Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[OH:25])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].Br[CH2:27][CH:28]([CH3:30])[CH3:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[O:25][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccccc1-c1ccccc1-c1cc(Cl)ccc1O
Reactant: CC(C)CBr
Product: CCOC(=O)c1ccccc1-c1ccccc1-c1cc(Cl)ccc1OCC(C)C

Procedure:
Prepared as in procedure A from 5-chloro-2-hydroxy-[1,1′;2′,1″]terphenyl-2″-carboxylic acid ethyl ester and 1-bromo-2-methyl-propane.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([NH2:32])=[CH:30][C:29]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:28][N:27]=2)[CH2:22][CH2:21]1.Cl.O1CCOCC1>CN1C(=O)CCC1>[N:23]1([C:26]2[C:31]([NH:32][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)[C:3]=3[CH3:19])=[CH:30][C:29]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:28][N:27]=2)[CH2:22][CH2:21][O:20][CH2:25][CH2:24]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (95 mg, 0.35 mmol), 2,5-dimorpholinopyridin-3-amine (92 mg, 0.35 mmol) and a 4.0M solution of HCl in dioxane (0.017 mL, 0.07 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinyl-3-pyridinyl)-7-fluoro-3-methyl-2-(3-pyridinyl)-4-quinolinamine was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.87 (1H, d, J=2.7 Hz), 8.73 (1H, dd, J=5.1, 2.0 Hz), 7.99 (1H, dt, J=7.8, 2.0 Hz), 7.74-7.89 (2H, m), 7.62 (1H, d, J=2.7 Hz), 7.49 (1H, dd, J=8.0, 4.9 Hz), 7.31 (1H, ddd, J=9.3, 7.9, 2.7 Hz), 6.80 (1H, s), 6.21 (1H, d, J=2.7 Hz), 3.89-3.99 (4H, m), 3.75 (4H, ddd, J=4.3, 2.7, 2.3 Hz), 3.23 (4H, t, J=4.9 Hz), 2.87-3.01 (4H, m), 2.31 (3H, s). Mass Spectrum (ESI) m/e=501.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[N:16]([CH3:21])[N:17]=[C:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1>>[CH3:21][N:16]1[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:28]5[CH:27]=[N:26][C:25]([CH3:24])=[CH:30][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])=[CH:19][C:18]([CH3:20])=[N:17]1
Reactant: Cc1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)n(C)n1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cc(C)nn2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate C, 50 mg, 0.135 mmol) and 2-methylpyridine-5-boronic acid (Frontier Scientific, Logan, USA, 28 mg, 0.181 mmol) to give the title compound as a red solid. (HPLC: tR 2.20 min (Method A); M+H=385 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.02 (s, 1H), 8.62-8.52 (m, 1H), 8.17-8.08 (m, 1H), 8.00-7.91 (m, 1H), 7.81-7.73 (m, 1H), 7.39-7.32 (m, 1H), 7.13 (s, 1H), 6.52 (s, 1H), 3.62 (s, 3H), 3.51 (s, 3H), 2.55-2.45 (3H), 2.29 (s, 3H))
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.C([O-])(O)=O.[Na+].F[C:19](=[O:34])[C@H:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:21]1[CH:25]=[CH:24][S:23][CH:22]=1>O.C(Cl)Cl>[OH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:19](=[O:34])[C@H:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc2c(O)nccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccsc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1ccc2c(O)nccc2c1)c1ccsc1
Reaction time: 4 h

Procedure:
To 6-aminoisoquinolin-1-ol in H2O was added NaHCO3 followed by a solution of (R)-tert-butyl 2-fluoro-2 oxo-1-(thiophen-3-yl)ethylcarbamate in CH2Cl2. The solution was stirred for 4 hours, extracted with EtOAc and NH4Cl(sat)/HCl (1N) and then with NaHCO3 (0.05%), dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5% MeOH, CH2Cl2) gave pure (R)-tert-butyl 2-(1-hydroxyisoquinolin-6-ylamino)-2-oxo-1-(thiophen-3-yl)ethylcarbamate (95% ee by Chiracel OD-RH)
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14]([OH:27])([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:27][C:14]1([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2ccc(C(F)(F)F)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: OC1(c2ccc(C(F)(F)F)cc2)CCNCC1
Reaction time: 2.5 h
Yield: 62.7 %

