Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[OH-:19].[Na+].[O-:21][Mn](=O)(=O)=O.[K+]>C(O)(C)C>[C:1]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:17][CH:18]=1)([OH:21])=[O:19]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(C(=O)c2cccnc2C(=O)O)cc1
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)O
Product: O=C(O)c1ccc(C(=O)c2cccnc2C(=O)O)cc1
Temperature: 25 °C

Procedure:
To a mixture of 3-(4-methylbenzoyl)-2-pyridinecarboxylic acid (6.0 g) and 0.1N-NaOH (340 ml) was added portionwise KMnO4 (8.0 g), while stirring at room temperature. After this mixture was heated at 90°-100° C. for 1.5 hour, isopropanol was added to the mixture, and the resulting precipitate was filtered off. To the filtrate was added c.HCl to adjust the pH 2. The solution was saturated with NaCl and extracted with ethyl acetate-THF (about 3:1). The extract was washed with ag. NaCl, dried, and the solvent was evaporated to give 3-(4-carboxybenzoyl)-2-pyridinecarboxylic acid as colorless crystals (1.50 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28](Cl)=[O:29].CO>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:28](=[O:29])[C:27]2[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:26]=2[Cl:25])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2c(C)cccc2Cl)Cc2ccccc2C1
Yield: 115.9 %

Procedure:
A test tube (25×150 mm) containing a stirring bar and 2-amino-indan-2-carboxylic acid ethyl ester (0.53 g, 2.58 mmol) is charged with dry DCM (3 mL). Stirring is initiated. After dissolution, the DIPEA (1.50 mL, 8.6 mmol) and 4-dimethylaminopyridine (2 mg, 17 μmol) are added. A solution of 2-chloro-6-methylbenzoyl chloride (5.8 mmol) in dry DCM (4 mL), as prepared above, is added to the reaction tube. After stirring for 18 h, tlc analysis (silica, 10% CH3OH in DCM) indicates complete consumption of the amine. The reaction mixture is diluted with DCM (10 mL) and washed with 5% aqueous HCl (2×5 mL) and brine (5 mL), dried over MgSO4 filtered and evaporated by pumping to constant weight gives 1.07 g of light brown solid. This material is purified by chromatography (silica, 2% to 20% EtOAc in DCM) on the ISCO Companion using a 40 g cartridge. Fractions 6-10 are combined, evaporated and pumped to yield a constant weight 550 mg of white amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:16][C@H:15]3[C@H:10]([NH:11][CH2:12][CH2:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:16][C@H:15]3[C@H:10]([N:11]([CH3:17])[CH2:12][CH2:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: Brc1ccc(N2C[C@@H]3CCCN[C@@H]3C2)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC#N
Product: CN1CCC[C@H]2CN(c3ccc(Br)cn3)C[C@H]21
Temperature: 25 °C
Yield: 64.2 %

Procedure:
Compound 23a (600 mg, 2.13 mmol) was dissolved in acetonitrile. Potassium carbonate (590 mg, 4.26 mmol) and iodomethane (652 mg, 3.20 mmol) were added. The resulting mixture was allowed to react overnight at 80° C. and monitored by TLC. After the reaction completed, it was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated saline solution, and dried over anhydrous sodium sulfate. Column chromatography afforded 405 mg of white solid (compound 23b), yield 64%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@:12]([CH3:20])([CH2:18]I)[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH3:29])[NH2:25].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Zn]>[NH2:25][C:24]1[CH:23]=[CH:22][C:28]([CH3:29])=[C:27]([CH2:18][C@@:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])([CH3:20])[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:26]=1
Reactant: COC(=O)C[C@](C)(CI)NC(=O)OCc1ccccc1
Reactant: Cc1ccc(N)cc1I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Zn]
Product: COC(=O)C[C@](C)(Cc1cc(N)ccc1C)NC(=O)OCc1ccccc1

