Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][CH2:31][CH2:30]2)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[CH2:32][CH2:31][CH2:30]4)[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: O=C=Nc1ccc2c(c1)CCC2
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc4c(c3)CCC4)c(=O)n(C3CCCC3)c12
Yield: 49.1 %

Procedure:
1-Cyclopentyl-3-indan-5-yl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (21 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 5-isocyanato-indan (0.5 mmol) following general procedure C. LCMS: m/z 428 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C([N:15](CC)CC)C.C(OC(Cl)=O)C(C)C.N>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH2:15])=[O:6]
Reactant: CCN(CC)CC
Reactant: COc1ccc(C(=O)O)cc1F
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(N)=O)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzoic acid (400 mg, 2.4 mmol) and triethylamine (560 μl, 3.5 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was added isobutylchloroformate (320 μl, 2.4 mmol), and the mixture was stirred at 0° C. for 1 hour. The solution was warmed to room temperature and was saturated with ammonia gas, then stirred for 15 hours at room temperature. The mixture was diluted with ethyl acetate, then washed with 20% aqueous citric acid, saturated aqueous sodium bicarbonate, and brine, then dried over anhydrous sodium sulfate. Filtration and concentration afforded 280 mg, 1.7 mmol (70%) of 3-fluoro-4-(methyloxy)benzamide. MS (EI) for C8H8FNO2: 170 (MH+).
Reaction SMILES: [CH:1]1[C:6]([C:7](/[C:9](/Cl)=[N:10]/[OH:11])=[O:8])=[CH:5][CH:4]=[C:3]([Cl:13])[CH:2]=1.[F:14][C:15]([F:25])([F:24])[C:16]([C:20]([F:23])([F:22])[F:21])([OH:19])[C:17]#[CH:18].C(N(CC)CC)C>C1COCC1>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:18]=[C:17]([C:16]([OH:19])([C:15]([F:24])([F:14])[F:25])[C:20]([F:21])([F:23])[F:22])[O:11][N:10]=2)=[O:8])=[CH:1][CH:2]=1
Reactant: O=C(/C(Cl)=N/O)c1ccc(Cl)cc1
Reactant: C#CC(O)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1cc(C(O)(C(F)(F)F)C(F)(F)F)on1
Yield: 46.7 %

Procedure:
To a solution of commercially available 4-chlorophenyl glyoxylohydroxamyl chloride (109 mg, 0.5 mmol) in 1,1,1-trifluoro-2-trifluoromethyl-but-3-yn-2-ol from step 1 (about 1 mmol) was added a solution of triethylamine (60 mg, 0.6 mmol) in THF (10 ml) dropwise by syringe pump at r.t. over 30 h. The mixture was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with 1N HCl, H2O and dried over MgSO4. Solvent was evaporated under reduced pressure and the residue was purified by preparative TLC (Hexanes:EtOAc, 5:1) to afford the title compound as a white solid (87.2 mg). 1H NMR (DMSO-d6) δ 7.37 (s, 1H), 7.60 (d, 2 H), 8.14 (d, 2H), 9.92 (s, 1H); ESIMS: m/z 372 (M−H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][N:18]=1)[CH2:6]/[CH:7]=[CH:8]/[C:9]#[C:10][C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[CH3:4].Br[CH2:26]/[CH:27]=[CH:28]/[C:29]1[CH:33]=[CH:32][S:31][CH:30]=1.C(OCC)C>O1CCCC1>[CH2:3]([N:5]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][O:24][CH2:26]/[CH:27]=[CH:28]/[C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[CH:20]=[CH:19][N:18]=1)[CH2:6]/[CH:7]=[CH:8]/[C:9]#[C:10][C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[CH3:4]
Reactant: CCN(C/C=C/C#CC(C)(C)OC)Cc1cc(CO)ccn1
Reactant: BrC/C=C/c1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(C/C=C/C#CC(C)(C)OC)Cc1cc(COC/C=C/c2ccsc2)ccn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
11.6 mg of 60% oily sodium hydride was suspended in 0.5 ml of tetrahydrofuran at 0 ° C., under a nitrogen atmosphere, and a tetrahydrofuran solution( 2 ml) of 87.5 mg of (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-4-hydroxymethyl-2-pyridylmethylamine was added dropwise. The mixture was stirred for 20 minutes, and a tetrahydrofuran solution (1 ml) of 50 mg of (E)-3-bromo-1-(3-thienyl)-1-propene was added dropwise. The mixture was stirred overnight at room temperature, and then ice water and ethyl ether were added. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by medium-pressure liquid chromatography [silica gel column, chloroform→chloroform/methanol=20/1] to give 56 mg (yield 46%) of the captioned compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:12]=[C:11]([C:33]2[CH:41]=[C:40]3[C:36]([C:37]4[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][C:38]=4[NH:39]3)=[CH:35][CH:34]=2)[C:10]=1[CH2:53][CH3:54])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.[SiH](C(C)C)(C(C)C)C(C)C>[CH2:26]([O:25][C:13]1[N:12]=[C:11]([C:33]2[CH:41]=[C:40]3[C:36]([C:37]4[CH2:45][CH2:44][NH:43][CH2:42][C:38]=4[NH:39]3)=[CH:35][CH:34]=2)[C:10]([CH2:53][CH3:54])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]=1[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCc1c(-c2ccc3c4c([nH]c3c2)CN(C(=O)OC(C)(C)C)CC4)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(-c2ccc3c4c([nH]c3c2)CNCC4)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.9 %

