Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]1[O:27][CH2:26]1>CCOC(C)=O>[N+:9]([C:5]1[CH:4]=[N:3][C:2]2[NH:1][CH:25]([CH2:26][OH:27])[CH2:24][O:8][C:7]=2[CH:6]=1)([O-:11])=[O:10]
Reactant: Nc1ncc([N+](=O)[O-])cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc2c(c1)OCC(CO)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
Into a 75 mL sealed tube were combined 2-amino-3-hydroxy-5-nitropyridine (0.138 g, 0.000890 mol), N,N-dimethylformamide (4.1 mL) and potassium carbonate (0.39 g, 0.0028 mol). The mixture was allowed to stir at room temperature for 10 minutes then 1-bromo-2,3-epoxypropane (0.12 g, 0.00089 mol) was added in one portion. The flask was sealed, then heated to 110° C. and stirred overnight. After allowing to cool, the mixture was concentrated under vacuum to give a crude solid which was dissolved in EtOAc (75 mL), washed with water and brine, then dried (Na2SO4), filtered and concentrated under vacuum to leave a crude residue. The residue was purified by column chromatography on silica gel using MeOH/CH2Cl2 (0-10% gradient) as eluent to give a solid (0.092 g, 46%). LC-MS 1.92 min. M/Z=212.0 (M+1). 1H NMR (d6-DMSO) δ 8.8 (d, 1 H), 7.8 (d, 1 H), 5.1 (t, 1H),4.2 (m, 1 H), 4.0 (m, 1H), 3.62 (m, 1H), 3.45 (m, 1H), 3.21 (m, 1H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23](=[O:48])[CH2:24][CH2:25][C:26]1[C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]/[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:30][CH:29]=[C:28](I)[N:27]=1>>[CH3:21][O:22][C:23](=[O:48])[CH2:24][CH2:25][C:26]1[C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]/[C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)=[CH:30][CH:29]=[C:28]([C:19]#[C:18][C:15]2[CH:14]=[CH:13][C:12]([C:11]([NH:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[O:20])=[CH:17][CH:16]=2)[N:27]=1
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Reactant: C#Cc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1
Product: COC(=O)CCc1nc(C#Cc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 30 %

