Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH2:5][C:6]#[N:7])#[N:2].[CH2:11]([NH:14][CH2:15][CH:16]=[CH2:17])[CH:12]=[CH2:13]>O1CCCC1>[C:1]([N:3]=[C:4]([N:14]([CH2:15][CH:16]=[CH2:17])[CH2:11][CH:12]=[CH2:13])[CH2:5][C:6]#[N:7])#[N:2]
Reactant: C=CCNCC=C
Reactant: CCOC(CC#N)=NC#N
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(CC#N)=NC#N

Procedure:
A solution of 4.00 g (0.0292 m) ethyl N,2-dicyanoacetimidate and 2.83 g (0.0292 m) diallylamine in 60 ml tetrahydrofuran is stirred at 0° C. for twelve hours. The reaction is concentrated and filtered through silica gel (2% MeOH/CH2Cl2 eluent). The organic phase is concentrated and the residue chromatographed (HPLC, 1"× 40" of 30-50 μ silica gel, 2% MeOH/CH2Cl2) to give product. A minor impurity (200 mg) crystallizes out from CH2Cl2 -C6H12. The residual oil (3.08 g, 56%) has nmr, ir, and mass spec which are consistent.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][CH2:10][OH:11])=[C:4]([CH3:12])[N:3]=1.[CH3:13][O-].[Na+].IC>C(O)C>[NH2:1][C:2]1[N:7]([CH3:13])[C:6](=[O:8])[C:5]([CH2:9][CH2:10][OH:11])=[C:4]([CH3:12])[N:3]=1
Reactant: C[O-]
Reactant: Cc1nc(N)[nH]c(=O)c1CCO
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: Cc1nc(N)n(C)c(=O)c1CCO
Reaction time: 4 h
Yield: 79.6 %

Procedure:
To a stirred mixture of 67.7 parts of 2-amino-5-(2-hydroxyethyl)-6-methyl-4(3H)-pyrimidinone and 800 parts of ethanol were added 80 parts of a sodium methoxide solution 30%. The reaction mixture was heated to reflux temperature and 62.5 parts of iodomethane were added dropwise. Upon complete addition, stirring was continued for 4 hours at reflux temperature. The reaction mixture was evaporated and the residue was suspended in 400 parts of water. The precipitated product was filtered off, washed with 40 parts of ethanol and dried, yielding 58.3 parts (79.6%) of 2-amino-5-(2-hydroxy-ethyl)-3,6-dimethyl-4(3H)-pyrimidinone (interm. 12).
Reaction SMILES: [C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13][CH3:14])[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C1(C2[O:26]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13]([CH3:14])=[O:26])[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][N:8]=3)[CH2:2][CH:3]([CH2:4]1)[CH2:5]2
Reactant: CSc1nc(NC23CC(C2)C3)ncc1C(N)=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)c1nc(NC23CC(C2)C3)ncc1C(N)=O
Temperature: 25 °C
Yield: 91 %

Procedure:
To a stirring solution of 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-(methylthio)pyrimidine-5-carboxamide (410 mg, 1.638 mmol) in chloroform (39.0 mL) was added portionwise, 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (514 mg, 1.965 mmol). The resulting pale yellow solution was stirred at ambient temperature for two nights under nitrogen. The reaction mixture was concentrated under reduced pressure to give the crude product as a white solid. Ethyl acetate (15 mL) was added to these solids and the slurry was stirred at room temp for 1 h, filtered, washed with ethyl acetate, and dried in a vacuum oven for a few hours to afford 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-(methylsulfinyl)pyrimidine-5-carboxamide (397 mg, 1.491 mmol, 91% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67-9.14 (m, 2H), 7.93-8.11 (m, 1H), 7.41-7.54 (m, 1H), 2.68-2.79 (m, 3H), 2.43-2.48 (m, 1H), 2.02-2.21 (m, 6H). MS (ESI) m/z 267.0 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[CH2:29]([CH:31]1[CH2:33][O:32]1)[CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[OH:32][CH:31]([CH2:29][CH3:30])[CH2:33][N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)CC)c2ncnn12
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 2-ethyloxirane (1.17 mL), potassium carbonate (0.38 g) and N,N-dimethylacetamide (10 mL) was stirred in a sealed tube at 100° C. for 8 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution 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 (0.45 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=1.S(Cl)([Cl:20])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:15]([Cl:20])=[O:17])=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccccc1-c1ccccc1C(=O)O
Product: COc1ccccc1-c1ccccc1C(=O)Cl

