Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:43])[C@H:7]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[N:12]1[C:23](=[O:35])[CH2:24][CH2:25][S:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[C:27]([S:26][CH2:25][CH2:24][C:23]([N:12]1[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[CH2:14][CH2:15][C@H:11]1[C:9]([NH:8][C@H:7]([C:6]([OH:43])=[O:5])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:10])=[O:35])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CCSC(=O)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(SCCC(=O)N1C(c2ccccc2O)CC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
The mixture of 0.7 g of (2S)-N-[[1-(S-benzoyl-3-mercaptopropanoyl)-5-(2-hydroxyphenyl)-2-pyrrolidinyl]carbonyl]-phenylalanine t-butyl ester obtained in Example 15, 2.7 g of trifluoroacetic acid and 0.6 g of anisole is stirred at room temperature for 4 hours. After removing trifluoroacetic acid and anisole from it, the reaction mixture is purified by silica gel column chromatography to give 0.5 g (79%) of the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH3:18][S:19][CH2:20]Cl>CC(C)=O>[CH3:18][S:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: CSCCl
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSCOc1cccc(C=O)c1
Reaction time: 80 h
Yield: 36.3 %

Procedure:
3-Hydroxybenzaldehyde (6.106 g, 50.00 mmol) was dissolved in acetone at room temperature. K2CO3 (13.821 g, 100.00 mmol), NaI (7.569 g, 50.00 mmol) and chloromethyl methyl sulfide (4.19 mL, 50.00 mmol) were added, and the mixture was allowed to stir for 80 h. The mixture was filtered, the filtrate concentrated to an oil, and the residue purified by SiO2 eluted with 99:1 CH2Cl2/MeOH to give 3.309 g (36.31%) of a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10]([C:35]1[CH:34]=[C:33]([F:46])[C:32]([OH:47])=[C:31]([Cl:30])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl (trans-4-((3-acetyl-6-bromoquinolin-4-yl)amino)cyclohexyl)carbamate (46 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) to afford the desired product (38 mg, 72%) as a light brown solid. ESI MS m/z 528 [C28H31ClFN3O4+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([Br:28])=[CH:26][C:25]([NH:29][CH2:30][CH2:31][CH2:32][NH2:33])=[CH:24][C:23]=1[Br:34]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:33][CH2:32][CH2:31][CH2:30][NH:29][C:25]3[CH:24]=[C:23]([Br:34])[C:22]([NH2:21])=[C:27]([Br:28])[CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: NCCCNc1cc(Br)c(N)c(Br)c1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCCNc1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 3-(4-amino-3,5-dibromophenylamino)-propylamine analogously to Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Br:20]
Reactant: COC(=O)c1ccc(F)cc1Oc1ccc(N)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1Oc1cnc(N)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of EXAMPLE 318B (1.6 g) in N,N-dimethylformamide (50 mL) was cooled to 0° C., followed by the addition of N-bromosuccinimide (1.195 g) in N,N-dimethylformamide (10 mL) solution. The reaction mixture was stirred at 0° C. for 1 hour, and quenched with ice-cold saturated NaHCO3 aqueous solution. The reaction mixture was extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified using flash column purification with 30-40% ethyl acetate/hexane to provide the title compound.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.Br[CH2:9][C:10]([O:12]CC)=[O:11].Cl>O.CS(C)=O>[N:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: c1cc[nH]c1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)Cn1cccc1
Reaction time: 1 h

