Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cccc([N+](=O)[O-])c2)c1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (89.7 mg, 0.20 mmol), 1-bromo-3-nitro-benzene (41.3 mg, 0.20 mmol), and Pd[P(Ph)3]4 (15.5 mg, 6.7 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 7.0 mg. MS: 446.1 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 1.77-2.04 (m, 3H), 2.16-2.47 (m, 1H), 3.38-3.60 (m, 2H), 4.32-4.42 (m, 1H), 4.90-5.13 (m, 2H), 7.02-8.38 (m, 13H), 10.15-10.23 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[C:5]1[C:10]([CH:11]([NH:15][CH3:16])[CH:12]([CH3:14])[CH3:13])=[CH:9][N:8]=[CH:7][N:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[C:5]1[C:10]([CH:11]([N:15]([CH3:16])[C:36](=[O:37])[CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:12]([CH3:13])[CH3:14])=[CH:9][N:8]=[CH:7][N:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ncncc1C(NC)C(C)C
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(OCC)c1ncncc1C(C(C)C)N(C)C(=O)Cc1ccccc1
Yield: 70.3 %

Procedure:
8.3 g (0.031 mol) of [1-(4-diethoxymethylpyrimidin-5-yl)-2-methylpropyl]methylamine and 6.4 g (46 mmol) of potassium carbonate were added to 100 ml of acetonitrile, and then 5.8 g (0.038 mol) of phenylacetyl chloride was dropwise added at room temperature and reacted for 2 hours. After completion of the reaction, the product was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution, water and an aqueous sodium chloride solution in this order, dried and concentrated, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5 to ethyl acetate), to obtain 8.4 g (yield: 70%) of N-[1-(4-diethoxymethylpyrimidin-5-yl)-2-methylpropyl]-N-methyl-2-phenyl acetamide as colorless viscous liquid (nD2=1.5253)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:7]=[C:8]([N:19]2[CH:23]=[C:22]([CH2:24]OS(C)(=O)=O)[N:21]=[N:20]2)[CH:9]=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1.CS(O)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([N:19]2[CH:23]=[C:22]([CH2:24][N:1]=[N+:2]=[N-:3])[N:21]=[N:20]2)[CH:9]=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: CS(=O)(=O)OCc1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Temperature: 90 °C
Yield: 45 %

Procedure:
Sodium azide (1.10 g, 16.90 mmol) was added to the mixture of methanesulfonic acid 1-(3,5-difluoro-4-thiomorpholin-4-yl-phenyl)-1H-[1,2,3]triazol-4-ylmethyl ester and methanesulfonic acid 3-(3,5-(difluoro-4-thiomorpholin-4-yl-phenyl)-3H-[1,2,3]triazol-5-ylmethyl ester, obtained in Example 9, in DMF (10 mL) and heated to 90° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL). The solution was washed with water (100 mL×2) followed by brine (50 mL) and dried over sodium sulfate. Removal of volatiles and purification of the residual material by silica gel column chromatography (eluent, 1:9-3:7 ethyl acetate/hexane) yielded compounds 1-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-1H-1,2,3-triazol-4-ylmethyl azide (13A) (800 mg, 45%) followed by 1-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-1H-1,2,3-triazol-5-ylmethyl azide (13B) (850 mg, 50%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:17])[C:15]=1[CH3:16])=[CH:12][CH:11]=[CH:10][C:9]=2[C:18]([OH:20])=[O:19])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH2:32][OH:33].Cl>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:17])[C:15]=1[CH3:16])=[CH:12][CH:11]=[CH:10][C:9]=2[C:18]([O:20][CH2:31][CH2:32][OH:33])=[O:19])[CH3:2]
Reactant: CCOc1ccccc1-c1oc2c(C(=O)O)cccc2c(=O)c1C
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1oc2c(C(=O)OCCO)cccc2c(=O)c1C
Temperature: 0 °C
Yield: 70.4 %

