Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60][CH:61]=[CH:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:60][CH:61]=[CH:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: N=C(OCC=Cc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg in 3 ml 33% methylene chloride in cyclohexane), cinnamyl trichloroacetimidate (52 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 15 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate: hexane (1:1)+1% methanol) gave the title compound (17 mg).
Reaction SMILES: [N:1](OC(C)(C)C)=[O:2].Cl.[CH3:9][O:10][N:11]=[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH2:13]1>C(OCC)(=O)C>[CH3:9][O:10][N:11]=[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][C:13]1=[N:1][OH:2]
Reactant: CON=C1COc2ccccc21
Reactant: CC(C)(C)ON=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CON=C1C(=NO)Oc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
At −10° C., 2 g (0.019 mol) of tert-butyl nitrite are added dropwise to 30 ml of ethyl acetate which is saturated with dry hydrogen chloride, and the mixture is stirred at this temperature for 15 minutes. At −10° C., 1.6 g (0.0098 mol) of benzofuran-3-one O-methyl-oxime dissolved in 5 ml of ethyl acetate are then added, the temperature is allowed to increase to 0° C. and the mixture is stirred at this temperature for 30 minutes. The crystalline product is filtered off, affording 1.08 g of crystalline benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime as a mixture of two stereoisomers comprising, according to HPLC analysis, 54.7% (56% of theory) of isomer B and 42.9% of isomer A.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:17]1[C:19]2([CH2:24][CH2:23][NH:22][CH2:21][C@H:20]2[OH:25])[CH2:18]1.C(N(CC)CC)C.N1C=CC=CC=1.CC(O)=O>CCO.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][N:22]1[CH2:23][CH2:24][C:19]2([CH2:17][CH2:18]2)[C@H:20]([OH:25])[CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CNCCC12CC2
Reactant: O=CCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=C(NCCCN1CCC2(CC2)[C@H](O)C1)OCc1ccccc1
Yield: 87.5 %

Procedure:
To a solution of 3-[(benzyloxycarbonyl)amino]-1-propanal (300 mg, 1.45 mmol) in EtOH (2 mL) and CH2Cl2 (2 mL) were added (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (284 mg, 1.74 mmol), triethylamine (176 mg, 1.74 mmol), borane pyridine complex solution (8 M in pyridine 0.34 mL, 3.2 mmol), and AcOH (400 mg, 6.66 mmol) at RT, then after 1 h the reaction mixture was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; EtOAc-MeOH gradient) produced the title compound (404 mg, 88%). Colorless gum, MS: 319.1 (M+H)+.
Reaction SMILES: Br[CH:2]([CH2:10][C:11]([Cl:14])(Cl)[Cl:12])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5]([OH:7])=[O:6].[Na]>C(O)C>[Cl:12][C:11]([Cl:14])=[CH:10][CH:2]1[O:6][C:5](=[O:7])[CH2:4][C:3]1([CH3:9])[CH3:8]
Reactant: CC(C)(CC(=O)O)C(Br)CC(Cl)(Cl)Cl
Agent: [Na]
Solvent: CCO
Product: CC1(C)CC(=O)OC1C=C(Cl)Cl

Procedure:
4-Bromo-3,3-dimethyl-6,6,6-trichlorohexanoic acid (0.8 g.) was added to a stirred solution of sodium (0.2 g.) in dry ethyl alcohol (25 ml.) at the ambient temperature, and the mixture refluxed for 1 hour, during which time a white precipitate was formed. The ethyl alcohol was removed by evaporation under reduced pressure and residual material partitioned between chloroform (10 ml.) and water (25 ml.). The aqueous phase was separated, acidified with concentrated hydrochloric acid to pH 1, and extracted with petroleum ether (boiling range 40° to 60° C., 3×15 ml). The combined petroleum ether extracts were washed with water (10 ml.), dried over anhydrous sodium sulphate, and concentrated by evaporation of the solvent under reduced pressure. The residual oil was purified by preparative thin layer chromatography using silica on glass plates with a methanol (20% by volume) and chloroform (80% by volume) mixture as eluent. 5(2,2-Dichlorovinyl)-4,4-dimethyl-2-oxotetrahydrofuran was obtained as a colourless oil having an Rf ca. 0.8 in the above t.l.c. system, and characterised by mass spectroscopic and infra-red spectral examination (m/e 208).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)CCC>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cnccn3)cccc2c1N
Yield: 45.4 %

