Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.CS(OC1CCN(C2N=CC(C3CC3)=CN=2)CC1)(=O)=O.[Cl:39][C:40]1[C:41](O)=[CH:42][C:43](=[O:56])[N:44]([C:46]2[CH:51]=[CH:50][C:49]([S:52]([CH3:55])(=[O:54])=[O:53])=[CH:48][C+:47]=2)[CH:45]=1.OC1C(C#N)=CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)C=1>>[Cl:39][C:40]1[C:41]([O:5][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)=[CH:42][C:43](=[O:56])[N:44]([C:46]2[CH:47]=[CH:48][C:49]([S:52]([CH3:55])(=[O:53])=[O:54])=[CH:50][CH:51]=2)[CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CS(=O)(=O)C1=C[C+]=C(n2cc(Cl)c(O)cc2=O)C=C1
Agent: CS(=O)(=O)OC1CCN(c2ncc(C3CC3)cn2)CC1
Agent: CS(=O)(=O)c1ccc(-n2cc(C#N)c(O)cc2=O)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3)cc2Cl)CC1

Procedure:
Example 226 was prepared according to the procedures described in Example 221 substituting tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate for 1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl methanesulfonate, 2-(5-chloro-4-hydroxy-2-oxopyridin-1(2H)-yl)-5-(methylsulfonyl)benzene-1-ylium for 4-hydroxy-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile in Step B. 1H NMR (500 MHz, CDCl3) δ ppm 8.07 (d, J=8.25 Hz, 2 H), 7.61 (d, J=8.80 Hz, 2 H), 7.42 (s, 1 H), 6.03 (s, 1 H), 4.52-4.68 (m, 1 H), 3.57-3.73 (m, 2 H), 3.40-3.56 (m, 2 H), 3.08 (s, 3 H), 1.76-2.02 (m, 4 H), 1.46 (s, 9 H). MS (ESI) 482 (M+H).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]=[C:13]3[CH3:37])[CH:10]=2)[O:5][C:4]([CH3:39])([CH3:38])[CH2:3]1.[H-].[Na+].I[CH3:43].S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[CH3:43][O:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]=[C:13]3[CH3:37])[CH:10]=2)[O:5][C:4]([CH3:38])([CH3:39])[CH2:3]1
Reactant: CI
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(OC)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of 4′-{[1-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.52 g) in N,N-dimethylformamide (5 mL) were added sodium hydride (0.080 g) and iodomethane (0.13 mL), and the mixture was stirred for 1 hr. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.41 g, 77%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:41]=[CH:40][C:32]([C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=1>>[C:36]([NH:35][C:33]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][NH:27][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:41][CH:40]=1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)NC(=O)c1ccc(CN)cc1
Product: CC(C)(C)NC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1

