Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23].Cl[CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>CN1CCCC1=O>[CH2:20]([C:7]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[CH2:25][CH2:26][CH2:27][S:28]2(=[O:30])=[O:29])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN1CCCS1(=O)=O
Yield: 11.3 %

Procedure:
Using the general method of Example 266 except that 1-methyl-2-pyrrolidinone was used in place of dichloromethane, 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (5.0 g, 16.0 mmol) was reacted with 3-chloropropanesulfonyl choride (2.83 g, 16.0 mmol) to provide 0.75 g of 2-butyl-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 173.0-176.0° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of (5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1019, 25.2 g, 74.8 mmol) in methylene chloride (CH2Cl2, 150 mL) was treated with triethylamine (TEA, 15.15 g, 20.9 mL, 150 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled down to 0-5° C. before methanesulfonyl chloride (MsCl, 10.28 g, 6.95 mL, 89.7 mmol, 1.2 equiv) was dropwise introduced into the reaction mixture at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 1 h under N2. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (100 mL) and CH2Cl2 (100 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude, (5R)-methanesulfonic acid 3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020, 30.71 g, 31.04 g theoretical, 98.9%) as off-white powders, which was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1020: C11H11FINO5S, LCMS (EI) m/e 416 (M++H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.P(Br)(Br)[Br:28].C(OC)(C)(C)C>C(Cl)Cl>[Br:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1
Reactant: Cc1cccnc1COc1ccn(CCc2ccc(CO)cc2)c(=O)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: Cc1cccnc1COc1ccn(CCc2ccc(CBr)cc2)c(=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 280 mg (0.80 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(3-methyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 14.1a) in 8.0 mL of DCM is added 75 μL (0.80 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and tert-butylmethylether is added. The formed precipitate is collected, washed with tert-butylmethylether and dried.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O[CH:24]([CH3:34])[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:28][C:27]([NH:26][CH2:25][CH:24]([O:1][C:2]1[C:7]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:34])=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3O)c2c1C
Reactant: CC(O)CNC(=O)OC(C)(C)C
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OC(C)CNC(=O)OC(C)(C)C)c2c1C

Procedure:
Prepared analogously to example 9.1 using methyl 4-(2-hydroxypyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate and tert-butyl N-(2-hydroxypropyl)-carbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:20]2[CH2:21][CH2:22][N:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH2:18][CH2:19]2)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
To 4-fluoro-2-(methyloxy)-1-nitrobenzene (Example 22, step A) (1 g, 5.8 mmol) in 10 mL of DMSO was added, 1-(methylsulfonyl)piperazine (1.15 g, 7.02 mmol), and K2CO3 (2.42 g, 17.5 mmol). The mixture was heated to 80° C. overnight. In the morning, the mixture was poured into 100 mL of H2O, Solid precipitated and was filtered off, washed with H2O and let air dried for a few hours. After drying under high vacuum overnight, the title compound of step A was isolated as a yellow solid. (1.09 g, 3.46 mmol, 60%). MS (ESI): 316 [M+H]+.
Reaction SMILES: [Cl-:1].[NH2:2][C:3]1[N:7]([C@@H:8]2[O:16][C@H:15]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]2[F:22])[CH:6]=[N:5][C:4]=1[C:23]([OH:25])=O>O1CCCC1>[C:12]([O:11][C@@H:10]1[C@@H:15]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[O:16][C@@H:8]([N:7]2[C:3]([N:2]=[CH:6][N:7]([CH3:8])[CH3:3])=[C:4]([C:23]([Cl:1])=[O:25])[N:5]=[CH:6]2)[C@H:9]1[F:22])(=[O:14])[CH3:13]
Reactant: [Cl-]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)O)c2N)[C@@H](F)[C@@H]1OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)Cl)c2N=CN(C)C)[C@@H](F)[C@@H]1OC(C)=O

Procedure:
In step f, compound (35) is dissolved in tetrahydrofuran and reacted with N,N-dimethylchloroforminium chloride under ice-cooling. This reaction may be carried out in the same manner as in the step 12 of SYNTHETIC PROCESS CHART (A). By this reaction, 1-(3,5-di-O-acetyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-(dimethylaminomethyleneamino)imidazole-4-carbonyl chloride [compound(36)] is produced.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:25])[CH2:12][C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].B.O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:25])[CH2:12][CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(CC(=O)O)N2Cc3ccccc3C2=O)cc1OC
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(CCO)N2Cc3ccccc3C2=O)cc1OC
Temperature: 25 °C