Procedure:
Following the General Procedure of Description 15 (Part B), the zinc insertion product of (9c) is used in situ to cross couple with commercial 3-iodo-4-methyl-aniline (466 mg, 2.0 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (46 mg, 0.05 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (60 mg, 0.20 mmol, 10 mol-%) in anhydrous degassed DMF (6 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography furnish the title compound (9d).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)[CH:6]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[NH:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=2)[CH:20]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.Cl.CCOCC>>[Cl:18][C:12]1[CH:11]=[C:10]([C:7]2[CH:6]=[C:5]([CH2:4][CH2:3][NH:2][C:30]([C:27]3[CH:26]=[C:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[NH:29][N:28]=3)=[O:31])[O:9][N:8]=2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: O=C(O)c1cc(-c2cccnc2)[nH]n1
Reactant: N#Cc1ccc(-c2cc(CCN)on2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc(-c2cc(CCNC(=O)c3cc(-c4cccnc4)[nH]n3)on2)cc1Cl
Yield: 47.4 %

Procedure:
The title compound was prepared from 4-(5-(2-aminoethyl)isoxazol-3-yl)-2-chlorobenzonitrile hydrochloride (0.080 g, 0.282 mmol), 5-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid (0.053 g, 0.282 mmol), DIPEA (0.196 ml, 1.126 mmol 1), HOBt hydrate (0.065 g, 0.422 mmol) and EDCI (0.081 g, 0.422 mmol) using the method of Example 274. The title compound was converted to HCl salt by treatment of 1 M HCl ether solution for 2 h affording 0.056 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): 3.15 (t, 2H), 3.66 (m, 2H), 7.16 (s, 1H), 7.42 (bs, 1H), 7.90 (m, 1H), 8.02 (d, 1H), 8.13 (d, 1H), 8.21 (s, 1H), 8.63 (d, 1H), 8.75 (d, 1H), 8.83 (bs, 1H), 9.19 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][C:35]([F:38])([F:37])[CH2:34][CH2:33][C@@H:32]2[C:39]2[N:43](COCCOC)[N:42]=[CH:41][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.Cl>CO.ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][C:35]([F:38])([F:37])[CH2:34][CH2:33][C@@H:32]2[C:39]2[NH:43][N:42]=[CH:41][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COCCOCn1nccc1[C@H]1CCC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1Cl
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(O[C@H]2CC(F)(F)CC[C@@H]2c2ccn[nH]2)cc1F
Yield: 41 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 155i by using the 5-chloro-4-{[(1S*,2R*)-5,5-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (105 mg, 0.145 mmol) prepared in Example 156a, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL), dichloromethane (3.0 mL), 6 M hydrochloric acid (5.0 mL) and methanol (15 mL), to yield the title compound (29 mg, 41%) as a colorless solid.
Reaction SMILES: P([O-])([O-])[O-].[C:5]([O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][O:13][C:14](=[O:16])[CH3:15])(=O)[CH3:6].[CH2:17](O)[CH2:18]CC.C(OC(OCCCC)=CCC)CCC>[Pd]>[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH:5]=[CH:6][CH2:17][CH3:18])(=[O:16])[CH3:15]
Reactant: CCCCO
Reactant: CC(=O)OC/C=C\COC(C)=O
Agent: [Pd]
Agent: CCC=C(OCCCC)OCCCC
Agent: [O-]P([O-])[O-]
Product: CCC=COCCCCOC(C)=O
Reaction time: 5 h
Yield: 25.7 %

