Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:17]=[CH:16][C:15]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([F:33])[CH:27]=3)(C3C=CC(O)=C(F)C=3)[S:14]2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH2:36](I)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(O)CCC>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:28]([F:33])[CH:27]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C2N=CC(c3ccc(O)c(F)c3)(c3ccc(O)c(F)c3)S2)cc1
Reactant: CCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCOc1ccc(-c2cnc(-c3ccc(CCCCCC)cc3)s2)cc1F
Yield: 89.5 %

Procedure:
In a 30 ml-round-bottomed flask, 1.07 g (3.01 mM) of 2-(4-hexylphenyl)-5-(3-fluoro-4-hydroxyphenyl)-5-(3-fluoro-4-hydroxyphenyl)thiazole prepared in Synthesis Example 7, 0.23 g (3.48 mM) of potassium hydroxide and 5 ml of butanol were placed and heated to provide a solution. To the solution, 0.74 g (3.49 mM) of hexyl iodide was gradually added under heat stirring, followed by stirring for 5 hours at about 90° C. After the reaction, the solvent in the reaction mixture was distilled off under reduced pressure and water was added to the residue to precipitate a crystal. The crystal was recovered by filtration and washed with water. The resultant crystal was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene-methanol) to obtain 0.90 g of 2-(4-hexylphenyl)-5-(3-fluoro-4-hexyloxyphenyl)thiazole (Yield: 68.0%). ##STR51##
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10])(=[O:5])=[O:4].C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[F:1][C:2]([F:16])([F:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([Cl:20])=[O:10])(=[O:5])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(S(=O)(=O)C(F)(F)F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(S(=O)(=O)C(F)(F)F)c1

Procedure:
A solution of the product of Example 6A (198 mg, 0.8 mmol) in dichloromethane (10 mL) was stirred with oxalyl dichloride (Aldrich, 2.0 mmol) and 1 drop of dimethylformamide at ambient temperature for 2 hours. The title compound was obtained by removing the solvent under vacuum as a yellow oil (250 mg) and the compound was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH2:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[CH3:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=2[Cl:32])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:41]([C:40]2[CH:44]=[CH:45][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)=[O:42])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCN)CCCC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCNC(=O)c2ccc(OC)cc2)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.1 %

Procedure:
To a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(2-aminoethyl)cyclopentyl]-carbonyl]-L-phenylalanine methyl ester (0.2 mmol, 101 mg) and 4-methoxybenzoyl chloride (0.25 mmol, 52.1 mg) in dichloromethane (1 mL) was added DIPEA (0.3 mmol, 38.7 mg) at room temperature. The reaction mixture was stirred for 15 h at room temperature and then diluted with 20 mL of dichloromethane. The dichloromethane layer was washed successively with water (20 mL) and brine solution (20 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent afforded a crude product which was purified by revesrsed phase HPLC to obtain 0.1 g (78%) of a yellow syrup. HR MS (C33H35Cl2N3O6): Obs. mass, 662.1778. Calcd. mass, 662.1801 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:43]=[CH:42][C:32]([C:33]([NH:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:34])=[C:31]([F:44])[CH:30]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:43]=[CH:42][C:32]([C:33]([NH:35][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:34])=[C:31]([F:44])[CH:30]=1
Reactant: NCc1ccc(C(=O)NC2CCCCC2)c(F)c1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(NC1CCCCC1)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1F

Procedure:
Use a method similar to the General Procedure 5-2 to react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.17 mmol) with 4-aminomethyl-N-cyclohexyl-2-fluoro-benzamide (441 mg, 1.76 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1, 7:1 and 5:1) to give 7-chloro-6-[4-(cyclohexylaminocarbonyl-)3-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[OH-].[Na+].[H][H]>[Pd]>[NH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:2]([CH3:1])[C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5]
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)Nc1nnn[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(N)c1C(=O)Nc1nnn[nH]1

