Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH2:16])[CH:10]=2)=[O:5])[CH3:2].N1C=CC=CC=1.[F:23][C:24]([F:41])([F:40])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([C:37](Cl)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:37]([C:32]1[C:31]([C:28]3[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:40])[F:41])=[CH:26][CH:27]=3)=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:38])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(N)ccc2c1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Yield: 159.1 %

Procedure:
7-Amino-quinoline-3-carboxylic acid ethyl ester (8.6 g, 39.8 mmol) was combined with pyridine (12.9 ml, 159 mmol) and 4-N,N-dimethylamino-pyridine (0.5 g, 4 mmol) in 100 ml of chloroform. The mixture was stirred as 4′-trifluoromethyl-biphenyl-2-carbonyl chloride (22.64 g, 79.5 mmol) was added as a solution in 100 ml of chloroform. After heating at reflux for 2 h, the mixture was concentrated under vacuum, the residue taken up in ethyl acetate (600 ml) and washed sequentially with a 1 N aqueous hydrochloric acid solution (2×200 ml), water, and brine. The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to yield 29.4 g of a red oil. This oil was purified by chromatography on silica, eluting sequentially with a 70:30 dichloromethane/hexanes solution, followed by dichloromethane, then a 10:90 ethyl acetate/dichloromethane solution. Concentration under vacuum of the product containing fractions afforded 13.15 g of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:20][C:21]1[CH:22]=[C:23]([OH:28])[C:24](=[CH:26][CH:27]=1)O.Cl>C1C=CC=CC=1.C(OCC)C>[CH3:20][C:21]1[CH:27]=[CH:26][C:24]2[O:8][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:28][C:23]=2[CH:22]=1
Reactant: Cc1ccc(O)c(O)c1
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1(c2ccccc2)Oc2ccc(C)cc2O1
Temperature: 25 °C
Yield: 15.7 %

Procedure:
To a solution of ethyl benzoylformate (520 mg, 2.92 mmoL) in dry benzene 5 mL) was added PCl5 (608 mg, 1.0 equiv). After stirring at reflux for 16 h TLC analysis indicated that all the starting material appeared consumed. The solvent was removed in vacuo and the crude dichloride (Rf=0.61 6:1 hexane/ethyl acetate) was mixed with 4-methyl-catechol (724 mg 2.0 equiv) and heated to 175° C. until HCl evolution ceased (ca. 20 min). The mixture was cooled to rt and the glue-like material was dissolved in diethyl ether and washed several times with 1N NaOH and then brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo and the residue was chromatographed on a silica column eluting with hexane/ethyl acetate (20:1). Removal of the solvent afforded 130 mg (16%) of the titled compound. Rf=0.57 (6:1 hexane/ethyl acetate).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cl
Product: COC(=O)Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
Hydrogen chloride was bubbled through a solution of (4-hydroxyphenyl) acetic acid (25 g, 0.16 mole) in methanol (100 ml) at room temperature. An exotherm resulted in the solution refluxing for about 10 minutes. The mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo to afford methyl(4-hydroxyphenyl)acetate as a yellow oil (27.5 g) which crystallised on seeding, m.p. 46-52° C.
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=1)[O:25][CH2:26][C:27]([O:29]C(C)C)=[O:28])=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>O>[CH2:3]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=1)[O:25][CH2:26][C:27]([OH:29])=[O:28])=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCc1cnc2c(C(=O)Nc3cccc(OCC(=O)OC(C)C)c3)cccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCCCc1cnc2c(C(=O)Nc3cccc(OCC(=O)O)c3)cccc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.6 %