Procedure:
To a mixture of potassium hydroxide (16.7 g) and dry DMSO (150 mL), pyrrole (5 g) was added dropwise at 20-25° C., with stirring under nitrogen atmosphere. Stirring was continued for 1 hr at 20-25° C. Ethyl bromoacetate (24.5 g) was added dropwise at 20-25° C. and stirring was continued for 2 hr. In the reaction mixture (150 mL) DM water was added and pH was made acidic (pH=3) with 20% HCl (50 mL). The reaction mixture was extracted with diethyl ether (2×100 mL). The combined organic extract was washed with DM water (100 mL), saturated brine (100 mL) and dried over Na2SO4. The solvent was evaporated to obtain pyrrol-1-yl-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:6]=1[C:7]([NH2:9])=[O:8].CO[C:18](OC)([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:19][C:18]1([CH3:20])[NH:1][C:2]2[N:3]=[C:4]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:5][C:6]=2[C:7](=[O:8])[NH:9]1
Reactant: COC(C)(C)OC
Reactant: NC(=O)c1sc(N2CCOCC2)nc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)NC(=O)c2sc(N3CCOCC3)nc2N1
Temperature: 100 °C
Yield: 16 %

Procedure:
A mixture of 4-amino-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide (0.22 g, 0.98 mmol; prepared according to Liebigs Annalen der Chemie, 1986, 4, 780-4), 2,2-dimethoxypropane (3 mL, excess), acetone (2 mL, excess) and p-toluenesulfonic acid monohydrate (cat. amount) was heated to 100° C. in a sealed tube, under microwave irradiation, for 1 h. The reaction mixture was then concentrated in vacuo and purification by preparative HPLC gave the title compound (0.04 g, 16%) as an off-white solid. δH (DMSO-d6) 7.54 (1H, s), 7.01 (1H, s), 3.73-3.63 (4H, m), 3.49-3.38 (4H, m), 1.38 (6H, s). LCMS (ES+) 269.0 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][O:20][CH3:21])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.CS(O)(=O)=O.[C:27](=O)(O)[O-:28].[Na+]>CO>[CH3:21][O:20][CH:19]([O:28][CH3:27])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH:5]([O:4][CH3:1])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:13][CH:14]=1
Reactant: COC=Cc1ccc(C(OC(C)=O)c2ccccc2)cc1
Reactant: O=C([O-])O
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CO
Product: COC(Cc1ccc(C(OC)c2ccccc2)cc1)OC

Procedure:
By the method of example 48, 1-bromo-4-(2-methoxyethenyl)benzene is lithiated and added to benzaldehyde. The crude product is acetylated with acetic anhydride in the presence of DMAP, providing alpha-(4-(2-methoxyethenyl)phenyl)benzyl acetate as a colorless oil. This ester (1.76 g) is treated with methanesulfonic acid (0.5 ml) in methanol (25 ml) at 50° for 16 hr. The acetoxy group and the enol ether are both solvolyzed in this reaction. The mixture is cooled, poured into saturated aqueous sodium bicarbonate, and extracted with three portions of ether, which are dried and evaporated to leave 1-(2,2-dimethoxyethyl)-4-((methoxy)(phenyl)methyl)benzene as a colorless oil (1.62 g). The methoxy group is hydrogenolyzed by dissolving this material in ethyl acetate (100 ml), and shaking with 10% Pd/C under 50 psi hydrogen for 60 hr. Filtration and evaporation provide 1-(2,2-dimethoxyethyl)-4-(phenylmethyl)benzene as a colorless oil (1.46 g). By the method of example 1(B&C), this is converted into the title compound, which is obtained as a pale yellow solid, mp 148°-150° after recrystallization from hexaneethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O1CCOCC1.O>[N:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][N:5]3[CH:8]=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccncc1
Reactant: Clc1ccn2ccnc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1COCCO1
Product: c1cc(-c2ccn3ccnc3c2)ccn1
Temperature: 65 °C
Yield: 88 %