Procedure:
To a solution of tert-butyl 7-(4,6-bis(benzyloxy)-5-(benzyloxycarbonyl)-3-ethylpyridin-2-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (130 mg, 0.18 mmol) in CH2Cl2 (0.3 mL) and TIPSH (0.3 mL) was added TFA (0.3 mL). The mixture was stirred at room temperature for 20 min. The solvents were removed and the residue was treated with 2N NH3 in MeOH (0.5 mL). The mixture was concentrated and chromatographed (0-5% 2N NH3 in MeOH/CH2Cl2) to give the title compound (111 mg, 99%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:33][CH:32]([CH3:34])[N:31]([CH3:35])[CH:30]([CH3:36])[CH2:29]2)=[O:27])[NH:23][C:22]=1[CH:37]=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:37][C:22]4[NH:23][C:24]([C:26]([N:28]5[CH2:29][CH:30]([CH3:36])[N:31]([CH3:35])[CH:32]([CH3:34])[CH2:33]5)=[O:27])=[CH:25][C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C(=O)N2CC(C)N(C)C(C)C2)[nH]c1C=O
Product: Cc1cc(C(=O)N2CC(C)N(C)C(C)C2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one was condensed with 3-methyl-5-(3,4,5-trimethyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde to give the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.41 (br s, 1H, NH), 11.78 (br s, 1H, NH), 9.23 (br s, 1H), 8.33 (s, 1H), 7.72 (dd, J=2.5 & 6.5 Hz, 1H), 7.43 (m, 1H), 7.33-7.38 (m, 2H), 6.58 (m, 1H), 4.19 (m, 2H, CH2), 2.78 (m, 2H), 2.23 (s, 3H, CH3), 2.18 (s, 3H, CH3), 2.11 (m, 2H), 1.06 (d, J=6.6 Hz, 6H, 2×CH3). MS 524 [M++1].
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:17]2[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]2=[CH:15][N:14]=1.C(N=C=NCCCN(C)C)C.O[N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=CC=2N=N1.C(N(CC)CC)C.C1(NC)CC1>CN(C=O)C>[CH:42]1([CH2:41][NH:37][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[N:17]([C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])=[N:14][CH:15]=3)[CH:18]=2)=[O:23])[CH2:44][CH2:43]1
Reactant: On1nnc2ccccc21
Reactant: Cc1onc(-c2ccccc2)c1-c1ncc2ccc(C(=O)O)cn12
Agent: CCN=C=NCCCN(C)C
Agent: CNC1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1-c1ncc2ccc(C(=O)NCC3CC3)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
A solution containing 3-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,5-a]pyridine-6-carboxylic acid (58 mg, 0.18 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (52 mg, 0.27 mmol), 1-hydroxybenzotriazole (24 mg, 0.18 mmol), triethylamine (60 μL, 0.45 mmol) and cyclopropyl methylamine (20 mg, 0.27 mmol) in DMF (1 mL) was stirred at room temperature overnight. Purification by preparative HPLC on reversed phase (0.1% aqueous ammonia (25%) afforded the title compound (34 mg, 50%) as a light yellow solid. MS: m/e: 373.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:19]4[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=4[O:17][C:16]([CH3:27])([CH3:26])[CH:15]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(OCC)(=[O:30])C>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]2[O:17][C:16]([CH3:27])([CH3:26])[CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:13][N+:12]=3[O-:30])[C:19]=2[CH:20]=1)#[N:25]
Reactant: Cc1ccc(-c2ccc(C3=CC(C)(C)Oc4ccc(C#N)cc43)nc2)cc1
Reactant: CCOC(C)=O
Product: Cc1ccc(-c2ccc(C3=CC(C)(C)Oc4ccc(C#N)cc43)[n+]([O-])c2)cc1

