Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]=1[C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:45][CH2:46][CH2:47][OH:48]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:17][CH2:18][C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:22]([NH2:24])=[O:23])[CH2:20][CH2:21]2)=[O:15])=[CH:11][C:10]=1[C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:45][CH2:46][CH2:47][OH:48])=[CH:35][CH:36]=1
Reactant: NC(=O)C1(c2ccccc2)CCN(C(=O)c2cc(-c3ccc(O)cc3)c(-c3ccc(Cl)cc3Cl)s2)CC1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)C1(c2ccccc2)CCN(C(=O)c2cc(-c3ccc(OCCCO)cc3)c(-c3ccc(Cl)cc3Cl)s2)CC1
Temperature: 90 °C
Yield: 65.8 %

Procedure:
1.65 g of the compound obtained in stage 1G), 0.57 g of K2CO3 and 0.83 g of 3-chloropropan-1-ol are added to 10 ml of DMF. The reaction medium is heated at 90° C. for 3 hours. The reaction medium is then poured onto distilled water and the expected compound is extracted with ethyl acetate. The organic phase is dried and evaporated. After crystallizing in ethyl acetate, 1.2 g of the expected compound are obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.Cl.[Br:13][C:14]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:15]=1[O:16][CH:17]1[CH2:20][NH:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:13][C:14]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:15]=1[O:16][CH:17]1[CH2:20][N:19]([C:2]2[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH2:18]1
Reactant: Fc1ccc(Br)c(OC2CNC2)c1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CC(Oc3cc(F)ccc3Br)C2)cn1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a mixture of methyl 5-chloropyrazine-2-carboxylate (0.47 g, 2.7 mmol), 3-(2-bromo-5-fluorophenoxy)azetidine hydrochloride salt (0.80 g, 3.2 mmol) and potassium carbonate (0.75 g, 5.42 mmol) in dioxane (13 mL) was heated at 100° C. After a period of 4 h, the reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The resulting solid was taken in ether and filtered to give the title compound.
Reaction SMILES: CNC1N=C(C2C=CC=CN=2)C=C(C2C=NC=CC=2)C=1[C:21]1[CH:22]=[N:23][N:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=1.Br[C:33]1[CH:34]=[C:35]([C:39]2[CH:44]=[C:43]([NH:45][CH3:46])[N:42]=[C:41]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=3)[CH:40]=2)[CH:36]=[N:37][CH:38]=1>>[CH3:46][NH:45][C:43]1[N:42]=[C:41]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=2)[CH:40]=[C:39]([C:35]2[CH:36]=[N:37][CH:38]=[C:33]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:34]=2)[CH:44]=1
Reactant: CNc1nc(-c2ccccn2)cc(-c2cccnc2)c1-c1cnn(C2CCNCC2)c1
Reactant: CNc1cc(-c2cncc(Br)c2)cc(-c2cccc(C)n2)n1
Product: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2cccc(C)n2)n1

Procedure:
This compound is prepared analogously to Methyl-[5″-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.183) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1, step1) with (5″-Bromo-6-methyl-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 1.27).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH2:9].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CCOCC>[C:24]1([CH3:34])[CH:25]=[CH:26][C:27]([S:30]([OH:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1.[CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=1
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Yield: 47 %

Procedure:
This titled amide was prepared by general procedure B from trans-2-(dimethylamino)cyclohexylamine and 3-trifluoromethylbenzoyl chloride. The crude oil was converted to the salt with 1 mole of p-toluenesulfonic acid in ether, and was crystallized from MeOH-ether, 47% yield, colorless plates, m.p. 208°-209°.uv λmax 222 nm (ε22,150); sh 227 (17,900); sh 259 (1,550); sh 266 (1,100); sh 274 (566). ir NH/NH+ 3280, 3040; C=O 1660; C=C/amide II 1615, 1595, 1550, 1495; CF3 /SO3- /CN 1335, 1320, 1275, 1200, 1180, 1160, 1120, 1075, 1035, 1010; aromatic/SO3- 705, 690, 680. NMR in CDCl3 (100 MHz) was in accord. Mass spectrum M+ 3l4.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:9][C:3]1[C:2]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Cc1cnc(N)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cnc(N)c(-c2ccc(O)cc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 48.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.716 g) was added to a suspension of 3-bromo-5-methylpyridin-2-amine (3.86 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5 g) and sodium carbonate (2.19 g) in DME (150 mL) and water (30 mL) and the mixture was stirred at 80° C. under nitrogen for 5 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (1.99 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Br:14]Br.C([O-])(O)=O.[Na+]>>[Br:14][CH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-methanesulfonylacetophenone (480 mg; 2.42 mmol) in 15 mL HOAC was added Br2 (2.42 mmol). The reaction was stirred overnight at r.t. The reaction mixture was carefully poured into NaHCO3 solution and extracted with EtOAC. The reaction yielded a light yellow solid which was used with no further purifiCation.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19](OCC3C=CC=CC=3)=O)[CH2:16][C:14]2([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[Si](C)(C)C.C(N(C(C)C)CC)(C)C.[F:50][C:51]1[CH:52]=[N:53]C(Cl)=[N:55][CH:56]=1>C(#N)C>[Br:35][C:31]1[CH:30]=[C:29]([C:14]23[CH2:16][N:17]([C:19]4[N:53]=[CH:52][C:51]([F:50])=[CH:56][N:55]=4)[CH2:18][CH:13]2[CH2:12][S:11][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:15]3)[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(NC1=NC2(c3cccc(Br)c3)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Reactant: Fc1cnc(Cl)nc1
Agent: C[Si](C)(C)I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NC1=NC2(c3cccc(Br)c3)CN(c3ncc(F)cn3)CC2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 74 %