Procedure:
Under the conditions of example 5 A, 1.31 g of the crude N-benzenesulfonyl-4-ethinylbenzoic acid amide is reacted with 1.9 g of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with dichloromethane/0-5% methanol. 750 mg of 3-{3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-[2-(4-benzenesulfonamidocarbonylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:68])/[C:40](/[C:43]2[N:44]=[C:45]([NH:48][C:49]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[S:46][CH:47]=2)=[N:41]\[OH:42])[C:19]3=[O:69])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:76][CH2:77][C:78]([O:80][C:81]1[C:89]([O:90][C:91](=[O:94])[CH2:92][Cl:93])=[CH:88][C:84]([C:85](Cl)=[O:86])=[C:83]([CH3:95])[CH:82]=1)=[O:79]>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:68])/[C:40](/[C:43]2[N:44]=[C:45]([NH:48][C:49]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:62]4[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=4)[S:46][CH:47]=2)=[N:41]\[O:42][C:85](=[O:86])[C:84]2[CH:88]=[C:89]([O:90][C:91](=[O:94])[CH2:92][Cl:93])[C:81]([O:80][C:78](=[O:79])[CH2:77][Cl:76])=[CH:82][C:83]=2[CH3:95])[C:19]3=[O:69])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(OC(=O)CCl)c(OC(=O)CCl)cc1C(=O)Cl
Reactant: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](NC(=O)/C(=N\O)c5csc(NC(c6ccccc6)(c6ccccc6)c6ccccc6)n5)[C@H]4SC3)sc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](NC(=O)/C(=N\OC(=O)c5cc(OC(=O)CCl)c(OC(=O)CCl)cc5C)c5csc(NC(c6ccccc6)(c6ccccc6)c6ccccc6)n5)[C@H]4SC3)sc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To an ice-cooled solution of the product obtained in Step 4 (0.6 g) in dry dichloromethane (15 ml) was added potassium carbonate (0.1 g) at once, followed by dropwise addition of a solution of 4,5-bis(chloroacetoxy)-2-methylbenzoyl chloride (0.25 g) in dry dichloromethane (10 ml). The mixture was stirred under ice cooling for one hour and then at room temperature for an additional two hours. After filtering off the insoluble matters, the filtrate was washed with water and with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 0.47 g of the objective compound.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][C@@H:17]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:21]4=[CH:20][CH2:19][C@H:18]3[C@@H:13]2[CH2:12][CH2:11]1)[CH2:3][CH2:4][C@H:5]([CH:7]([CH3:9])[CH3:8])[CH3:6].[C:30](OC(=O)C)(=[O:32])[CH3:31].O>N1C=CC=CC=1>[CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][C@@H:17]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([O:27][C:30]([CH3:31])=[O:32])[CH2:26][C:21]4=[CH:20][CH2:19][C@H:18]3[C@@H:13]2[CH2:12][CH2:11]1)[CH2:3][CH2:4][C@H:5]([CH:7]([CH3:8])[CH3:9])[CH3:6]
Reactant: CC(C)[C@H](C)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](C)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 24.0 g (0.06 mol) of campesterol (1) in 180 ml of anhydrous pyridine was added 18.5 ml (0.196 mol) of acetic anhydride. The mixture was stirred at room temperature overnight and then 600 ml of water was added. The precipitate was filtered and washed three times with 200 ml portions of acetonitrile, and then air dried to yield 20.0 g (75%) of (2).
Reaction SMILES: F[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=CC2NC=C3C(=O)N(C4C=CC=CC=4)N=C3C=2C=1.F[C:29]1[C:30]([F:49])=[CH:31][C:32]2[C:33]3[C:34]([C:39](=[O:48])[N:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:41]=3)=[CH:35][NH:36][C:37]=2[CH:38]=1.CN1CCCNCC1>>[F:49][C:30]1[C:29]([N:15]2[CH2:14][CH2:2][CH2:11][N:12]([CH3:13])[CH2:17][CH2:16]2)=[CH:38][C:37]2[NH:36][CH:35]=[C:34]3[C:39](=[O:48])[N:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:41]=[C:33]3[C:32]=2[CH:31]=1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Agent: CN1CCCNCC1
Product: CN1CCCN(c2cc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3cc2F)CC1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27a and 1-methylperhydro[1,4]-diazepine. 1H-NMR (DMSO-d6) δ (ppm): 1.98 (2H, brm), 2.27 (3H, s), 2.68 (4H, brm), 3.24 (4H, brm), 7.15 (2H, m), 7.40 (2H, m), 7.76 (1H, d, J=2.91 Hz), 8.20 (2H, m), 8.64 (1H, s). m/z 392.2 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17][C:16]=1[N:22]([CH3:39])[C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:25]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17][C:16]=1[N:22]([CH3:39])[C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[C:26]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:25]=1
Reactant: Cc1cc(-c2ccccc2OCc2ccccc2)c(N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(-c2ccccc2O)c(N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1
Reaction time: 5 h

Procedure:
To a solution of N-(4-(2-(benzyloxy)phenyl)-6-methylpyridin-3-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (1.63 g, 2.94 mmol) in MeOH (16 mL) and EtOAc (16 mL) was added Pd on carbon (10%, 200 mg, 2.94 mmol) under argon atmosphere. The reaction was evacuated and purged with hydrogen. The reaction was stirred for 5 hours at 1.7 bar under hydrogen atmosphere. The reaction mixture was filtered over dicalite. The filtrate was concentrated under vacuum and the compound was purified by silica gel chromatography on a 50 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (1.367 g, 100%). MS (ESI): m/z=465.109 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:17](=O)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[O:5])[CH3:2].CC[O-].[Na+].Cl.[NH2:33][C:34]1[N:38]2[CH2:39][CH2:40][CH2:41][N:37]2[C:36](=[O:42])[CH:35]=1>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[C:35]2[C:36](=[O:42])[N:37]3[CH2:41][CH2:40][CH2:39][N:38]3[C:34]=2[NH:33][C:17]=1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(C(=O)O)cc1)C(=O)CCc1ccc(F)cc1
Reactant: Nc1cc(=O)n2n1CCC2
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(CCc2ccc(F)cc2)Nc2c(c(=O)n3n2CCC3)C1c1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 41 %

