Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH:18]=[C:17]([C:19]2[C:20]([C:47]([O:49]C(C)(C)C)=[O:48])=[N:21][C:22]([N:25]3[CH2:34][CH2:33][C:32]4[C:27](=[C:28]([C:35](=[O:46])[NH:36][C:37]5[S:38][C:39]6[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=6[N:41]=5)[CH:29]=[CH:30][CH:31]=4)[CH2:26]3)=[CH:23][CH:24]=2)[CH:16]=[N:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.CO>[S:38]1[C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=[C:37]1[NH:36][C:35]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:27]=1[CH2:26][N:25]([C:22]1[N:21]=[C:20]([C:47]([OH:49])=[O:48])[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:1]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:18]=3)=[CH:24][CH:23]=1)[CH2:34][CH2:33]2)=[O:46]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1cnn(C(c2ccccc2)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ccc(-c3cnn(C(c4ccccc4)c4ccccc4)c3)c(C(=O)O)n1)CC2

Procedure:
A suspension of EXAMPLE 75B (30 mg) and lithium hydroxide (2 mg) in tetrahydrofuran and methanol (2:1, 1 mL) was heated at 60° C. for 16 hours. The reaction mixture was quenched with HCl (0.2 mL, 1M), concentrated and purified by chromatography on silica gel using 0-5% methanol/dichloromethane as eluent to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 13.14 (s, 1H), 12.87 (s, 1H), 8.04 (d, 1H), 7.82 (s, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.66 (s, 1H), 7.61 (d, 1H), 7.44-7.51 (m, 1H), 7.40-7.44 (m, 1H), 7.29-7.40 (m, 5H), 7.19 (d, 4H), 6.93 (t, 2H), 4.94 (s, 2H), 3.94 (s, 1H), 3.86 (t, 2H), 2.99 (t, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][SH:16].[Na].O>CN(C)C=O>[CH3:15][S:16][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CS
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1SC
Reaction time: 0.5 h

Procedure:
To a solution of 10.02 g of methyl 2-chloro-5-nitrobenzoate dissolved in 100 ml of N,N-dimethylformamide, was added 23.92 g of a 15% aqueous solution of sodium methylmercaptan dropwise under ice cooling. The mixture was stirred for 30 minutes. Water was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The crude product obtained by removal of the solvent under reduced pressure was recrystallized from ethyl acetate—hexane, to yield 8.76 g of methyl 2-methylthio-5-nitrobenzoate (melting point: 126.5-127.5° C.) (Reaction Scheme (42) described below).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH2:11][CH2:12][N:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:25])[C:15]([C:26]([OH:28])=O)=[CH:14]1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[NH2:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]2[C:64]([NH2:85])=[N:65][CH:66]=[C:67]([C:69]3[CH:74]=[CH:73][C:72]([O:75][CH2:76][C@H:77]4[CH2:82][O:81][CH2:80][CH2:79][O:78]4)=[C:71]([O:83][CH3:84])[CH:70]=3)[CH:68]=2)=[CH:59][CH:58]=1>CN(C=O)C.O>[NH2:85][C:64]1[C:63]([C:60]2[CH:59]=[CH:58][C:57]([NH:56][C:26]([C:15]3[C:16](=[O:25])[C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:18][N:13]([CH2:12][CH2:11][F:10])[CH:14]=3)=[O:28])=[CH:62][CH:61]=2)=[CH:68][C:67]([C:69]2[CH:74]=[CH:73][C:72]([O:75][CH2:76][C@H:77]3[CH2:82][O:81][CH2:80][CH2:79][O:78]3)=[C:71]([O:83][CH3:84])[CH:70]=2)=[CH:66][N:65]=1
Reactant: COc1cc(-c2cnc(N)c(-c3ccc(N)cc3)c2)ccc1OC[C@H]1COCCO1
Reactant: O=C(O)c1cn(CCF)cc(-c2ccccc2)c1=O
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc(N)c(-c3ccc(NC(=O)c4cn(CCF)cc(-c5ccccc5)c4=O)cc3)c2)ccc1OC[C@H]1COCCO1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
DIPEA (60 μl) was added to a solution of the compound obtained in Step 2 of Example 19 (50 mg) and COMU (96 mg) in DMF (3.0 ml) at room temperature, and the mixture was stirred for one hour. The compound obtained in Step 1 of Example 42 (70 mg) was added at room temperature. The mixture was stirred for five hours, followed by the addition of water. The organic layer was extracted with ethyl acetate, and then washed with water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=19:1->9:1 (v/v)] to give 87 mg of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:5]=[CH:6][C:7]=1[F:8].CO.[OH-].[Na+].Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(F)c(Br)c3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(F)c(Br)c2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.1 %

