Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11]>>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1cncc(Cl)n1
Product: CS(=O)(=O)c1ccc(-c2cncc(N)n2)cc1

Procedure:
6-(4-Methanesulfonyl-phenyl)-pyrazin-2-ylamine was prepared from 6-chloro-pyrazin-2-ylamine and (4-methylsulfonylphenyl)boronic acid in a manner analogous to Step 2c to afford an off-white solid (99%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.39 (s, 1H), 8.25 (d, 7.6 Hz, 2H) 8.02 (d, 7.6 Hz, 2H), 7.95 (s, 1H), 6.70 (bs, 2H), 3.26 (s, 3H). 107b) 5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine was prepared from 6-(4-methanesulfonyl-phenyl)-pyrazin-2-ylamine in a manner analogous to Steps 2a-b. (37%), MS=291.1 (MH)+. 107c) [5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine and 1-(3-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a pale orange lyophilate (3% yield). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.0 (s, 1H), 9.62 (bs, 1H), 9.14 (s, 1H), 8.42-8.40 (m, 3H), 8.20 (d, J=8.2 Hz, 2H), 7.58 (s, 1H), 7.18 (m, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 3.72 (bd, 2H), 3.52 (bd, 2H), 3.39 (s, 3H), 3.17 (m, 2H), 2.93 (m, 2H), 2.87 (s, 3H). MS=464.1 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C@@H:4]2[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8].[N:26]([CH2:29][C:30](Cl)=[O:31])=[N+:27]=[N-:28]>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[N:26]([CH2:29][C:30]([NH:1][C:2]1[CH2:3][C@@H:4]2[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)=[O:8])=[O:31])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NCC(=O)Cl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N)C[C@H]12
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(NC(=O)CN=[N+]=[N-])C[C@H]12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of p-nitrobenzyl (5R,6S)-2-amino-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (35 mg, 0.1 mmol) in anhydrous tetrahydrofuran (2 ml) is cooled to -25° C. and treated with 4-dimethylaminopyridine (15.9 mg, 0.13 mmol) and, dropwise over 5 minutes, with a solution of 2-azidoacetyl chloride (14.3 mg, 0.12 mmol) in tetrahydrofuran (0.5 ml). The resulting mixture is stirred under a nitrogen atmosphere at 0° C. for 4 hours. The mixture is diluted with ethyl acetate, washed with pH 3 phosphate buffer, water, 5% aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and evaporated under vacuum. The residue is chromatographed on a silica gel thin layer preparative plate to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])(=[O:23])[NH2:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[C:21](=[O:23])[NH2:22])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: NC(=O)c1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 78.7 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and o-carbamoylaniline (75 mg, 0.55 mmol) to give 180 mg of the title compound (79%): mp 186° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.04 (bs, 1H), 11.64 (s, 1H), 8.38 (d, 1H, J=8.1 Hz), 7.77 (d, 2H, J=8.1 Hz), 7.50 (t, 1H, J=8.1 Hz), 7.21 (s, 1H), 7.14 (s, 1H), 7.12 (t, 1H, J=8.1 Hz), 5.15~5.24 (m, 1H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.67 (dd, 1H, J=14.5, 5.0 Hz), 2.61 (dd, 1H, J=14.5, 9.0 Hz), 2.17 (dm, 1H, J=13.5 Hz), 1.81~1.96 (m, 1H).
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.[CH2:10]([Li])[CH2:11][CH2:12][CH3:13].[CH3:15][Si:16]([CH3:26])([CH3:25])[C:17]1[CH:24]=[CH:23]C(C=O)=[CH:19][CH:18]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.C([Mg]Br)C>O1CCCC1>[CH2:12]([CH:11]([C:10]1[CH:23]=[CH:24][C:17]([Si:16]([CH3:26])([CH3:25])[CH3:15])=[CH:18][CH:19]=1)[NH2:3])[CH3:13]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: C[Si](C)(C)c1ccc(C=O)cc1
Reactant: [Li]CCCC
Agent: CC[Mg]Br
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CCC(N)c1ccc([Si](C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of hexamethyldisilazane (4.3 mL, 20 mmole) in tetrahydrofuran (5 mL) at 0° C. was added n-butyllithium (8.4 mL of 2.5M, 21 mmole) dropwise. The mixture was allowed to warm to room temperature for 20 minutes and then recooled to 0° C. In a separate flask, the product of Step B (3.0 g, 17 mmole) in tetrahydrofuran (10 mL) was cooled to 0° C. The lithiohexamethyldisilazane solution was added via cannula to the aldehyde solution. The reaction mixture was warmed to 22° C. for 20 minutes and then ethyl magnesium bromide (14 mL of 3.0M, 42 mmole) was added dropwise. After heating the mixture at reflux for 12 hours, it was cooled and quenched with saturated aqueous ammonium chloride solution. The aqueous phase was separated and extracted with ether. Combination of the organic phases, drying (MgSO4), and concentration gave a crude residue which was chromatographed on silica gel with ethyl acetate. The desired product was obtained as a colorless oil (0.95 g, 27% yield).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:8])C=CC=CC=1.C([N:20]([CH2:23][CH3:24])[CH2:21]C)C.[CH2:25]([O:27][C:28]([C@@H:30]1C[C@H]1C(O)=O)=[O:29])[CH3:26]>C1(C)C=CC=CC=1>[CH2:25]([O:27][C:28]([C@@H:30]1[CH2:24][C@H:23]1[N:20]=[C:21]=[O:8])=[O:29])[CH3:26]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1N=C=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Diphenylphosphoryl azide (0.54 mL, 2.53 mmol) and triethyl amine (0.35 mL, 2.53 mmol) were added dropwise to a solution of trans-2-ethoxycarbonyl-cyclopropane carboxylic acid (0.4 g, 2.53 mol) in toluene (5 mL) at room temperature. After 1 hour, the mixture was diluted with toluene (10 mL), washed with water (1×), 0.1N HCl (1×) and brine (1×), and dried (Na2SO4). The solution of trans-2-carboethoxy-cyclopropane carbonyl azide was heated at 100° C. for 1 hour producing a solution of the title compound which was used as is.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][S-:20].[Na+]>CS(C)=O.O>[CH3:19][S:20][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1onc(-c2ccccc2)c1-c1ccccc1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1onc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 83.7 %