Procedure:
One gram of 2'-ethoxy-3-methylflavone-8-carboxylic acid prepared by the same way as Example 1 is dissolved in 30 ml of dimethyl formamide, 0.5 gram of anhydrous potassium carbonate is added thereto, 2 grams of ethylene bromohydrin is dropped thereinto with stirring, and the mixture is stirred at 50° C. for four hours. Then it is poured into ice water, the mixture is neutralized with 10% hydrochloric acid, extracted with ethyl acetate, the extract is washed with water, dried with anhydrous magnesium sulfate, the solvent is evaporated therefrom, and the residue is recrystallized from a mixture of benzene and n-hexane to give 0.8 gram of beta-hydroxyethyl 2'-ethoxy-3-methylflavone-8-carboxylate, colorless needles, melting point 143° to 144.5° C.
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:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([S:21][C:22]2[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=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: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2cccc(O)c2)c(N)c1
Product: Cc1ccc(Sc2cccc(O)c2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 7d (277 mg, 1.56 mmol) was reacted with the product from Example 25b (245 mg, 1.56 mmol) for 5 h following the procedure from Example 7g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (399 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.38 (s, 3 H) 2.75 (s, 3 H) 6.30 (d, J=6.99 Hz, 1 H) 6.53-6.58 (m, 2 H) 6.61 (d, J=8.09 Hz, 1 H) 6.90-7.08 (m, 1 H) 7.27-7.47 (m, 3 H) 7.77 (d, J=8.46 Hz, 1 H) 8.39 (d, J=6.99 Hz, 1 H) 8.94 (d, J=8.82 Hz, 1 H) 9.58 (s, 1 H) 10.96 (s, 1 H) 14.34 (s, 1 H); MS (ESI+) m/z 374 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:23](=[O:25])[CH3:24])[C:12]([O:18][CH2:19][CH2:20][CH2:21]Br)=[CH:13][CH:14]=2)[CH:9]=1.[OH:27][C:28]1[C:33]([CH2:34][CH2:35][CH3:36])=[C:32]([OH:37])[CH:31]=[CH:30][C:29]=1[C:38](=[O:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:23](=[O:25])[CH3:24])[C:12]([O:18][CH2:19][CH2:20][CH2:21][O:37][C:32]3[CH:31]=[CH:30][C:29]([C:38](=[O:40])[CH3:39])=[C:28]([OH:27])[C:33]=3[CH2:34][CH2:35][CH3:36])=[CH:13][CH:14]=2)[CH:9]=1
Reactant: COC(=O)CCCOc1ccc2ccc(OCCCBr)c(C(C)=O)c2c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCOc2ccc3ccc(OCCCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 63.1 %