Procedure:
In an analogous manner to that described in the first paragraph of Example 6, from 4-[5-(4-methylphenyl)-2-pyridyl]-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile there was obtained 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-(4-methylphenyl)pyridine N-oxide of melting point 173°-175° C. (decomposition) (from ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24](O)=[O:25])=[N:13]2)=[O:10])=[CH:4][CH:3]=1.[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][C:24](=[O:25])[CH2:23][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(O)Cc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)Cc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product of Example 114 and tert-butylamine were treated using a method similar to that described in Example 112 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.30 (d, J=7.9, 1H), 8.02-7.85 (m, 4H), 7.45-7.37 (m, 4H), 3.78 (s, 2H), 3.67 (s, 2H), 1.25 (s, 9H); MS (ESI−) M/Z 425 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])=[CH:8][CH:9]=1)=[O:4].[CH3:15][C:16]1[CH:21]=[C:20](O)[CH:19]=[C:18]([CH3:23])[C:17]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][O:12][C:20]2[CH:21]=[C:16]([CH3:15])[C:17]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][CH:25]=3)=[C:18]([CH3:23])[CH:19]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(C)(C)CO)s1
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(C)(C)COc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
A mixture of 5-(2-hydroxy-1,1-dimethyl-ethyl)-thiophene-2-carboxylic acid methyl ester (0.436 g, 2.04 mmol), 2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ol (0.596 g, 2.24 mmol), and PPh3 (0.793 g, 3.02 mmol) is dissolved in toluene (20 mL), treated with 1,1′-(azodicarbonyl)dipiperidine (ADDP, 0.763 g, 3.02 mmol), and stirred overnight at 80° C. The mixture is then cooled to rt, diluted with MeOH until homogeneous, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 40% to afford 5-[2-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-1,1-dimethyl-ethyl]-thiophene-2-carboxylic acid methyl ester (0.394 g, 42%). MS (ES): 463.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][OH:36]>CN(C)C=O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:33][CH2:34][CH2:35][OH:36])[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (45 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (56 mg) and 3-bromo-1-propanol (0.04 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (36 mg, yield 71%).
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:13][CH2:14][C:15]1[C:16](=[O:23])[C@@H:17]2[O:22][CH2:21][C@H:19]([CH:20]=1)[O:18]2>CO>[CH3:2][O:13][CH2:14][C:15]1[C:16](=[O:23])[C@@H:17]2[O:22][CH2:21][C@H:19]([CH:20]=1)[O:18]2
Reactant: O=C1C(CO)=C[C@H]2CO[C@@H]1O2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COCC1=C[C@H]2CO[C@H](O2)C1=O
Yield: 44.7 %

Procedure:
2 g of p-toluene sulfonic acid monohydrate was added to 150 ml of a methanol solution containing 2.8 g of 1,6-anhydro-3,4-dideoxy-3-hydroxymethyl-β-D-glycero-hex-3-enopyranos-2-ulose obtained in the above step (1), and the mixture was refluxed under heating for one hour. Disappearance of the starting material was confirmed by TLC, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane =1:2) to obtain 0.8 g of the desired product (Intermediate No. 48). The NMR analytical data of this product are as follows.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=1[F:32].[CH:33]1([C:36]#[C:37][C:38]([O:40][CH3:41])=[O:39])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:33]1([C:36]2[C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]4[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=4[F:32])[N:15]3[N:14]=2)[CH2:35][CH2:34]1
Reactant: Cc1cc[n+](N)c(OCc2c(F)ccc(F)c2F)c1
Reactant: COC(=O)C#CC1CC1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(C2CC2)nn2c(OCc3c(F)ccc(F)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
1.45 g (3.00 mmol, purity 98%) of 1-amino-4-methyl-2-[(2,3,6-trifluorobenzyl)oxy]pyridinium 2,4,6-trimethylbenzenesulphonate from Example 155A were dissolved in 9.7 ml of DMF and admixed with 670 mg (5.40 mmol) of methyl 3-cyclopropylprop-2-ynoate. 747 mg (5.40 mmol) of potassium carbonate was added and the mixture was stirred at RT for 3 h. Subsequently, the mixture was poured onto 73 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. 462 mg of the title compound were obtained (33% of theory; 85% purity).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[C:4]([CH3:18])[CH:3]=1.[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>ClCCl.C1(C)C=CC=CC=1>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=[C:4]([CH3:18])[CH:3]=1)=[O:24]
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2C)cc1
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(NC(=O)NCCCl)cc2C)cc1
Yield: 69.6 %