Procedure:
Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.2 g, 0.35 mmol) and 4-aminomethyl-N-tert-butyl-benzamide (0.2 g, 1.06 mmol), to give 6-(4-tert-butylcarbamoyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]1([C:19]2[CH:28]=[C:27]([C:29](O)=[O:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.[NH2:42][CH2:43][CH2:44][CH2:45][CH2:46][N:47]1[C:59]2[C:58]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[N:52]=[C:51]([NH2:60])[C:50]=2[N:49]=[C:48]1[CH2:61][CH2:62][O:63][CH3:64]>ClCCl.N1C=CC=CC=1>[NH2:60][C:51]1[C:50]2[N:49]=[C:48]([CH2:61][CH2:62][O:63][CH3:64])[N:47]([CH2:46][CH2:45][CH2:44][CH2:43][NH:42][C:29]([C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:28]=3)=[O:30])[C:59]=2[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[N:52]=1
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccccc12
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1cc(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Yield: 44.6 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.57 g, 3.0 mmol) was added dropwise to a chilled (0° C.) solution of 2-phenyl-4-quinolinecarboxylic acid (0.5 g, 3.7 mmol), 1-hydroxybenzotriazole (0.5 g, 3.7 mmol), pyridine (2.2 ml), and dichloromethane (20 ml). The reaction was maintained for 15 min followed by the dropwise addition of 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.8 g, 2.55 mmol) in dichloromethane (100 ml). The reaction was maintained at room temperature overnight. The solvent was removed in vacuo and the residue was purified by flash column chromatography (silica gel, 9:1 dichloromethanemethanol). The fractions containing product were combined, washed with saturated aqueous sodium bicarbonate, dried (MgSO4), filtered, and concentrated to provide 0.62 g of N4-[4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenyl-4-quinolinecarboxamide as a yellow crystalline solid, m.p. 118° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.88 (t, J=5.7 Hz, 1H), 8.24-8.21 (m, 2H), 8.13-8.01(m, 4H), 7.83-7.78 (m, 1H), 7.62-7.48 (m, 5H), 7.36 (m, 1H), 7.20 (dt, J=7.6, 1.2 Hz, 1H), 6.54 (broad s, 2H), 4.62 (t, J=7.2 Hz, 2H), 3.83 (t, J=6.7 Hz, 2H), 3.45 (m, 2H), 3.29-3.20 m, 5H), 1.96 (m, 2H), 1.79 (m, 2H); MS (EI) m/e 544.2589 (544.2587 calcd for C33H32N6O2).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:9])[CH2:6][CH2:7][CH3:8].C([O:12][C:13]([C:15]([CH:38]([CH3:40])[CH3:39])=[CH:16][CH:17]1[O:21][C:20]([CH3:23])([CH3:22])[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:18]1[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=O)C.Cl>CCCCCC.C(Cl)(Cl)Cl.ClCCCl>[CH2:5]([NH:9][C:13]([C:15]([CH:38]([CH3:40])[CH3:39])=[CH:16][CH:17]1[O:21][C:20]([CH3:23])([CH3:22])[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:18]1[CH2:31][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:12])[CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)C(=CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1)C(C)C
Reactant: CCCCN
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCCl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)C(=CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1)C(C)C
Temperature: 70 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
The procedure of Poss, M. A. and Reid, J. A. (Tet. Lett. 1992, 33 (11), 1411-14) was used. A 2.0M solution of trimethylaluminum (1.25 mL, 2.5 mmol) in hexane was added to a 1,2-dichloroethane (1.25 mL) solution containing butylamine (0.25 mL, 2.5 mmol) at r.t. and stirred for one h. A 1,2-dichloroethane (1.25 mL) solution containing 5-[2-[(ethoxy)carbonyl]-3-methyl-1-butenyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylic acid, 1,1-dimethylethyl ester (424 mg, 1.0 mmol) was added to the reactants prepared above and heated at 70° C. for 16 h. The reaction was cooled to 0° C., diluted with CHCl3, and treated with 1N HCl. The organic phase was separated and the aqueous phase extracted with CHCl3 (2×). The combined organic extracts were dried (Na2SO4), filtered through MgSO4 and concentrated in vacuo. Silica gel chromatography (5:1 hexane:Et2O) of the concentrate afforded the title compound (408 mg, 88%). MS (ESI) m/e 463 (M-H)-.
Reaction SMILES: [N+](C1C=CC(N(C[C:15]2[C:16](=[O:42])[C:17]3[C:22]([C:23](=[O:41])[C:24]=2CCCCCCCCCCCCCCCC)=[CH:21][CH:20]=[CH:19][CH:18]=3)C(Cl)=O)=CC=1)([O-])=O.ClCCl>N1C=CC=CC=1.C(OCC)(=O)C>[CH:19]1[CH:20]=[CH:21][C:22]2[C:23](=[O:41])[CH:24]=[CH:15][C:16](=[O:42])[C:17]=2[CH:18]=1
Reactant: CCCCCCCCCCCCCCCCC1=C(CN(C(=O)Cl)c2ccc([N+](=O)[O-])cc2)C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C1C=CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
N-4-Nitrophenyl-N-(3-hexadecyl-1,4-naphthoquinonylmethyl)carbamoyl chloride (6.72 g, 11.3 mmol) was dissolved in 10 ml dry pyridine, using a minimum quantity of dichloromethane to aid in dissolution. The dye (as the methylsulfamoyl form) ##STR8## (4.2 g, 4.72 mmol) was then added and the resulting solution was stirred at room temperature overnight. The mixture was then diluted with ethyl acetate, extracted with 2N hydrochloric acid, dried with anhydrous magnesium sulfate, and filtered. The ethyl acetate was removed in vacuo and the residue was dissolved in 20 percent ethyl acetate in toluene. This solution was passed through a short column of silica gel, eluting first with 20 percent ethyl acetate in toluene to remove some impurities, then with 30 percent ethyl acetate in toluene. This second elutant was concentrated under reduced pressure to yield the crude product (60 percent).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.O=S(Cl)Cl.[CH3:11][NH:12][C:13]1[C:14]([I:27])=[C:15]([C:24]([Cl:26])=[O:25])[C:16]([I:23])=[C:17]([C:21]=1[I:22])[C:18]([Cl:20])=[O:19]>CC(N(C)C)=O>[CH3:1][O:2][CH2:3][C:4]([N:12]([C:13]1[C:21]([I:22])=[C:17]([C:18]([Cl:20])=[O:19])[C:16]([I:23])=[C:15]([C:14]=1[I:27])[C:24]([Cl:26])=[O:25])[CH3:11])=[O:6]
Reactant: COCC(=O)O
Reactant: CNc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: COCC(=O)N(C)c1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reaction time: 0.5 h