Procedure:
A mixture of 1.8 g of 4-[[8-acetyl-7-(3-bromopropoxy)-2-naphthlenyl]oxy]butanoic acid methyl ester, 1 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 0.9 g of anhydrous potassium carbonate in 30 ml of anhydrous acetone and 6 ml of anhydrous dimethylformamide was stirred at reflux for 15 hours. The mixture was filtered and the filtrate was concentrated in vacuo to an oil which was dissolved in ethylacetate and washed with water, 1N sodium hydroxide solution and sodium chloride solution. The oil resulting from the ethyl acetate extract was purified by flash column chromotography to yield 1.44 g (63%) of 4-[[8-Acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-naphthalenyl]oxy]butanoic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:18])[NH:5][C:6]=1[C:7](=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:19]([O:23][C:24]([O-:26])=O)(=O)OC>>[CH3:15][O:14][C:12]([N:5]1[C:6]([C:7](=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:2]([CH3:1])[N:3]([C:24]([O:23][CH3:19])=[O:26])[C:4]1=[O:18])=[O:13]
Reactant: CCOC(=O)CCCCC(=O)c1[nH]c(=O)[nH]c1C
Reactant: COC(=O)OC(=O)[O-]
Product: CCOC(=O)CCCCC(=O)c1c(C)n(C(=O)OC)c(=O)n1C(=O)OC
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
A mixture of 1.88 g (7.4 mmol) of 4-methyl-5-(5-ethoxycarbonylpentanoyl)-4-imidazolin-2-one and 20 ml methyl pyrocarbonate was heated to 90° C., and stirred for 1.5 hours whereupon a complete solution was obtained. After removal of the volatiles in vacuo, the oily residue was treated with 20 ml hexanes to give a white solid which was collected by filtration and washed with two 5 ml portions of hexanes. Recrystallization from 100 ml ethyl ether gave 2.1 g (76.6%) of the title compound; m.p. 74°-76° C.; 1H-NMR (CDCl3): 1.27 (t, 3, OCH2CH3), 1.58-1.76 (m, 4, 2CH2 's), 2.33 (t, 2, CH2), 2.38 (s, 3, CH3), 2.57 (t, 2, CH2), 3.98 (s, 3, NCOOCH3), 4.01 (s, 3, NCOOCH3) and 4.14 ppm (q, 2, OCH2CH3); 13C-NMR δ (CDCl3) 11.9, 14.2, 23.1, 24.3, 34.0, 41.8, 54.8, 55.1, 60.3, 120.9, 126.5, 146.4, 149.9, 150.2, 173.2, and 192.6 ppm.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16]1[O:24][C:23]2[CH:22]=[CH:21][C:20]([CH2:25]Cl)=[CH:19][C:18]=2[O:17]1>C(O)C>[CH2:14]([O:13][C:5](=[O:12])[CH:6]([CH2:25][C:20]1[CH:21]=[CH:22][C:23]2[O:24][CH2:16][O:17][C:18]=2[CH:19]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:15]
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc2c(c1)OCO2)C(=O)OCC
Yield: 87.9 %

Procedure:
60.17 g of sodium ethoxide were dissolved in 1127 ml of ethanol. To this solution, 336.4 g of diethyl malonate and 119.42 g of [(3,4-methylendioxy)phenyl]methyl chloride were added and the mixture was refluxed for 3 hours. After the reaction was completed, the solvent was removed under reduced pressure and water was added to the residue. After extraction with ethyl acetate, the ethyl acetate was dried with sodium sulfate anhydride. After removing the solvent under reduced pressure and purification with distillation, 181.1 g of 2-[[(3,4-methylenedioxy)phenyl]methyl]malonic acid diethyl ester were obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>CO>[CH3:1][N:2]([CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN(C)Cc1ccccc1
Yield: 100 %

Procedure:
A! Using N-methylbenzylamine (53 ml, 0.41 mole) and methyl acrilate (184 ml, 2.05 mole) in 430 ml of methanol, according to the procedure of Example 15,A!, there were obtained 85 g (quantitative yield) of methyl 3-(N-methyl-N-benzylamino)propanoate which was used as such in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:13][C:14](=[O:16])[CH3:15].[I-].[K+]>CC(C)=O>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=1)([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(=O)CCl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCC(C)=O)cc1
Yield: 188.2 %