Procedure:
To a stirred suspension of 3-(3',4'-dimethoxyphenyl)-3-(1'-oxoisoindolinyl)propionic acid (3.74 grams, 10.96 mmol) in THF (60 mL) at -10°-15° C. (ice-salt bath), was added borane in THF (11 mL, 1M, 11 mmol). The suspension was allowed to warm to room temperature slowly overnight. To the resulting clear solution was added water (20 mL), followed by potassium carbonate (6 g). The organic layer was separated. The aqueous layer was extracted with methylene chloride (2×50 mL). The combined organic layers were washed with sodium carbonate (20 mL, sat), brine (20 mL), and dried over magnesium sulfate. Removal of solvent and chromatography (silica gel, 100 grams, 1:2, 1:1 EtOAc/CH2Cl2) gave 3-(3',4'-dimethoxyphenyl)-3-(1'-oxoisoindolinyl)-1-propanol as an oil, (2.52 grams, 70%). Ether (6 mL) and 2 drops of methanol were added to the oil. Hexane was added until the solution was turned cloudy. The mixture was stirred for 30 minutes to give a white solid and the solid was filtered: mp, 101.5°-103.0° C.; 1H NMR (CDCl3)δ1.99-2.36 (m, 3H, CH2, OH), 3.49-3.80 (m, 2H, OCH2), 3.85 (s, 3H, CH3), 3.89 (s, 3H, CH3), 3.91 (d, J=17.2 Hz, 1H, CHH), 4.19 (d, J=17.2 Hz, 1H, CHH), 5.75 (dd, J=4, 11.5 Hz, 1H, NCH), 6.86-7.00(m, 3H, Ar), 7.27-7.56 (m, 3H, Ar), 7.86-7.89 (m, 1H, Ar); 13C NMR (CDCl3)δ33.87, 46.22, 50.61, 55.91, 56.01, 58.55, 111.04, 111.73, 119.66, 122.81, 123.89, 128.64, 131.33, 131.56, 132.09, 141.35, 148.81, 148.24, 169.45; Anal Calcd for C19H21 NO4 : C, 69.71; H, 6.47; N, 4.28. Found: C, 69.5I; H, 6.27; N, 4.12.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[CH3:2].[NH2:12][C@@H:13]([CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=2)=[N:16]1>>[C:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([NH:12][C@@H:13]([CH3:29])[CH2:14][N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=3)=[N:16]2)=[O:11])[N:8]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1nc(C(=O)O)cs1
Product: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 93 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 2-acetylthiazole-4-carboxylic acid (1.444 g, 8.44 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (2.0 g, 7.67 mmol). The product was purified by recrystallization from ethanol. Yield 93%. 1H-NMR (400 MHz; DMSO-d6): δ 1.20 (d, 3H), 2.70 (s, 3H), 4.37 (dd, 1H), 4.44 (dd, 1H), 4.48-4.56 (m, 1H), 6.96 (d, 1H), 7.87 (d, 1H), 7.92 (dd, 1H), 7.97 (dd, 1H), 8.04 (d, 1H), 8.48 (d, 1H), 8.61 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH2:19][OH:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].CS(C)=O.[CH3:25][C:26](OC(C)=O)=[O:27]>O>[CH2:1]([C:3]1([CH2:18][CH2:19][O:20][C:26](=[O:27])[CH3:25])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Reactant: CC(=O)OC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCOC(C)=O)OCC3
Yield: 78 %

