Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10](CC#N)[CH:9]=2)=[CH:4][CH:3]=1.Cl.[Li+].[OH-:28].[CH2:29]([OH:31])[CH3:30]>O>[NH2:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][C:10]([CH2:30][C:29]([OH:28])=[O:31])=[N:11]2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CCO
Reactant: N#CCc1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2nc(CC(=O)O)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 4-[5-(4-chlorophenyl)-3-(cyanomethyl)-1H-pyrazol-1-yl]benzenesulfonamide from step 2 (0.340 g, 3.594 mmol) in ethanol (250 mL) at −10° C., HCl gas was added via a fritted gas inlet tube over 6 hours. The reaction mixture was concentrated in vacuo yielding an oil. The oil was dissolved in 50 mL of ethanol and 15 mL of water, treated with LiOH until the pH was 12, and stirred at room temperature overnight. The reaction was concentrated in vacuo, diluted with water, acidified with dil HCl, and extracted with ethyl acetate. The ethyl acetate phase was dried over anhydrous MgSO4, filtered and concentrated yielding [[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]acetic acid as a brown solid (1.072 g, 76%): mp 120-122° C. High resolution mass spectrum Calc'd. for C17H15ClN3O4S (M+H): 392.0472. Found: 392.0467. 1H NMR (CDCl3 and CD3CO2D) 7.84 (d, J=8.66 Hz 2H), 7.37 (d, J=8.66 Hz, 2H), 7.31 (d, J=8.66 Hz, 2H), 7.15 (d, J=8.66 Hz, 2H), 6.54 (s, 1H), 3.84 (s, 2H)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:23])[CH:8]=2)[N:3]=1.[C:24]([Cl:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(NC(C)C)(C)C>ClCCl.[OH-].[Na+]>[ClH:32].[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(N)ccc2n1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(NC(=O)c3ccccc3)ccc2n1
Product: Cl
Yield: 29.3 %

Procedure:
2-Methyl-6-amino-4-(3-phenylpyrrolidin-1-yl)quinoline (0.07 g; see Example 45 below), benzoyl chloride (0.035 g) and diisopropylamine (0.065 g) was stirred in dichloromethane (3 mL). The reaction mixture was diluted with 1 N sodium hydroxide and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated to give a brown oil. The residue was purified by chromatography on silica eluting with a mixture of dichloromethane, and methanol. The desired fractions were concentrated, after which hydrochloric acid was added and the sample evaporated to dryness. Trituration from ether gave the title compound as a white solid (0.03 g).
Reaction SMILES: Br.[N:2]1([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.O>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:17]=[C:16]4[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]4)=[CH:10][CH:9]=3)[CH2:3][CH2:4]2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C1CCc2ccc(N3CCNCC3)cc2N1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2ccc(N3CCN(C(=O)c4ccc(Cl)cc4)CC3)cc2N1
Yield: 73.9 %