Procedure:
To methyl 4-[(2-{1-[5-(3-bromo-4-fluorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.051 mmol, 24.9 mg), methanol (2.5 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.255 mL) was added at room temperature. After 10 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.255 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was dried to give the desired product as a yellow solid (9.0 mg, yield 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:36](Br)[CH:37]=[CH2:38]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[CH:21]([CH2:38][CH:37]=[CH2:36])[C:22]([O:24][CH3:25])=[O:23]
Reactant: C=CCBr
Reactant: COC(=O)Cc1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)OC)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-(4-(2,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (60 mg, 0.179 mmol) in tetrahydrofuran (THF) (2 mL) was treated with LiHMDS (0.358 mL, 0.358 mmol) and allyl bromide (0.232 mL, 2.68 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The combined extracts were washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated. The material was used crude in the next step (64 mg, 95%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.44-8.54 (m, 1 H) 7.41-7.56 (m, 2 H) 7.06-7.19 (m, 2 H) 6.97-7.05 (m, 1 H) 6.80-6.91 (m, 1 H) 5.40-5.70 (m, 1 H) 4.85-5.06 (m, 2 H) 3.89-4.05 (m, 1 H) 3.68 (s, 3 H) 3.53 (s, 3 H) 2.91-3.06 (m, 1 H) 2.43-2.55 (m, 1 H) 2.41 (s, 3 H) 2.03 (s, 3 H). LC/MS (m/z) ES+=376 (M+1).
Reaction SMILES: CO.[Cl:3][C:4]1[CH:5]=[C:6]([C:27]2[C:28]([CH3:42])=[CH:29][C:30]([O:33][CH2:34][C:35]([CH3:41])([CH3:40])[C:36]([O:38]C)=[O:37])=[N:31][CH:32]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1.[OH-].[Na+].Cl>C(OCC)(=O)C.O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:27]2[C:28]([CH3:42])=[CH:29][C:30]([O:33][CH2:34][C:35]([CH3:40])([CH3:41])[C:36]([OH:38])=[O:37])=[N:31][CH:32]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:14]=1
Reactant: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)c(Cl)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 104.3 %