Procedure:
Aqueous 2 N lithium hydroxide (0.7 mL, 1.4 mmol) and water (0.7 mL) were added to a solution of isopropyl 2-(3-(3-hexylquinoline-8-carboxamido)phenoxy)acetate (210 mg, 0.47 mmol) in THE (5.0 mL) and the solution was stirred at room temperature. After 20 h, the THF was removed in vacuo. The residual aqueous phase was adjusted to pH 4-5 with 1 N aqueous HCl and extracted with EtOAc (3×). The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford 177 mg (93%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][CH2:16][CH:17]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[S:19][CH2:18]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Cl:27][CH2:28][C:29](Cl)=[O:30]>ClCCl>[C:8]([O:12][C:13]([NH:15][CH2:16][CH:17]1[N:22]([C:29](=[O:30])[CH2:28][Cl:27])[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[S:19][CH2:18]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC1CSc2ccccc2N1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1CSc2ccccc2N1C(=O)CCl
Temperature: 0 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A 0.48 ml (3.47 mmol) portion of triethylamine was added to dichloromethane solution (10 ml) containing 0.81 g (2.89 mmol) of 3-(t-butoxycarbonyl)aminomethyl-3,4-dihydro-2H-1,4-benzthiazine and cooled to 0° C. This was mixed with 0.28 ml (3.47 mmol) of chloroacetyl chloride and stirred at room temperature for 3 hours. The reaction solution was poured into ice water and extracted with chloroform. The extract was washed with dilute hydrochloric acid and dried (Na2SO4), and then the solvent was removed by evaporation under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (180 cc; elution by ethyl acetate-hexane=1:1) and further recrystallized from ethyl acetate-hexane to obtain 0.64 g of the title compound (62% in yield).
Reaction SMILES: B(Cl)(Cl)Cl.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C@H:21]2[C@H:26]([O:27]CC3C=CC=CC=3)[C@@H:25]([O:35]CC3C=CC=CC=3)[C@H:24]([O:43]CC3C=CC=CC=3)[C:23]([CH2:51][O:52]CC3C=CC=CC=3)=[CH:22]2)=[CH:9][CH:8]=1.CO>C(Cl)Cl>[OH:52][CH2:51][C:23]1[C@@H:24]([OH:43])[C@H:25]([OH:35])[C@@H:26]([OH:27])[C@H:21]([O:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:12][CH:11]=2)[CH:22]=1
Reactant: COc1ccc(Cc2ccccc2O[C@@H]2C=C(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Cc2ccccc2O[C@@H]2C=C(CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.9 %

Procedure:
In a nitrogen stream, a boron trichloride 1.0 M methylene chloride solution (6.0 mL, 6.0 mmol) was added to a solution of 1-(4-methoxyphenyl)methyl-2-[(1R,4R,5S,6S)-4,5,6-trisbenzyloxy-3-(benzyloxymethyl)cyclohex-2-enyloxy]benzene (312 mg, 0.426 mmol) in methylene chloride (12 mL) at −78° C., and the mixture was stirred at the temperature for 1.5 hours. After addition of methanol, the temperature of the resulting solution was raised to room temperature and the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=methanol:methylene chloride (1:8)] to obtain the title compound (37.9 mg, 24%).
Reaction SMILES: C([O:8][NH:9][C:10]([C@@H:12]1[C@@H:17]([C:18](=[O:39])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[C:30]([CH3:38])[CH:29]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:15][CH:14]([CH2:40][C:41](O)=[O:42])[CH2:13]1)=[O:11])C1C=CC=CC=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:77]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]1.CN1CCOCC1>CN(C=O)C>[OH:8][NH:9][C:10]([C@H:12]1[CH2:13][CH:14]([CH2:40][C:41](=[O:42])[N:77]2[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]2)[CH2:15][CH2:16][C@@H:17]1[C:18]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[C:30]([CH3:38])[CH:29]=2)=[CH:22][CH:21]=1)=[O:39])=[O:11]
Reactant: C1CCNCC1
Reactant: Cc1cc(COc2ccc(NC(=O)[C@H]3CCC(CC(=O)O)C[C@@H]3C(=O)NOCc3ccccc3)cc2)c2ccccc2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(COc2ccc(NC(=O)[C@H]3CCC(CC(=O)N4CCCCC4)C[C@@H]3C(=O)NO)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 110.6 %