Procedure:
2'-Methoxy-[1,1'-biphenyl]-2-carboxylic acid (32 g., 100 mmole) was dissolved in thionyl chloride (40 ml) and the solution was refluxed for 3 hours. The solution was evaporated to provide the title compound.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])(=O)=O)=CC=1.[C:27]([O-])(=[S:29])[CH3:28].[K+].Cl>CN(C)C=O>[C:27]([O:10][CH2:11][CH2:12][C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])(=[S:29])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reactant: CC([O-])=S
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=S)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 57.6 %

Procedure:
A mixture of 42.65 g of 3,3,4,4,5,5,6,6,6-nonafluorohexyl p-toluenesulfonate, 100 ml of N,N-dimethylformamide and 11.65 g of potassium thioacetate was heated and stirred at 80° C. for 4 hours under a nitrogen atmosphere. A reaction vessel was cooled in an ice bath. To the reaction mixture was added an aqueous 1N hydrochloric acid solution, and the mixture was extracted with 200 ml of ethylacetate twice. Organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 18.91 g of 3,3,4,4,5,5,6,6,6-nonafluorohexyl thioacetate represented by the formula:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.CCCCCC>[Cl:17][C:8]1[CH:9]=[CH:10][N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CN(C)S(=O)(=O)n1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)n1ccc(Cl)n1
Temperature: -78 °C

Procedure:
To a solution of N-dimethylsulfamoylpyrazole (188.0 g, 1.07 mol) in dry tetrahydrofuran (1500 mL) at −78° C. was added dropwise a solution of 2.5 M n-butyllithium (472 mL, 1.18 mol) in hexane while maintaining the temperature below −65° C. Upon completion of the addition the reaction mixture was maintained at −78° C. for an additional 45 minutes, after which time a solution of hexachloroethane (279 g, 1.18 mol) in tetrahydrofuran (120 mL) was added dropwise. The reaction mixture was maintained for an hour at −78° C., warmed to −20° C. and then quenched with water (1 L). The reaction mixture was extracted with methylene chloride (4×500 mL); the organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by chromatography on silica gel using methylene chloride as eluent to afford the title product compound as a yellow oil (160 g).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:19])[C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[CH2:6][CH2:5]2)OC1.[ClH:21].Cl.[NH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([NH2:28])=[NH:27]>>[ClH:21].[C:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]([N:7]2[CH2:6][CH2:5][C:4]3([N:27]=[C:26]([NH2:28])[C:25]4[C:24](=[CH:32][CH:31]=[CH:30][C:29]=4[F:33])[NH:23]3)[CH2:9][CH2:8]2)=[O:19])=[CH:16][CH:15]=1)#[N:18]
Reactant: N#Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cc1
Reactant: N=C(N)c1c(N)cccc1F
Agent: Cl
Product: N#Cc1ccc(C(=O)N2CCC3(CC2)N=C(N)c2c(F)cccc2N3)cc1

Procedure:
This was prepared from 1-(4-cyanobenzoyl)-4-piperidone ethylene ketal (Example U(b)) and 2-amino-6-fluorobenzamidine dihydrochloride (Example C) by the method of Example 1, to give the title compound as pale yellow crystals, m.p. 299°-300° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=3[CH3:45])[N:36]=[CH:37][C:30]=12)[C:24](OC)=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1C=CC=CC=1)[C:2]1C=CC=CC=1.[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([NH2:53])=[N:51][CH:52]=1>>[Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:29]1[C:30]2[CH:37]=[N:36][N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=3[CH3:45])[C:31]=2[N:32]=[CH:33][N:34]=1)[C:24]([NH:53][C:50]1[CH:49]=[CH:48][C:47]([Cl:46])=[CH:52][N:51]=1)=[O:25])([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:8])[CH3:2]
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(F)c1C
Reactant: Nc1ccc(Cl)cn1
Product: Cc1c(F)cccc1-n1ncc2c(O[C@@H](COCCO[Si](C)(C)C(C)(C)C)C(=O)Nc3ccc(Cl)cn3)ncnc21

