Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:13][O:12]1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[CH:19][C:20]2[S:25][CH2:24][C:23](=[O:26])[NH:22][C:21]=2[CH:27]=1>CCO.O>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:12])[CH2:13][NH:16][C:17]1[CH:18]=[CH:19][C:20]2[S:25][CH2:24][C:23](=[O:26])[NH:22][C:21]=2[CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Reactant: CC(C)(C)[Si](C)(C)OCCCCC1CO1
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCC(O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 42 %

Procedure:
A solution of 2-[4-[(tert-butyl)dimethylsiloxy]butyl]oxirane (10.0 g) and 6-amino-4H-benzo[1,4]thiazin-3-one (7.81 g; commercial) in EtOH/water (300 mL; 9:1) was refluxed for 2 days. The solvents were removed under reduced pressure and the residue was taken up in EA/Hex (1:1; 100 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by CC (EA/Hex; 1:1), affording an orange solid (7.40 g; 42% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl.Cl[CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]([O:44][CH3:45])[CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([O:33][CH2:37][C:38]3[CH:43]=[CH:42][N:41]=[C:40]([O:44][CH3:45])[CH:39]=3)=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Reactant: COc1cc(CCl)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6ccnc(OC)c6)cc5C)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 4-(chloromethyl)-2-methoxypyridine hydrochloride (58.2 mg) were suspended in dimethylformamide (1.8 mL) and potassium carbonate (62 mg) was added. The reaction mixture was shaken for 24 h at 60° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 42 mg; LC (method 23): tR=2.21 min; Mass spectrum (ESI+): m/z=584 [M+H]+.
Reaction SMILES: C[O:2][C:3]([CH2:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH2:17][C:18]#[C:19][CH3:20])[C:12]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]3)=[N:11][C:10]=2[N:9]([CH3:35])[C:7]1=[O:8])=[O:4].[OH-].[K+]>O1CCCC1.CO>[C:3]([CH2:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH2:17][C:18]#[C:19][CH3:20])[C:12]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]3)=[N:11][C:10]=2[N:9]([CH3:35])[C:7]1=[O:8])([OH:4])=[O:2]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)OC)c(=O)n2C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)O)c(=O)n2C

Procedure:
Prepared by saponifying 1-methoxycarbonylmethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with 4 N potassium hydroxide solution in a mixture of tetrahydrofuran and methanol (5:1) at ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.Cl[CH:22]([CH3:25])[C:23]#[CH:24]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:20][CH:23]([CH3:24])[C:22]#[CH:25])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Reactant: C#CC(C)Cl
Product: C#CC(C)Oc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Yield: 62 %

Procedure:
The title compound was prepared in 62% yield from 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine and 3-chloro-1-butyne by the procedure of Example 1A. Crystallization from methanol gave white solid; mp 153°-155°. Anal. Calcd for C17H20N4O3 : C, 62.18; H, 6.14; N, 17.06. Found: C, 61.93; H, 6.22; N, 16.98.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC(O)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC(O)CC2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(4-hydroxypiperidin-1-yl)benzamido)-4-phenylbenzoate (0.22 g) in methanol (2.2 mL) and ethyl acetate (1.1 mL), 10% palladium-carbon (0.11 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.18 g of tert-butyl 2-(2-hydroxy-5-(4-hydroxypiperidin-1-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH:13][CH2:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[Cl:1][C:2]1[N:3]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:14][OH:13])[CH:20]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OCc1cccc(B(O)O)c1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: O=Cc1c(Cl)n(-c2cccc(CO)c2)c2ccccc12
Yield: 17 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 3-(hydroxymethyl)-phenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(3-hydroxymethylphenyl)-1H-indole-3-carboxaldehyde (17% yield) as a pink solid. ESI/MS 286 (M+H); RT 2.85 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 4-(trifluoromethyl)phenylboronic acid, followed by hydrolysis in accordance with the procedure described in Example 1(c).
Reaction SMILES: II.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[SH:11].COC1C=CC(S([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=3)[N:25]([CH2:33][C:34]([OH:36])=[O:35])[C:24]=2[CH3:37])(=O)=O)=CC=1>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[S:11][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=2)[N:25]([CH2:33][C:34]([OH:36])=[O:35])[C:24]=1[CH3:37]
Reactant: Sc1c(Cl)cccc1Cl
Reactant: COc1ccc(S(=O)(=O)c2c(C)n(CC(=O)O)c3ccc(C)cc23)cc1
Agent: II
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(Sc1c(Cl)cccc1Cl)c(C)n2CC(=O)O