Procedure:
To a solution of 800 mg of 7-(1-piperazinyl)-3,4-dihydrocarbostyril hydrobromide in 10 ml of DMF was added 1.2 ml of triethylamine, and then a solution of 730 mg of 4-chlorobenzoyl chloride in 2 ml of DMF was added dropwise to the mixture while stirring. After completion of addition, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a large amount of water. Crystals which formed were collected by filtration, washed with water and dried. The crystals were purified through silica gel column chromatography and recrystallized from chloroform-methanol to give 700 mg of 7-[4-(4-chlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 289°-291° C., colorless powders.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH:24](OCC)[C:23]3[CH:22]=[C:21]4[CH:28]=[CH:29][CH:30]=[CH:31][C:20]4=[CH:19][C:18]=3[C:17]2=[O:32])=[O:8])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[C:17](=[O:32])[C:18]3[CH:19]=[C:20]4[CH:31]=[CH:30][CH:29]=[CH:28][C:21]4=[CH:22][C:23]=3[CH2:24]2)=[O:8])=[CH:33][CH:34]=1
Reactant: CCOC1c2cc3ccccc3cc2C(=O)N1c1ccccc1NC(=O)c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2N2Cc3cc4ccccc4cc3C2=O)cc1
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a solution of N-(4-methoxybenzoyl)-2-(1-ethoxy-1,3-dihydro-3-oxo-2H-benz[f]isoindol-2-yl)benzeneamine (140 mg, 0.31 mmol) in methylene chloride (2 mL) was added triethylsilane (0.5 mL) and trifluoroacetic acid (0.5 mL). After standing at room temperature for 16 h, the mixture was concentrated in vacuo. The residue was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, dried (magnesium sulfate), filtered, and concentrated in vacuo to yield 120 mg (95%) of the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([N:22]3[C:27](=[O:28])[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=5)=[CH:32][CH:31]=4)=[C:25]([O:44][CH2:45][CH3:46])[N:24]=[C:23]3[CH3:47])=[CH:21][C:16]=2[CH2:15][CH2:14]1>C(OCC)(=O)C>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([N:22]3[C:27](=[O:28])[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[C:42]5[NH:3][C:4](=[O:7])[O:5][N:43]=5)=[CH:32][CH:31]=4)=[C:25]([O:44][CH2:45][CH3:46])[N:24]=[C:23]3[CH3:47])=[CH:21][C:16]=2[CH2:15][CH2:14]1
Reactant: CCOc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.47 g), sodium hydrogen carbonate (0.76 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[1-(2,3-dihydro-1-benzofuran-5-yl)-4-ethoxy-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.21 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.088 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.074 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then 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 as colorless crystals (0.083 g, 35%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C:13]#[N:14].[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:15][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C:13]#[N:14]
Reactant: Cc1cc2ccccc2c(O)c1C#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(C#N)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
The suspension of 1-hydroxy-3-methyl-2-naphthonitrile (47.23 g), potassium carbonate (71.3 g), iodomethane (100 ml), and DMF (250 ml) was-stirred overnight at ambient temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. The residue was recrystallized from water/methanol to give the titled compound (50 mg).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:38][C:39]1[CH:40]=[C:41]([NH2:45])[CH:42]=[N:43][CH:44]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:45][C:41]5[CH:42]=[N:43][CH:44]=[C:39]([F:38])[CH:40]=5)=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1cncc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3cncc(F)c3)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.5 %

Procedure:
A solution of the product of Example 19C (259 mg, 0.488 mmol) in anhydrous tetrahydrofuran (5 mL) was treated with the product of Example 224C (60.2 mg, 0.537 mmol) and diisopropylethylamine (0.128 mL, 0.732 mmol), and stirred at room temperature under a nitrogen atmosphere for 15 hours. The solvent was removed by rotary evaporation in vacuo, and the residue was taken up in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (25 mL), water (2×25 mL), and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with 3% methanol/methylene chloride provided the title compound as a yellow solid (176 mg, 60%).
Reaction SMILES: O[C:2]1[C:11]2C(=C(C(F)(F)F)C=CC=2)N=C(C(O)CC)[C:3]=1C(NC1SC=CN=1)=O.[C:28]([OH:41])(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[C:28]([O:41][CH2:3][CH2:2][CH3:11])(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CCC(O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Product: CCCCCCCCCCCC(=O)OCCC

Procedure:
Using the procedure of Example 15, 5 g of 4-hydroxy-2(1-hydroxypropyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide and 2.8 g of lauric acid were reacted to obtain 6 g of 1-[4-hydroxy-3-(2-thiazolylamino)-carbonyl]-8-(trifluoromethyl)-2quinolinyl]-propyl dodecanoate melting at 158° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:13][N:12]([C:14]([C:16]3[O:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)=[O:15])[CH2:11]2)=[CH:5][CH:4]=1.S(Cl)([Cl:29])=O>ClCCl>[Cl:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:13][N:12]([C:14]([C:16]3[O:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)=[O:15])[CH2:11]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CO)cc2)C1
Solvent: ClCCl
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CCl)cc2)C1
Yield: 80.2 %

