Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[C:15]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:20][C:16]=2[N:17]=[CH:18][N:19]=1.[OH-].[Na+]>C1COCC1>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]2[C:15]3[C:14]([NH:13][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[CH2:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[N:19][CH:18]=[N:17][C:16]=3[O:20][C:21]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)CCCc1ccccc1Nc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4ccccc4CCCC(=O)O)c23)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Dissolve 28.9 mg (0.059 mmol) of 4-(2-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)butanoic acid methyl ester in 1 ml of THF, add 0.176 ml of 1N sodium hydroxide solution at RT and stir at 50° C. for 1 h. Cool to RT and remove the THF under reduced pressure. Add water to the residue, and then 1N hydrochloric acid. Filter off the precipitated solid, wash repeatedly with water and dry at 40° C. under reduced pressure overnight. 16.9 mg (60.2% of theory) of the target compound are obtained as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]([NH:18][S@](C(C)(C)C)=O)[CH2:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=2[F:17])[CH2:3][CH2:2]1.[C:25]1([S:31]([CH2:34][CH2:35][C:36](O)=[O:37])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:18][C@@H:7]([CH:4]1[CH2:3][CH2:2][N:1]([C:36](=[O:37])[CH2:35][CH2:34][S:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:33])=[O:32])[CH2:6][CH2:5]1)[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17]
Reactant: CC(C)(C)[S@](=O)N[C@H](Cc1cc(F)c(F)cc1F)C1CCNCC1
Reactant: O=C(O)CCS(=O)(=O)c1ccccc1
Product: N[C@H](Cc1cc(F)c(F)cc1F)C1CCN(C(=O)CCS(=O)(=O)c2ccccc2)CC1

Procedure:
The title compound is prepared analogously as described in example G1 using (S)-2-methyl-propane-2-sulfinic acid [(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide instead of 3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane and 3-benzenesulfonyl-propionic acid instead of N-acetyl-L-alanine.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[CH3:16].[C:17](OCC)(=[O:22])[CH2:18][C:19]([CH3:21])=O>C(O)(=O)C>[OH:22][C:17]1[N:6]2[N:5]=[C:4]([CH3:7])[C:3]([C:8]3[C:13]([CH3:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=3[CH3:16])=[C:2]2[N:1]=[C:19]([CH3:21])[CH:18]=1
Reactant: Cc1cc(Cl)cc(C)c1-c1c(C)n[nH]c1N
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(O)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
Dissolve 5-amino-4-(4-chloro-2,6-dimethylphenyl)-3-methylpyrazole in 20 mL glacial acetic acid at ambient temperature, and add ethyl acetoacetate (2.0 mL, 1.99 g). Heat to reflux (130° C.) under N2 overnight. Evaporate down to concentrate and add 200 mL Et2O to precipitate out product. Stir at ambient temperature for 1 hour, then filter and wash the resulting white solid (1.25 g) with copious amounts of Et2O. LCMS=302.2 (MH+); 300.2 (M−).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.[H][H]>CCO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[O:19])[CH2:6][CH2:7]1
Reactant: CN1CCN(C(=O)Cc2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(C(=O)Cc2ccc(N)cc2)CC1

Procedure:
A solution of 1-methyl-4-[(4-nitrophenyl)acetyl]piperazine (1.5 g, 5.70 mmol) in EtOH (30 mL) was reduced over palladium/charcoal (10% wt, 50% wet, 150 mg) with hydrogen under atmospheric pressure and RT for 18 h. The catalyst was separated by filtration through Celite® and the solvent evaporated to the title compound as a brown oil, 1.12 g.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([N:20]=CN(C)C)[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CO>[C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([NH2:20])[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N=CN(C)C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
(Z)-N-(2-Phenylethyl)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide (130 mg, 0.36 mmol) was dissolved in 4 ml of methanol, followed by the addition of 1 ml of 2N hydrochloric acid. The mixture so obtained was stirred at 60° C. for 3 hours and 30 minutes. The reaction mixture was then added with 20 ml of a saturated aqueous solution of sodium hydrogencarbonate and 20 ml of ethyl acetate. The resulting mixture was then allowed to separate into an organic phase and an aqueous phase. The aqueous phase was further extracted twice with 10 ml portions of ethyl acetate. All the organic phases were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, whereby 107 mg of the title compound were obtained (yield: 97.5%).
Reaction SMILES: [CH2:1](OC(N1C[C@H](OC(C)(C)C)C[C@H]1C(O)=O)=O)[C:2]1[CH:7]=CC=C[CH:3]=1.[CH2:24]([O:31][C:32]([N:34]1[CH2:38][C@@H:37]([NH2:39])[CH2:36][C@H:35]1[C:40]1[O:41][CH:42]=[CH:43][N:44]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]([N:34]1[CH2:38][C@@H:37]([NH2:39])[CH2:36][C@H:35]1[C:40]1[O:41][C:42]([C:2]([CH3:7])([CH3:3])[CH3:1])=[CH:43][N:44]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Product: CC(C)(C)c1cnc([C@@H]2C[C@H](N)CN2C(=O)OCc2ccccc2)o1