Procedure:
A solution of compound 1 (273 mg, 1.0 mmol), dry DMSO (3 mL), dry Ac2O (2 mL), and dry TEA (1 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with water and extracted three times with EtOAc. The combined organic phases were washed with saturated NaHCO3 and brine, dried with Na2SO4, concentrated, and purified by column chromatography using 10:90:EtOAc:Hexane to give a yellow solid (245 mg, 78%): mp 126-127° C. 1HNMR (CDCl3, δ TMS): 0.91 (t, 3H), 1.38 (t, 3H), 1.88 (s, 3H), 1.90 (m, 2H), 2.21 (t, 2H), 2.78 (m, 2H), 2.87 (q, 2H), 4.01 (t, 2H), 4.14 (m, 2H), 7.02-7.37 (m, 3H, Ar—H), 7.71 (br, 1H, NH). MS−: m/z 350 (MCl−), 314 ([M−H]−). Anal. (C19H25NO3): C, H, N.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[C@@H:3]1[NH:22][C:23]([C@@H:25]([O:27][C:28](=O)[O:29]C1C=CC([N+]([O-])=O)=CC=1)[CH3:26])=[O:24].[F:40][C:41]([F:48])([C:44]([F:47])([F:46])[F:45])[CH2:42][NH2:43]>ClCCl.C(OC(=O)C)C>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[C@@H:3]1[NH:22][C:23]([C@@H:25]([O:27][C:28](=[O:29])[NH:43][CH2:42][C:41]([F:48])([F:40])[C:44]([F:47])([F:46])[F:45])[CH3:26])=[O:24]
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](OC(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Yield: 86 %

Procedure:
0.065 g (0.12 mmol) carbonic acid 4-nitro-phenyl ester (S)-1-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester and 0.26 ml 2,2,3,3,3. pentafluoropropylamine were stirred at room temperature over night. Chromatography on silicagel with dichloromethane/ethylacetate (100-40/0-60) yielded 0.06 g (86%) (2,2,3,3,3-Pentafluoro-propyl)-carbamic acid (S)-1-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester as white foam, MS: m/e: 554.3 (M+H+), [α] 589=−4.40° (0.75% in CHCl3).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:31]=[CH:30][CH:29]=[C:7]2[C:8]([N:10]([CH:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=3)[CH2:14][C:15]([OH:17])=O)[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:45][OH:46]>O1CCCC1>[C:1]([NH:4][C:5]1[CH:31]=[CH:30][CH:29]=[C:7]2[C:8]([N:10]([CH:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=3)[CH2:14][C:15]([NH:45][OH:46])=[O:17])[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 48.2 %

Procedure:
3-(3-Acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide was prepared by the procedure of Example 1 from 3-(3-acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (2.0 g, 4.7 mmol), carbonyldiimidazole (1.14 g, 7.03 mmol) and hydroxylamine hydrochloride (651 mg, 9.37 mmol) in tetrahydrofuran (10 mL) to afford 3-(3-acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide as a white solid (1.0 g, 48% yield): mp, 117.0-119.0° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=6.9 Hz, 3H, CH3), 2.19 (s, 3H, CH3), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.98 (q, J=7.0 Hz, 2H, CH2), 5.65 (t, J=7.8 Hz, 1H, NCH), 6.87-6.95 (m, 2H, Ar), 6.99 (br s, 1H, Ar), 7.54 (d, J=6.9 Hz, 1H, Ar), 7.77 (t, J=7.45 Hz, 1H, Ar), 8.41-8.47 (m, 1H, Ar), 8.80 (br s, 1H, OH), 9.71 (s, 1H, NH), 10.59 (br s, 1H, NH); 13C NMR (DMSO-d6) δ24.69, 34.20, 44.09, 60.04, 65.48, 73.79, 121.78, 122.43, 126.69, 127.97, 129.64, 135.83, 141.00, 141.44, 145.75,146.38, 157.70, 158.59, 175.97, 177.13, 178.19, 179.22; Anal Calcd for C22H23N3O7+0.3 H2O: C, 59.14; H, 5.32; N, 9.40. Found: C, 59.32; H, 5.33, N, 9.02.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[Br:9]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][CH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: Cc1sccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: N#Cc1ccsc1CBr
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
2-Methyl-3-cyanothiophene (2.108 g) was dissolved in benzene (30 ml), followed by the addition of N-bromosuccinimide (4.8 g) and 70% benzoyl peroxide (202 mg), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled, and the resulting precipitates were filtered off. Then the filtrate was diluted with ethyl acetate, washed with an aqueous solution of saturated sodium bicarbonate, dried (over MgSO4) and then evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (2.746 g, yield; 82%).
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:40]([O:42]C)=[O:41])=[C:12]([CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:30][CH2:29]3)[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[N:14]2)=[CH:9][C:8]=1[S:44]([CH3:47])(=[O:46])=[O:45])[CH3:5]>CO.O>[CH3:5][CH:4]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:40]([OH:42])=[O:41])=[C:12]([CH2:27][N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:32][CH2:33]3)[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)=[N:14]2)=[CH:9][C:8]=1[S:44]([CH3:47])(=[O:46])=[O:45])[CH3:3]
Reactant: COC(=O)c1c(CN2CCC(N3CCOCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC(C)C)c(S(C)(=O)=O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Oc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(C)(=O)=O
Temperature: 25 °C
Yield: 95.8 %