Procedure:
30 ml. (400 mmol) of methoxyacetic acid is dissolved in 100 ml. of DMA, cooled to 0° C., and 29 ml. (400 mmol) of SOCl2 is added dropwise. The mixture is stirred for 30 minutes at this temperature, a solution of 61 g. (100 mmol) of 5-methylamino-2,4,6-triiodoisophthalic acid dichloride in 200 ml. of DMA is added dropwise thereto, and the reaction solution is stirred for 20 hours at room temperature. Then, the solution is stirred into 4 l. of water, the precipitate is vacuum-filtered, dissolved in 2 l. of ethyl acetate, successively extracted with respectively 250 ml. of saturated bicarbonate solution, saturated sodium chloride solution, and water; the ethyl acetate phase is dried over Na2SO4 and evaporated. Yield: 61.4 g. (90 mmol)=90% of theory.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(-c3ccncc3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (100 mg, 0.191 mmol) in 1,4-dioxane (2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (58.7 mg, 0.286 mmol), bis(triphenylphosphine)palladium(II) chloride (13.40 mg, 0.019 mmol), potassium carbonate (79 mg, 0.573 mmol) and water (1 mL). The reaction mixture was heated at 100° C. in a microwave for 15 min (×2) and then for 30 min (×1). Another portion of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (58.7 mg, 0.286 mmol) and additional bis(triphenylphosphine)palladium(II) chloride (13.40 mg, 0.019 mmol) were added and heating continued, at 100° C. in a microwave, for another 15 min. The solvent was then removed in vacuo and the residue dissolved in ethyl acetate (30 mL) and washed with water (30 mL). The aqueous phase was re-extracted with ethyl acetate (30 mL×2). All organic phases were combined, dried over MgSO4, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane and then further purified using MDAP (acidic conditions), to give the title compound (37 mg). LCMS (A) m/z: 520 [M−1]−, Rt 1.22 min (acidic).
Reaction SMILES: [BH4-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5](C=O)[CH:4]=1.[CH3:15][OH:16]>>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:15][OH:16])[CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cccc2cccnc12
Yield: 75 %

Procedure:
Sodium borohydride (280 mg, 7.4 mmol) was added in portions to a solution of 3-quinoline-carboxaldehyde (1.06 g, 6.7 mmol) in methanol at room temperature. Reaction was quenched after 3 hours stirring with 10 mL (aq) sat. NH4Cl. Mixture was extracted with ethyl acetate (3×30 ml). Combined organics were washed with brine and dried over MgSO4. Crude material was purified by chromatography using (20-40% EA/Hex gradient) to afford quinolin-8-yl-methanol as an off white solid (800 mg; 75% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Cl:12][S:13](O)(=[O:15])=[O:14].S(Cl)(Cl)=O>>[Cl:12][S:13]([C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Reaction time: 8 h
Yield: 94 %

Procedure:
Commercially available 2-methoxybenzoic acid (15.2 g, 0.1 mol) was added portionwise to chlorosulphonic acid (52.43 g) over 30 min with ice cooling. Thionyl chloride (11.9 g, 0.1 mol) was added and the reaction stirred overnight. The reaction was quenched onto ice/water (250 g/65 ml) and the precipitated product granulated for 1 hr, filtered, water washed and oven dried to give the title compound (23.56 g, 93.9%) as a white solid with m.p. 138-140° C. δ (CDCl3): 4.18 (3H, s), 7.23 (1H, d), 8.21 (1H, d), 8.78 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccccc1Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4Cl)nc23)CC1
Yield: 92.4 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0067 mL (0.053 mMol) 2-chlorobenzoyl chloride, 0.015 gm (91%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][N:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:18]1[CH:17]=[N:16][C:15]([Cl:14])=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1ccc(Cl)nc1