Procedure:
Methanol (1.5 mL) and tetrahydrofuran (1.5 mL) were added to methyl 3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (274 mg), and after adding 2N aqueous sodium hydroxide solution (1.5 mL) to the mixture, the resulting mixture was stirred 50° C. for 2 hours. Ethyl acetate was added to the reaction mixture, and the resulting mixture was neutralized by 1N hydrochloric acid. The organic layer was separated, washed with a saturated brine, and concentrated under reduced pressure to obtain 3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid (279 mg).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][CH:9]([CH:12]([OH:17])[CH:13]([CH3:16])[CH:14]=[CH2:15])[CH:10]=[CH2:11].[N+]([C:21]1[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[C:22]=1[C:29]#[N:30])([O-])=O>C1(C)C=CC=CC=1.O>[CH3:8][CH:9]([CH:12]([O:17][C:21]1[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[C:22]=1[C:29]#[N:30])[CH:13]([CH3:16])[CH:14]=[CH2:15])[CH:10]=[CH2:11]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: C=CC(C)C(O)C(C)C=C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(C)C(Oc1cccc(C#N)c1C#N)C(C)C=C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
9.6 g (0.24 mol) of 60% sodium hydride and 150 ml of N,N-dimethylformamide were placed in a container equipped with a stirrer, a reflux condenser and a nitrogen-introducing tube, and the solution was then stirred under the feed of nitrogen. Afterward, 35 g (0.25 mol) of 3,5-dimethyl-1,6-heptadiene-4-ol was added dropwise thereto at 20°-30° C. over 1 hour, and the solution was then stirred at the same temperature for 3 hours to prepare a sodium alcoholate solution. Next, 34.6 g (0.2 mol) of 3-nitrophthalonitrile and 150 ml of N,N-dimethylformamide were placed in a container equipped with a stirrer, and the above-mentioned sodium alcoholate solution was added dropwise thereto at 0° C. or less over 5 hours. After completion of the addition, the temperature of the solution was raised up to a level of 20°-30° C., and the solution was then stirred for 3 hours to bring reaction to an end. The thus obtained reaction solution was poured into 3 l of water and then stirred for 30 minutes, and 500 ml of toluene were added. After stirring for 30 minutes, the resulting toluene layer was separated. After toluene was distilled off under reduced pressure, recrystallization was carried out from 600 ml of n-hexane to obtain 44.7 g of 3-(3,5-dimethyl-1,6-heptadiene-4-oxy)phthalonitrile (yield=84.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][S:12]([CH:15]([CH:20]([CH3:22])[CH3:21])[C:16](OC)=[O:17])(=[O:14])=[O:13])[N:4]=1.C([NH2:25])=O.C[O-].[Na+].Cl>CN(C)C=O.O.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][S:12]([CH:15]([CH:20]([CH3:22])[CH3:21])[C:16]([NH2:25])=[O:17])(=[O:14])=[O:13])[N:4]=1
Reactant: COC(=O)C(C(C)C)S(=O)(=O)Nc1nc(OC)cc(OC)n1
Reactant: NC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(NS(=O)(=O)C(C(N)=O)C(C)C)n1
Temperature: 100 °C

Procedure:
A solution of the product of Example 1 (3.0 g) and formamide (1.22 g) in dimethylformamide (10 ml) was heated to 80° C. Sodium methoxide (3.3 ml of a 25% w/v methanol solution) was slowly introduced with stirring. The reaction mixture was maintained at about 100° C. for 4 hours prior to addition to water (150 ml) and acidification (hydrochloric acid). The product was extracted into ethyl acetate, the ethyl acetate solution being washed with water (twice), dried over magnesium sulfate and run down under vacuum. The residual oil was triturated with a mixture of diethyl and diisopropyl ethers to yield a white solid. The solid was washed thoroughly with the ether mixture and dried. The yield was 1.1 g (39%), mp 147°-50° C.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:10][CH:11]=2)[S:4]1(=[O:6])=[O:5].[Na].[C:24]1([N:30]2[C:34]([SH:35])=[N:33][N:32]=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ClCCl.CC(C)=O>C(C(C)=O)C>[C:24]1([N:30]2[C:34]([S:35][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:10][CH:11]=4)[S:4]3(=[O:6])=[O:5])=[N:33][N:32]=[N:31]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: [Na]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCC(C)=O
Product: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(CSc1nnnn1-c1ccccc1)C2=O
Yield: 84021.1 %