Procedure:
The product from Step C (920 mg, 2.48 mmol) and NaOEt (170 mg, 2.50 mmol) were added portionwise to a stirred solution of 3-amino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one hydrochloride (refs. R. B. Greenwald, U.S. Pat. No. 4,128,425 and E. E. Boros, F. Bouvier, S. Randhawa and M. H. Rabinowitz, J. Heterocyclic Chem., 2001, 38, 613–616.) (440 mg, 2.51 mmol) in EtOH (6 mL). The reaction mixture was heated at reflux for 5.5 h and then allowed to cool to rt and filtered to remove NaCl. The filtrate was concentrated at reduced pressure and the remaining material was triturated with CH2Cl2 to yield D as an off-white solid (500 mg, 1.02 mmol, 41%): 1H NMR (400 MHz, DMSO-d6) δ 12.63 (br, 1H), 9.76 (s, 1H), 7.77 (d, 2H, J=8), 7.27 (dd, 2H, J=8, 6), 7.20 (d, 2H, J=8), 7.11 (t, 2H, J˜9), 4.76 (s, 1H), 3.87 (q, 2H, J=7), 3.42 (m, 2H), 3.27 (m, 2H), 2.98 (m, 2H), 2.85 (m, 2H), 2.26 (m, 2H), 0.96 (t, 3H, J=7) ppm; ESI-MS m/z 492 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:17]([O:21]CC2C=CC=CC=2)=[CH:16][C:3]=1[O:4][C:5]1[C:13]2[CH2:12][C:11](C)(C)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:29]([OH:31])[CH3:30]>[Pd]>[CH3:9][C:13]1([CH3:5])[O:31][C:29]2[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:5][O:4][C:3]3[CH:16]=[C:17]([OH:21])[CH:18]=[C:19]([Cl:20])[C:2]=3[Cl:1])=[CH:8][CH:7]=[CH:6][C:30]=2[CH2:12]1
Reactant: CCO
Reactant: CC1(C)Cc2c(Oc3cc(OCc4ccccc4)cc(Cl)c3Cl)cccc2O1
Agent: [Pd]
Product: CC1(C)Cc2cccc(OCCCCOc3cc(O)cc(Cl)c3Cl)c2O1

Procedure:
A mixture of 0.5 gram (0.001 mole) of 7-{4-[2,3-dichloro-5-(phenylmethoxy)phenoxy}-2,2-dimethyl-2,3-dihydrobenzo[b]furan and 0.1 gram (catalyst) of 10% palladium on carbon in 75 mL of ethanol was placed in a Parr hydrogenation bottle and hydrogenated using a Parr hydrogenation apparatus. Upon the theoretical uptake of hydrogen gas, the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 100% methylene chloride, then 5% methanol in methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.17 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]#[N:8])[C:4]([C:9]2[O:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[N:3]1.S(=O)(=O)(O)[OH:18]>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([NH2:8])=[O:18])[C:4]([C:9]2[O:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[N:3]1
Reactant: O=S(=O)(O)O
Reactant: Cn1cc(C#N)c(-c2ccc([N+](=O)[O-])o2)n1
Product: Cn1cc(C(N)=O)c(-c2ccc([N+](=O)[O-])o2)n1
Temperature: 25 °C
Reaction time: 21 h
Yield: 97 %

Procedure:
While cooling and stirring 80 ml of concentrated sulfuric acid at room temperature, add 40 g of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carbonitrile thereto. Then stir the resulting mixture for 21 hours at room temperature. Pour thus-obtained solution onto ice for a 97% yield of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carboxamide [m.p. 251° to 252.5° C].
Reaction SMILES: [CH2:1]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6][CH2:5][CH2:4][S:3](=[O:17])(=[O:16])[CH2:2]1.[H-].[Na+].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl>>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH2:1][CH2:2][S:3](=[O:16])(=[O:17])[CH2:4][CH2:5][CH2:6][C:7]1=2
Reactant: CN(C)CCCl
Reactant: O=S1(=O)CCCc2[nH]c3ccccc3c2CC1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCn1c2c(c3ccccc31)CCS(=O)(=O)CCC2

Procedure:
A mixture of 12.47g (0.05 mole) of 1,2,4,5,6,7-hexahydrothiocino[5,4-b]indole 3,3-dioxide, 2.1g (0.05 mole) of 57% dispersion sodium hydride and 5.44g (0.05 mole) of 2-dimethylaminoethyl chloride is treated according to the procedure in Example 6. There is deposited 15.3g (96%) of a solid, m.p. 154°-155° C. Recrystallization from ethyl acetate gives 11.2g (70%) of an analytical sample, m.p. 155°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O>C1C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: Clc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1Cl
Yield: 50 %