Procedure:
(2S,4S)-4-Amino-2-(5-tert-butyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester. MS calcd. for C19H26N3O3 [(M+H)+] 344, obsd. 344.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[NH:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[NH:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c[nH]c(Sc2cccc(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2cccc(Cl)c2)c1
Yield: 92.9 %

Procedure:
Methyl 5-(3-chlorophenylthio)pyrrole-3-carboxylate (1.5 g.) was refluxed with 10 ml. of 1N sodium hydroxide and 20 ml. of methanol, at which time thin layer chromatography (silica gel with hexane-5/ethyl acetate-1/5% acetic acid as eluant) indicated hydrolysis was complete. The methanol was allowed to evaporate. The aqueous residue was diluted with approximately one volume of water and extracted twice with ether. The aqueous phase was acidified with 6N hydrochloric acid and product extracted multiply into ethyl acetate. The combined ethyl acetate extracts were back-washed with water and then with saturated brine, dried over anhydrous sodium sulfate and evaporated to an oil. Trituration of the oil with hexane gave 5-(3-chlorophenylthio)pyrrole-3-carboxylic acid (1.32 g., m.p. 134°-137° C., m/e 253).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)O)c2)=C(C)C1=O
Reactant: C1CCNCC1
Product: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 32.6 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (90 mg, 0.27 mmol) obtained in Example 57 and piperidine (0.040 ml, 0.41 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (35 mg, 0.088 mmol, yield 33%).
Reaction SMILES: [CH:1]1([C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH:21]=[CH:22]2>>[CH:8]1([C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)([OH:7])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH:23]3[CH2:25][CH:20]2[CH:21]=[CH:22]3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C(C1CCCC1)C1CCCC1
Reactant: ClCCCCCC1CC2C=CC1C2
Product: OC(CCCCCC1CC2C=CC1C2)(C1CCCC1)C1CCCC1
Yield: 85 %

Procedure:
1,1-Dicyclopentyl-6-(5-norbornen-2-yl)hexanol (yield: 85%) was obtained in the same manner as in Synthesis Example 1, except that dicyclopentyl ketone and 1-chloro-5-(5-norbornen-2-yl)pentane were used in place of acetone and 1-chloro-4-(5-norbornen-2-yl)butane, respectively.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:28]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].CS(C)=O>[CH2:14]([O:13][C@@H:12]1[C@H:19]([OH:20])[C@@H:21]([CH2:23][OH:24])[O:22][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:28])[C:5]=2[N:6]=[CH:7]1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
2,6-diamino-9-(2′-O-pentyl-β-D-ribofuranosyl) purine (1.9 g) in 0.1 M sodium phosphate buffer (50 ml, pH 6.0) and DMSO (25 ml) was treated with adenosine deaminase (added in two aliquots—first aliquot 50 mg, second aliquot 80 mg) at 35° C. as per the procedure of Example 3 to yield 1.4 g of product. 1H NMR (DMSO-d6) δ 0.8 (t, 3, CH3), 1.16 (a, 4, 2x CH2), 1.4 (m, 2, CH2), 3.38, 3.6 (s, 4, OCH2, H-5′), 3.93 (s, 1, H-4′), 4.28 (m, 2, H-2′, H-3′), 5.17 (br, 2, 5′, 3′—OH), 5.8 (d, 1, H-1′), 6.53 (br s, 2, NH2), 8.0 (s, 1, H-8) and 10.68 (br, 1, NH).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:16](=[O:31])[N:17]2[CH:21]([C:22]([NH:24][C:25]3[N:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[O:23])[CH2:20][CH:19]=[N:18]2)[CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([CH2:6][C@@H:7]([C:16](=[O:31])[N:17]2[CH:21]([C:22]([NH:24][C:25]3[N:26]=[CH:27][CH:28]=[CH:29][N:30]=3)=[O:23])[CH2:20][CH:19]=[N:18]2)[CH2:8][C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ncccn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ncccn1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-oxo-4-{5-[(2-pyrimidinylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoate (0.21 g, 0.49 mmol) in 1,4-dioxane (10.0 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (6.11 mL, 24.4 mmol) at room temperature. The reaction mixture was stirred overnight. The solvent was then removed by reduced pressure to afford the crude product (−100% yield), which was used directly in the next step. MS: 374 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][OH:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][O:8][N:29]1[C:30](=[O:39])[C:31]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:32]2[C:33]1=[O:34]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COCOCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCOCCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.8 %