Procedure:
A 950 mg (5.1 mmol) sample of 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol, prepared as in Example 7b above, and 550 mg (4.25 mmol) of 2-chloro-5-hydroxypyridine were reacted with triphenylphosphine and DEAD (5.1 mmol each) in 20 mL of THF according to the procedure of Example 14a, to give 1.09 g of the title compound. MS (DCI/NH3) m/e: 299/301 (M+H)+. 1H NMR (DMSO-d6, 300 MHz) δ: 8.14 (d, J=3.3 Hz, 1H), 7.48 (dd, J=8.8, 3.3 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 4.47-4.42 (m, 1H), 4.36 (dd, J=11.0, 4.4 Hz, 1H), 4.20 (dd, J=11.0, 3.3 Hz, 1H), 3.77 (t, J=7.7 Hz, 2H), 2.36-2.29 (m, 1H), 2.19-2.12 (m, 1H), 1.36 (s, 9H). [α]D25 =-67.3° (c=1.1, CHCl3).
Reaction SMILES: C1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([F:19])=[C:14](F)[C:15]=3[F:17])[C:10](=[O:20])[C:9]([C:21]([OH:23])=[O:22])=[CH:8]2)CCCCC1.C(NCC1CCNC1)C>C(#N)C>[F:19][C:13]1[CH:12]=[C:11]2[C:16](=[C:15]([F:17])[CH:14]=1)[NH:7][CH:8]=[C:9]([C:21]([OH:23])=[O:22])[C:10]2=[O:20]
Reactant: O=C(O)c1cn(C2CCCCC2)c2c(F)c(F)c(F)cc2c1=O
Agent: CCNCC1CCNC1
Solvent: CC#N
Product: O=C(O)c1c[nH]c2c(F)cc(F)cc2c1=O

Procedure:
To 0.80 g (2.46 mmol) of 1-cyclohexyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 15 ml of acetonitrile was added 0.37 g (2.46 mmol) of 1,8-diazobicyclo[5.4.0]undec7-ene and 0.33 g (2.58 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for one hour, cooled, filtered, and the solids washed with ether to give 0.86 g of 1-cyclohexyl-7-[3-(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 194°-196° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](OCC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl.O>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH2:16][OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2c(Cl)cccc2-n2cnc(CO)c2[C@@H]2CCN12

Procedure:
A suspension of 13.3 g (40 mmol) of ethyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate in 85 ml of tetrahydrofuran is heated to 50° and a suspension of 1.06 g (48.7 mmol) of lithium borohydride in 15 ml of tetrahydrofuran is then added dropwise to the solution obtained. The white suspension is subsequently heated to boiling under reflux for 70 minutes. The mixture is cooled to 20° and 54 ml of a solution consisting of 27 ml of conc. hydrochloric acid and 27 ml of water is added dropwise thereto. The tetrahydrofuran is distilled off in vacuo and the aqueous residue is made alkaline with 25 percent ammonia. The mixture is left to crystallize in an ice-bath for 1 hour, the precipitated material is filtered off under suction, rinsed with water and dried at 80° in a high vacuum. There is obtained (S)-8-chloro-12,12 a-dihydro-1-(hydroxymethyl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of decomposition point 256°-258°.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[CH:39]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:40]([O:42][CH3:43])=[O:41]>CN(C=O)C>[C:44]1([CH:39]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)[C:40]([O:42][CH3:43])=[O:41])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Yield: 86.4 %

Procedure:
A mixture of intermediate (6) (0.023 mole) and Na2CO3 (0.023 mole) in DMF (150 ml) was stirred. Methyl α-bromo-α-phenylacetate (0.023 mole) was added dropwise. The mixture was stirred overnight. The solvent was evaporated. The residue was dissolved in DCM. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 11.4 g of methyl α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-1-piperazineacetate identified as compound No. 40 in the following table F-1.
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].P(Br)(Br)[Br:20]>N1C=CC=CC=1.C(OCC)C>[Br:20][CH2:1][C:2]#[C:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: BrP(Br)Br
Reactant: CCCCCCCCC#CCC#CCC#CCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCC#CCC#CCC#CCBr

Procedure:
A mixture of 5 g of 2,5,8-heptadecatriyn-1-ol, one drop of pyridine and 2 g of phosphorus tribromide in 20 cm3 of ethyl ether is heated under reflux for 3 hours. The ether phase is then washed initially with sodium bicarbonate and then with water, and then dried over magnesium sulphate.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH2:23][CH2:24][NH:25]4)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[H-].[Na+].[C:34](Cl)(=[O:36])[CH3:35].O>CN(C=O)C>[C:34]([N:25]1[C:26]2[C:22](=[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=4)[O:20][N:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:23][CH2:24]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCc2c(-c3noc(-c4ccc(OC(C)C(F)(F)F)c(C(F)(F)F)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}indoline (100 mg) in DMF (1.0 ml) was added 60% NaH (10.9 mg) at 0° C., followed by stirring at room temperature for 0.5 hour. Acetyl chloride (24.1 μl) was added thereto at 0° C., followed by stirring at room temperature for 3 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, n-hexane:EtOAc=90:10 to 60:40) to obtain 1-acetyl-4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}indoline (56.8 mg) as a white crystal.