Procedure:
Part 10: 4-(2-Oxo-2-piperidin-1-yl-ethyl)-cyclohexan-1-(S)-,2-(S)-dicarboxylic acid 2-(S)-(benzyloxy-amide) 1-(S)-{[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-amide. To an oven-dried 5 mL conical vial equipped with a magnetic stir bar and under a nitrogen gas atmosphere was placed sequentially: {3-(S)-benzyloxycarbamoyl-4-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexyl}-acetic acid (20 mg, 0.034 mmol), anhydrous DMF (1 mL), PyBOP reagent (20 mg, 0.038 mmol), piperidine (0.010 mL, 0.101 mmol), and 4-methyl morpholine (0.01 mL, 0.092 mmol). After stirring the reaction mixture overnight, the reaction was quenched with 5% citric acid (1 mL) and the reaction mixture was diluted with ethyl acetate (15 mL) and water (4 mL). The aqueous layer was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with saturated sodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO4), and concentrated in-vacuo. Purification by Combiflash (0 to 10% methanol in methylene chloride over 30 min) to afford 21 mg (95%) of the desired amide. LCMS (ESI): 649 (M+1H).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:20]([CH3:22])[CH3:21])[C:9]([CH:18]=O)=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:25][C:26]([CH3:28])=[O:27]>>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:20]([CH3:22])[CH3:21])[C:9](/[CH:18]=[CH:25]/[C:26](=[O:27])[CH3:28])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CC(C)c1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1C=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)/C=C/c1c(C(C)C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carbaldehyde (40 mg) was added 1N sodium hydroxide (19.3 mg) and acetone (0.425 mL) at ambient temperature. After 8 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate=5-1) to give (3E)-4-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-3-buten-2-one as an yellow solid (33 mg).
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][C:15]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:16]=1[NH2:17]>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:17][C:16]1[C:18]([CH3:23])=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=1[CH3:14])#[CH:3]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: O=C([O-])OCC=Cc1ccccc1
Product: C#CC(Nc1c(C)cc(C)cc1C)c1ccccc1
Reaction time: 12 h
Yield: 84.8 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and 2,4,6-trimethylaniline (0.170 g, 1.25 mmol). The reaction was conducted at room temperature for 12 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 97/3. The mixture was purified by flash column chromatography on silica gel (1% ethyl acetate in hexanes) to give the title compound (0.207 g, 85%). HPLC analysis indicated the enantiomeric excess of the product was 96% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99.75/0.25; flow rate=0.6 mL/min; detection wavelength=254 nm; TR=17.0 (major), 19.5 (minor) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.38-7.23 (m, 5H), 6.78 (s, 2H), 6.05 (ddd, J=17.2, 10.0, 6.4 Hz, 1H), 5.25 (dt, J=16.8, 1.6 Hz, 1H), 5.17 (dt, J=10.4, 1.3 Hz, 1H), 4.61 (t, J=6.4 Hz, 1H), 3.12 (br s, 1H), 2.22 (s, 3H), 2.11 (s, 6H). 13C NMR (100.59 MHz, CDCl3) δ 142.92, 141.89, 139.34, 130.89, 129.77, 129.34, 128.41, 127.10, 126.93, 115.51, 64.19, 20.56, 18.61. Anal. Calcd for C18H21N: C, 86.01; H, 8.42; N, 5.57. Found: C, 86.18; H, 8.49; N, 5.62.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(C(C)=O)C>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([NH:7][C:16](=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:1][CH:2]=1
Reactant: Nc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCCC(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
Under a nitrogen atmosphere, p-aminophenol (109 g) was suspended in methyl ethyl ketone (2000 ml). To this suspension was added triethylamine (253 g) and then was added nonadecanoyl chloride (331 g), followed by refluxing with heating for 2 hours. The reaction mixture was cooled to room temperature to precipitate a white crystal. This crystal was filtered off under reduced pressure and recrystallized from methyl ethyl ketone to obtain 323 g of the desired product. Yield 80%; m.p. 138° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[N:14]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N[C@@H]2CCCC[C@H]2C(=O)OC(C)(C)C)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@@H]2CCCC[C@H]2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a solution of 1.146 g (3.1 mmol) of the product from Example 3 in 31 mL of DMF was added 0.137 g (3.42 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at 25° C. and then 0.42 mL (3.50 mmol) of benzyl bromide was added all at once. This reaction mixture was stirred for 10 hr at 55° C. and then poured into water and extracted with ether. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide a white solid which was recrystallized from EtOAc/Hexanes to provide 1.364 g (95%) of the desired product. 1H NMR(CDCl3): 7.7 ppm (dd, 2H, Ar), 7.1-7.4 (m, 5H, Ar), 6.9 ppm (dd, 2H, Ar), 4.5-4.7 ppm (AB quartet, 2H, CH2 --Ar), 3.9 ppm (s, 3H, OMe), 4.0 ppm (m, 1H, N--CH), 2.9 ppm (m, 1H, CH--CO2 --), 1.0-2.3 ppm (m, 17H, hydrocarbon protons).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br.Br[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:20]=1
Reactant: BrCc1cccnc1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Agent: Br
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1Cc1cccnc1

Procedure:
The title compound, MS: m/e=309.3 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-(bromomethyl)pyridine hydrobromide.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.CCN=C=NCCCN(C)C.[OH:31][C:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH:35]3[CH2:42][C:43](O)=[O:44])[CH2:33]1)[CH2:39]2>C(Cl)Cl>[OH:31][C:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH:35]3[CH2:42][C:43]([N:12]3[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]3)=[O:44])[CH2:33]1)[CH2:39]2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1C2CC3CC1CC(O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CC4CC1CC(O)(C4)C3)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Triethylamine 0.38 ml was added to a methylene chloride 15 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.44 g, and stirred at 0° C. for 30 min. WSC 0.53 g and 5-hydroxy-2-adamantyl acetic acid 0.44 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 14.5 hours. The reaction mixture was washed with saturated sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(5-hydroxy-2-adamantyl acetyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 95.5 mg and refluxed under heating for 1.5 hours. The reaction mixture was cooled, then added water, and removed the insoluble material by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform: methanol=150:1) to obtain the product. Yield: 556 mg (Yield 79%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[O:22][C:21](=[O:23])[C:20]([S:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:19]([OH:32])[CH:18]=2)[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][Si](C)(C)C(C)(C)C.Cl>C1COCC1>[OH:32][C:19]1[CH:18]=[C:17]([C:4]2[CH:3]=[C:2]([CH3:1])[C:7]([OH:8])=[C:6]([CH3:16])[CH:5]=2)[O:22][C:21](=[O:23])[C:20]=1[S:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc(C)c1O
Reaction time: 48 h