Procedure:
To a solution of racemic benzyl 2-benzamido-7a-(3-bromophenyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (1.6 g, 2.9 mmol) in acetonitrile (60 mL) is added iodotrimethylsilane (1.3 mL, 9.1 mmol). The resultant solution is stirred at ambient temperature for 3 hours and concentrated to dryness. The residue is purified by ion exchange chromatography (first elute with MeOH/CH2Cl2 (¼, 50 mL), followed by 7 N NH3 in MeOH/CH2Cl2 (¼, 50 mL)) to give after evaporation of the solvent 1.7 g of intermediate, N-[7a-(3-bromophenyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide. This is then dissolved in 1,4-dioxane (30 mL) and diisopropylethylamine (2.0 mL, 11 mmol) and 5-fluoro-2-chloropyrimidine (850 μL, 8.90 mmol) are added sequentially. The resulting solution is heated at 110° C. for 1 hour before additional diisopropylethylamine (1.0 mL, 5.7 mmol) is added and heating is continued for another 17 hours before it is cooled to room temperature and concentrated to dryness. The residue is purified by silica gel flash chromatography, eluting with gradient of ethyl acetate/dichloromethane (0% to 30%) to give the title compound (1.1 g, 73%). ES/MS (m/z): (79Br/81Br) 512/514 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[N-:16]=[N+:17]=[N-:18].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:16]([C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cccc(C2(O)CCCCC2)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C2(N=[N+]=[N-])CCCCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a solution of 1-[3-(methyloxy)phenyl]cyclohexanol (2.93 g, 14.22 mmol, 1 equiv) in CH2Cl2 (25 ml) under nitrogen at 0° C. was added sodium azide (1.85 g, 28.44 mmol, 2 equiv) then TFA (4.4 ml, 56.89 mmol, 4 equiv) slowly. 40 Ml of CH2Cl2 were then added and the resulting suspension was stirred at room temperature for 16 h then partitioned between Et2O and H2O. The two layers were separated and the organic phase was washed with H2O and a 1N aqueous NaOH solution then dried over MgSO4 and concentrated in vacuo to give 1-(1-azidocyclohexyl)-3-(methyloxy)benzene (D315) (2.78 g, 85%) as a clear oil which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:14]2[N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=O.[NH3:21]>CO>[C:15]1([C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][CH2:7][CH2:6][CH:5]([C:3]([NH2:21])=[O:2])[C:14]=3[N:13]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1CCCc2ccc(-c3ccccc3)nc21
Reactant: N
Solvent: CO
Product: NC(=O)C1CCCc2ccc(-c3ccccc3)nc21
Temperature: 100 °C

Procedure:
Methyl-2-phenyl-5,6,7,8-tetrahydroquinoline-8-carboxylate (4 g.) was dissolved in methanol previously saturated with ammonia (90 ml.) and heated in a bomb at 100° C for 4 days. Removal of the solvent in vacuo gave an oily solid which on recrystallisation from ethyl acetate gave the title compound as colourless needles (1.5 g.) mp 145° C. Found: C, 76.4; H, 6.5; N, 11.1% C16H16N2O requires: C, 76.2; H, 6.4; N, 11.1%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[CH3:7][S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O>>[CH3:7][S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: CSc1ccccc1C=O
Reactant: COC(=O)CN
Product: COC(=O)CNCc1ccccc1SC
Yield: 50 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 2-(methylthio)benzaldehyde. Yield 50%. MS M+H calculated 226.1; found 226.1
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.CCN(CC)CC>C(O)C>[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(-n2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 27.2 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 4-methylphenylhydrazine hydrochloride (237 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (108 mg, 27%).
Reaction SMILES: [CH3:1][N:2]1[CH2:10][CH2:9][CH:5]([C:6](O)=[O:7])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[CH3:31][NH:32][O:33][CH3:34].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:34][O:33][N:32]([CH3:31])[C:6](=[O:7])[CH:5]1[CH2:9][CH2:10][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CNOC
Reactant: CN1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(C)CC1
Reaction time: 0.08 h
Yield: 132.8 %