Procedure:
Repeating Example 21 in every detail except that a chlorobenzene solution of 2-chloro-4-nitrobenzoic acid was employed in lieu of the benzene solution of the same, there is obtained a 50% yield of 2,4'-dichloro-4-nitrobenzophenone in good yield and purity having a melting point of 117° C.-117.5° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[CH:5]=[C:4]([Cl:12])[N:3]=1.[OH-:13].[Na+].Cl>O1CCOCC1>[Cl:12][C:4]1[NH:3][C:2](=[O:13])[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[CH:5]=1
Reactant: Cn1ccc2c(Cl)nc(Cl)cc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1ccc2c(=O)[nH]c(Cl)cc21
Temperature: 160 °C
Yield: 93.6 %

Procedure:
A microwave reaction vial was charged with 4,6-dichloro-1-methyl-1H-pyrrolo[3,2-c]pyridine (60 mg, 0.29 mmol), a 2M aqueous sodium hydroxide solution (10 mL) and 1,4-dioxane (1 mL). The vial was sealed and then heated in the microwave at 160° C. for 30 min. At this time, the resulting mixture was acidified to pH 6.5 with a 4M aqueous hydrochloric acid solution and then concentrated in vacuo. The residue was diluted with ethanol. The solids were removed by filtration, and the filtrate was concentrated in vacuo. Flash chromatography (10/1 methylene chloride/methanol) afforded 6-chloro-1-methyl-1,5-dihydro-pyrrolo[3,2-c]pyridine-4-one (51 mg, 93.6%). LC-MS calcd. for C8H7ClN2O2 [(M+H)+] 183, obsd. 182.9.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)=[O:7]>Br>[OH:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([CH:8]1[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]1)=[O:7]
Reactant: COc1cccc(C(=O)C2CCN(C)CC2)c1
Agent: Br
Product: CN1CCC(C(=O)c2cccc(O)c2)CC1
Yield: 99.5 %

Procedure:
A solution of 4-[3-methoxybenzoyl]-1-methylpiperidine (260 mg, 1.1 mmol) in 48% hydrobromic acid (10 mL) was refluxed for 1 h. The reaction mixture was concentrated under reduced pressure to a brown oil. The oil was dissolved in water, basified to pH 9 with ammonium hydroxide, and extracted with methylene chloride. Sodium chloride was added to the aqueous phase and extracted with chloroform/isopropanol (3:1). The organic extracts were combined, dried over sodium sulfate, and concentrated in vacuo to give 240 mg of a tan solid. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 214 mg (88%) of a tan crystalline solid. Mp 161-4° C. MS(m/e): 220(M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][CH2:39][CH2:40][OH:41]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][CH2:39][CH2:40][OH:41])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Reactant: NCCCO
Product: O=C(NCCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-1-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (d, J=4.42 Hz, 4 H), 1.60-1.76 (m, 6 H), 2.36-2.44 (m, 2 H), 3.33-3.39 (m, 4 H), 3.39-3.52 (m, 4 H), 4.15-4.24 (m, 4 H), 4.60 (t, J=5.05 Hz, 1 H), 7.14 (ddd, J=9.00, 6.69, 2.00 Hz, 2 H), 7.38-7.44 (m, 2 H), 7.99 (d, J=1.47 Hz, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.33 (t, J=5.90 Hz, 1 H), 17.23 (s, 1 H); ES+ MS: 525 (M+H+).
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:14]2[CH2:15][N:16]=[CH:17][CH:18]=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[CH:11]3)[C:7](=[O:19])[CH2:6]1)=O.[Li+].[BH4-].C(OCC)(=O)C.Cl>CO>[OH:2][CH2:3][CH:5]1[C:14]2[CH2:15][N:16]=[CH:17][CH:18]=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[CH:11]3)[C:7](=[O:19])[CH2:6]1
Reactant: COC(=O)C1CC(=O)c2cccc3c2=C1CN=CC=3
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CC(CO)C2=c3c1cccc3=CC=NC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-oxo-1,2,3,4-tetrahydronaphtho[1,8-cd]azepine-3-carboxylic acid methyl ester (70 mg, 0.28 mmol) in MeOH (5 mL) is added LiBH4 (18.3 mg, 0.83 mmol) and the mixture is stirred at RT for 1 h. Ethyl acetate is added followed by ice and 1N HCl. The mixture is washed with brine then water and the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by preparative HPLC to give the title compound.
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])[C:22]=1[CH3:23].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:24]2[CH:25]=[C:26]([NH:27][C:14]([C:1]3[C:13]4[CH2:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:15])[CH:28]=[CH:29][CH:30]=2)[C:22]=1[CH3:23]
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Reactant: Cc1ncn(-c2cccc(N)c2)c1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ncn(-c2cccc(NC(=O)c3cccc4c3Cc3ccccc3-4)c2)c1C
Reaction time: 24 h
Yield: 64.6 %