Procedure:
A solution was prepared from 7.5 g of 2-methyl-6-nitro-N-(1H-tetrazol-5-yl)benzamide in 100 ml of aqueous 1N sodium hydroxide. A 0.5-g quantity of 5% Pd/C was added and the mixture was hydrogenated in a Parr apparatus at 3.3 atmospheres until uptake of hydrogen stopped (75 minutes). The catalyst was removed by filtration and the filtrate was treated with 100 ml of aqueous 1N hydrochloric acid. The white solid which formed was separated by filtration and air dried to give 2-amino-6-methyl-N-(1H-tetrazol-5-yl)benzamide melting at about 248° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:20]3[CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: NCCCN1CCOCC1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCN1CCOCC1
Reaction time: 10 h
Yield: 68.2 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.22 ml (0.01525 mol) of N-(3-aminopropyl)-morpholine were added thereto and the mixture was boiled for 43 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 120° and 140 bar for 10 hours. The product was chromatographed over silica gel with ethyl acetate/methanol 5:1, dissolved in hot isopropyl ether and crystallized at room temperature. There were obtained 3.58 g (68%) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-morpholin-4-yl-propyl)-2H-benzo[e]indol-2-one as white crystals with m.p. 65°-67° and 0.93 g (18%) of oily material from the mother liquors.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([NH:22][CH3:23])=[O:21])[O:19][C:15]=2[C:14](F)=[C:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]=1[CH3:31])#[N:10].C(N(CC)CC)C>CS(C)=O>[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([NH:22][CH3:23])=[O:21])[O:19][C:15]=2[C:14]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]=1[CH3:31])#[N:10]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CNC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CNC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Reaction time: 0.83 h

Procedure:
A dimethyl sulfoxide (1.5 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (57 μl, 446 μmol) was added to a dimethyl sulfoxide (6 ml) solution of 4-cyano-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-113) (115 mg, 372 μmol) and triethylamine (67 μl, 484 μmol) at 150° C., followed by stirring at the same temperature for 50 minutes under nitrogen atmosphere.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.CO[CH:17](OC)[CH2:18][CH2:19][C:20]#[N:21]>>[CH3:14][O:13][C:9]1[CH:8]=[C:7]2[C:4](=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12])[CH:5]=[C:19]([C:20]#[N:21])[CH:18]=[CH:17]2
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: COC(CCC#N)OC
Product: COc1cc2ccc(C#N)cc2c(OC)c1OC

Procedure:
2,3,4-Trimethoxybenzaldehyde (9.8 g) and 3-cyanopropionaldehyde dimethylacetal (6.35 mL) were treated under the same conditions as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: CO[C:3]1([CH3:24])[CH2:8][CH2:7][C:6]2[C:9]([CH3:23])=[C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1.[Cl-:25].[Ca+2].[Cl-].CCCCCC.Cl>C(OCC)C>[Cl:25][C:3]1([CH3:24])[CH2:8][CH2:7][C:6]2[C:9]([CH3:23])=[C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: COC1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(Cl)O2
Reaction time: 2 h
Yield: 100.6 %

Procedure:
A mixture of 10 g of rac-2-methoxy-3,4-dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran, 10 g of calcium chloride, 100 ml of hexane and 50 ml of diethyl ether was stirred at -5° to -10° C. while HCl gas was bubbled in for 1 hr. An additional 10 g of calcium chloride was added and stirring was continued at room temperature for 2 hr. The mixture was filtered and the filtrate was concentrated in vacuo giving 10.2 g of title product as a light-brown oil. Proton NMR analysis revealed that this product consisted of 66% of the title compound and 33% of the starting 2-methoxy chroman.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1>O.CO.[Pd]>[N:11]1([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:23])[F:25])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Temperature: 75 °C
Yield: 86.2 %

Procedure:
NH4COOH (15.5 g, 247 mmol) and 10% Pd/C (1.8 g) in water (2 mL) were added to a stirred solution of (4-benzyl-piperazin-1-yl)-(2-trifluoromethyl-phenyl)-methanone (8.6 g, 24.7 mmol) in MeOH (40 mL) and the resulting mixture was heated to reflux at 75° C. for 4 hrs. The reaction mixture was then filtered over celite and the filtrate evaporated. The resulting residue was dissolved in ethyl acetate, washed with 10% NaOH solution then brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 5.5 g (86%) of piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone. 1H NMR: (DMSO-d6): δ 7.8 (d, 1H), 7.7 (t, 1H), 7.6 (t, 1H), 7.4 (d, 1H), 3.5 (m, 2H), 3.0 (m, 2H), 2.7 (m, 5H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][S@:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH3:2].[O:12]1[CH2:14][C@@H:13]1[CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C(O)(C)C>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][S@:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH2:14][C@@H:13]([OH:12])[CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[CH3:2]
Reactant: N#Cc1ccc(OC[C@H]2CO2)cc1
Reactant: CCC[S@](=O)CCCNCC
Solvent: CC(C)O
Product: CCC[S@](=O)CCCN(CC)C[C@@H](O)COc1ccc(C#N)cc1
Yield: 102.4 %