Procedure:
A mixture of 1-benzyloxycarbonyl-4-hydroxy-4-(4-trifluoromethylphenyl)-piperidine (12.3 g, 32.4 mmol), ethanol (150 mL), and 10% palladium on carbon (1.4 g) was hydrogenated in a Parr apparatus (initial hydrogen pressure was 48 psi). After 2.5 hours, the mixture was filtered through celite and concentrated. The residue was triturated with ether/hexane to obtain 4.98 g (63%) of 4-hydroxy-4-(4-trifluoromethylphenyl)-piperidine as a white solid which had mp 130.5°-132° C. Analysis calculated for C12 H14F3NO--0.25 H2O: C, 57.71; H, 5.85; N, 5.61. Found: C, 57.91; H 5.77; N, 5.54.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)([OH:12])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([C:10]4([OH:12])[CH2:11][NH:8][CH2:9]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (620 mg, 1.16 mmol) in DCM (5 mL) was added TFA (2 mL) and the resulting mixture allowed to stir for 1.5 h at r.t. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH and the product eluted with 2M NH3/MeOH affording 3-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]azetidine-3-ol as a yellow oil (450 mg, 89%). LCMS: (method A): RT 1.84 min [M+H]+ 435.2
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][C:9]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH2:27]([O:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:20][CH:19]=1)[CH2:12][OH:14])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCc1ccc(Cc2ccc(C(=O)OC)cc2O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2ccc(CO)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of methyl 4-(4-ehtylbenzyl)-3-hydroxybenzoate (1.3 g) in N,N-dimethylformamide (15 mL) were added potassium carbonate (0.79 g) and benzyl bromide (0.62 mL), and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether (10 mL). The resulting solution was added to a suspension of lithium aluminium hydride (0.57 g) in diethyl ether (50 mL) at 0° C., and the mixture was heated under reflux for 1.5 hours. The reaction mixture was cooled to 0° C., water (0.60 mL), 15% aqueous sodium hydroxide solution (0.60 mL) and water (1.8 mL) were successively added to the reaction mixture, and the mixture was stirred for 5 minutes. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give 3-benzyloxy-4-(4-ethylbenzyl)benzyl alcohol (1.3 g).
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[NH:11][C:10](=[O:12])[C@H:9]2[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[N:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:50](Cl)(=[O:52])[CH3:51]>C1COCC1>[C:1]1([S:7][CH:8]2[N:11]([C:50](=[O:52])[CH3:51])[C:10](=[O:12])[CH:9]2[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[N:18][C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: O=C(N=C(NCCC[C@@H]1C(=O)N[C@H]1Sc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1C(=O)C(CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C1Sc1ccccc1
Reaction time: 0.5 h

Procedure:
To a -78° C. THF (7 mL) solution of compound 14 (450 mg, 0.82 mmol) was added 1N THF solution of sodium bis(trimethylsilyl)amide (0.8 mL) dropwise. The resultant solution was stirred for 10 min, followed by the addition of acetyl chloride (0.054 mL, 0.76 mmol). The resultant solution was warmed to room temperature and stirred for an additional 30 min and concentrated- The residue was partitioned between ethyl acetate and H2O. The organic phase was dried (MgSO4) and concentrated to afford 450 mg (93%, crude yield) of the title compound which was directly used in Step B.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([O:24][CH3:25])[N:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:26].[Br:27]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([O:24][CH3:25])[N:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH2:26][Br:27]
Reactant: COc1nc(N(C(=O)OC(C)(C)C)c2ccc(Br)c(C)c2)ccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1nc(N(C(=O)OC(C)(C)C)c2ccc(Br)c(CBr)c2)ccc1C#N
Temperature: 95 °C
Yield: 162.2 %

Procedure:
To a solution of tert-butyl 4-bromo-3-methylphenyl(5-cyano-6-methoxypyridin-2-yl)carbamate (2.85 g, 6.81 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (0.909 g, 5.11 mmol) and azobisisobutyronitrile (0.042 g, 0.26 mmol). The mixture was refluxed under nitrogen at 95° C. for two hours. The reaction was cooled to room temperature, water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water and brine, and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crude tert-butyl 4-bromo-3-(bromomethyl)phenyl(5-cyano-6-methoxypyridin-2-yl)carbamate (4.12 g). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[CH:28]1(O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([O:23][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:25])[F:26])[CH:3]=1
Reactant: OC1CCCCC1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)OC3CCCCC3)cs2)CC1