Procedure:
Potassium hydroxide (1.38 g, 24.63 mmol) was added to a solution of methyl 7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.6 g, 2.463 mmol) in methanol (60 mL) and water (20 mL). The reaction mixture was heated to reflux overnight, cooled to room temperature and diluted with water. The methanol was removed under reduced pressure. The residual mixture was acidified to pH 6 with 2N HCl and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford 7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1.5 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ8.82 (s, 1H), 8.03 (s, 1H), 7.91 (t, J=7.91 Hz, 2H), 7.79 (t, J=7.78 Hz, 1H), 7.70 (s, 1H), 5.08 (dt, J=5.93, 11.98 Hz, 1H), 4.11 (br. s., 2H), 3.56 (br. s., 4H), 3.38 (s, 3H), 2.99 (d, J=11.29 Hz, 2H), 2.53-2.59 (m, 1H), 2.42 (br. s., 4H), 2.34 (br. s., 1H), 1.78 (d, J=12.30 Hz, 2H), 1.43 (s, 3H), 1.41 (s, 3H), 1.22-1.39 (m, 3H); MS (m/z) 636.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][NH:32][CH2:31][CH2:30][O:29][CH3:28])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: COCCN
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: COCCNCC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), 2-methoxyethanamine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 319 (M+, 1), 274 (23), 88 (bp), 70 (8), 56 (13).
Reaction SMILES: [OH2:1].[OH-].[Na+].[C:4]([C:6]([NH:11][C:12]([C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])=O)([CH3:10])[CH:7]([CH3:9])[CH3:8])#[N:5].Cl>C(Cl)Cl>[CH:7]([C:6]1([CH3:10])[NH:11][C:12]([C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[N:5][C:4]1=[O:1])([CH3:9])[CH3:8]
Reactant: O
Reactant: CC(C)C(C)(C#N)NC(=O)c1ncccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)C1(C)NC(c2ncccc2C(=O)O)=NC1=O

Procedure:
To a stirred mixture of 20 mL of water and 8.40 g (0.105 mol) of 50% sodium hydroxide solution is added 7.83 g (0.030 mol) of 2-[(1-cyano-1,2-dimethylpropyl)aminocarbonyl]nicotinic acid. External heating is applied to raise the temperature to 70°-75° C. where it is maintained for five hours. After cooling the reaction mixture to 20°-30° C., 50 mL of methylene chloride is added and the pH is adjusted to 3.0 by the addition of 37% hydrochloric acid. The organic layer is separated and the solvent is removed by distillation to give 6.71 g of solid 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)nicotinic acid which is 90% pure in 77% yields.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19]C)=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([CH3:33])[CH:26]=1)[NH2:24].C(O)C>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:24]2)=[CH:26][C:27]=1[CH3:33])#[N:30]
Reactant: COC(=O)c1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Reactant: Cc1cc(NN)ccc1C#N
Agent: Cl
Solvent: CCO
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)ccc1C#N
Yield: 64 %