Procedure:
The reaction was carried out by adding 0.0020 g (0.0040 mmol) of trisdibenzylideneacetone dipalladium having a palladium content of 21.5 wt % and 0.0173 g (0.0162 mmol) of the above (L-26) bidentate phosphite in an amount of 4 equivalents to a container substituted with nitrogen, adding 1.418 g (8.233 mmol) of cis-1,4-diacetoxy-2-butene and 2.327 g (31.395 mmol) of 1-butanol thereto under nitrogen atmosphere, and heating the resultant mixture at 100° C. After reacting 5 hours, the resultant solution composition was analyzed by gas chromatography, and it was found that cis-1,4-diacetoxy-2-butene was converted at a conversion rate of 97.5%, and 71.8% of dibutoxybutene and 25.7% of acetoxybutoxybutene were produced.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:13]2[C:8](=[C:9]([CH3:17])[C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[S:7][CH2:6][CH2:5]1)[CH3:2].OO.[OH2:20].C(O)(=[O:23])C>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:17][C:9]1[C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=[C:13]2[C:8]=1[S:7](=[O:23])(=[O:20])[CH2:6][CH2:5][CH:4]2[O:3][CH2:1][CH3:2]
Reactant: CC(=O)O
Reactant: CCOC1CCSc2c1ccc(C(=O)O)c2C
Reactant: O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CCOC1CCS(=O)(=O)c2c1ccc(C(=O)O)c2C
Reaction time: 2 h

Procedure:
8.4 g (0.033 mol) of 4-ethoxy-8-methylthiochroman-7-carboxylic acid are initially introduced in 60 ml of acetic acid. A spatula tipful of sodium tungstate is added. 7.9 g (0.07 mol) is of 30% strength hydrogen peroxide solution are slowly added dropwise at 50° C. and the reaction mixture is subsequently stirred for 2 hours. It is then poured into water and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with bisulfite solution, then dried and concentrated.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)C>>[CH:10]([S:9][C:4]1[C:3]([CH2:2][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][C:16]([OH:28])=[O:15])=[CH:20][C:21]=2[O:26][CH3:27])=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCc1ccc(O)c(OC)c1
Reactant: CC(C)Sc1ncccc1CCl
Product: COc1cc(CCC(=O)O)ccc1OCc1cccnc1SC(C)C
Yield: 58.8 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (33 mg, 0.16 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-3-methoxy-phenyl]-propionic acid ethyl ester (40 mg, 0.17 mmol) obtained in Step C of Preparation Example 38 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (34 mg, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH3:2]
Reactant: CCOC(=O)C(CCCCOC1CCCCC1)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(CCCCOC1CCCCC1)C(=O)OCC