Procedure:
Charge a 250 mL round bottom flask equipped with a magnetic stirrer, temperature controlled heating mantle, under N2 atmosphere, condenser, with 7-chloro-imidazo[1,2-a]pyridine (4.0 g, 26.2 mmol), 4-pyridyl boronic acid (3.54 g, 28.8 mmol 1.1 Eq), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (600 mg) [X-Phos can be used as an alternate ligand in this reaction], Pd(OAc)2 (145 mg), K3PO4 (11.1 g, 52.6 mmol), and dioxane: H2O 2:1 (170 mL). Warm the reaction while purging with a N2 needle, then heat to 65° C. for 18 hours. Cool the reaction to room temperature and transfer to a separatory funnel and siphon off the bottom layer (25 mL). Add EtOAc and evaporate the solvents under reduced pressure off. Take the solids up into EtOAc again, and evaporate under reduced pressure to azeotrope off traces of water. Dissolve the brown solid into CH2Cl2 and 5% MeOH and then chromatograph using SiO2 eluting with a slow gradient of 0% to 10% of 2 M NH3 in MeOH with the balance CH2Cl2. Evaporate the product fractions under reduced pressure to give a light yellow/tan solid 4.5 g (89%). MS (ES), m/z 196 (M+1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12]C(=O)C)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.OS(O)(=O)=O>CO>[C:1]1([C:7]2[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1nc(-c2ccccc2)c[nH]1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Nc1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Yield: 41.9 %

Procedure:
To a solution of the above 0.5 g (2.4 mmol) N-(4-phenyl-1H-imidazol-2-yl)-acetamide in MeOH (20 mL) was added water (20 mL) and conc. H2SO4 (1 mL). The mixture was refluxed under nitrogen for 2 days. After cooling to rt, the organic solvent was removed under vacuum. The reaction mixture was neutralized with saturated sodium bicarbonate aq. solution (50 mL) and extracted with ethyl acetate (150 mL). The organic layer was dried and condensed. The residue was purified by a flash column chromatography eluting with EtOAc then EtOAc/MeOH=7:1 to give 4-phenyl-1H-imidazol-2-ylamine (160 mg, 41%). LCMS: 160 (M+1)+.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[C:63]([CH3:76])=[N:64][N:65]([CH2:68][C:69]5[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[CH:70]=5)[C:66]=4[CH3:67])=[CH:60][N:59](S(C4C=CC(C)=CC=4)(=O)=O)[C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[CH:87]1[CH2:92][CH2:91][N:90]([C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])[CH2:89][CH2:88]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[C:63]([CH3:76])=[N:64][N:65]([CH2:68][C:69]5[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[CH:70]=5)[C:66]=4[CH3:67])=[CH:60][NH:59][C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[CH:87]1[CH2:88][CH2:89][N:90]([C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])[CH2:91][CH2:92]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)cc12
Yield: 69.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (200 mg, 0.265 mmol) was hydrolyzed by lithium hydroxide (56 mg, 1.329 mmol) in THF/methanol/water (5/3/1 mL) to yield 110 mg (69.6% yield) of the titled compound. MS: m/z=598.5 (M+1).
Reaction SMILES: N1C=CC=CC=1.S(Cl)([Cl:9])=O.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[S:21]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([I:33])=[CH:30][CH:31]=2)[C:26]([C:35]2[C:36]([O:41][CH2:42][CH3:43])=[N:37][CH:38]=[CH:39][CH:40]=2)(O)[C:25]1=[O:44])(=[O:23])=[O:22]>ClCCl>[Cl:9][C:26]1([C:35]2[C:36]([O:41][CH2:42][CH3:43])=[N:37][CH:38]=[CH:39][CH:40]=2)[C:27]2[C:32](=[CH:31][CH:30]=[C:29]([I:33])[CH:28]=2)[N:24]([S:21]([C:14]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=2[O:12][CH3:11])(=[O:23])=[O:22])[C:25]1=[O:44]
Reactant: CCOc1ncccc1C1(O)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(I)cc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ncccc1C1(Cl)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(I)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyridine (40 μl, 0.46 mmol) and thionyl chloride (35 μl, 0.46 mmol) were added successively to an ice-cooled solution of 1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydroindol-2-one (100 mg, 0.15 mmol) in dichloromethane (30 ml). The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Ice-water was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product (110 mg) was employed without further purification in the next stage.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH:20]2[CH2:22][CH2:21]2)[OH:19])[C:13]=1[O:23][CH3:24].C(N(CC)CC)C>ClCCl.O>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[C:13]=1[O:23][CH3:24]
Reactant: COc1c(Cl)ccnc1C(O)C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Cl)ccnc1C(=O)C1CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 90.6 %