Procedure:
Methyl 4'-amino-2'-methylbiphenyl-4-carboxylate (D2) (1.00 g, 4.1 mmol) and 2-chloroethylisocyanate (0.39 ml, 4.5 mmol) were stirred in dichloromethane (20 ml) for 72 h. The suspension was then diluted with toluene (20 ml), and the solid was filtered off and dried. This gave the title compound (0.99 g, 69%) as a cream solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:30][CH2:29][CH2:28][C@@:15]3([C:19](=[O:20])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])[CH2:17][CH2:16]3)[CH2:14]2)=[N:11][CH:12]=1.N1C=CC=CC=1.C(Cl)Cl>>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:18]1[CH2:17][CH2:16][C@:15]2([CH2:28][CH2:29][CH2:30][N:13]([C:10]3[N:11]=[CH:12][C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])=[CH:8][CH:9]=3)[CH2:14]2)[C:19]1=[O:20]
Reactant: COC(=O)Cl
Reactant: Nc1ccc(N2CCC[C@]3(CCN(c4ccccc4Cl)C3=O)C2)nc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc(N2CCC[C@]3(CCN(c4ccccc4Cl)C3=O)C2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of (5S)-7-(5-aminopyridin-2-yl)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-one (18.5 mg, 0.0000478 mol) and pyridine (13 μL, 0.00016 mol) in methylene chloride (1.0 mL, 0.016 mol) and the mixture was stirred for 0.5 h at rt. The volatiles were removed in-vacuo and the crude product was purified by prep-HPLC. LC-MS: 415.1/417.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40](Cl)=[O:41]>ClCCl>[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:8]2)=[CH:21][CH:22]=1)=[O:41]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1nn(Cc2ccc(N)cc2)c2ncccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ncccc12
Yield: 66.6 %

Procedure:
Methyl 2-[1-(4-aminobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetate (58 mg, 0.20 mmol) and triethylamine (41 mg, 0.41 mmol) were dissolved in 15 mL dichloromethane. In an ice bath, 2-naphthoyl chloride (38 mg, 0.20 mmol) was added. Upon completion of addition, it was moved to react at room temperature for 1 hour. It was rotate evaporated to dryness to remove the solvent, and chromatographed on a column (PE:EA=15:1) to obtain a white oil 60 mg, at a yield of 65%.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S([O:25][CH2:26][C@@H:27]2O[CH2:28]2)(=O)=O)=CC=1>CN(C=O)C>[O:2]1[C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4][CH2:28][C@@H:27]1[CH2:26][OH:25]
Reactant: Oc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC[C@H]1COc2ccccc2O1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60° C. for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol—50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][NH:13]3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O:26][C:27]([NH:29][CH:30]([CH2:34][C:35]1[C:40]([CH3:41])=[CH:39][C:38]([C:42](=[O:44])[NH2:43])=[CH:37][C:36]=1[CH3:45])[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:22]([O:26][C:27](=[O:28])[NH:29][CH:30]([CH2:34][C:35]1[C:36]([CH3:45])=[CH:37][C:38]([C:42](=[O:44])[NH2:43])=[CH:39][C:40]=1[CH3:41])[C:31](=[O:32])[N:13]1[CH:12]([C:9]2[NH:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: c1ccc(-c2c[nH]c(C3Cc4ccccc4CN3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 220 mg (0.8 mmol) of 3-(4-phenyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydro-isoquinoline, 269 mg (0.8 mmol) of 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid, 216 mg (1.6 mmol) of of hydroxybenzotriazole hydrate and 184 mg (0.96 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added 3 mL of dimethylformamide. The resulting mixture was allowed to stir overnight at room temperature under argon. The mixture was then partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and concentrated. The product {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamic acid tert-butyl ester was taken to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@:20]([N:25]=[C:26]=[O:27])([CH3:24])[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@:20]([NH:25][C:26]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:27])([CH3:24])[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[C@@]1(N=C=O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: C1CCNC1
Solvent: CN1CCCC1=O
Product: C[C@@]1(NC(=O)N2CCCC2)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1

Procedure:
A solution of 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S,3R)-3-isocyanato-3-methylcyclohexyl)pyrimidin-4-amine, 52m, (0.035 g, 0.087 mmol) in 3 mL of NMP with 0.5 mL of pyrrolidine was warmed to 200° C. in a microwave for 30 minutes. The reaction was then concentrated in vacuo and purified by reverse phase HPLC chromatography, yielding 8.7 mg of desired product as a tan solid.