Procedure:
Prepared using a procedure analogous to that described for Intermediate AE1 using (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AF4) and 5-chloropyridin-2-amine. 1H NMR (400 MHz, DMSO) d 0.87 (9H, s), 1.96 (3H, d), 3.75 (4H, m), 4.10-4.02 (1H, m), 4.15 (1H, m), 6.00 (1H, m), 7.38 (9H, m), 7.63-7.57 (4H, m), 7.88 (1H, dd), 8.03 (1H, d), 8.40 (1H, d), 8.52 (1H, s), 8.56 (1H, s), 11.25 (1H, s).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:15]=[C:14](Cl)[S:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18]>>[NH2:10][C:11]1[CH:15]=[C:14]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18]
Reactant: OB(O)c1ccccc1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Product: Nc1cc(-c2ccccc2)sc1S(N)(=O)=O

Procedure:
The title compound was prepared from phenylboronic acid and 3b by following the procedure in example 3c. This compound is a white solid: MS (ES) 255 (M+H)+; 1H NMR (400 MHz, CD3OD)δ7.61 (m, 2 H), 7.42–7.37 (m, 3 H), 6.89 (s, 1H).
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].CO[C:22](OC)([CH3:24])[CH3:23].CC(C)=O>CCCCCC>[CH3:23][C:22]1([CH3:24])[O:3][CH:2]2[CH:4]([CH:6]([CH2:7][OH:8])[O:9][CH:1]2[N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:5]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: COC(C)(C)OC
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC1(C)OC2C(CO)OC(n3cnc4c(N)ncnc43)C2O1
Reaction time: 3 h

Procedure:
A solution of adenosine (43 g) and 2,2-dimethoxypropane (5 eq.) in acetone (75 eq.) was treated with D-camphorsulphonic acid (1 eq) at and the resulting reaction was allowed to stir for 3 hr. The reaction mixture was concentrated in vacuo and diluted with a mixture of saturated aqueous NaHCO3 (250 mL) and ethyl acetate (250 mL). The resulting solution was transferred to a separatory funnel and the organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to provide a solid residue. The solid residue was suspended in hexane, filtered, washed with hexane and dried to provide 2′,3′-Isopropylidene-adenosine (43 g). 1H NMR (DMSO-d6, 300 MHz): δ 4.12-4.17 (m, 1H), 4.22-4.26 (m, 1H), 4.59 (d, J=4.8 Hz, 1H), 4.74-4.85 (m, 2H), 5.49-5.52 (m, 1H), 5.51 (d, J=5.1 Hz, 1H), 5.84 (d, J=5.1 Hz, 1H), 7.85 (s, 2H), 8.33 (s, 1H). MS t/z 347.11 [M+H]+.
Reaction SMILES: O=[CH:2][C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H]([O:37][C@@H:38]2[O:43][C@@H:42](CO)[C@H:41](O)[C@@H:40](O)[C@@H:39]2[NH:48]C)[C@@]1(O)C=O>>[NH2:48][C@H:39]([C:38]([OH:37])=[O:43])[CH2:40][CH:41]([CH3:42])[CH3:2]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Product: CC(C)C[C@H](N)C(=O)O
Reaction time: 2 h

Procedure:
pseudomesenteroides was cultivated in 10 ml M17 (0.5% glucose) for 3 days followed by cultivation for 120 minutes in the presence of 150 μl of EMS. After EMS treatment, 0.2 ml of the culture was inoculated into ten tubes each containing 10 ml of M17 and incubated for 3 days for phenotypic expression. The mutation frequency was monitored by plating 0.1 ml from each tube onto M17 plates containing 500 μg/ml of streptomycin.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([C:26](O)=[O:27])#[C:22][C:23]([OH:25])=[O:24]>>[O:27]=[C:26]1[C:21](=[CH:22][C:23]([OH:25])=[O:24])[S:11][C:10](=[N:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C#CC(=O)O
Reactant: S=C(NCCc1ccccc1)NCCc1ccccc1
Product: O=C(O)C=C1SC(=NCCc2ccccc2)N(CCc2ccccc2)C1=O
Yield: 52.6 %