Procedure:
The title compound was prepared from Methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 18 (310.5 mg, 1.09 mmol) and 4-hydrazinyl-2-methylbenzonitrile hydrochloride; Preparation 2 (265 mg, 1.45 mmol) according to Method B and Method C (hydrolysis conducted at 60° C.). The crude precipitate was purified by reverse phase chromatography with 60-95% acetonitrile/water to give the title compound (yellow solid, 280 mg, 0.563 mmol, 64% yield). The title compound was largely present as (±)-(3SR,3aRS)-2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.56 (m, 7H), 1.64-1.74 (m, 1H), 1.76-1.92 (m, J=12.89, 4.30 Hz, 1H), 2.01-2.14 (m, 1H), 2.18-2.29 (m, 1H), 2.41 (s, 3H), 2.81-2.96 (m, 1H), 3.04-3.14 (m, 1H), 3.51-3.63 (m, 1H), 4.89 (dd, J=9.67, 5.37 Hz, 1H), 7.09 (dd, J=8.59, 2.15 Hz, 1H), 7.22 (d, J=1.88 Hz, 1H), 7.52 (d, J=8.59 Hz, 1H), 7.82 (dd, J=8.19, 1.48 Hz, 1H), 7.85 (s, 1H), 8.07 (d, J=8.06 Hz, 1H), 13.01 (s, 1H). ES-MS m/z 400 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]1[CH2:18][N:19]1C(=O)C2=CC=CC=C2C1=O.O.Cl>CCO>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]1[CH2:18][NH2:19]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CN2C(=O)c3ccccc3C2=O)n1C
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(=O)c(OCc2ccccc2)c(CN)n1C
Temperature: 4 °C
Yield: 92.3 %

Procedure:
10 g of 59 (26 mmol, 1 equiv) was dissolved in 100 ml EtOH. 17 ml N2H4 (5.5% aqueous) was added and the solution was refluxed for 3 hours. 59 did not fully dissolve until refluxing had begun. The solution was allowed to cool, at which point it solidified. Water was added and the pH adjusted to 1 with conc. HCl. After overnight cooling at 4° C., the solution was filtered. The pH of the filtrate was adjusted to 14 with 10 N NaOH and extracted with 5×100 ml CH2Cl2. The extracts were combined and dried over Na2SO4. The solvent was removed in vacuo to give 6.2 g of a white solid in 92% yield.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[N:18]([C:24]([C:26]1[C:30]3[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:29]=3[S:28][N:27]=1)=[O:25])[CH2:17][CH2:16]2.[CH:36]1([CH2:39]O)[CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:36]1([CH2:39][O:35][C:33]2[CH:32]=[CH:31][C:30]3[C:26]([C:24]([N:18]4[CH:19]5[CH2:20][CH2:21][N:15]([CH2:23][CH2:22]5)[CH2:16][CH2:17]4)=[O:25])=[N:27][S:28][C:29]=3[CH:34]=2)[CH2:38][CH2:37]1
Reactant: O=C(c1nsc2cc(O)ccc12)N1CCN2CCC1CC2
Reactant: OCC1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1nsc2cc(OCC3CC3)ccc12)N1CCN2CCC1CC2
Temperature: 25 °C
Yield: 39 %

Procedure:
Diisopropyl azodicarboxylate (0.396 mmol) was added dropwise to a solution of 3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-ol (0.359 mmol), cyclopropyl carbinol (0.432 mmol), and triphenylphosphine (0.541 mmol) in tetrahydrofuran (2.2 mL). The reaction mixture was maintained at rt for 16 h, and then the reaction mixture was concentrated. The residue was purified by chromatography using a gradient of 50/50 to 0/100 ethyl acetate/[(70/30/1) ethylacetate/methanol/ammonium hydroxide)]. The compound was further purified by preparative HPLC to provide the product in 39% yield. 1H NMR (CD3OD) δ 8.06 and 8.05 (two d, J=9.0 ea, 1H), 7.56 (d, J=1.8, 1H), 7.14 and 7.13 (two dd, J=8.7, 2.2 ea, 1H), 5.00 (m, 0.79H), 4.50 (m, 0.34H), 4.25 (t, J=5.6, 0.68H), 4.09 (t, J=5.6, 1.34H), 3.95 (d, J=6.9, 2H), 3.63 (t, J=5.7, 0.70H), 3.62-3.36 (m, 5H), 2.45-2.37 (m, 2H), 2.26-2.02 (two m, 2H), 1.37-1.27 (m, 1H), 0.69-0.62 (m, 2H), 0.42-0.37 (m, 2H); LC/MS (EI) tR3.91 min, m/z 358 (M++1).