Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CN(C)[CH:36]=[O:37]>>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:23][CH2:24][N:25]([CH2:11][CH2:10][CH2:9][CH2:14][CH2:13][CH2:12][O:37][CH2:36][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: O=C(NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: O=C(N(CCCCCCOCCc1ccccc1)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(F)(F)F
Temperature: 70 °C

Procedure:
A solution of N-[2-[3,4-Bis(phenylmethoxy) phenyl]ethyl]-2,2,2-trifluoroacetamide (11g) in dry dimethylformamide (30 ml) was added dropwise to a stirred suspension of sodium hydride (0.615 g) in dry dimethylformamide (20 ml) in (a) nitrogen atmosphere. The mixture was heated at 70° C. for 1 hour and then cooled to room temperature.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[C@@H:24]1([NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[NH2:30]>CN1C(=O)CCC1>[NH2:30][C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[NH:31][C:16]1[S:17][C:13]2[CH:12]=[C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:23])[CH:9]=3)[CH:22]=[CH:21][C:14]=2[N:15]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4N)sc3c2)ccn1
Temperature: 105 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (15 mg, 43 μmole) in 400 μL of NMP was added (1R,2R)-cyclohexane-1,2-diamine (17 mg, 150 μmole). The reaction solution was stirred at 105° C. for 24 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give 4-(2-((1R,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (12 mg, 30 μmole) as white powder. ES/MS m/z 398.1 (MH+).
Reaction SMILES: [NH:1]([C:3](=[O:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:2].[C:21](OCC)(OCC)(OCC)[CH3:22].CC(O)=O>C1(C)C=CC=CC=1>[CH3:21][C:22]1[O:20][C:3]([C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:1][N:2]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1nnc([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)o1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To (S)-tert-butyl (1-hydrazinyl-1-oxo-3-phenylpropan-2-yl)carbamate (120 mg, 0.43 mmol) in PhMe (4.3 mL) was added triethyl orthoacetate (396 μL, 2.15 mmol) and AcOH (443 μL, 7.73 mmol). The resulting solution was stirred at 80° C. for 2 h, then concentrated in vacuo and used in the subsequent step without purification. MS (ESI+) m/z 304.3 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:29][CH:30]=1
Reactant: Cc1cccc2c(C3=CCNCC3)c[nH]c12
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.499 g, 2.4 mmol) and 7-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.509 g, 2.4 mmol) in the presence of 2.0 equivalents of K2CO3 (0.593, 4.3 mmol) in dimethylformamide at 90° C. Yield 0.383 g (41%) of a tan powder. mp 166-169 C. FDMS m/e=405 (M+ of free base).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:22][CH2:23][O:24][CH3:25])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[CH2:26][CH2:27][CH3:28])(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)=[CH2:40].Cl>O1CCOCC1.O>[F:16][C:14]([F:17])([F:15])[C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([CH:39]=[CH2:40])[CH:46]=2)=[C:8]([CH2:26][CH2:27][CH3:28])[CH:9]=1)([O:22][CH2:23][O:24][CH3:25])[C:18]([F:20])([F:19])[F:21]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OS(=O)(=O)C(F)(F)F
Reactant: C=Cc1cccc(B(O)O)c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cccc(-c2ccc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc2CCC)c1
Yield: 81.4 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenyl trifluoromethanesulfonate (238 mg, 497 μmol) in 1,4-dioxan, potassium phosphate (401 mg), 3-vinylphenylboronic acid (88 mg), and tetrakis triphenylphosphine palladium complex (57 mg) were added at room temperature under an argon atmosphere, and the resultant mixture was heated at 80° C. After completion of the reaction, the reaction solution was neutralized by adding water and 2 mol/L of hydrochloric acid, extracted with ethyl aceate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and the title compound (175 mg, yield 81%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH2:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH2:32](Br)[CH2:33][CH2:34][CH3:35]>C(#N)C>[CH2:32]([NH:15][CH:13]1[CH2:14][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[O:10])[CH2:12]1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCBr
Reactant: NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCNC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (0.09 M in acetonitrile, 500 μL, 0.045 mmol), prepared using procedures similar to those described in Example 2, was added triethylamine (20 μL, 0.135 mmol) and n-butylbromide (6.14 μL, 0.054 mmol) followed by additional acetonitrile (1.0 mL). The reaction mixture was stirred at room temperature for 16 h, at which time it was purified directly by reverse phase HPLC to afford the title compound (8.4 mg). 1H NMR (400 MHz, CDCl3): 8.50 (s, 1H), 7.39 (dd, 1H), 7.32 (dd, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.35 (br s, 2H), 4.00 (br s, 1H), 3.87 (br s, 1H), 3.74-3.68 (m, 1H), 3.20 (br s, 3.5H), 2.56 (t, 2H), 2.03 (s, 2H), 1.50-1.42 (m, 2H), 1.39-1.29 (m, 2H), 0.91 (t, 3H). MS (EI) for C20H21F3IN3O: 504 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1>>[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=3[C:12]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[N:13]2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1
Yield: 25.3 %