Procedure:
By a method similar to that of Example 44 condensation of 2-chloromethyl-6-[2-(2-methoxyethoxy)-ethoxy]saccharin (34 g.) and 1-phenyltetrazol-5-thiol sodium salt (0.19 g) in methyl ethyl ketone at 60° C. and purification of the product (470 mg) by column chromatography on silica gel first with dichloromethane and then with dichloromethane-acetone (up to 97:3) as eluant afforded 2-(1-phenyltetrazol-5-yl)thiomethyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin as an oil (390 g, 82% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13](=[O:15])[CH3:14].[OH-].[K+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl>CS(C)=O.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:1]([CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[F:18])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13](=[O:15])[CH3:14]
Reactant: Fc1ccccc1CCl
Reactant: CC(=O)c1c(C)nc2ccccc2c1N
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1c(C)nc2ccccc2c1N(Cc1ccccc1F)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-amino-2-methyl-3-quinolinyl)-ethanone in dimethylsulfoxide (150 ml) was added to a stirred slurry of pulverized 85% potassium hydroxide (7 g) in dimethylsulfoxide (40 ml). This mixture was stirred at ambient temperature for twenty minutes, and thereafter a solution of o-fluorobenzylchloride (15.2 g) in dimethylsulfoxide (40 ml) was added dropwise. The mixture was stirred for two hours and allowed to stand overnight at room temperature. Thereafter, it was then poured onto ice and diluted with water to form a tacky lump. This was allowed to stand for fifteen minutes, and the aqueous dimethylsulfoxide was decanted. The tacky precipitate was dissolved in dichloromethane, washed with water (3x) and saturated sodium chloride solution, and dried over sodium sulfate. Removal of the sodium sulfate by filtration and the solvent by evaporation gave 26.5 g of viscous oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](OCC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)C>O1CCCC1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH:11]=[O:12]
Reactant: CCOC(=O)c1cnc2ccccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=Cc1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
A solution of ethyl 2-quinoxalinecarboxylate (10-1) (2.34 g, 11.6 mmol) in tetrahydrofuran (22 mL) was cooled to −78° C. This solution was treated with a 1.0 molar THF solution of lithium aluminum hydride (5.80 mL, 5.80 mmol) added over a period of 6 min. After 30 min, the reaction was quenched with glacial acetic acid (1.30 mL, 22.71 mmol). The reaction mixture was warmed to room temperature and diluted with water (14 mL). The water was extracted five times with ethyl acetate and the combined organics washed with brine and dried (Na2SO4). The solvent was removed in vacuo. Preparative centrifugal TLC (SiO2, 5 mm, CH2Cl2) afforded solid 10-2 (874 mg).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[C:38](=[O:42])[NH:37][CH2:36]3)O1>>[O:42]=[C:38]1[C:39]2[C:35](=[CH:34][C:33]([C:2]3[N:7]4[N:8]=[CH:9][N:10]=[C:6]4[C:5]([NH:11][CH:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)=[N:4][CH:3]=3)=[CH:41][CH:40]=2)[CH2:36][NH:37]1
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)n3ncnc23)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3ccc4c(c3)CNC4=O)n3ncnc23)CC1

Procedure:
Prepared from the product of Step 1 and Intermediate 4 (5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one) using the procedure described in Example 1, Step 2. 1H-NMR (400 MHz, d6-DMSO) =1.45 (s, 9H), 1.61-1.65 (m, 2H), 1.88-1.95 (m, 2H), 2.82-2.99 (brm, 2H), 3.99-4.04 (m, 2H), 4.27-4.38 (brm, 1H), 4.50 (s, 2H), 7.81 (d, 1H, J=8), 7.92 (s, 1H), 8.03-8.11 (m, 2H), 8.18 (s, 1H), 8.63 (s, 1H), 8.67 (s, 1H). LCMS: Rt 3.07 min (98.3%), m/z (APCI) 450 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>>[ClH:1].[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:3]=[C:2]2[NH:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25])([O-:14])=[O:13]
Reactant: NCC(O)CO
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccccc3)cc(Cl)c2c1
Product: Cl
Product: O=[N+]([O-])c1ccc2nc(-c3ccccc3)cc(NCC(O)CO)c2c1