Procedure:
Using method C, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (178 mg, 0.500 mmol) and 2-(tributylstannyl)pyrazine (219 mg, 0.600 mmol) were reacted to afford the title compound (70 mg, 45% yield) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 9.41 (m, 1H), 8.74 (m, 1H), 8.61 (d, J=2.5 Hz, 1H), 8.54 (br, 1H), 8.22 (m, 1H), 7.99 (m, 1H), 7.85-7.78 (m, 1H), 3.48 (apparent quartet, J=7.0 Hz, 2H), 1.69 (apparent sextet, J=7.0 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H). MS APCI, m/z=309 (M+H) HPLC 1.49 min.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30]([C:32]1([CH2:37][NH2:38])[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CO>[C:25]([O:29][C:30]([C:32]1([CH2:37][NH:38][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=3)=[O:4])[CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C1(CN)CCCC1
Solvent: CO
Product: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CCCC1

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (200 mg) and 1-aminomethyl-cyclopentanecarboxylic acid tert-butyl ester (250 mg, commercially available from J & W PharmLab LLC, Levittown Pa.) in MeOH (3 mL) was heated at 100° C. in an oil bath for 24 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (164 mg). LC MS ESI+: 488 (M+1)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[CH2:15][CH2:14][CH2:13][C:9]2=[N:10][C:11]=1[NH2:12])=[O:5])C.[OH-].[Na+].Cl>C(O)C>[NH2:12][C:11]1[N:10]=[C:9]2[CH2:13][CH2:14][CH2:15][C:8]2=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2c(nc1N)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc2c(cc1C(=O)O)CCC2
Temperature: 100 °C
Yield: 82.5 %

Procedure:
2-Amino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid ethyl ester (0.2 g, 0.97 mmol) described in Preparation Example C-4 was dissolved in ethanol (15 mL), an aqueous solution of 1N sodium hydroxide (7.5 mL) was added thereto, followed by heating at 100° C. for 30 minutes. The reaction solution was allowed to room temperature, then cooled on an ice bath, and neutralized with 1N hydrochloric acid. The precipitated solid was collected by filtration, rinsed with water, then dried, and the title compound (143 mg, 0.8 mmol, 83%) was obtained.
Reaction SMILES: [C:1]([Cu])#[N:2].[CH2:4]([C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10](I)[C:9]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)[CH2:5][CH2:6][CH3:7]>N1C=CC=CC=1.C(Cl)Cl>[CH2:4]([C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:1]#[N:2])[C:9]=1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([I:23])=[CH:21][CH:22]=1)[CH2:5][CH2:6][CH3:7]
Reactant: N#C[Cu]
Reactant: CCCCc1nc(C)nc(I)c1Cc1ccc(I)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc(C)nc(C#N)c1Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.5 %

Procedure:
A mixture of 800 mg (8.94 mmol) CuCN and 10 mL pyridine was heated to 110° C. until all of the CuCN went into solution (7 minutes). To this mixture was added a solution of 440 mg (0.894 mmol) 6-butyl-4-iodo-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine in 3 mL pyridine. After 5 minutes, the reaction mixture was cooled to room temperature, diluted with CH2Cl2, filtered through powdered cellulose flock, stripped of solvent in vacuo, and was medium pressure chromatographed on silica gel using 13% EtOAc/hexane to give 306 mg of the title compound, 87% yield. Rf 0.29 in 15% EtOAc/hexane, visualized by UV and ammonium molybdate/ceric sulfate stain;
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33]>[Pd].C(OCC)(=O)C>[OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33]
Reactant: CCCCCCC=CCc1cccc2c(=O)c(O)c(-c3cc(OC)c(OC)cc3OC)oc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCc1cccc2c(=O)c(O)c(-c3cc(OC)c(OC)cc3OC)oc12
Reaction time: 43 h
Yield: 77.7 %

Procedure:
A stirring suspension of 3-hydroxy-8-non-2-enyl-2-(2,4,5-trimethoxy-phenyl)-chromen-4-one 76 (0.258 g, 0.6 mmol) and 10% palladium on carbon (0.024 g) in ethyl acetate (30 ml) was placed under an atmosphere of hydrogen for 43 hours. The reaction was filtered through celite, the residue washed with ethyl acetate and the combined filtrates concentrated in vacuo to give a grey solid. Recrystallisation (petrol:ethyl acetate 2:1) yielded 3-hydroxy-8-nonyl-2-(2,4,5-trimethoxy-phenyl)-chromen-4-one 77 (0.212 g, 82%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[N:17]=1)=[O:14].CC1(C)C(C)(C)OB(C2CCN(C(OC(C)(C)C)=O)CC=2)O1.[O:45]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH2:48][CH2:47][CH2:46]1>>[O:45]1[CH2:50][CH2:49][CH2:48][C:47]([C:18]2[N:17]=[C:16]([NH:15][C:13]([NH:12][C:7]3[C:6]4[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[O:14])[CH:21]=[CH:20][CH:19]=2)=[CH:46]1
Reactant: CC1(C)OB(C2=COCCC2)OC1(C)C
Reactant: O=C(Nc1cccc(I)n1)Nc1ccnc2c(F)cccc12
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: O=C(Nc1cccc(C2=COCCC2)n1)Nc1ccnc2c(F)cccc12