Procedure:
A solution of 3-(methoxymethoxy)propanol (5 g, 41.6 mmol), triphenylphosphine (13.1 g, 50 mmol) and N-hydroxyphthalimide (7.25 g, 44 mmol) in dry tetrahydrofuran (150 ml) was cooled to 0°-5° C. and treated with diethyl azodicarboxylate (8.7 g, 50 mmol) in dry tetrahydrofuran (10 ml) over 1/2 hr. The reaction was then stirred at ambient temperature for 18 hr. The solvent was removed in vacuo and the residue was dissolved in diethyl ether (100 ml) and the mixture cooled to 0°-5° C. for 3 hr. The solid was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica eluting with hexane:ethyl acetate (70:30) to give the title compound as an oil (4.5 g, 41%). νmax (Film) 2960, 2900, 1800, 1740, 1620, 1480 and 1380 cm-1 ; δH (CDCl3) 2.07 (2H, quintet, J=6.3 Hz, CH2CH2CH2), 3.38 (3H, s, OCH3), 3.77 (2H, t, J=6.3 Hz, CH2OCH2OCH3), 4.33 (2H, t, J=6.3 Hz, CH2ON), 4.66 (2H, s, OCH2O), 7.83 (4H, m, ArH).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C(O)(=O)C.[Br:27]Br.O>ClCCl>[Br:27][C:10]1[N:9]=[C:8]([CH:11]2[CH2:12][CH2:13][N:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:15][CH2:16]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: Cc1nccn2c(C3CCN(C4CCOCC4)CC3)ncc12
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nccn2c(C3CCN(C4CCOCC4)CC3)nc(Br)c12
Yield: 76.6 %

Procedure:
8-Methyl-3-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)imidazo[1,5-a]pyrazine (0.303 mmol, 91 mg) was dissolved in dichloromethane (2 ml) and acetic acid (30.3 mmol, 1.734 ml). With stirring, bromine (0.303 mmol, 0.016 ml) in dichloromethane (0.2 mL) was added. After stirring at room temperature for one hour water was added and the mixture concentrated in vacuo. To the residue was added saturated aqueous sodium hydrogencarbonate and the mixture extracted twice with dichloromethane/methanol. The combined organic layers were concentrated in vacuo to yield 1-bromo-8-methyl-3-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)imidazo[1,5-a]pyrazine (88 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][C:4](=[O:5])[C:3]1[C:2]([NH:1][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])=[CH:18][CH:17]=[CH:16][C:15]=1[S:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccccc1NC(=O)c1c(N)cccc1Sc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: COc1ccccc1NC(=O)c1c(NS(=O)(=O)c2ccccc2)cccc1Sc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
Compound 25 (1.0 equiv.) was dissolved in azabenzene (40 mL) at room temperature. To this mixture was added benzenesulfonyl chloride (1.2 equiv.). After being stirred for 10 Hours at room temperature, the reaction mixture was concentrated under reduced pressure. The crude residue was diluted ethyl acetate (50 mL), washed with water (3×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:4 v/v ethyl acetate/petroleum ether) to provide a white solid. 67% yield;
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC[O-].[Na+].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>C(O)C>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 ml of diethyl malonate in 350 ml of ethyl alcohol were treated portionwise with 18.6 g of sodium ethylate at room temperature and the mixture was then treated with 12 g of o-trifluoromethylbenzyl bromide within 30 minutes. The reaction mixture was stirred at room temperature overnight. The alcohol was distilled under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed twice with water and once with NaCl solution, dried under reduced pressure and evaporated. The residue was chromatographed over 300 g of SiO2 with CH2Cl2 /AcOEt 95:5 and yielded 11 g of diethyl [o-(trifluoromethyl)benzyl]malonate as a colourless oil.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[N:18]=2)[CH2:13]1)C1C=CC=CC=1>[Pd].CO>[NH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[N:18]=2)[CH2:13]1
Reactant: O=C(NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Under an N2 atmosphere, a mixture of benzyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (0.770 g, 1.6 mmol) and MeOH (5 mL) was added to Pd/C (77 mg, 10% weight Pd on carbon) weighed into a 100 mL flask. After the atmosphere in the flask was evacuated and purged with N2 three times, the reaction mixture was vigorously stirred under an H2 atmosphere at ambient pressure overnight and then filtered through a pad of Celite, concentrated, and dried to obtain 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (0.45 g, 81%). LC/MS: m/z 459.5 (M+H)+ at 2.81 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:8]=[N+:9]=[N-:10].[Na+].O>C(#N)C>[N:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CBr
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN=[N+]=[N-]