Procedure:
A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 6.00 g) is reacted analogously to Example I-811 with cyclohexanol (1.94 g). This gives, after chromatographic purification, cyclohexyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (5.00 g, 69%).
Reaction SMILES: [NH2:1]C1N=C(C2C(Cl)=CC3COCC4C=3C=2C=CC=4)N=C(SCCC(O)=O)N=1.[Cl-].[NH4+].[NH2:30][C:31]1[N:36]=[C:35]([C:37]2[C:38]([Cl:50])=[CH:39][C:40]3[CH2:41][O:42][CH2:43][C:44]4[C:49]=3[C:48]=2[CH:47]=[CH:46][CH:45]=4)[N:34]=[C:33]([S:51][CH2:52][CH:53]([CH3:57])[C:54]([OH:56])=O)[N:32]=1>>[NH2:30][C:31]1[N:36]=[C:35]([C:37]2[C:38]([Cl:50])=[CH:39][C:40]3[CH2:41][O:42][CH2:43][C:44]4[C:49]=3[C:48]=2[CH:47]=[CH:46][CH:45]=4)[N:34]=[C:33]([S:51][CH2:52][CH:53]([CH3:57])[C:54]([NH2:1])=[O:56])[N:32]=1
Reactant: Nc1nc(SCCC(=O)O)nc(-c2c(Cl)cc3c4c(cccc24)COC3)n1
Reactant: CC(CSc1nc(N)nc(-c2c(Cl)cc3c4c(cccc24)COC3)n1)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Product: CC(CSc1nc(N)nc(-c2c(Cl)cc3c4c(cccc24)COC3)n1)C(N)=O
Yield: 65 %

Procedure:
Proceeding in the same manner as in Step 2 of Example 205 and replacing N-methylamine hydrochloride and 3-[4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-[1,3,5]triazin-2-ylsulfanyl]-propionic acid by ammonium chloride (963 mg, 18 mmol) and 3-[4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-[1,3,5]triazin-2-ylsulfanyl]-2-methyl-propionic acid (1.5 g, 3.6 mmol) respectively, there was obtained 3-[4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-[1,3,5]triazin-2-ylsulfanyl]-2-methyl-propionamide (978 mg, 65%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)=[O:20])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[C:19]([NH:18][C:14]1[CH:13]=[C:12]([NH:11][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=1)=[O:20]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc(NC(=O)c2ccc3ccccc3c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(Nc1cccc(Nc2ncccc2[N+](=O)[O-])c1)c1ccc2ccccc2c1
Yield: 50.1 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (0.87 g), N-(3-aminophenyl)-2-naphthalenecarboxamide (1.31 g) and potassium carbonate (1.0 g) in 1,4-dioxane (20 ml) was stirred under reflux for 20 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-[3-(2-naphthoylamino)phenylamino]-3-nitropyridine (961 mg) as an orange solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)=[CH:7][CH:6]=1)([OH:3])=[O:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][N:20]=[N+:21]=[N-:22])=[CH:7][CH:6]=1)([OH:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCCCc1ccc(CC(=O)O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCc1ccc(CC(=O)O)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
Compound 6 (6 g, 0.02 mol) was dissolved in 80 ml of dry DMF then sodium azide (1.8 g, 0.027 mol) was added. The suspension was stirred at 80° C. (oil bath) for 3 h. The solvent was then removed at reduced pressure and the residual oil was treated with CH2Cl2 (100 mL). The resulting solution was washed with water (2×100 mL), brine and dried over magnesium sulfate. The solvent was removed under reduced pressure then the residue was redissolved in a 1:1 mixture of ethyl acetate/hexanes (200 mL) and passed through a pad of silica gel. The solvent was removed under reduced pressure to give 4.1 g (85%) of 7 as clear oil. 1H NMR (300 MHz, CDCl3) δ 1.68 (m, 4H), 2.22 (t, 2H), 3.29 (t, 3H), 3.92 (s, 3H), 7.28 (d, 2H) 7.98 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:22][C@H:23]([C:25]([OH:27])=[O:26])[CH3:24].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:22][C@@H:23]([CH3:24])[C:25]([OH:27])=[O:26])=[O:10]
Reactant: CCOC(=O)c1ncc2c(-c3ccccc3)noc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ncc2c(-c3ccccc3)noc2c1O)C(=O)O
Temperature: 25 °C
Yield: 79.4 %