Procedure:
10.22 ml of oxalyl chloride was dissolved in 300 ml of anhydrous dichloromethane, and under cooling at −78° C., 100 ml of anhydrous dichloromethane solution of 8.95 ml of anhydrous dimethylsulfoxide was dropped thereto. The resulting mixture was stirred at −78° C. for 40 minutes, and thereafter, 200 ml of anhydrous dichloromethane solution of 19.25 g of (4-chloro-3-methoxy-2-pyridyl)cyclopropylmethane-1-ol (IX) was dropped thereto. The resulting mixture was stirred at −78° C. for 30 minutes, and thereafter, the reaction temperature was elevated to −45° C. and the resulting mixture was stirred at the same temperature for 1 hour, and thereafter, 62.79 ml of triethylamine was dropped and the temperature of the resulting mixture was elevated to a room temperature. Water was added thereto and the resulting mixture was extracted with chloroform, and the resulting organic layer was washed with water and saturated salt water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; chloroform:ethyl acetate=20:1) to obtain 17.27 g of (4-chloro-3-methoxy-2-pyridyl)cyclopropylketone (X).
Reaction SMILES: [Cl-].[Cl-].[Ca+2:3].C=CC=C.C=CC1C=CC=CC=1.[NH4+].[OH:17][P:18]([O-:21])([OH:20])=[O:19]>>[P:18]([O-:21])([O-:20])([O-:19])=[O:17].[Ca+2:3].[P:18]([O-:21])([O-:20])([O-:19])=[O:17].[Ca+2:3].[Ca+2:3]
Reactant: O=P([O-])(O)O
Agent: C=CC=C
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C=Cc1ccccc1
Product: O=P([O-])([O-])[O-]

Procedure:
5 g of 30% aqueous CaCl2 (calcium chloride) solution was added into 100 g of cationic styrene-butadiene latex, BUTONAL® NX1118 from BASF Corporation. The latex remained as a stable dispersion. After mixing, 5 g of 35% aqueous (NH4)2HPO4 (ammonium biphosphate) solution was added under agitation. The latex pH remained below 4.5 during and at the end of (NH4)2HPO4 addition. This procedure was expected to produce approximately 2 wt % of calcium phosphate (Ca-phosphate) nano-crystals in the latex polymer. A thin latex film of approximately 250 μm was prepared by diluting the latex dispersion from 65% solids to 45% solids with water, spreading the dispersion on a polytetrafluoroethylene plate, and drying at room temperature. Masking tape was applied at four corners of the plate to keep the latex dispersion wetting the plate. After completely drying, the film was cut to expose a thin cross-section, and the cross-section was observed under the optical microscope. The presence of fine nano-crystals was apparent in the entire polymer film as shown in FIG. 2.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([CH3:18])[CH:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][C:5]1[CH:4]=[C:3]([C:1]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19](=[O:27])[N:2]=2)[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:6]=1
Reactant: Cc1cc(C#N)nc(CCC(=O)OC(C)(C)C)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(CCC(=O)OC(C)(C)C)nc(-c2nc(=O)c3ccccc3s2)c1
Yield: 55 %