Procedure:
The title compound (0.03 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 4-bromomethyl-benzoic acid methyl ester (0.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C22H22ClN3O2, 395.14. found, m/z 396.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.63-7.19 (m, 7H), 7.03-7.02 (m, 2H), 5.27 (s, 2H), 3.15 (s, 2H), 2.79-2.67 (m, 8H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl[Sn]Cl.O.Cl>C(O)C>[NH2:1][C:4]1[C:5]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1-n1cccn1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cccnc1-n1cccn1
Yield: 63.1 %

Procedure:
To a suspension of 3-nitro-2-(pyrazol-1-yl)pyridine (670 mg, 3.72 mmol) in ethanol (10 mL) was added a 1M solution of SnCl2.H2O in 6N aqueous HCl (14.5 mL, 14.5 mmol). The mixture was heated at reflux for 10 min, and the solvent was removed with a rotary evaporator. 10% aqueous sodium hydroxide solution was added until most of the material dissolved, and the mixture was extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated to afford 376 mg (68%) of 3-amino-2-(pyrazol-1-yl)pyridine as a brown oil. 1H NMR (CDCl3) δ5.62 (br s, 2), 6.46 (m, 1), 7.05 (dd, 1, J=5, 8), 7.24 (dd, 1, J=2, 8), 7.74 (m, 1), 7.85 (dd, 1, J=2, 5), 8.54 (d, 1, J=3).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[C:12](O)[CH:11]=1>CC(C)=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[C:14]([O:4][CH3:1])[CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: CCCC(=O)c1ccc(Br)cc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCC(=O)c1ccc(Br)cc1OC
Yield: 67.7 %

Procedure:
Potassium carbonate (9.07 g) and methyl iodide (3.92 ml) were added to a solution of the compound of Example B220 (13.30 g) in acetone (75 ml), and this reaction mixture was stirred while heating under reflux for 4 hours. The reaction mixture was filtered through celite, ether was added to remove insoluble material by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (9.52 g).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20](Cl)[CH:19]=3)[N:16]=[CH:17][C:10]=2[N:9]([CH3:30])[C:8]1=[O:31])=[O:2].C(OCCCN1C(=O)C2C(CCC(C)C)=C(C3C=CC=C([Cl:55])C=3)NCC=2N(C)C1=O)=O>C(Cl)Cl.O.O=[Mn]=O>[CH:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:55])=[CH:20][CH:19]=3)[N:16]=[CH:17][C:10]=2[N:9]([CH3:30])[C:8]1=[O:31])=[O:2]
Reactant: CC(C)CCc1c(-c2cccc(Cl)c2)ncc2c1c(=O)n(CCCOC=O)c(=O)n2C
Reactant: CC(C)CCC1=C(c2cccc(Cl)c2)NCc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: O=[Mn]=O
Solvent: O
Solvent: ClCCl
Product: CC(C)CCc1c(-c2ccc(Cl)cc2)ncc2c1c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To a solution of 3-(6-(3-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate and 3-(6-(3-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (21 mg, 0.047 mmol) in DCM (1 mL) was added MnO2 (40.8 mg, 0.47 mmol). The reaction was stirred at RT for 3 h then diluted with DCM (5 mL) and water (1 mL). The organic layer was washed with brine (1 mL), dried over Na2SO4, and concentrated to give 3-(6-(4-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (14 mg, 66.7% yield) as an oil. LCMS: MH+ 444 and TR=1.942 min. Used without further purification.
Reaction SMILES: Cl.C([O:9][CH:10]([NH:27][C:28](=[O:39])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([NH2:38])=[NH:37])[C:11](=[O:26])[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])C1C=CC=CC=1.CN(C)C=O>C(O)(=O)C.[Pd]>[NH:35]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:28](=[O:39])[NH:27][CH:10]([OH:9])[C:11](=[O:26])[NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:36]([NH2:38])=[NH:37]
Reactant: N=C(N)NCCCCCCC(=O)NC(OCc1ccccc1)C(=O)NCCCC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: N=C(N)NCCCCCCC(=O)NC(O)C(=O)NCCCC(=O)O
Yield: 57.5 %