Procedure:
Iodine (0.51 g) was added to a solution of 2,6-dichlorobenzenethiol (0.36 g) and the product from example 13 step a) (0.2 g) in DMF (5 ml). After 1 h the solution was purified by reverse phase HPLC. The solvent was evaporated in vacuo and the oily residue treated with ether to give a solid. Filtered off and dried to yield the title compound as a white solid (0.22 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[CH:19][N:20]=[CH:21][C:13]2=3)=[O:11])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[C:28]([O:31][CH2:32]Br)(=[O:30])[CH3:29]>CN(C)C=O>[CH3:32][O:31][C:28](=[O:30])[CH2:29][O:8][C:7]1[C:6]([Br:9])=[CH:5][C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[CH:19][N:20]=[CH:21][C:13]2=3)=[O:11])=[CH:3][C:2]=1[Br:1]
Reactant: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ccncc21
Reactant: CC(=O)OCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1c(Br)cc(C(=O)N2CCOc3ccncc32)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
In a 25 ml flask, (3,5-dibromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (100 mg, 0.24 mmol) was dissolved in N,N-dimethyl formamide (2.4 ml), and potassium carbonate (37 mg, 0.266 mmol) was added thereto dropwise at room temperature. After stirring at room temperature for 10 minutes, bromo-methyl acetate was added dropwise and then stirred for 40 minutes at room temperature. The reaction mixture was filtered on celite and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=20:1 to obtain the target compound 24 as white foam (48 mg, 41.0%).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([O:8][CH2:9][C:10]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:11]=1)([CH3:7])[CH3:6])C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[N:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:11]=[C:10]([CH2:9][O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:31])=[O:3])[C:14]=2[CH3:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)OCc1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(COC(C)(C)C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
To a solution of 735 mg of 2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionic acid ethyl ester in 10 ml THF was added a solution of 51 mg of LiOH in 1 ml water at room temperature. After 16 h the mixture was brought to pH 2 by addition of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 677 mg.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[C:30]([OH:35])[CH:29]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[C:30]([OH:35])[CH:29]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCc2ccc(Br)c(O)c2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCc2ccc(Br)c(O)c2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 84 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(4-bromo-3-hydroxybenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.0 g.), conc.hydrochloric acid (1.1 g.), methanol (16 ml.) and tetrahydrofuran (10 ml.) was stirred at room temperature for 2 hours. After methanol was removed in vacuo, the residue was dissolved in a sodium bicarbonate aqueous solution and adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorous pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-(4-bromo-3-hydroxybenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.6 g.).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OCC5C=CC=CC=5)[CH2:25][CH2:24]4)[C:20]([F:40])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:29][CH:26]1[CH2:27][CH2:28][N:23]([C:21]2[C:20]([F:40])=[CH:19][N:18]=[C:17]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([N:7]4[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:15][CH:14]=3)[N:22]=2)[CH2:24][CH2:25]1
Reactant: [H][H]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(NC(=O)OCc5ccccc5)CC4)n3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(N)CC4)n3)cc2)CC1
Yield: 85.5 %

Procedure:
A solution of benzyl 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-fluoropyrimidin-4-yl)piperidin-4-ylcarbamate (370 mg, 0.676 mmol) and Pd—C (10%, 55 mg) in MeOH (12 mL) was hydrogenated under balloon hydrogen for 20 h. It was then filtered through celite. The filtrate was concentrated in vacuo to give the titled compound (239 mg). MS 414.3 (M+H); UV 202.8, 268.8 nm.
Reaction SMILES: C(OC([N:8]1[CH2:32][CH2:31][C:11]2([CH2:16][CH2:15][C:14]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:14]2([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:13][CH2:12][C:11]3([CH2:31][CH2:32][NH:8][CH2:9][CH2:10]3)[CH2:16][CH2:15]2)[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(OCCN1CCCC1)(c1cccnc1)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(C2(OCCN3CCCC3)CCC3(CCNCC3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Pyridin-3-yl-3-(2-pyrrolidin-1-yl-ethoxy)-9-azaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester (0.282 mmol, 1 equiv.) was dissolved in DCM (3 ml). At 0° C., trifluoroacetic acid (1.5 ml) was added, and the mixture was stirred for 2 hours at 25° C. The solvent was concentrated under reduced pressure and the residue was taken up in DCM (2×10 ml) and dried to yield the desired product.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)=[C:21]3[N:20]=2)=[CH:5][CH:4]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccn1
Yield: 52.6 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (111 mg, 53%). MS (ISP) 423.0 [(M+H)+]; mp 243° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=[S:22])[CH2:13][N:14]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCc1cc2c(s1)NC(=O)CN=C2c1ccccc1Cl
Solvent: c1ccncc1
Product: CCc1cc2c(s1)NC(=S)CN=C2c1ccccc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 136 %