Procedure:
To a stirred solution of 5-chloro-3,4-diphenylisoxazole (Step 1) (1.75 g, 6.84 mmol) in DMSO (30 mL) was added sodium thiomethoxide (0.58 g, 8.21 mmol). After stirring for 30 hours at room temperature, the reaction was diluted with water and extracted twice with Et2O . The combined ethereal phases were washed with NaHCO3 saturated solution, KHSO4 solution (0.25N), and brine, dried over MgSO4, filtered and concentrated in vacuo yielding 5-methylthio-3,4-diphenylisoxazole (1.53 g, 84%): mp 83°-86° C. 1H NMR (CDCl3 /300 MHz) 7.50-7.18 (m, 10H), 2.63 (s, 3H). FABLRMS m/z 268 (M+H). FABHRMS m/z 268.0781 (M+H C16H14NOS requires 268.0796). Anal. Calc'd for C16H13NOS: C, 71.88; H, 4.90; N, 5.24. Found: C, 71.71; H, 4.95; N, 5.17.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[Br:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1>>[Br:8][C:9]1[CH:10]=[C:11]([S:15]([NH:1][C:2]([CH2:5][OH:6])([CH3:7])[CH2:3][OH:4])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(N)(CO)CO
Product: CC(CO)(CO)NS(=O)(=O)c1cccc(Br)c1
Yield: 56.1 %