Procedure:
0.79 g (1.41 mmol) of benzyl 7-benzyloxy-15-guanidino-6,9-dioxo-5,8-diazapentadecanoate hydrochloride was dissolved in 10 ml of 1N acetic acid and 10 ml of dimethylformamide and catalytically reduced in the presence of palladium black at room temperature under a hydrogen pressure of 10 kg/cm2 for 34 hours. After filtering off the catalyst, the filtrate was adsorbed on 100 ml of CM-Sephadex® C-25 (Na) and subjected to gradient elution between 500 ml of distilled water and 500 ml of 0.3M sodium chloride. Fractions containing the aimed compound were combined and concentrated to dryness under reduced pressure. 90% ethanol was added to the residue and the insoluble sodium chloride was filtered off. Next, the filtrate was subjected to gradient elution between 500 ml of distilled water and 500 ml of a 30% aqueous solution of acetone by using a column packed with 100 ml of Diaion® HP-20. Fractions containing the aimed compound were combined and concentrated under reduced pressure. The residue was dissolved in a small amount of distilled water and the insoluble matters were filtered off. By lyophilizing the product, 0.280 g of the aimed compound was obtained (yield: 57.8%).
Reaction SMILES: [Br-].[F:2][C:3]([F:13])([F:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Zn+].Cl[C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=1)[C:18]([O:20][CH3:21])=[O:19]>O1CCCC1>[F:2][C:3]([F:13])([F:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: FC(F)(F)c1ccccc1C[Zn+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccccc2C(F)(F)F)c1
Temperature: 60 °C
Yield: 80 %

Procedure:
Freshly made (2-(trifluoromethyl)benzyl)zinc(II) bromide (8.91 g, 29.28 mmol) in tetrahydrofuran (50 mL) was added to a solution of methyl 2-chloroisonicotinate (3.35 g, 19.52 mmol) and bis(tri-tert-butylphosphine)Pd(0) (0.399 g, 0.78 mmol) in tetrahydrofuran (50 mL) under nitrogen in a dried flask. The resulting red mixture was heated to 60° C. overnight (16 h). After cooling to room temperature, the reaction was quenched by the addition of 10% aq NH4Cl and diluted with ethyl acetate. After phase separation, the organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was dissolved in 100 mL MTBE. Insolubles were filtered off and the filtrate was evaporated. Purification via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 1 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 6 CV to yield methyl 2-(2-(trifluoromethyl)benzyl)isonicotinate (4.61 g, 80%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.91 (s, 3H), 4.43 (s, 2H), 7.28-7.40 (m, 2H), 7.47 (t, 1H), 7.54-7.65 (m, 1H), 7.65-7.72 (m, 2H), 8.71 (d, 1H). MS m/z 296 (M+H)+
Reaction SMILES: O[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([CH:20]=[N:21]O)[CH:3]=1.O=P(Cl)(Cl)[Cl:25].N1C=CC=CC=1C>>[Cl:25][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([C:20]#[N:21])[CH:3]=1
Reactant: ON=Cc1cc(O)nc(SCc2ccc3ccccc3c2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccn1
Product: N#Cc1cc(Cl)nc(SCc2ccc3ccccc3c2)n1