Procedure:
[a] To a solution of 40 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e][1,4]diazepin-2-one in 200 ml of pyridine is added 32 g of phosphorus pentasulfide, and the mixture is stirred at 60°C for 1 hour. After allowing to cool, the reaction mixture is poured into 2 liters of ice water with stirring. The precipitate formed is collected with suction filtration and washed with water. The precipitate is dissolved in chloroform, and the solution is washed with a saturated sodium bicarbonate and washed with water. The chloroform layer is dried over sodium sulfate and concentrated in vacuo. The residue is recrystallized from a mixture of ethanol and chloroform to give 31.4 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e][1,4]diazepine-2-thione as yellowish crystals melting at 198°-199°C (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:4][CH:3]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)OC1C=CC=CC=1)#[N:25]>C(OCC)(=O)C.CO>[C:24]([NH:26][C:27]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:17])=[N:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)#[N:25]
Reactant: CN(CCCCN)CCC(c1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(CCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.8 g (2.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine and 0.95 g (2.5 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 95+5) analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=597 ([M+H]+ 1), 214 (100); IR (KBr): 2162 cm-1 (C≡N).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[Na].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:12][N:13]=[N+:14]=[N-:15]>C(O)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:12][N:13]1[C:1]([NH2:2])=[C:3]([C:4]([NH2:6])=[O:5])[N:15]=[N:14]1
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1ccc(Cl)c(Cl)c1
Agent: [Na]
Solvent: CCO
Product: NC(=O)c1nnn(Cc2ccc(Cl)c(Cl)c2)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A stirred mixture of 3,4-dichlorobenzyl chloride (12.6 g, 64.5 mmol) and sodium azide (7.0 g, 0.11 mole) in absolute ethanol (70 ml) was refluxed for 4.75 hours, cooled and filtered to provide a solution of 3,4-dichlorobenzyl azide. Separately, 2-cyanoacetamide (5.5 g, 65 mmol) was added to a 35° C. solution of sodium (1.5 g, 65 mmol) in absolute ethanol (125 ml), and to the resulting suspension was added the above azide solution dropwise over 10 minutes. The combined mixtures were refluxed for 1 hour, kept 16 hours at ambient temperature and 1 hour at 5° C., and filtered. The crude product was dried under vacuum, dissolved in boiling ethanol (290 ml), filtered hot, and cooled to 0° C. The solid was collected by filtration and dried under vacuum to provide 12.4 g (67%) of 1-(3,4-dichlorobenzyl)-5-amino-1,2,3-triazole-4-carboxamide, m.p. 221°-222° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:43][CH:44]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50]>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:43][CH:44]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(NC(=O)c1ccc(Br)s1)c1ccccc1
Reaction time: 16 h
Yield: 299.5 %

Procedure:
To a solution of 5-bromo-2-thiophenecarboxylic acid (3.2 g, 15.2 mmol), PyBrOP (8.5 g, 18.2 mmol) and diisopropylethyl amine (10.6 mL, 60.9 mmol) in DCM (76 mL) at 25° C. was added 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate (3.6 g, 3.14 mmol)[prepared in Preparation 1]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fraction were dried (Na2SO4), concentrated and purified via column chromatography (silica, 1% MeOH in DCM) affording the title compound (4 g, 62%) as a white solid: LC-MS (ES) m/z=426 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:22][C:23]1[N:32]=[C:31](Cl)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>O1CCCC1>[Cl:22][C:23]1[N:32]=[C:31]([NH:14][CH2:13][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: NCC1(c2ccccc2)CCCCC1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1nc(NCC2(c3ccccc3)CCCCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of C-(1-phenyl-cyclohexyl)-methylamine (0.28 g; 1.48 mmol) in tetrahydrofuran (10 mL) at room temperature was treated with triethylamine (0.3 mL; 2.2 mmol) and 2,4-dichloro-quinazoline (0.32 g; 1.62 mmol). The reaction was stirred at room temperature 12 h at which time the solvent was removed by rotary evaporation. The crude residue was portioned between ethyl acetate and 10% aqueous HCl. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (magnesium sulfate), filtered and concentrated. The product was recrystallized from methylene chloride to give (2-chloro-quinazolin-4-yl)-(1-phenyl-cyclohexylmethyl)-amine as a white solid. LCMS m/z=352.2 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH:4]=O.[CH:11](=[O:15])[CH2:12][CH2:13][CH3:14]>>[CH2:13]([CH:12]([CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:11]=[O:15])[CH3:14]
Reactant: CCCC=O
Reactant: CC(CC=O)CC(C)(C)C
Product: CCC(C=O)CCC(C)CC(C)(C)C

Procedure:
2-Ethyl-5,7,7-trimethyloctanal was prepared from 3,5,5-trimethylhexanal and n-butanal similarly to Examples 1 and 2; it was obtained in the form of a diastereomeric mixture.