Procedure:
4.9 g of 6-cyclohexyloxy-2-methylenehexanoic acid ethyl ester, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 7.4 g of [4-(cyclohexyloxy)-butyl]-malonic acid ethyl ester, 0.85 g of paraformaldehyde, 5.2 ml of pyridine and 0.3 ml of piperidine.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1[S:61][C:62]([CH2:66]O)=[C:63]([CH3:65])[N:64]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:66][C:62]2[S:61][C:60]([CH3:59])=[N:64][C:63]=2[CH3:65])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1nc(C)c(CO)s1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2sc(C)nc2C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (2,4-dimethyl-1,3-thiazol-5-yl)methanol (0.6 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.33 g, 99%).
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(OCC)(=O)C.[ClH:26]>C(OCC)(=O)C>[Cl:26][C:1]1[NH:2][C:10]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cl
Reactant: CCOC(=O)C(C#N)CC(=O)c1c(F)cccc1F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2c(F)cccc2F)[nH]c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
A solution (14 mL) of ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate (13.83 g) in ethyl acetate was added dropwise to 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) at 10-15° C. The mixture was stirred at room temperature for 12 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→8:2) to give the title compound as yellow crystals (yield 10.0 g, 68%).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14][C:15]([NH2:17])=[S:16])=[CH:11][CH:10]=2)[O:8]CCO1.C([CH:20](Br)[C:21](=O)[C:22]([O-:24])=[O:23])C.[CH2:27](O)[CH3:28]>>[CH2:27]([O:24][C:22]([C:21]1[N:17]=[C:15]([CH2:14][C:12]2[O:13][C:9]([C:4](=[O:8])[CH3:3])=[CH:10][CH:11]=2)[S:16][CH:20]=1)=[O:23])[CH3:28]
Reactant: CC1(c2ccc(CC(N)=S)o2)OCCO1
Reactant: CCO
Reactant: CCC(Br)C(=O)C(=O)[O-]
Agent: N#N
Product: CCOC(=O)c1csc(Cc2ccc(C(C)=O)o2)n1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-yl]-thioacetamide (3.20 g, 14.06 mmol) and ethylbromopyruvate (2.07 mL, 14.06 mmol) in ethanol (40 mL) was stirred for 30 min at reflux. The solvent was removed under reduced pressure and the residue was dissolved in EA (150 mL) and washed with 7% aq. NaHCO3 (100 mL). The org. phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as an orange oil. TLC: rf (1:1 hept-EA)=0.24. LC-MS-conditions 02: tR=0.86 min, [M+H]+=280.30.
Reaction SMILES: [CH2:1]([NH:3][C:4](=S)[NH:5][C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[N:7]=1)[CH3:2].[NH3:18]>>[CH2:1]([N:3]=[C:4]([NH2:18])[NH:5][C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[N:7]=1)[CH3:2]
Reactant: N
Reactant: CCNC(=S)Nc1cnn(CCCCC#N)n1
Product: CCN=C(N)Nc1cnn(CCCCC#N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-[4-(3-ethylthioureido)-1,2,3-triazol-2-yl]valeronitrile (2.2 g.) in methanolic ammonia (6M; 20 ml.) was treated with yellow mercuric oxide (2.08 g.) and the resulting suspension stirred at room temperature for 18 hours. The suspension was filtered through diatomaceous earth and the filtrate evaporated to give an oil which was purified by medium pressure chromatography using EtOAc then MeOH/EtOAc 1:1 v/v as eluants to give 5-[4-[2-ethylguanidino)-1,2,3-triazol-2-yl]valeronitrile (1.35 g.).
Reaction SMILES: [CH2:1]1[C:6]2([C:16](=[O:17])[NH:15][C:14](=[O:18])[C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>CO.CN(C=O)C.CCOCC>[CH2:38]([N:15]1[C:16](=[O:17])[C:6]2([CH2:5][CH2:4][CH2:3][CH2:2][CH2:1]2)[NH:7][C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:14]1=[O:18])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: O=C1NC(=O)C2(CCCCC2)NC12CCCCC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCN1C(=O)C2(CCCCC2)NC2(CCCCC2)C1=O
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To a solution of 10.0 g (0.04 moles) of 7,15-diazadispiro [5,1,5,3] hexadecane-14,16-dione in 150 ml of anhydrous methanol in a 500 ml flask was added 2.6 g. of 86% KOH (0.04 moles) and the mixture was shaken until solution was obtained. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was transferred to a 300 ml 3-necked flask equipped with a stirrer, thermometer, condenser with drying tube, dropping funnel and nitrogen inlet with the aid of a small amount of dry DMF. To the potassium imide salt, under a nitrogen atmosphere, was added 150 ml of dry DMF. To the stirred solution was added dropwise a solution of 13.3 g. (0.04 moles) of n-octadecyl bromide in 50 ml of DMF. The reaction mixture was heated slowly to 75° C. and held at that temperature for 3 hours. The reaction mixture was cooled and allowed to stand at room temperature overnight. The reaction mixture was then taken up in 500 ml ether, the ether solution washed well with water, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue, which crystallized on standing, was recrystallized from methanol yielding 14.3 g of white needles as the product, m.p. 39°-40° C.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3](=[O:32])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl[C:35]1[C:36]2[C:43]([CH3:44])=[CH:42][NH:41][C:37]=2[N:38]=[CH:39][N:40]=1.C(N(CC)C(C)C)(C)C.C(O)(C)C>C(Cl)Cl>[CH3:1][N:2]([CH3:33])[C:3](=[O:32])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:19][CH2:18][N:17]([C:35]3[C:36]4[C:43]([CH3:44])=[CH:42][NH:41][C:37]=4[N:38]=[CH:39][N:40]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(CNC(=O)OCc3ccccc3)CCNCC2)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c[nH]c2ncnc(N3CCC(CNC(=O)OCc4ccccc4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 120 °C
Yield: 54 %