Procedure:
6-hydroxy-2-(2-naphthylmethyl)thio-4-pyrimidine carboxaldehyde oxime (720 mg, 2.31 mmol), POCl3 (3 ml), and 2-picoline (0.5 ml) are heated to reflux for 2 hrs. The reaction mixture is poured onto ice/water, extracted thrice with ethyl acetate, dried with MgSO4, and concentrated in vacuo. The product is purified by chromatography (SiO2, ethyl acetate/hexane, 5/95): 524 mg (1.67 mmol, 73%), mp 120-121° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[N:10][C:9]=2[N:8]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:7]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.O>[C:24]([N:8]1[C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[S:12][C:13]=2[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(NC(=O)c3ccc(C)cc3)sc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2nc3c(s2)c(C(=O)O)cn3C(C)(C)C)cc1
Yield: 83.7 %

Procedure:
Water (50 ml) was added to a stirred suspension of 4-tert-butyl-2-(4-methyl-benzoylamino)-4H-pyrrolo[2,3-d]thiazole-6-carboxylic acid ethyl ester (4.0 g, 10.5 mmol) and lithium hydroxide (1.0 g, 42.6 mmol) in THF (105 ml). The mixture was held at reflux for 18 hours, cooled, diluted with water (200 ml), and washed with ethyl acetate. The aqueous phase was chilled, then acidified (6M HCl), with stirring, to precipitate product. The solid was filtered and dried to yield 3.14 g (84%) of the product. MS: M+H=358.
Reaction SMILES: C(OC(=O)[N:7]([C:39]1[CH:40]=[N:41][C:42](Cl)=[CH:43][CH:44]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:16]2[C:24]3[C:23]([CH:25]4[CH2:27][CH2:26]4)=[N:22][CH:21]=[N:20][C:19]=3[N:18]([Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH:17]=2)[OH:15])=[C:10]([F:38])[N:9]=1)(C)(C)C.[CH:47]1([Mg]Br)[CH2:49][CH2:48]1.O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:47]1([C:42]2[N:41]=[CH:40][C:39]([NH:7][C:8]3[N:9]=[C:10]([F:38])[C:11]([CH:14]([C:16]4[C:24]5[C:23]([CH:25]6[CH2:26][CH2:27]6)=[N:22][CH:21]=[N:20][C:19]=5[N:18]([Si:28]([CH:32]([CH3:33])[CH3:34])([CH:35]([CH3:36])[CH3:37])[CH:29]([CH3:31])[CH3:30])[CH:17]=4)[OH:15])=[CH:12][CH:13]=3)=[CH:44][CH:43]=2)[CH2:49][CH2:48]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(N(C(=O)OC(C)(C)C)c3ccc(Cl)nc3)nc2F)c2c(C3CC3)ncnc21
Reactant: Br[Mg]C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(Nc3ccc(C4CC4)nc3)nc2F)c2c(C3CC3)ncnc21
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
To (6-chloro-pyridin-3-yl)-{5-[(4-cyclopropyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-carbamic acid tert-butyl ester (81, 0.51 g, 0.77 mmol) in 12 mL of toluene, [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (0.13 g, 0.17 mmol) is added under nitrogen and the reaction stirred for 5 minutes. Cyclopropylmagnesium bromide (17, 15.29 mL, 0.50 M in tetrahydrofuran, 7.65 mmol) is added slowly and the reaction is heated at 65° C. for 2 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (82, 400 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:24][OH:25])[CH:19]=[C:20]([F:23])[C:21]=1[F:22]>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:25][CH2:24][C:18]3[CH:19]=[C:20]([F:23])[C:21]([F:22])=[C:16]([F:15])[CH:17]=3)[CH:3]=2)[CH2:9][C:10]1([CH3:14])[CH3:13]
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)c(F)c(F)c1
Product: CN1c2cc(OCc3cc(F)c(F)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3,4,5-trifluorophenyl)methanol.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.B(F)(F)F.[CH3:12][CH2:13][O:14][CH2:15][CH3:16].O1CCOCC1>C(OCC)C>[O:14]1[C:15]2[C:6](=[CH:1][CH:2]=[CH:3][CH:16]=2)[CH2:5][CH2:12][CH2:13]1
Reactant: CCOCC
Reactant: Oc1ccccc1
Agent: FB(F)F
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 0 h