Procedure:
Prepared by general procedure III from 2-amino-2-methyl-1,3-propanediol (2.71 g, 25 mmol) and commercially available 3-bromobenzenesulfonyl chloride (0.72 mL, 5 mmol) to give the title compound as a white solid (0.91 g, 12%). MS (ISN) 322.1 [(M−H)−], 324.1 [(M+2−H)−].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=O)=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[C:35]([C:36]([F:37])([F:38])[F:39])[C:29]=3[F:28])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cccc(C(F)(F)F)c3F)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 36.4 %

Procedure:
The title compound was prepared following the procedure described for Example-137 using methyl 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-15, 0.100 g, 0.256 mmol), 2-fluoro-3-(trifluoromethyl)aniline (0.068 g, 0.379 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.050 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 3.13 (s, 2H), 7.32 (m, 2H), 7.42-7.45 (m, 4H), 8.76 (m, 1H), 10.20 (s, 1H), 11.20 (s, 2H); MS [M+H]+: 537.19.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:2]1([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][CH:39]=[CH:40][C:12]=3[F:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2F)CN1
Reactant: O=C(O)Cn1ccnn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2F)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 264, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): δ 8.96 (s, 1H), 7.76 (d, 2H), 7.43-7.39 (m, 2H), 7.26-7.19 (m, 2H), 7.14-6.85 (m, 8H), 5.29 (d, 1H), 5.18 (d, 1H), 4.76 (d, 1H), 3.74-3.68 (m, 1H), 3.33 (t, 1H), 3.03-2.77 (m, 3H), 2.58 (dd, 1H), 1.83-1.74 (m, 1H). MS (EI) for C28H25F2N5O3 found 518 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][NH:25]3)=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][N:25]3[CH3:31])=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)NCCC2(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[3-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoic acid methyl ester (0.36 g, 0.88 mmole) in 10 mL of THF was cooled to −78° C. and was treated with 1.1 mL of a 1M lithium bis(trimethylsilyl)amide solution in hexanes. After 30 minutes at −78° C., 0.06 mL of methyl iodide was added. The mixture was stirred at room temperature for 7 hours, quenched by the addition of 10 mL of saturated aqueous ammonium chloride solution and extracted with two 10 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to yield 0.23 g of 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoic acid methyl ester as a pale yellow oil.
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]([F:23])([F:22])[C:8]1[CH:9]=[C:10]([CH2:18][C:19]([OH:21])=[O:20])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.IC.S(=O)(O)[O-].[Na+].[CH:31]1([NH:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[CH3:1][CH:18]([C:10]1[CH:9]=[C:8]([C:7]([F:22])([F:23])[F:6])[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=1)[C:19]([O-:21])=[O:20].[CH:38]1([NH2+:37][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: [Li]CCCC
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: CC(C(=O)[O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
n-Butyllithium (2.5M solution in hexanes, 67.6 mL, 169 mmol) was added slowly to a stirred, cooled (−78° C.) solution of 3,5-bis(trifluoromethyl)benzeneacetic acid (20.0 g, 73.5 mmol) in tetrahydrofuran (400 mL) and the mixture was stirred at −78° C. for 1 hour. Iodomethane (6.87 mL, 110 mmol) was added slowly and the mixture was allowed to warm to room temperature and stirred overnight. Aqueous sodium bisulfite (20%) was added until the mixture was acidic. The mixture was extracted with ethyl acetate, the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (400 mL), dicyclohexylamine (10 mL, 80.85 mmol) was added and the mixture was heated under reflux for 1 hour. The mixture was cooled and the solid was collected and dried in vacuo to give the title compound as a colorless solid (31.13 g, 91%). 1H NMR (400 MHz, CDCl3) δ 7.83 (2H, s), 7.68 (1H, s), 3.66 (1H, q, J 7.1 Hz), 2.83–2.75 (2H, m), 1.87–1.84 (4H, m), 1.71–1.68 (4H, m), 1.60–1.57 (2H, m), 1.48 (3H, d, J 7.1 Hz), 1.28–1.08 (8H, m), and 1.03–0.92 (2H, m).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(OC)cc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3ccc(OC)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a5) and commercially available (2-chloromethoxy-ethyl)trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].CS(C)=O.[C:20]1([C:26]2[O:30][N:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-:32].[K+].[K+]>O>[C:20]1([C:26]2[O:30][N:29]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=3[N+:13]([O-:15])=[O:14])[C:28](=[O:32])[CH:27]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C([O-])[O-]
Reactant: c1ccc(-c2ccno2)cc1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2oc(-c3ccccc3)cc2=O)c([N+](=O)[O-])c1
Reaction time: 5 h
Yield: 94.6 %