Procedure:
The title compound was prepared as described in example 27 step 2, substituting 1-(6-bromo-quinolin-4-yl)-3-(6-trifluoromethyl-pyridin-2-yl)-urea by 1-(8-fluoroquinolin-4-yl)-3-(6-iodopyridin-2-yl)urea (example 47, step 1) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate by 2-(3,4-dihydro-2H-pyran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)#[N:2].C(O)(C)C.C(N(CC)CC)C>O>[C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)#[N:2]
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C#N)CC[C@@H]12
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C#N)CC[C@@H]12

Procedure:
A solution of 17β-cyano-5α-androstan-3-one (1.0 g.) in the minimum volume of isopropanol (ca. 75 ml.) was added to a stock solution of chloroiridic acid/trimethyl phosphite complex (50 ml.) preneutralised to pH4 with triethylamine (4 ml.). This solution, after being refluxed for 20 hours, was poured into water (200 ml.) and extracted with chloroform. The chloroform solution was washed with water, dried (MgSO4), filtered and evaporated to a gum (1.13 g.). This was subjected to preparative t.l.c. eluting successively with ethanol/chloroform (1:49) and ethyl acetate/benzene (1:19). The main band was removed between the eluant change and the final elution was repeated four times before removing the main band. This gave pure title compound (195 mg.) as a white solid; m.p. 156°-159°; [α]D + 56° (c 0.4%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[CH2:12]([N:16]=[C:17]=[O:18])[CH:13]([CH3:15])[CH3:14].C(OCC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:17]([NH:16][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:18])=[O:6]
Reactant: CC(C)CN=C=O
Reactant: NNC(=O)c1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CNC(=O)NNC(=O)c1cccc(Br)c1
Reaction time: 8 h

Procedure:
5.00 g (23.3 mmol) of 3-bromobenzoic acid hydrazide are placed in 50 ml tetrahydrofuran at room temperature. 2.70 g (27.2 mmol) of isobutyl isocyanate, dissolved in 10 ml tetrahydrofuran, are rapidly added dropwise with stirring to this suspension. The mixture is firstly further stirred at room temperature and then allowed to stand overnight. The precipitate formed after addition of 100 ml diethyl ether is filtered off and then washed with diethyl ether. An initial quantity of 1.42 g (19% of theory) of the target compound is thus obtained. The mother liquor is concentrated, and the residue again slurried in diethyl ether and filtered. After washing with diethyl ether and drying in vacuo, a further 5.62 g (77% of theory) of the target compound remain.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C([O-])(=O)C.[Na+].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:16](OC)=[O:17]>C(O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]2[C:16](=[O:17])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2)=[CH:21][CH:22]=1
Reactant: Nc1ccccc1S
Reactant: COC(=O)C(Br)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2ccccc2SC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-aminothiophenol (12.6 g) and o sodium acetate (23.6 g) in ethanol (150 ml) is added methyl α-bromo-4-fluorophenylacetate (23.6 g), and the mixture is stirred at room temperature overnight. After the solvent is distilled off, water is added to the residue. The resulting precipitate is separated by filtration, washed, dried, and then recrystallized from tetrahydrofuran-n-hexane to give 2-(4-fluorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (21.7 as crystals. M.p. 216°-219° C.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=2)=[CH:5][N:4]=1)=O.Cl.[CH:24]([C@H:27]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1)([CH3:26])[CH3:25].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:24]([C@H:27]1[CH2:32][CH2:31][C@H:30]([NH:33][CH2:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:5][N:4]=2)[CH2:29][CH2:28]1)([CH3:26])[CH3:25]
Reactant: CC(C)[C@H]1CC[C@H](N)CC1
Reactant: NC(=O)c1ccc(Oc2cnc(C=O)c3ccccc23)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)[C@H]1CC[C@H](NCc2ncc(Oc3ccc(C(N)=O)cn3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 6-(1-formylisoquinolin-4-yloxy)nicotinamide (Preparation 20) (150 mg, 0.51 mmol) and trans-4-isopropylcyclohexylamine hydrochloride (Preparation 9) (273 mg, 1.53 mmol) in 1,2-dichloroethane (10 mL) under argon was added acetic acid (30 μL, 0.51 mmol) followed by NaBH(OAc)3 (325 mg, 1.53 mmol). The mixture was stirred at rt for 16 h then the reaction solvent was removed in vacuo. The residue was partitioned between EtOAc (50 mL) and NaHCO3 (30 mL), and the organic phase washed with NaHCO3 (30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (SiO2, NH4OH:MeOH:DCM 0.5:5:95) to give the title compound: RT=2.85 min; m/z (ES+)=419.3 [M+H]+.
Reaction SMILES: O([C:8]([NH:10][C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][N:12]=1)=[O:9])C1C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.CN(C)C=O>O>[CH2:18]([NH:17][C:15]1[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][N:12]=[C:11]([NH:10][C:8]([NH:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[O:9])[N:16]=1)[CH2:19][CH3:20]
Reactant: CCCNc1nc(NC(=O)Oc2ccccc2)ncc1C(=O)OCC
Reactant: Nc1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCNc1nc(NC(=O)Nc2ccncc2)ncc1C(=O)OCC
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 28.7 %