Procedure:
A mixture of methyl 4-hydroxybenzoate (30.4 g), chloroacetone (8.5 g) potassium carbonate (54 g) and potassium iodide (33.3 g) was refluxed in acetone for 4 hours. The reaction mixture was cooled, the solids filtered and the solvent evaporated. The residue was partitioned between water and ether, the layers separated and the organic layer dried (MgSO4). Removal of the solvent gave the title compound (36 g). τ(CDCl3) 7.75 (3H, s), 6.11 (3H, s) 5.39 (2H, s), 3.09 (2H, d, J=9 Hz), 2.0 (2H, d, J=9 Hz).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([Cl:19])=[N:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:20][C:21](=[O:34])[NH:22][C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH3:31])=[CH:25][C:24]=2[O:32][CH3:33])[C:9]1=[O:35])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:19][C:15]1[C:12]2[C:13](=[O:14])[N:8]([CH2:7][C:6]([OH:36])=[O:5])[C:9](=[O:35])[N:10]([CH2:20][C:21](=[O:34])[NH:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH3:31])=[CH:25][C:24]=3[O:32][CH3:33])[C:11]=2[CH:18]=[CH:17][N:16]=1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3c(Cl)nccc32)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3c(Cl)nccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vial containing a solution of {5-Chloro-1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-pyrido[4,3-d]pyrimidin-3-yl}-acetic acid tert-butyl ester (Intermediate T) (10.1 mg, 0.019 mmol) in DCM (1 ml), TFA (1 ml) is added. The reaction mixture is stirred at RT for 2 hours, transferred to a 10 ml round bottomed flask, diluted with a minimal amount of DCM and concentrated in vacuo. The residue is taken up in a minimal amount of DCM and concentrated in vacuo. This process is repeated once with DCM, twice with EtOAc, and once with MeOH, the solvent being concentrated in vacuo each time, finally giving the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([C:23]([NH2:25])=[O:24])[O:20][C:19]2=[O:26])[CH:5]=[C:6]([F:17])[C:7]=1[C:8]1([CH3:16])[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]1.[CH3:27]N>CO>[CH3:27][NH:25][C:23]([C@@H:21]1[O:20][C:19](=[O:26])[N:18]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([C:8]3([CH3:16])[CH2:9][N:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:11]3)=[C:6]([F:17])[CH:5]=2)[CH2:22]1)=[O:24]
Reactant: CN
Reactant: COC(=O)N1CC(C)(c2c(F)cc(N3C[C@H](C(N)=O)OC3=O)cc2F)C1
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2cc(F)c(C3(C)CN(C(=O)OC)C3)c(F)c2)C(=O)O1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
A suspension of methyl (5R)-3-[3,5-difluoro-4-(1-methoxycarbonyl-3-methylazetidin-3-yl]-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 57, Step 4, 500 mg, 1.30 mmol) in MeOH (10 mL) is heated at 50° C. to achieve full dissolution, then cooled to 0° C. and treated with methylamine (15 mL, 2.0 M in MeOH). The reaction mixture is stirred for 20 min at 0° C. and then concentrated under reduced pressure. Trituration (Et2O) affords the title compound as a white solid in 90% yield; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, 1 H), 7.35 (d, 2 H), 5.09 (dd, 1 H), 4.26 (m, 2 H), 4.25 (t, 1 H), 4.02 (dd, 1 H), 3.86 (d, 2 H), 3.56 (s, 3 H), 2.66 (d, 3 H), 1.56 (s, 3H); hMS (ESI) calcd for C17H19F2N3O5+H1 384.1371, found 384.1360; [α]25D=−35 (c 0.90, DMSO).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:12])=[NH:11].[CH:13](=[C:20]([C:23]#[N:24])[C:21]#[N:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:24][CH2:23][C:20]1[C:21]([NH2:22])=[N:11][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N=C(N)c1cc2ccccc2[nH]1
Reactant: N#CC(C#N)=Cc1ccccc1
Product: NCc1c(N)nc(-c2cc3ccccc3[nH]2)nc1-c1ccccc1