Procedure:
Intermediate 60A (3.48 g, 9.47 mmol) was dissolved in dichloromethane (150 mL) and the mixture was cooled in an ice bath. While stirring, thionyl chloride (0.76 mL, 10.4 mmol) was added dropwise. The cooling bath was removed after 30 min. The mixture was stirred for 2.5 h and then evaporated to dryness. The residue was purified by column chromatography eluting with dichloromethane. There was obtained 2.93 g (80%) of 60B as a solid. 1H NMR (500 MHz, CDCl3): δ 4.22 (m, 2H), 4.57 (s, 2H), 4.65 (m, 2H), 5.14 (m, 1H), 7.29 (d, 2H), 7.36 (d, 2H), 7.53 (t, 2H), 7.59 (t, 1H), 8.16 (d, 2H), MS (APCI+) m/z 386 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[CH:11]1([NH:10][C:6]2[C:7]([CH:8]=[O:9])=[C:2]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[F:16])[N:3]=[C:4]([S:14][CH3:15])[N:5]=2)[CH2:13][CH2:12]1
Reactant: OB(O)c1ccccc1F
Reactant: CSc1nc(Cl)c(C=O)c(NC2CC2)n1
Product: CSc1nc(NC2CC2)c(C=O)c(-c2ccccc2F)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-cyclopropylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.66 (m, 2H), 0.92 (m, 2H) 2.60 (s, 3H), 3.11 (m, 1H), 7.10-7.30 (m, 2H), 7.41-7.57 (m, 2H), 9.10 (br s, 1H), 9.66 (s, 1H). LC MS (m/e)=304 (MH+).
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH2:26][CH2:27][CH2:28][NH2:29]>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH2:26][CH2:27][CH2:28][NH:29][C@H:4]1[CH2:5][CH2:6][C@H:1]([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: NCCCc1ccc(F)cc1F
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4F)CC3)cc2o1

Procedure:
Coupling of ketone 5 and 3-(2,4-difluorophenyl)-1-propylamine, using the method given in Example 1, gave (a) 6-{trans-4-[3-(2,4-difluorophenyl)-propylamino]-cyclohexyl}-3H-benzoxazol-2-one and (0.75 g, 37%), isolated as the HCl salt: 1H NMR (500 MHz, DMSO-d6): δ 11.49 (s, 1H), 8.84 (br s, 2H), 7.40 (ddd, J=9, 9, 7 Hz, 1H), 7.22-7.18 (m, 2H), 7.05 (ddd, J=8, 8, 2 Hz, 1H), 7.01 (dd, J=8, 1 Hz, 1H), 6.99 (d, J=8 Hz, 1H), 3.11-3.02 (m, 1H), 2.98-2.92 (m, 2H), 2.70 (t, J=8 Hz, 2H), 2.56-2.49 (m, 1H), 2.18-2.11 (m, 2H), 1.96-1.86 (m, 4H), 1.51 (m, 4H), and
Reaction SMILES: CC1C=CC(S(N[C@H:12]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([N:34]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([OH:33])=[O:32])=S)[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)(=O)=O)=CC=1.[N:49]#[C:50][NH2:51].[NH4+:52].[Cl-]>CO>[CH3:48][C:45]1[CH:46]=[CH:47][C:42]([S:39]([NH:52][C@H:12]([C:23]([NH:49][C:50]#[N:51])=[N:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([N:34]([S:39]([C:42]2[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=2)(=[O:40])=[O:41])[CH2:35][CH:36]([CH3:37])[CH3:38])[C:31]([OH:33])=[O:32])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)(=[O:41])=[O:40])=[CH:43][CH:44]=1
Reactant: N#CN
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=S)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Cl-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)NC#N)cc1
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a stirred solution of thioamide Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-[N′α-(4-methylbenzenesulfonyl)-L-thiotryptophanyl]-L-lysine (240 mg, 0.33 mmol, example 73) in MeOH (3 mL) was added cyanamide (28 mg, 0.66 mmol). The mixture was stirred for 5 min, then mercuric acetate (209 mg, 0.66 mmol) was added. The reaction was stirred for 3 h then diluted with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with brine and concentrated then rediluted with THF/MeOH (2 mL/1 mL) and treated with 1N NaOH (0.8 mL). After stirring for 4 h, the reaction was acidified with 1N HCl and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated and purified by column chromatography to give 154 mg (65%) of the final product.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]4([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:60][C:61]1[CH:69]=[CH:68][C:64]([C:65](Cl)=[O:66])=[CH:63][CH:62]=1>>[Cl:60][C:61]1[CH:69]=[CH:68][C:64]([C:65]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C:51]5([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]5)[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:66])=[CH:63][CH:62]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCCC1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(Cl)cc5)cc4)cc3C2=O)CCCC1
Yield: 74 %

Procedure:
The compound of example 532 was prepared analogous to compound of example 97 by reaction of compound of example 527 with 4-chloro benzoyl chloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Nc1ccccn1
Product: COc1ccc2c(Nc3ccccn3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and pyridin-2-ylamine to give 6-Methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-N1-pyridin-2-yl-isoquinoline-1,3-diamine. LC-MS m/e 347(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][CH2:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=O)=O)=[CH:4][CH:3]=1.C([NH2:20])(=O)C.B(F)(F)F.CCOCC>>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[O:8][CH:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[N:20]=2)=[CH:4][CH:3]=1
Reactant: CC(N)=O
Reactant: O=C(OCC(=O)C1CC1)c1ccc(Br)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: Brc1ccc(-c2nc(C3CC3)co2)cc1
Yield: 16.4 %