Procedure:
Ethyl 7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (0.1 g, 0.35 mmol) was dissolved in 10 mL of DMF. L-Alanine (0.627 g, 7.04 mmol) and sodium ethoxide (0.36 g, 5.28 mmol) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 2. The resulting suspension was filtered and the solid dried under vacuum to give 91 mg of the title compound. MS: (+) m/z 328.00 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[O:31]=[C:26]1[NH:27][C:28](=[O:30])[C:29](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)=[CH:7][CH:8]=2)[S:25]1
Reactant: O=Cc1ccc(-c2cccc(CNC(=O)c3ccccc3)c2)cc1
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc(-c3cccc(CNC(=O)c4ccccc4)c3)cc2)S1
Yield: 90.5 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 1 g (3.2 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)benzamide with 370 mg (3.2 mmol) of 2,4-thiazolidine dione, 1.2 g (93%) of expected product are obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1.[CH2:18]([S:20][C:21]1[C:22]([C:31](O)=[O:32])=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH3:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[F:17][C:2]([F:1])([F:16])[CH2:3][NH:4][C:5]1[C:10]([NH:11][C:31]([C:22]2[C:21]([S:20][CH2:18][CH3:19])=[CH:26][C:25]([C:27]([F:29])([F:30])[F:28])=[CH:24][N:23]=2)=[O:32])=[CH:9][C:8]([C:12]([F:13])([F:14])[F:15])=[CH:7][N:6]=1
Reactant: Nc1cc(C(F)(F)F)cnc1NCC(F)(F)F
Reactant: CCSc1cc(C(F)(F)F)cnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: CCSc1cc(C(F)(F)F)cnc1C(=O)Nc1cc(C(F)(F)F)cnc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A mixture of N2-(2,2,2-trifluoroethyl)-5-trifluoromethylpyridin-2,3-diamine (0.52 g), 3-ethylsulfanyl-5-trifluoromethylpyridin-2-carboxylic acid (0.50 g), WSC (0.46 g), HOBt (27 mg) and pyridine (2 ml) was stirred at room temperature for 3 hours. To the reaction mixture was poured aqueous 10% citric acid solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give 3-ethylsulfanyl-5-trifluoromethylpyridin-2-carboxylic acid [2-(2,2,2-trifluoroethyl)amino-5-trifluoromethylpyridin-3-yl]amide (0.89 g), which is hereinafter referred to as “intermediate compound (M3-44)”.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16]C=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1OC(=O)C.[CH3:18][O-:19].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:18]([OH:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: CC(=O)Oc1ccc(-c2ccccc2)cc1Br
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(-c2cccc(Br)c2)cc1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1.07 g (3.67 mmole) of 3-bromo-4-acetoxybiphenyl in 10 mL methanol at ambient temperature under a nitrogen atmosphere was added 0.92 mL of 4.4 M sodium methoxide in methanol solution (4 mmole). The mixture was stirred for 20 minutes and partitioned between Et2O/ice-H2O/2N HCl (aq.) and the organic phase separated, washed with saturated NaCl solution, and then ice-H2O/saturated NaHCO3 (aq) solution, dried over Na2SO4, filtered, and evaporated. The product was dried in vacuo to give 1.05 g of crude 3-bromo-4'-hydroxybiphenyl which was used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([OH:16])[C@H:12]([NH2:15])[CH2:13][F:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)Cl.[Cl:20][CH:21]([Cl:25])[C:22](Cl)=[O:23]>O>[Cl:20][CH:21]([Cl:25])[C:22]([NH:15][C@H:12]([CH2:13][F:14])[C@@H:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[OH:16])=[O:23]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Yield: 69.8 %

Procedure:
To a solution of (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol (5 g, 0.02 moles) in methylene chloride (100 ml) triethylamine (3.0 g, 0.03 mole) and dichloro acetyl chloride (3.6 g; 0.025 mole) were added at 10–15° C. After completion of reaction in 30 minutes, water (10 ml) was added and layers were separated. Solvent was distilled off from reaction mass, toluene (25 ml) and water (5 ml) were added. The product thus precipitated was filtered, washed with methylene chloride (20 ml) and crystallized from ethanol/water (4:1) to give 5 g of the title compound with purity 99.5% by HPLC.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>CN(C)C=O.C(NCC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=[C:2]([C:27]#[C:26][C:24]([CH3:25])([OH:28])[CH3:23])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: C#CC(C)(C)O
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Yield: 51.9 %

Procedure:
A mixture of 382 mg (1 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 93 mg (1.1 mmole) 2-methyl-3-butyn-2-ol, 38 mg copper(I)-iodide and 35 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 1 hour in 5 ml dimethylformamide and 5 ml diethylamine. The solvents are removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with water, dried over magnesiumsulfate and concentrated in vacuo. Flash chromatography (silicagel, hexane/ethyl acetate 7/3 ) and recrystallisation of the residue from ethanol yields 200 mg (52%) pure 4-[4-(4-amino-benzenesulfonyl)-6-pyrrolidine-1-yl-pyridine-2-yl]-2-methyl-but-3-yn-2-ol als a white solid mp.: 168-170° C.