Procedure:
The title compound, MS: m/e=315.8 (M+H+), was prepared from 1H-indole-2-carboxamidine and 2-benzylidene-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31](O)=[O:32])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:32])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:14]=23)[CH2:2][CH2:3]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c6) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:40][N:41]([CH3:46])[S:42](Cl)(=[O:44])=[O:43]>ClCCl>[C:21]([O:20][CH:15]([C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]2[C:6]([C:7]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:42](=[O:44])(=[O:43])[N:41]([CH3:46])[CH3:40])[CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])([CH3:22])([CH3:23])[CH3:24]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CNS(=O)(=O)N(C)C)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
An ice cold solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (25 mg, 0.057 mmol) in dichloromethane (DCM) (1 mL) was treated with Et3N (0.012 mL, 0.086 mmol) and dimethylsulfamoyl chloride (7.33 μL, 0.069 mmol), stirred for 15 min, and then warmed to rt for 1 hour. Additional Et3N (25 uL) and dimethylsulfamoyl chloride (15 uL) were added, the reaction was stirred at rt overnight. The reaction was concentrated and purified by column chromatography (0-10% MeOH/DCM) to afford methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-7-(((N,N-dimethylsulfamoyl)amino)methyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (22.6 mg, 0.042 mmol, 72.6% yield) as clear oil. The methyl ester was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-7-(((N,N-dimethylsulfamoyl)amino)methyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid (18.4 mg, 0.034 mmol, 82% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.42 (s, 1 H), 7.54 (td, J=1.9, 8.2 Hz, 1 H), 7.41-7.30 (m, 1 H), 7.30-7.23 (m, 1 H), 7.16 (dd, J=8.4, 12.9 Hz, 1 H), 7.09-6.99 (m, 1 H), 5.35 (s, 1 H), 4.53 (br. s., 1 H), 4.36 (br. s., 2 H), 3.69 (d, J=1.0 Hz, 3 H), 2.81 (s, 3 H), 2.80 (s, 3 H), 2.36 (s, 3 H), 2.32 (s, 3 H), 1.07 (s, 4.5 H), 1.06 (s, 4.5 H); LCMS (m/z) ES+=530 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:21]Br>C(Cl)Cl.C(O)(=O)C>[Br:21][C:10]1[S:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: BrBr
Reactant: CSc1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CSc1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1
Reaction time: 1.5 h

Procedure:
A solution of 2-(4-fluorophenyl)-3-(4-methylthiophenyl)thiophene (7.5 g, 25 mmole) in methylene chloride (75 ml) was diluted with 75 ml of acetic acid, cooled to about 5°, and treated dropwise with a 1M solution of bromine in acetic acid (28 ml, 1.1 equiv). The reaction mixture was stirred at 5° for 1.5 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution washed with saturated aqueous sodium bicarbonate and brine, dried, and evaporated. Recrystallization from methanol, with cooling in Dry Ice, gave the title compound in two crops (7.60 g), m.p. 75°-78°. Infrared and NMR spectral data were consistent with the assigned structure.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[C:24]12([C:34]3[N:35]=[C:36]([NH2:39])[S:37][CH:38]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>>[C:24]12([C:34]3[N:35]=[C:36]([NH:39][C:1]([C:4]45[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]6[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]6[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]4)[CH2:6][CH2:5]5)=[O:2])[S:37][CH:38]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2
Reactant: Nc1nc(C23CC4CC(CC(C4)C2)C3)cs1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nc(C45CC6CC(CC(C6)C4)C5)cs3)(CC1)CC2
Yield: 35.3 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-adamantyl-2-aminothiazole (79.7 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-adamantylthiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (29.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:15][CH3:16])[CH2:9][CH2:10][C:11](OC)=[O:12])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:9][CH2:10][CH2:11][OH:12])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCC(CCC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CCCO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-(4-chlorophenyl)-4-(4-(methylsulfonamido)-1H-indol-1-yl)hexanoate (20 mg, 0.045 mmol), as described in Example 44 Step E, in tetrahydrofuran (2 mL) was added lithium aluminium hydride (2.5 mg, 0.0675 mmol) at 0° C. The mixture was gradually warmed to room temperature and stirred for 4 h. Water (1 mL) was carefully added to the reaction mixture, and extracted with ethyl acetate. The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by PREP-TLC eluting with PE/EA (2/1, v/v) to give the title compound as colorless oil. LC/MS m/z=421.0[M+H]+.