Procedure:
A mixture of 3 g of ethyl (3-(S*)-propylsulfinyl)propylamine and 3.18 g of (R)-4-(oxiranylmethoxy)benzonitrile was refluxed for 16 h in 25 ml of isopropyl alcohol. After evaporation of the solvent, the crude product was dissolved in 2M hydrochloric acid, washed with ether, the solution brought to pH 11.5 with 2M sodium hydroxide and extracted with dichloromethane. Evaporation of the organic phase gave 6.11 g of an oil,
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:24]=[C:23]([C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[C:21]([CH3:33])[C:16]=1[O:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:19][CH2:18][O:17][C:16]2[C:15]([CH3:14])=[CH:24][C:23]([C:25](=[O:32])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:22][C:21]=2[CH3:33])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C(=O)c2ccccc2)cc(C)c1OCCBr
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2ccccc2)cc(C)c1OCCSc1cnn(C(C)(C)C)c(=O)c1Cl
Temperature: 25 °C
Yield: 94.1 %

Procedure:
In 50 ml of N,N-dimethylformamide were dissolved 6.6 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 10 g of 2-(2',6'-dimethyl-4'-benzoylphenoxy)ethyl bromide, and thereto was added 5 g of anhydrous sodium carbonate. The solution was stirred at room temperature for seventeen hours. The resulting solution was poured into water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure to give a crude product. The crude product thus obtained was purified by means of column chromatography (on silica gel, eluting with benzene) and crystallization (from 50 ml of n-hexanediethyl ether (4:1)) to give 13.3 g of the intended compound. m.p. 94.6°~96.2° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH:43]([Mg]Br)([CH3:45])[CH3:44].C(OCC)(=O)C>O1CCCC1>[OH:37][CH:36]([CH:43]([CH3:45])[CH3:44])[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:42])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: CC(C)[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(C)C)CC2)c2ccnn12
Reaction time: 1.5 h

Procedure:
To a solution of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.57 g) in tetrahydrofuran (5 mL) was added dropwise isopropylmagnesium bromide (1 M tetrahydrofuran solution, 2 mL) at 0° C., and the mixture was stirred for 1.5 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (10 mL), sodium borohydride (0.04 g) was added, and the mixture was stirred for 18 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.31 g, 56%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]([CH3:19])([CH2:17][CH3:18])[CH2:13][CH2:14][C:15]#N.[OH2:20].Cl>C(OCC)C.O1CCOCC1>[CH3:11][C:12]([CH3:19])([CH2:17][CH3:18])[CH2:13][CH2:14][CH:15]=[O:20]
Reactant: O
Reactant: CCC(C)(C)CCC#N
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCC(C)(C)CCC=O

Procedure:
Diisobutylaluminium hydride (1M solution in toluene, 18.5 ml.) was added to a solution of 4,4-dimethylhexanenitrile (2.0 g.) in dry diethyl ether (100 ml.) stirred under nitrogen. The mixture was refluxed for 3 hours and cooled. A solution of water (2 ml.) and dioxane (10 ml.) was added dropwise followed by dilute hydrochloric acid (80 ml.) and the solution stirred for 1 hour. Diethyl ether was added and the ethereal extracts separated. The ethereal extracts were dried (anhydrous magnesium sulphate) and evaporated to give 4,4-dimethylhexanal (1.3 g.). Nuclear Magnetic Resonance Spectrum (NMR) was as follows: 0.9,6H,s; 1.4,7H,m; 2.4,2H,m; 9.7,1H,t.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=[CH:3]1.[Li]CCCC.CN([CH:17]=[O:18])C>O1CCCC1>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=[C:3]1[CH:17]=[O:18]
Reactant: Cc1ncn(C)c1C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(C=O)n(C)c1C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a solution of 1,4,5-trimethyl-1H-imidazole (550 mg, 5 mmol) in dry tetrahydrofuran (15 mL) was added dropwise n-BuLi (3 mL, 2.5 M in hexane) at −40° C. After stirring for 2 h at this temperature, to the solution was added dried DMF (840 mg, 11.5 mmol) at −70° C. The resulting yellow suspension was stirred at −70° C. for 1 h, then at 0° C. for 0.5 h and quenched with ice-water. The mixture was extracted with ethyl acetate, and the organic extracts were dried with Na2SO4 before evaporation to afford an oily residue. The residue was purified by silica column (petroleum ether:ethyl acetate=3:1) to obtain 340 mg of white solid, yield: 50%. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.21 (s, 1H), 2.25 (s, 1H), 3.90 (s, 1H), 9.66 (s, 1H). LC-MS (ESI) m/z: 138(M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[O:5][C:4](=[O:10])[CH:3]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C)C=O>[Si:16]([O:9][CH2:8][C:6]1[O:5][C:4](=[O:10])[CH:3]=[C:2]([OH:1])[CH:7]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1cc(O)cc(CO)o1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(O)cc(=O)o1
Yield: 47 %