Procedure:
3-(4-((Benzyloxycarbonylamino)methyl)piperidine-4-carboxamido)phenyl dimethylcarbamate (0.216 g, 0.441 mmol) from step D, 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.073 g, 0.441 mmol), N,N-diisopropylethylamine (0.230 mL, 1.32 mmol), and isopropanol (5 mL) were combined and heated at 120° C. overnight in a pressure vessel. The crude reaction was diluted with CH2Cl2 and washed with H2O and brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (MeOH:CH2Cl2 gradient) to give the title compound in 54% yield.
Reaction SMILES: [C-]#N.[Na+].[Cu][C:5]#[N:6].Br[C:8]1[N:9]=[C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])[C:11]([NH2:15])=[N:12][C:13]=1[NH2:14]>CN(C)C=O>[C:5]([C:8]1[N:9]=[C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])[C:11]([NH2:15])=[N:12][C:13]=1[NH2:14])#[N:6]
Reactant: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)nc1Br
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nc(-c2cc(Cl)cc(Cl)c2Cl)c(N)nc1N
Temperature: 130 °C

Procedure:
A mixture of 97% sodium cyanide (0.064 g, 1.306×10−3 mole) and 90% copper(I) cyanide (0.135 g, 1.306×10−3 mole) in dry dimethylformamide (5 ml) was stirred and heated to 130° C. To the resulting clear solution was added 5-Bromo-2,6-Diamino-3-(2,3,5-trichlorophenyl)pyrazine (0.35 g, 0.95×10−3 mole) in small portions, and the solution was maintained at 140-150° C. for 16 hrs. The reaction mixture was cooled and evaporated in vacuo. The residue was extracted with ethyl acetate (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was purified by ‘flash chromatography’ using 5-17% ethyl acetate in cyclohexane as the eluent. Yield 0.152 g (51%), M.p. 277-279° C. Anal. Calcd for C11H6N5Cl3 0.02 C6H12: C, 42.23; H, 1.99; N, 22.15. Found: C, 42.36; H, 1.78; N, 21.79.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:10]([SiH2:14][O:15][C:16]([CH3:26])([CH3:25])[C:17]1([CH:23]=O)[CH2:22][CH2:21][CH:20]=[CH:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH2:27](Cl)Cl>>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:27]/[CH2:23][C:17]1([C:16]([CH3:26])([CH3:25])[O:15][SiH2:14][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:22][CH2:21][CH:20]=[CH:19][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1(C=O)CC=CCC1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)CN
Product: CC(C)(C)OC(=O)C/N=C/CC1(C(C)(C)O[SiH2]C(C)(C)C)CC=CCC1
Yield: 100 %

Procedure:
Step B In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.2 g, 9 mmol) was reacted with 1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enecarbaldehyde (2.5 g, 9 mmol) in CH2Cl2 at room temperature for 18 h to give [2-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a light yellow oil (3.5 g, 100%).
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].Cl.[CH3:7][N:8]1[CH2:14][C:13]2[CH:15]=[C:16](/[CH:19]=[CH:20]/[C:21](O)=O)[CH:17]=[N:18][C:12]=2NC(=O)[CH2:9]1.CNCC1C2C(=CC=CC=2)N(C)C=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[CH3:17][N:18]([CH2:12][C:13]1[C:15]2[C:9](=[CH:21][CH:20]=[CH:19][CH:16]=2)[N:8]([CH3:7])[CH:14]=1)[C:1](=[O:5])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cn(C)c2ccccc12
Agent: Cl
Product: C=CC(=O)N(C)Cc1cn(C)c2ccccc12
Yield: 58 %

Procedure:
According to the procedure of Example 1 (a), except substituting acrylic acid for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-3-ylmethyl)amine for the methyl-(1-propyl-napthalen-2-ylmethyl)amine, the title compound (1.51 g, 58%) was prepared as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.71-7.50 (s, 1H), 7.34-7.21 (m, 2H), 7.15-6.90 (m, 2H), 6.80-6.53 (m, 1H), 6.45-6.35 (s, 1H), 5.72-5.67 (m, 1H), 4.80-4.75 (m, 2H), 3.77 (s, 3H), 3.05-2.99 (m, 3H).