Procedure:
A solution of ethyl bromoacetate (150 g, 0.901 mol) in dry acetonitrile (800 ml) was treated with sodium azide (58.57 g, 0.901 mol) under a nitrogen atmosphere, and the mixture was heated at reflux for 20 hours. After cooling, water (50 ml) was added and the mixture was stirred for half an hour; the upper phase was separated out and the lower phase was treated with a salt and extracted with diethyl ether. The organic phases were combined and the solvent removed at a temperature not exceeding 50° C., in order to give a yellow oil.
Reaction SMILES: Cl.[C:2]1(N)[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[OH:12][PH2]=O.N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O.C(OCC)(=O)C>[C:2]1(=[O:12])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: Nc1nccc2c1CCC2
Reactant: O=[PH2]O
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]ccc2c1CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
The title compound of step 4 (400 mg, 2.33 mmol) was dissolved in water (6.5 mL) and H3PO2 (2 mL, 50% w/w in water, 18.64 mmol) was added. The mixture was cooled to 0° C. and a solution of NaNO2 (180 mg 2.68 mmol) in water (6.5 mL) was added dropwise. The mixture was stirred at 0° C. for 1 h and then at room temperature overnight. The pH was adjusted to about 7 by careful addition of NaHCO3. Extractive work up using ethyl acetate gave the title compound (300 mg, 95%) as a yellow solid. 1H NMR (CDCl3, 300 MHz): δ 12.55 (s, 1H), 7.24 (d, J=6.3 Hz, 1H), 6.26 (d, J=6.3 Hz, 1H), 2.84-2.89 (m, 4H), 2.04-2.11 (m, 2H). LCMS: 136 (M+1)+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[C:9]([Cl:18])[CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)Nc1ccccc1C(C)(C)C
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
A mixture of N-(2-tert-butylphenyl)acetamide (Reference Example 17, 5.93 g, 31.0 mmol) and sulfuryl chloride (10.5 g, 77.5 mmol) in acetic acid (190 mL) was stirred at 50° C. for 16 h. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with 10% aqueous NaHCO3, and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was recrystallized from toluene/diethyl ether to give the title compound (3.73 g) as a white solid. The mother liquid was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 4:1-1:4 hexane/ethyl acetate) to provide the title compound (1.05 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[F:10][C:11]1[C:12]([NH2:18])=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1>>[NH2:18][C:12]1[C:11]([F:10])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:17][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Cc1cscc1N=C=S
Reactant: Nc1cccc(F)c1N
Product: Cc1cscc1NC(=S)Nc1cccc(F)c1N

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3-fluoro-1,2-diaminobenzene. Crystalline solid, point of decomposition >240° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@H:8]2[CH2:12][C@@H:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.I[CH:18]([CH3:20])[CH3:19]>>[CH3:7][C:4]1[N:3]([C@H:8]2[CH2:12][C@@:11]([CH:18]([CH3:20])[CH3:19])([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9]2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CC(C)I
Reactant: COC(=O)[C@H]1C=C[C@@H](n2c(C)ccc2C)C1
Product: COC(=O)[C@@]1(C(C)C)C=C[C@@H](n2c(C)ccc2C)C1

Procedure:
reacting said methyl (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylate with 2-iodopropane to form methyl (1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxylate; and
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[O:12]=[C:7]1[C:6]2[NH:13][CH:14]=[CH:15][C:5]=2[C:4]2[CH:3]=[C:2]([CH:21]=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:11]=[CH:10][C:9]=2[NH:8]1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: O=c1[nH]c2ccc(Br)cc2c2cc[nH]c12
Reactant: C=Cc1ccccc1
Agent: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(C=Cc3ccccc3)cc2c2cc[nH]c12
Yield: 13.2 %

Procedure:
This compound is prepared according to synthesis 68, from 70 mg (0.21 mmol) of 8-bromo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 71) and 26 μL (0.23 mmol) of styrene. After filtration and trituration in diethyl ether, 10 mg (14%) of 4-oxo-8-styryl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a light brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(=O)(=O)(O)O.[CH3:19][CH2:20]O>>[CH2:19]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=1)[CH3:20]
Reactant: CCO
Reactant: COc1ccc(CC(=O)O)cc1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(OC)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-hydroxy-4-methoxyphenylacetic acid (5.0 g, 23.8 mmol) in EtOH (100 mL) was added sulfuric acid (1 mL), and the reaction was stirred overnight at room temperature. Once no starting material was seen by analytical tlc, the mixture was concentrated to give the desired product.