Procedure:
Prepared by the method described in Example 1 from N,N'-bis(2-phenylethyl)thiourea (20.0 g, 0.11 moles) and acetylenedicarboxylic acid (12.7 g, 0.11 moles). Rinsing the crude precipitate with toluene then hexane gave the product (22 g), mp 148°-149° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[CH3:10][C:11]1([CH3:20])[CH2:16][CH2:15][C:14](B(O)O)=[CH:13][CH2:12]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:14]2[CH2:15][CH2:16][C:11]([CH3:20])([CH3:10])[CH2:12][CH:13]=2)[CH:3]=1
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: Nc1ccc(Br)cc1I
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: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)CC=C(c2cc(Br)ccc2N)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 93.8 %

Procedure:
A mixture of 4-bromo-2-iodo-phenylamine (873 mg, 2.93 mmol), 4,4-dimethylcyclohexen-1-ylboronic acid (496 mg, 3.22 mmol), Pd(PPh3)4 (169 mg, 0.147 mmol) and 2.0 M aq Na2CO3 (11.7 mL, 23.4 mmol) in 20 mL of 1,4-dioxane was stirred at 80° C. for 12 h under Ar. After cooling to RT, the reaction was treated with EtOAc (50 mL) and washed with H2O (25 mL) and brine (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5% EtOAc/hexane) to afford 770 mg (91%) of the title compound as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C14H18BrN, 280.1 (M+H), found 280.1.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([F:24])([F:23])[CH2:6][C@H:7]([NH:11][C@@H:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([F:16])([F:15])[F:14])[C:8](O)=[O:9])[CH2:3][CH2:2]1.CN(C(ON1N=[N:40][C:35]2[CH:36]=[CH:37]C=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.C(C1CC1)#N>CN(C=O)C>[C:34]([C:35]1([NH:40][C:8](=[O:9])[C@@H:7]([NH:11][C@@H:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([F:15])([F:14])[F:16])[CH2:6][C:5]([F:23])([F:24])[CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH2:37][CH2:36]1)#[N:39]
Reactant: O=C(O)[C@H](CC(F)(F)CC1CC1)N[C@@H](c1ccccc1)C(F)(F)F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)[C@H](CC(F)(F)CC2CC2)N[C@@H](c2ccccc2)C(F)(F)F)CC1
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
A stirred solution of (S)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanoic acid (150 mg, 0.4 mmol) in DMF (15 mL) was treated with HATU (253 mg, 0.5 mmol) and DIPEA (0.3 mL, 1.7 mL mmol). After 15 min, 1-cyanocyclopropane hydrochloride (61 mg, 0.5 mmol) was added and the reaction mixture was stirred under a nitrogen atmosphere for 2 h. Once the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate & washed with 1HCl solution and brine, dried over Na2SO4, filtered and was concentrated. The crude compound was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane followed by re-crystallization from DCM and pentane to provide (S)-N-(1-cyanocyclopropyl)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanamide (65 mg, 37%) as white solid. 1H-NMR (500 MHz, DMSO-d6): 8.88 (1H, s, NH), 7.38 (5H, s, Ar—H), 4.23 (1H, m, CHCF3), 3.39 (1H, m, CH), 3.18 (1H, m, NH), 2.23 (2H, m, CH2), 1.94 (2H, m, CH2), 1.32 (2H, m, CH2), 0.82 (2H, m, CH2), 0.57 (1H, m, CH), 0.45 (2H, m, CH2), 0.12 (2H, m, CH2). 19F-NMR (500 MHz, CD3OD): −74.609 (CF2), 95.308, −95.507 (CF3). EIMS (m/z): 416 (M+H). HPLC: 97.37% (RT 16.39)Column used zorbax SB, C8, 250×4.6 mm, 5uMobile Phase: ACN (B): 0.1% TFA in water (A)Flow rate: 1.0 mL/Min
