81 (s, 1H), 5.28 (s, 2H), 4.45 (m, 1H), 4.21 (m, 1H), 3.79 (s, 2H), 3.41 (m, 3H), 2.98 (m, 3H), 2.78 (d, 3H). Mass spectrum (apci) m/z=424.2 (M+H-2HCl).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#[N:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)C=O.[BH4-].[Na+].Cl[C:25]1[CH:30]=NC=[CH:27][N:26]=1>O.CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:27]=[N:26][CH:25]=[CH:30][N:13]=2)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Reactant: Clc1cnccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(Sc2cnccn2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of 9.6 g. 1-acetamido-2-nitro-4-thiocyanatobenzene in 60 ml. dimethylformamide is treated under nitrogen with 1.52 g. of sodium borohydride, the exothermic reaction being controlled so that the temperature does not exceed 30° C. After stirring the mixture at 20°-25° C. for 1 hour, 15 ml. of acetone is added, then, after 2 hours, 9.1 g. of 2-chloropyrazine is added. The mixture is warmed slowly and kept at 100°-110° C. for 3 hours, cooled and diluted with water. The product is filtered off and washed with water, pentane and recrystallized from methanol affording 1-acetamido-2-nitro-4-(pyrazin-2-ylthio)benzene.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C@@:6]([CH3:14])([C:10]([F:13])([F:12])[F:11])[C:7](O)=[O:8].C(Cl)(=O)C([Cl:18])=O>C1(C)C=CC=CC=1.C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C@@:6]([CH3:14])([C:10]([F:13])([F:12])[F:11])[C:7]([Cl:18])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)O[C@](C)(C(=O)Cl)C(F)(F)F
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Acetyl chloride (11.7 ml) was added dropwise to a stirred solution of (R)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (10 g) (Method 9) in toluene (100 ml) cooled in an ice bath. The mixture was then heated to 80° C. and the suspension dissolved to give a clear solution. After 2 hours the reaction mixture was cooled and then concentrated to give an oil. This oil was then redissolved in DCM (140 ml) and DMF (4 drops) was added followed by oxalyl chloride (6 ml). The solution bubbled vigorously and the reaction mixture was left to stir for 15 hours. The resultant solution of the title compound was used directly without further purification.