Procedure:
After mixing 200 g of ethyl 4-chloro-3-nitrobenzoate, 500 ml of dimethyl sulfoxide, 169 g of 5-phenylisoxazole, and 146 g of potassium carbonate, the reaction was performed for 5 hours at 60° C. After the reaction was over, the reaction mixture was cooled and poured into water to deposit crystals which were then recovered, washed with water, and dried to provide 292 g of the desired product with a yield of 94.6%. The melting point thereof was 142° C. to 143° C.
Reaction SMILES: [C:1]([C:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:16][C:17]#[C:18][CH2:19][CH3:20])[CH:5]([CH:11](OC)[O:12]C)[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([C:4]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])([CH2:16][C:17]#[C:18][CH2:19][CH3:20])[CH:5]([CH:11]=[O:12])[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: CCC#CCC(C(C)=O)(C(=O)OC(C)(C)C)C(CC(=O)OC)C(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Product: CCC#CCC(C(C)=O)(C(=O)OC(C)(C)C)C(C=O)CC(=O)OC
Temperature: 28 °C
Reaction time: 12 h

Procedure:
Methyl 4-acetyl-4-tert-butoxycarbonyl-3-dimethoxymethyl-6-nonynoate (546 mg) is dissolved in 30 ml of tetrahydrofuran, and 25 ml of 1.5% aqueous solution of perchloric acid is added to the solution. The mixture is stirred at 28° C. for 12 hours. Subsequently the reaction mixture is neutralized with sodium bicarbonate and concentrated in a vacuum. The residue is extracted with ethyl acetate. The extract is dried and then concentrated to give methyl 4-acetyl-4-tert-butoxycarbonyl-3-formyl-6-nonynoate (compound (3), R1 =t-Bu, R2 =CH3) in a yield of 98.0%.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](=[O:13])([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]#C>C1(C)C=CC=CC=1.CC(C)=O>[CH2:10]([O:13][C:8]1[CH:9]=[CH:2][CH:3]=[CH:4][C:5]=1[CH:6]=[O:7])[C:16]#[CH:17]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Reactant: C#CCBr
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#CCOc1ccccc1C=O
Temperature: 25 °C

Procedure:
A solution of 4-hydroxybenzaldehyde (1 g, 8.2 mmol), of potassium carbonate (2.27 g, 16.4 mmol) and of propargyl bromide (1.4 ml of a solution at 80% in toluene) in 50 ml of anhydrous acetone is heated under reflux for 5 hours. The reaction medium is cooled to room temperature, filtered and concentrated. The crude reaction product obtained is purified using a chromatography column on silica gel, eluting with dichloromethane. 1.31 g (quantitative yield) of prop-2-ynyloxybenzaldehyde are obtained in the form of a white solid which is used as it is in the next step. 1H NMR (DMSO-d6, 400 MHZ, δ ppm): 9.89 (s, 1H); 7.89 (d, 2H); 7.18 (d, 2H); 4.95 (s, 2H); 3.65 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:13][CH:14]([OH:17])CO)=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.O.I([O-])(=O)(=O)=O.[Na+].[Cl-].[Na+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[C:4]([CH2:13][CH:14]=[O:17])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2ncccc2c1CC(O)CO
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2ncccc2c1CC=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 103 %