Procedure:
1-Methylisonipecotic acid (5.5 g, 38.4 mmol) was dissolved in dimethylformamide (100 ml) with heating. Diisopropylethylamine (8.0 ml, 46.1 mmol), 1-hydroxybenzotriazole (5.2 g, 38.4 mmol), and N,O-dimethylhydroxylamine hydrochloride (4.1 g, 42.2 mmol) were added and the reaction mixture was stirred 5 min. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.4 g, 38.4 mmol) was added and the resulting homogeneous solution was stirred for 63 hours at ambient temperature. The solvent was removed under reduced pressure. The residue was dissolved in water and the solution was basified to pH 9 with 5N sodium hydroxide solution. This aqueous solution was extracted with methylene chloride then saturated with sodium chloride and extracted with chloroform/isopropanol (3/1). The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give 9.5 g of a yellow liquid. Purification by flash chromatography (silica gel, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 5.7 g (80%) of product as a light yellow liquid.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][C:15]=1[CH3:16])=S)#[N:2].Cl.P(Cl)(Cl)(Cl)(Cl)Cl.[C:24](N=C(Cl)NCCSCC1N=CNC=1C)#[N:25]>C(Cl)Cl>[C:1]([N:3]=[C:4]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][C:15]=1[CH3:16])[NH:25][CH3:24])#[N:2]
Reactant: Cc1[nH]cnc1CSCCNC(Cl)=NC#N
Reactant: Cc1[nH]cnc1CSCCNC(=S)NC#N
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 1.5 %

Procedure:
To a suspension of N-cyano-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]thiourea (monohydrate, 765 mg) in CH2Cl2 (7 ml) was introduced dry HCl gas for a few minutes under ice-cooling. PCl5 (1.25 g) was added to the mixture and stirred at room temperature for 3 hrs. The reaction mixture containing N'-cyano-N-[2-(5-methylimidazol-4-ylmethylthio)ethyl]chloroformamidine was concentrated to small volume, diluted with CH2Cl2 (5 ml) and cooled to -5° C. To the mixture was added a solution of CH3NH2 in C2H5OH (40%, 15 ml) below 30° C. After stirring for 20 hrs. at room temperature, the reaction mixture was filtered and the filtrate was concentrated to small volume, diluted with CH3CN and filtered agein. The filtrate was dried up and the residue was purified with column chromatography [SiO2, CH3CN-CH3OH (4:1)], preparative thin layer chromatography [SiO 2, CH3COOC2H5 --CH3OH-- 28% NH3 (aq) (10:1:1)] and then recrystallization from CH3CN to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (10.4 mg). Yield 1.5%, m.p. 136.5°-138° C.
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC=CC=1>[Zn].C(O)(=O)C>[Cl:1][C:2](=[CH2:3])[CH2:4][C:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCCC1
Reactant: C=C(Cl)CCl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C(Cl)CC1(O)CCCCC1
Yield: 99 %

Procedure:
56.53 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 25.00 g of cyclohexanone, 75 g of toluene, 100 g of 5% acetic acid and 34.35 g of zinc powder at 45° C., and then the mixture was allowed to react at the same temperature for 3 hours. After the reaction was completed, zinc-derived insolubles were filtered off, and the resultant filtrate was subjected to separation. The organic phase was washed with a 7% sodium carbonate aqueous solution and dried over sodium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure to give 44.05 g of 1-(2'-chloroallyl)-1-cyclohexanol. The results were as follows.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].[S-:15][C:16]#[N:17].[K+]>C(O)C>[S:15]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4])[C:16]#[N:17]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Agent: [K+]
Solvent: CCO
Product: N#CSCC(=O)c1ccc(C(F)(F)F)cc1
Yield: 95.9 %

Procedure:
A solution of 25.64 g (96.0 mmole) of 2-bromo-1-(4-trifluoromethyl-phenyl)-ethanone, 10.27 g (105.7 mmole) of potassium thiocyanate and 130 mL of ethanol (130 mL) was heated to reflux for 2 hours, and then concentrated under reduced pressure. The residue was taken up in 700 mL of ethyl acetate, washed three times with 75 mL of water, then 75 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 22.57 g of 2-thiocyanato-1-(4-trifluoromethyl-phenyl)-ethanone as an orange-brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C@@H:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([OH:13])[C@H:11]([NH:22][C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O)c1ccccc1