Procedure:
tert-Butyl 3-(6-cyano-4-methyl-2-pyridyl)propanoate (0.72 g, 2.9 mmol) and methyl thiosalicylate (0.99 g, 5.9 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 14 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:2, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (0.61 g, 54%) as white crystals.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([CH3:14])[N:13]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: Cc1csc(N)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1csc(NC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.85 mL (8.28 mmol) of cyclohexanone and 1.0 g (8.75 mmol) of 2-amino-4-methylthiazole in 10 mL of tetrahydrofuran was added 0.5 mL (8.75 mmol) of acetic acid and 4.64 g (21.8 mmol) of sodium triacetoxyborohydride. After stirring for 16 hr at rt, a further 0.45 mL (4.37 mmol) of cyclohexanone and 0.926 g (4.37 mmol) of sodium triacetoxyborohydride was added and stirring continued for 72 hr at rt. Ethyl acetate (15 mL) was added and the mixture washed with saturated sodium bicarbonate (2×15 mL) then dried (Na2SO4). Purification by chromatography on silica gave the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].I[CH2:26][CH2:27][CH3:28]>>[CH2:26]([O:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:27][CH3:28]
Reactant: CCCI
Reactant: Cc1cc2c(cc1-c1ccc(O)c(C=O)c1)C(C)(C)CCC2(C)C
Product: CCCOc1ccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1C=O
Yield: 97.3 %

Procedure:
In a similar manner to Example 10(b), by reaction of 2 g (6.2 mmol) of 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)benzaldehyde [prepared in Example 16(a)] with 670 μl (6.8 mmol) of 1-iodopropane, 2.2 g (88%) of the expected product are obtained in the form of a colourless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][N:15]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH3:23])[NH:17][C:16]3=[C:12]2[C:11](=[O:24])[N:10]([CH2:25][CH2:26][CH3:27])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([N:8]1[C:13]2=[N:14][N:15]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH3:23])[N:17]([CH3:29])[C:16]3=[C:12]2[C:11](=[O:24])[N:10]([CH2:25][CH2:26][CH3:27])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1cn2nc3c(c(=O)n(CCC)c(=O)n3Cc3ccccc3)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCc1cn2nc3c(c(=O)n(CCC)c(=O)n3Cc3ccccc3)c2n1C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
In DMF (20 ml) was dissolved 1-benzyl-6-butyl-3-propyl-1,2,3,4-tetrahydro-5H-imidazo [2',1':5,1]pyrazolo[3,4-d]pyrimidine-2,4-dione (0.5 g). To the solution were added, at room temperature, K2CO3 (0.5 g) and methyl iodide (0.5 g). The mixture was stirred for 8 hours and concentrated to dryness. To the residue was added water, then precipitating crystals were recrystallized from aqueous methanol to give colorless crystals (0.51 g, 98%), m.p. 139°-140° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20](O)=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[CH3:45][O:46][C:47](=[O:50])[CH2:48][NH2:49]>CN(C=O)C.ClCCl>[CH3:45][O:46][C:47](=[O:50])[CH2:48][NH:49][C:20](=[O:21])[C@@H:19]1[CH2:23][CH2:24][CH2:25][N:18]1[C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)CN
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C

Procedure:
To a solution of N-Cbz-valylproline (Cbz-NH-[VP]-CO2H) (3.5 g, 10 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (1.6 g, 11 mmol) and triethylamine (2.0 g, 20 mmol) in DMF (15 mL) is added dropwise a solution of glycine methyl ester hydrochloride (1.38 g, 11 mmol) in DMF (5 mL). The solution is stirred at room temperature and the reaction monitored by TLC until the disappearance of N-Cbz-valylproline. The reaction solution is then diluted with dichloromethane (50 mL) and the organic layer is extracted with 0.1 N HCl (20 mL), water (20 mL), then dried over Na2SO4. The solvent is removed in vacuo to afford the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[I-:11].[Na+].Cl[O-].[Na+]>>[I:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: [I-]
Reactant: O=C(O)c1cccc(O)c1
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc(I)c(O)c1

Procedure:
3-Hydroxybenzoic acid (V) is iodinated in the presence of sodium iodide and of sodium hypochlorite in order to give 4-iodo-3-hydroxybenzoic acid (VI).