Procedure:
0.81 g of 3-(6-methoxyquinolin-5-yl)propane-1,2-diol was dissolved in 24 ml of tetrahydrofuran and 8 ml of methanol. Then, 12 ml of water containing 1.49 g of sodium metaperiodate was added to the reaction solution while cooling on ice, and the obtained mixture was then stirred at room temperature for 45 minutes. Thereafter, a saturated sodium chloride aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 0.72 g of (6-methoxyquinolin-5-yl)acetaldehyde. This compound was directly used in the following reaction without further purification.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C:21]([O:23][CH3:24])=[O:22])[CH2:9]1)C1C=CC=CC=1.CC(Cl)OC(Cl)=O>C(#N)C>[ClH:19].[Cl:20][C:15]1[CH:14]=[C:13]([C@H:11]2[CH2:12][NH:8][CH2:9][C@@H:10]2[C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: COC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC#N
Product: COC(=O)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 188.9 %

Procedure:
To a solution of the compound (33.4 g) obtained in step 2 in acetonitrile (250 mL) was added ACE-Cl (13.9 g) at room temperature, and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was cooled, and the solvent was evaporated under reduced pressure. Methanol (250 mL) was added to the residue, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled, and the solvent was evaporated under reduced pressure to give methyl (3R*,4S*)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate monohydrochloride (26.9 g, 98%) as a pale yellow powder.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21](Br)=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[C:25]1=[O:33]>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:26]4[C:25](=[O:33])[N:24]([CH3:23])[CH:29]=[CH:28][CH:27]=4)=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cn1cccc(B(O)O)c1=O
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Product: CC(C)OC(=O)N1CCN(c2ccn3ncc(-c4cccn(C)c4=O)c3n2)CC1

Procedure:
Prepared similarly to the preparation of example 5.6.9 from 4-(3-bromo-pyrazolo[1,5-a]pyrimidin-5-yl)-piperazine-1-carboxylic acid isopropyl ester and (1-methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid to provide a yellow powder as a free base, mp. 206-207° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.32 Hz, 6 H) 3.53 (s, 7 H) 3.70-3.82 (m, 4 H) 4.83 (spt, J=6.23 Hz, 1 H) 6.37 (t, J=6.82 Hz, 1 H) 6.78 (d, J=7.83 Hz, 1 H) 7.55 (dd, J=6.57, 1.26 Hz, 1 H) 8.64 (dd, J=7.20, 1.14 Hz, 1 H) 8.72 (d, J=7.83 Hz, 1 H) 8.96 (s, 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 21.97, 37.39, 42.84, 44.11, 68.16, 96.94, 100.56, 105.49, 122.80, 132.49, 135.00, 136.42, 144.40, 144.56, 154.29, 155.46, 160.29. LRMS (ESI) m/z 397.1 [(M+H)]+, calc'd for C20H24N6O3: 396.45.
Reaction SMILES: [C:1]1(/[CH:13]=[CH:14]/[C:15]#[N:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([CH2:13][CH2:14][C:15]#[N:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: [H][H]
Reactant: N#C/C=C/c1cn2c3c(cccc13)CCC2
Agent: [Pd]
Solvent: CO
Product: N#CCCc1cn2c3c(cccc13)CCC2

Procedure:
(E)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-acrylonitrile (348 mg, 1.7 mmol) and 10% Pd—C (50 mg) in methanol (20 ml) were stirred at room temperature under 1 atmosphere of hydrogen gas for 6 hours. The mixture was filtered through celite washed with methanol and evaporated to dryness to yield 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-propionitrile as an off white solid (310 mg). 400 MHz 1H NMR (CDCl3) δ: 7.32 (d, J=8.4 Hz, 1H), 7.03-6.96 (m, 2H), 6.91 (d, J=6.8 Hz, 1H), 4.11 (t, J=5.6 Hz, 2H), 3.11 (t, J=6.8 Hz, 2H), 2.97 (t, J=6.4 Hz, 2H), 2.66 (t, J=7.2 Hz, 2H), 2.26-2.19 (m, 2H); LCMS: 211 [M+H].