Procedure:
A solution of 29.7 g of 1-tert-butoxycarbonyl-3.4-epoxypyrrolidine and 41 ml of (R)-(+)-α-methylbenzylamine in 250 ml of ethanol was heated under reflux for 16 hours. The solvent was removed under reduced pressure, and a residue was subjected to silica gel column chromatography. From an eluant of a mixture of chloroform and methanol (98:2 by volume.), an oily titled compound weighing 15.3 g was obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[N:10]=[CH:11][C:12]3[N:13]([CH:24]=[N:25][CH:26]=3)[C:14]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=2[F:23])=[O:8])[CH2:3][CH2:2]1.COC(C1N=CC2N(C=NC=2)C=1NC1C=CC([Br:44])=CC=1F)=O>>[Br:44][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[N:13]3[CH:24]=[N:25][CH:26]=[C:12]3[CH:11]=[N:10][C:9]=2[C:7]([NH:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[O:8])=[C:17]([F:23])[CH:18]=1
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Reactant: O=C(NOCC1CC1)c1ncc2cncn2c1Nc1ccc(I)cc1F
Product: O=C(NOCC1CC1)c1ncc2cncn2c1Nc1ccc(Br)cc1F

Procedure:
The title compound was prepared in an analogous fashion to N-(cyclopropylmethoxy)-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide, using 5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester as the starting material. 1H NMR (MeOD, 400 MHz) 8 ppm 8.74 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.48 (dd, J=10.4 Hz, 3.2 Hz, 1H), 7.30 (d, 8.4 Hz, 1H), 6.75 (t, J=8.4 Hz, 1H), 3.79 (d, J=7.2 Hz, 2H), 1.26-1.13 (m, 1H), 0.62-0.55 (m, 2H), 0.36 to 0.30 (m, 2H); LCMS (method D1): RT=0.985 min, [M+H]+=420/422.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[CH3:26][C:27]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])[CH3:28]>ClCCl>[Si:30]([O:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[CH:9]2)=[CH:17][CH:16]=1)([C:27]([CH3:29])([CH3:28])[CH3:26])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccc(-n2cnc(-c3ccccc3)c2)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(-n2cnc(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a stirred mixture of 2-[4-(4-phenyl-1H-imidazol-1-yl)phenyl]ethanol (5.36 g, 20.3 mmol) and imidazole (2.7 g, 40.6 mmol) in dichloromethane (100 mL) was added TBSCl (3.67 g, 24.3 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The volatile components were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 5:1 to 2:1) to afford 5.6 g (73%) of the title compound as white solids: 1H-NMR (CDCl3)δ0.00 (6H, s), 0.88 (9H, s), 2.87 (2H, t, J=6.6 Hz), 3.84 (2H, t, J=6.6 Hz), 7.26-7.30 (2H, m), 7.35-7.44 (5H, m), 7.54-7.55 (1H, m), 7.82 (1H, br), 7.85 (2H, d, J=1.2 Hz).
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].N1C=CC=CC=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>ClCCCl.CN(C1C=CN=CC=1)C>[F:36][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:43](=[O:45])[CH3:44])=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13]
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)Oc1ccc(C(Cc2ccncc2)c2ccc(NCc3ccccc3)nc2)cc1OC(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1ccccc1)c1ccc(C(Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cn1
Reaction time: 24 h
Yield: 26.9 %

Procedure:
To a solution of 4-(2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(benzylamino)3-pyridyl]ethyl)pyridine from Example 1 (100 mg, 0.2 mmol) in 3 mL of 1,2-dichloroethane, was added 0.077 mL (0.96 mmol) of pyridine followed by 0.012 mg (0.1 mmol) of DMAP and 0.056 mL (0.6 mmol) of acetic anhydride. The solution was stirred 24 h at reflux, quenched with water and diluted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Gradient 100% ethyl acetate to 10% EtOH/ethyl acetate) to afford 29 mg (27%) of the acetamide.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=O)C.[C:16](#[N:20])[CH2:17][C:18]#[N:19]>>[NH2:19][C:18]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:6]=2[C:7](=[O:8])[C:17]=1[C:16]#[N:20]
Reactant: N#CCC#N
Reactant: COc1ccc(OC(C)=O)c(C(=O)Cl)c1
Product: COc1ccc2oc(N)c(C#N)c(=O)c2c1

Procedure:
In the same way as described in Example 3, 2-acetoxy-5-methoxy benzoyl-chloride and malononitrile are reacted to give crystals, mp 320°C after recrystallization from methanol.