Procedure:
To a suspension of 9H-fluorene-1-carboxylic acid (106 mg) and 3-(4,5-dimethylimidazol-1-yl)aniline (94 mg) in dichloromethane (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (135 mg) and 4-dimethylaminopyridine (31 mg), and the mixture was stirred for 24 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with methanol, and the insoluble material was collected by filtration and dried to give N-[3-(4,5-dimethylimidazol-1-yl)-phenyl]-9H-fluorene-1-carboxamide (123 mg, 64.7%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1)(=[O:7])=[O:6].O[N:25]1[C:29](=[O:30])[CH2:28][CH2:27][C:26]1=[O:31].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:15][C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([O:20][N:25]2[C:29](=[O:30])[CH2:28][CH2:27][C:26]2=[O:31])=[O:19])=[CH:12][CH:13]=1)(=[O:7])=[O:6]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)NCCO)cc2)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccc(S(=O)(=O)NCCO)cc2)[nH]c1=O

Procedure:
From 3.8 g. of 6-[4-[(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinic acid and 1.34 g. of N-hydroxysuccinimide in 60 ml. of dimethylformamide, and 2.56 g. of N,N'-dicyclohexylcarbodiimide in 5 ml. of dimethylformamide, following the procedure of a) above, there is obtained 6-[4-[(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinic acid, 2,5-dioxo-1-pyrrolidinyl ester; m.p. 203.5°-205° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[F:10][C:11]1([F:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CN(C)C=O>[F:10][C:11]1([F:17])[CH2:16][CH2:15][N:14]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: FC1(F)CCNCC1
Reactant: BrCc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: FC1(F)CCN(Cc2ccc(Br)cc2)CC1
Yield: 87.3 %

Procedure:
4-Bromobenzyl bromide (1.55 g) and 4,4-difluoropiperidine (1.50 g) were stirred in dimethylformamide (30 ml) for 18 h. The mixture was partitioned between diethyl ether (40 ml) and water (40 ml). The aqueous phase was extracted further with ether (40 ml) and the combined organic phases were washed with water (50 ml), dried (MgSO4) and concentrated in vacuo to give the product as a white crystalline solid (1.57 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[C:19]1([S:25]([CH2:27][CH2:28][CH2:29][CH2:30]Br)=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(S)C=CC=CC=1.BrCCCCBr.OO>CS(C)=O.C(O)(=O)C.O>[C:19]1([S:25]([CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: O=S(CCCCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: Sc1ccccc1
Solvent: BrCCCCBr
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCc2cc(OCCCCS(=O)c3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
32.6 gm (0.2 mol) of 6-hydroxy-3,4-dihydro-carbostyril [see F. F. Mayer et al., Ber. Dtsch. Chem. Ges. 60, 858 (1927)] and 27.6 gm (0.2 mol) of potassium carbonate were stirred for 5 minutes in 600 ml of dimethylsulfoxide which had been dried over a molecular sieve, and then 52.2 gm of 4-phenylsulfinyl-butyl bromide (0.2 mol) (prepared from thiophenol and 1,4-dibromo-butane and subsequent oxidation with hydrogen peroxide in glacial acetic acid analogous to Example 2; oily substance, solidified upon standing in the refrigerator) were added. After stirring it for 15 hours at 25° C., the reaction mixture was poured into 6 liters of water. After stirring the aqueous mixture for 30 minutes more, the precipitated product was suction-filtered off and thoroughly washed with water. After drying, the filter cake was recrystallized from about 600 ml of xylene in the presence of charcoal. White crystals with a melting point of 144.5°-145.5° C. were obtained.