Procedure:
4-Hydroxy-6-hydroxymethylpyran-2-one (14.6 parts) was dissolved in dimethyl formamide (30 parts) at 20° C., imidazole (17.2 parts) was added and the temperature of the mixture cooled to 13° C. t-Butyldimethylsilyl chloride (17.1 parts) was then added in portions, the temperature was allowed to rise to 25° C. and maintained at 25°-30° C. by external cooling. The mixture was stirred for a further hour at 25°-30° C., before pouring into water (1100 parts) and stirring for 30 minutes until the product crystallised. The product was filtered off, washed with water (2×200 parts) and dried at 40° C./20 mm to give 6-t-butyldimethylsilyloxymethyl-4-hydroxy pyran-2-one (12.1 parts, 47%) m.pt 139°-141° C. Extraction of the filtrates with dichlorometane gave a further 7.0 parts, 27% of the product.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:10]=[C:11]=[O:12])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[CH2:25][C:24](=[O:26])[CH:23]=[CH:22][NH:21]2)=[CH:16][CH:15]=1>>[Br:1][C:2]1[C:3]([NH:10][C:11]([N:21]2[CH:22]=[CH:23][C:24](=[O:26])[CH2:25][C@H:20]2[C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)=[O:12])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)c(N=C=O)n1
Reactant: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Product: COc1ccc(Br)c(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)n1

Procedure:
(S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (3-bromo-6-methoxy-pyridin-2-yl)-amide was prepared by reaction of 3-bromo-2-isocyanato-6-methoxy-pyridine with (S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one using the procedure of step 3 of Example 1. MS (M+H) 421.
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:15])[C:11]=2[O:13][CH3:14])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>O1CCCC1>[NH2:15][C:10]1[C:11]([O:13][CH3:14])=[C:12]2[C:7]([CH2:6][CH2:5][C:4]2=[CH:3][CH2:2][NH:1][C:23](=[O:25])[CH3:24])=[CH:8][CH:9]=1
Reactant: COc1c(N)ccc2c1C(=CCN)CC2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(N)ccc2c1C(=CCNC(C)=O)CC2
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
3-(2-Aminoethylidene)-4-methoxyindan-5-amine (15.3 mg, 0.076 mmol) and triethylamine (21.2 μL, 0.152 mmol) were dissolved in tetrahydrofuran (0.9 mL), a solution of acetic anhydride (7.18 μL, 0.076 mmol) in tetrahydrofuran (0.1 mL) was added under ice-cooling, and the mixture was stirred for 15 min. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) to give the title compound (16.2 mg, yield 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14].[N:17]1[CH:22]=NN=[CH:19][N:18]=1>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:12]([Si:13]([CH3:15])([CH3:14])[CH3:16])=[CH:19][N:18]=[N:17][CH:22]=1
Reactant: c1nncnn1
Reactant: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])ccc1F
Solvent: C1COCCO1
Product: C[Si](C)(C)c1cnncc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
(2-Fluoro-5-nitrophenylethynyl)trimethylsilane (8.8 g, 37.1 mmol) and 1,4-dioxane were added to a solution of 1,2,4,5-tetrazine (35 ml, 18.6 mmol, 0.53 M in dichloromethane). The dichloromethane was distilled off and the dioxane solution was stirred at reflux for 36 hours. The solvent was removed to leave a brown oil. Purification by chromatography on silica gel eluting with dichloromethane, then with dichloromethane containing 1% methanol, gave 4-(2-fluoro-5-nitrophenyl)-5-trimethylsilanylpyridazine as a brown oil: m/z (ES+) 292 (M++H) and 249 (M+-3CH2).