Procedure:
To a solution of phenol 4 (0.01 mol) and a catalyst, preferably boron trifluoride diethyl etherate (0.016 mol) in an organic solvent, preferably dry dioxane (10 mL), is added vinyl lactone 2 (0.016 mol) in an organic solvent, preferably dry dioxane (5.0 mL) over 1-60 minutes, preferably 60 minutes at 0-150° C., preferably 110° C., under an inert gas. The reaction mixture is stirred for 0 to 8 hours, preferably 0 hours, at the selected temperature, cooled to room temperature, and diluted with an organic solvent, preferably diethyl ether (200 mL). The reaction mixture is then washed with water (100 mL, 2×50 mL), dried over sodium sulfate (Na2SO4), and solvent is removed under reduced pressure to afford a brown oily residue. The residue is dissolved in alcohol, preferably methanol (30 mL), and the alcohol is then removed under reduced pressure. The brown oily liquid or semisolid is further purified by chromatography, preferably on silica gel, to afford pure racemic chroman derivative 5.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C2C(=CC(S(NC3(C(O)=O)CCCC3)(=O)=O)=CC=2)C(NC(N)=N)=NC=1.Cl.NC(N)=N.[CH2:40]([O:42][C:43](=[O:69])[C:44]1([CH2:68][CH2:67][CH2:66][CH2:65]1)[NH:45][S:46]([C:49]1[CH:58]=[C:57]2[C:52]([C:53]([Cl:64])=[CH:54][NH:55][C:56]2(Cl)[NH:59][C:60]([NH2:62])=[NH:61])=[CH:51][CH:50]=1)(=[O:48])=[O:47])[CH3:41]>CS(C)=O>[CH2:40]([O:42][C:43](=[O:69])[C:44]1([CH2:65][CH2:66][CH2:67][CH2:68]1)[NH:45][S:46]([C:49]1[CH:58]=[C:57]2[C:52]([C:53]([Cl:64])=[CH:54][N:55]=[C:56]2[NH:59][C:60]([NH2:62])=[NH:61])=[CH:51][CH:50]=1)(=[O:47])=[O:48])[CH3:41]
Reactant: CCOC(=O)C1(NS(=O)(=O)c2ccc3c(c2)C(Cl)(NC(=N)N)NC=C3Cl)CCCC1
Agent: Cl
Agent: N=C(N)N
Agent: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)O)CCCC3)cc12
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Temperature: 40 °C
Yield: 21.8 %

Procedure:
N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]cycloleucine trifluoroacetate ##STR48## NaH (1.12 g, 80% dispersion by wt in mineral oil, 37.3 mmol) was added portionwise to a stirred suspension of guanidine hydrochloride (5.85 g, 59.4 mmol) in DMSO (320 mL) and the mixture was heated at 30-50° C. under N2 for 30 min. N-[(1,4-Dichloro-1-guanidino-7-isoquinolinyl)sulphonyl]-cycloleucine ethyl ester (6.2 g, 14.9 mmol) was added in one portion and the mixture heated at 80° C. for 8 h. The cooled mixture concentrated in vacuo to ca. 160 mL and poured into water (800 mL). The aqueous mixture was extracted with EtOAc (4×150 mL) and the combined organic extracts were then washed with water, brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (95:5:0.5 to 90:10:1) as eluant and then recrystallised from EtOAc to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]cyclo-leucine ethyl ester (1.43 g, 3.25 mmol) as a yellow solid.