Procedure:
To ethyl 2-((phenoxycarbonyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (E7, 2.89 g) and 4-aminopyridine (3.16 g), N,N-dimethylformamide (30 mL) was added at room temperature, and the mixture was stirred at 70° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then the reaction mixture was poured into water (300 mL). The solid matter was taken by filtration, and purified by silica gel column chromatography (eluent, ethyl acetate) to obtain ethyl 4-(propylamino)-2-(3-(pyridin-4-yl)ureido)pyrimidine-5-carboxylate (E8, 830 mg) as white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][C:6]=1[OH:28])(=[O:3])[CH3:2].[CH3:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH2:31].CO>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:30]([CH3:31])([CH3:29])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][C:6]=1[OH:28])(=[O:3])[CH3:2]
Reactant: C=C(C)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCOc1ccc(NC(C)=O)c(O)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOc1cc(O)c(NC(C)=O)cc1C(C)(C)c1ccccc1
Reaction time: 7 h

Procedure:
In 150 ml of toluene was dissolved 20 g of 2-acetylamino-5-hexadecyloxyphenol obtained in Preparation Example 3, and it was then heated at 80°-90° C. together with 8 g of Amberlyst 15 (produced by Rohm & Haas Co.). To this mixture was added dropwise 30 ml of α-methylstyrene, and the resulting mixture was heated as it is for about 7 hours. After the reaction was completed, Amberlyst 15 was removed by filtration and the filtrate was condensed. After the addition of methanol, the condensed filtrate was cooled with ice whereupon the desired product precipitated. The product was collected by filtration and washed well with methanol. Yield: 6.6 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2ncccc2c1
Reaction time: 0.08 h
Yield: 20.8 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (164 mg, 0.728 mmol) in dichloromethane (4 mL) was added pyridine (140 μL, 1.74 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-aminoquinoline (100 mg, 0.694 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic: phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink solid (48 mg, 21%), single spot at Rf 0.71 (ethyl acetate). mp 228.0-228.5° C., HPLC purity 99+% (tR 2.43 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.83 (1H, dd, J=4.2, 1.7 Hz), 7.98 (3H, m), 7.54 (1H, d, J=7.9 Hz), 7.48 (1H, d, J=2.7 Hz), 7.39-7.32 (2H, m), 7.20 (1H, t, J=7.9 Hz), 7.05 (1H, s, N—H), 2.75 (3H, s). LCMS: 331.16 (M−). FAB-MS (MH+, C16H13CIN2O2S): calcd 333.0464, found 333.0461.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[NH:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH2:9][CH2:10][C:11]([O:13][N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21])=[O:12]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To mixture of Boc-β-alanine (N-Boc-β-Ala-OH; 1 g, 5.29 mmol) and N-hydroxysuccinimide (0.9 g, 7.82 mmol) in DMF (10 mL) were added 1-hydroxybenzotriazole hydrate (HOBt.xH2O; 0.7 g, 5.25 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl; 1 g, 5.23 mmol) at 5° C. The reaction mixture was warmed to RT and stirred for 16 h. The progress of the reaction was monitored by TLC. The reaction was quenched with water and the mixture was extracted with EtOAc (2×150 mL). The combined organic layers were washed with water (3×100 mL) and brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was triturated with ether (2×25 mL) to afford N-Boc-β-Ala-OSu (1.1 g, crude) as a white solid. 1H NMR (500 MHz, CDCl3): δ 5.10 (br s, 1H), 3.52 (q, J=6.0 Hz, 2H), 2.85-2.82 (m, 6H), 1.31 (s, 9H).