Procedure:
(RS)-3-(6-Nitro-2-phenyl-quinolin-4-ylamino)-propane-1,2-diol hydrochloride was prepared according to the general procedure described in example 1 from 4-chloro-6-nitro-2phenyl-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[F:21])[NH2:17]>>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:9]2[C:4]3[CH:3]=[C:2]([CH3:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1cc2c(=O)[nH]cnc2cn1
Product: Cc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cn1
Product: Cl

Procedure:
This product was prepared from 6-methyl-pyrido[3,4-d]pyrimid-4-one (1.0 eq.) and 3-chloro-4-fluoro-aniline (1.5 eq.) according to the procedure described for Example 61. The crude product from the filtrate was chromatographed on silica using a gradient of 0% to 10% methanol/methylene chloride to afford the free base of the title product which was converted to the title product as described for Example 60 (47%; M.P. 251-258° C.; LC-MS: 289, 291 (MH+); anal. RP-HPLC:4.18 min.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([N+:15]#[C-])[C:6]([CH3:14])([CH3:13])[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH3:2].Cl.[OH-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH2:15])[C:6]([CH3:14])([CH3:13])[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH3:2]
Reactant: [C-]#[N+]C(C(=O)OCC)C(C)(C)C(=O)OCC=C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCOC(=O)C(C)(C)C(N)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3-Isocyano-2,2-dimethyl-succinic acid 1-allyl ester 4-ethyl ester (3.75 g, 15.5 mmol) is dissolved in methanol the mixture is cooled to 0° C. with an ice bath. To this is added, dropwise, 37% aqueous hydrochloric acid (1.58 g). The reaction is stirred 20 minutes and neutralized with 1 M aqueous sodium hydroxide. The volatiles are removed under vacuum and then the product is extracted into ethyl acetate (2×) and washed with water (2×). The combined organic phases are dried over sodium sulfate and evaporated to give 3-amino-2,2-dimethyl-succinic acid 1-allyl ester 4-ethyl ester as a yellow oil.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH3:32])[C:25]([C:33]([O:35]C)=[O:34])=[CH:24][C:23]=5[C:22]4=[O:37])[CH2:17][CH2:16]3)[C:11]([O:38][CH2:39][CH3:40])=[CH:10][C:9]=2[C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH3:32])[C:25]([C:33]([OH:35])=[O:34])=[CH:24][C:23]=5[C:22]4=[O:37])[CH2:17][CH2:16]3)[C:11]([O:38][CH2:39][CH3:40])=[CH:10][C:9]=2[C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)[CH2:6][CH2:7]1
Reactant: CCOc1cc(-c2ccc(F)cc2)c(C2CC2)cc1CN1CCC(N2CCc3nc(CC)c(C(=O)OC)cc3C2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(-c2ccc(F)cc2)c(C2CC2)cc1CN1CCC(N2CCc3nc(CC)c(C(=O)O)cc3C2=O)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (2 mL)-THF (2 mL) solution of methyl 6-(1-((2-cyclopropyl-5-ethoxy-4′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (260 mg), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the mixture was concentrated. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (ethanol/hexane) to obtain the title compound (149 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([OH:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].F[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([O:28][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccccn1
Reactant: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC1CCCCC(Oc2ccccn2)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 138, 4-(7-chloro-4-quinolinyl)-N-(3-hydroxycycloheptyl)-1-piperazinecarboxamide, NaH, and 2-fluoropyridine are reacted to give the product after flash chromatography with CH2Cl2-MeOH. LC-MS: 480 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.05 (s, 1H), 8.0 (m, 2H), 7.60 (m, 1H), 7.45 (d, 1H), 6.85 (m, 2H), 6.75 (d, 1H), 6.05 (d, 1H), 5.20 (m, 1H), 4.10 (m, 1H), 3.75 (m, 4H), 3.25 (m, 4H), 2.28 (m, 1H), 2.10 (m, 3H), 1.85 (m, 2H), 1.70 (m, 1H), 1.40–1.60 (m, 3H).