Procedure:
To a mixture of 2-cyclopropyl-2-oxoethyl 4-bromobenzoate (4.51 g, 15.93 mmol) and acetamide (4.71 g, 79.74 mmol) was added BF3/Et2O (1 ml). The mixture was heated at 140C for 8 h. Upon cooling, the mixture was partitioned between water and Et2O. The aqueous phase was extracted with Et2O (1×125 ml). The combined organic phases were washed with Water and brine, dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (CH2Cl2/hexanes, 30:70 to 50:50) to yield the title compound as a white crystalline solid (0.69 g, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)=[N:4][CH:3]=1
Reactant: Oc1ccc(Oc2ncc(Cl)cn2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Oc2ncc(Cl)cn2)ccc1O
Yield: 53.5 %

Procedure:
A solution of 4-(5-chloro-2-pyrimidyloxy)phenol (1.4 g) in acetic acid (20 ml) was treated with fuming nitric acid (0.5 g) at 25° C. After 4 hours the mixture was poured into water and extracted with chloroform (2×100 ml). The chloroform extracts were dried (Mg2O4) and evaporated to a yellow solid which was chromatographed on silica gel (40 g). Elution with chloroform gave 4-(5-chloro-2-pyrimidyloxy)-2-nitrophenol (0.9 g) as pale yellow crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[OH:11][CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:12]=[CH:13][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: OCCCOc1ccc(CO)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=Cc1ccc(OCCCO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of the above 3-(4-hydroxymethyl-phenoxy)-propan-1-ol (1.50 g, 8.23 mmol) in acetonitrile (25 mL) is added N-methylmorpholine-N-oxide (1.50 g, 12.38 mmol) followed by tetrapropylammonium perruthenate (140 mg, 0.43 mmol). The dark solution is stirred at rt for 2 h before the solvent is removed in vacuo. The crude product is purified by column chromatography on silica gel (heptane/EA) to give 4-(3-hydroxy-propoxy)-benzaldehyde. 1H NMR (D6-DMSO): δ 9.83 (s, 1H), 7.85-7.81 (m, 2H), 7.12-7.07 (m, 2H9, 4.56 (t, J=5.3 Hz, 1H), 4.14 (t, J=6.4 Hz, 2H), 3.57-3.51 (m, 2H), 1.38 (p, J=6,4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([C:22]([F:25])([F:24])[F:23])[N:3]=1>[OH-].[Na+].O1CCOCC1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[CH:5]=[C:4]([C:22]([F:24])([F:25])[F:23])[N:3]=[C:2]([Cl:1])[CH:7]=2)(=[O:10])=[O:11])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Yield: 34.1 %

Procedure:
0.20 g (0.0005 mol) of N-[4-(2-chloro-6-trifluoromethyl-pyridin-4-ylsulfamoyl)-phenyl]-acetamide was dissolved in a mixture of 5 ml of 1N NaOH and 5 ml of dioxan and boiled at reflux for 5 hours. After cooling the dioxan was distilled off, the residue was adjusted to pH 6 with 0.1 N HCl, the aqueous phase was extracted with ethyl acetate, back-washed with saturated sodium chloride solution and the organic phase was dried over Na2SO4. Subsequently, chromatography was carried out on silica gel with ethyl acetate/hexane 1:4. There was obtained 0.06 g (34%) of 4-amino-N-(2-chloro-6-trifluoromethyl-pyridin-4-yl)-benzenesulfonamide as pale yellow crystals; m.p.: 179-181° C.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:18]([NH:25][C:26]([NH2:28])=[S:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:18]([NH:25][C:26]1[S:27][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[N:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Reactant: NC(=S)NCc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(NCc2ccccc2)nc1-c1cccc(C#N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
To a solution of ethyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (0.60 g, 2.03 mmol) in 20 mL of absolute ethanol was added N-benzylthiourea (0.34 g, 2.03 mmol). The resulting mixture was stirred at 80° C. for 3 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with saturated aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to-yield a solid. Trituration with hexanes/ethyl ether left the title compound as an off-white solid (0.36 g, 49%). MS (ESI) 364.1 (M+H)+.