Procedure:
To a THF (10 mL) solution of 6-[3,5-dimethyl-4-[[dimethyl(1,1-dimethylethyl)silyl]oxy]phenyl]-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one at 0° C. is added 3 N HCl (9.0 mL). The reaction is stirred for 48 hrs. at room temperature. The reaction is quenched by pouring onto ethyl acetate and washed in succession with water, saturated sodium chloride; dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by flash column chromatography (SiO2 -230 to 400 mesh) using 50% ethyl acetate/hexanes. m.p. 174-176° C.; 1H NMR (250 MHz, DMSO-d6) δ2.21 (s, 6 H), 2.60 (m, 1 H), 3.96 (s, 2 H), 6.52 (s, 1 H), 7.23 (s, 5 H), 7.38 (s, 2 H), 9.06 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH2:17][CH2:18][C:19](O)=[O:20])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH2:17][CH2:18][C:19]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:20])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN
Reactant: COc1ccc(N(CCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)CCNC(=O)CCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-3-(p-anisidino)propionic acid and ethyl 3-aminopropionate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-3-(p-anisidino)propionyl]-3-aminopropionate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-3-(p-anisidino)propionyl]-3-aminopropionic acid (M.P. 171° to 172°).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2SC)[CH:5]=[CH:6][CH:7]=1.C([NH2:30])=O>O>[NH2:30][C:10]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:27])[C:14]2[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:17][C:13]=2[C:12](=[O:24])[N:11]=1
Reactant: CSc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Reactant: NC=O
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(N)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 198 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
4-[(3-chloro-2-methylphenyl)methyl]-5-(methylthio)-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (500 mg, 1.182 mmol) in formamide (8 ml, 201 mmol) was heated at 192° C. and stirred for 1 h. The temperature was increased to 198° C. and stirring was continued for additional 3 h. After cooling, water was added in and the precipitate was collected, washed with water, then Et2O and dried to give 437 mg of crude. The material was purified by prep HPLC on a Kromasil Silica 5u 60 A 21×250 mm column, eluting with 95:5—CHCl3:CH3OH (2M NH3) at 20 mL/min and collecting fraction at about 7.2 min. 5-amino-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (151 mg, 0.380 mmol, 32.1% yield) was obtained from the crude as an off white powder. LC/MS (ES) m/z=392.1 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.36 (d, J=7.83 Hz, 1H), 7.16 (t, J=7.96 Hz, 1H), 6.97 (s, 2H), 6.51 (d, J=7.58 Hz, 1H), 5.31 (s, 2H), 3.61-3.70 (m, 4H), 3.42 (t, J—=4.80 Hz, 4H), 2.38 (s, 3H)
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:11]Br>>[Br:11][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: BrBr
Reactant: C1C2CC3CC1CC(C2)C3
Product: BrC12CC3CC(CC(C3)C1)C2

Procedure:
The reaction was conducted in accordance with the method of The Japanese Patent Publication No. 61980/1995 (JP-B-7-61980) to obtain an adamantane monoaclylate, namely, 15 mole of anhydrousbromine and 1.6 mole of adamantane were reacted at the reflux temperature of bromine for 7 hours, surplus bromine was distilled off under reduced pressure, and after the addition of 200 ml of carbon tetrachloride (IV), the residual bromine was resolved with sodium sulfite. A white powderly 1-bromoadamantane was provided by removing organic layer, and recrystallizing the obtained crude products from methanol.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11].I>ClCCl>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][C@@H:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: I
Solvent: ClCCl
Product: O[C@@H]1[C@@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1[C@H]1COC2(CCCCC2)O1
Temperature: 65 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a mixture of 150 ml of cyclohexanone and 120 ml of dichloromethane were added 10.0 g of D-mannose and 175 mg of hydriodic acid (57%) and the mixture was refluxed with stirring in a water bath at 65° C. for 8 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. The reaction mixture was diluted with benzene, washed with aqueous sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The solvent and cyclohexanone were distilled off under reduced pressure to give 11.9 g (82.6%) of 2,3:5,6-di-O-cyclohexylidene-α-D-mannofuranose. After recrystallization from cyclohexane, it melted at 122°-124° C.