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=O)=[CH:6]1.C(N(CC)CC)C.CCCP(O)(O)=O.Cl.[F:37][CH2:38][CH2:39][NH2:40]>C(Cl)Cl>[CH3:1][C:2]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([NH:40][CH2:39][CH2:38][F:37])=[O:16])=[CH:6]1
Reactant: NCCF
Reactant: Cc1ccc(Cn2cc(C(=O)O)c3ncccc32)c(C)c1
Agent: CCCP(=O)(O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cn2cc(C(=O)NCCF)c3ncccc32)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
See FIG. 24(b). 1-(2,4-dimethylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (200 mg, 0.71 mmol) was taken in a 100 ml single necked flask equipped with an air condenser connected to nitrogen source. Added CH2Cl2 (10 mL) to get a clear solution. Triethylamine (5 mL, 35.87 mmol) was added followed by the addition of 1-Propylphosphonic acid cyclic anhydride (2 mL, 1.43 mmol) and 2-Fluoroethylamine hydrochloride (142 mg, 1.43 mmol). The reaction mass was stirred at RT for overnight. This crude compound was subjected for reverse phase purification to obtain 1-(2,4-dimethylbenzyl)-N-(2-fluoroethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (50.00 mg, 22%) as a off white solid. ES+MS m/z: 326 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.21 (s, 3 H ) 2.24 (s, 3 H ) 3.57-3.86 (m, 2 H ) 4.50 (t, J=4.99 Hz, 1 H ) 4.66 (t, J=4.99 Hz, 1 H ) 5.41-5.60 (m, 2 H ) 6.72 (d, J=7.72 Hz, 1 H ) 6.94 (d, J=7.54 Hz, 1 H ) 7.05 (s, 1 H ) 7.28 (dd, J=8.29, 4.71 Hz, 1 H ) 7.98 (dd, J=8.38, 1.04 Hz, 1 H ) 8.13 (s, 1 H ) 8.51 (dd, J=4.62, 1.04 Hz, 1 H ) 8.94 (t, J=5.84 Hz, 1 H ).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[N:29][N:28]=1>>[S:32]([C:30]1[S:31][C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])=[N:28][N:29]=1)(=[O:34])(=[O:33])[NH2:35]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1nnc(S(N)(=O)=O)s1
Product: NS(=O)(=O)c1nnc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 5-amino-[1,3,4]thiadiazole-2-sulfonic acid amide [commercially available, CAS 14949-00-9] according to general procedure II.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14].C([Sn](CCCC)(CCCC)[C:21]([O:23]CC)=[CH2:22])CCC.Cl>C(OCC)(=O)C.CCCCCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:21]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14])(=[O:23])[CH3:22]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of 6-bromo-2,2,4,4-tetramethyl chroman (see U.S. Pat. No. 6,252,090, 0.9 g, 3.34 mmol) in anhydrous tetrahydrofuran (50 mL) was sparged with argon for 5 min. and treated with dichlorobis(triphenylphosphine)palladium(II) (0.117 g, 0.167 mmol) followed by tributyl(1-ethoxyvinyl)tin (2.41 g, 6.7 mmol). The resulting reaction mixture was heated at 80° C. under argon for 18 h. The reaction mixture was then cooled to ambient temperature and treated with 10% aqueous hydrochloric acid (5 mL) and stirred for 30 min. The reaction mixture was then diluted with ethyl acetate and washed with water (×1) and brine (×1). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 2-3%% ethyl acetate in hexane as the eluent to afford the title compound as a colorless oil (0.36 g, 46%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[Cl:11][C:12]1[C:13]([F:37])=[N:14][C:15](NCC(OC)=O)=[C:16]([Cl:30])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([CH:27]([CH3:29])[CH3:28])[CH:20]=1>>[Cl:11][C:12]1[C:13]([F:37])=[N:14][C:15]([NH:1][CH2:2][CH2:3][C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])=[C:16]([Cl:30])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH:27]([CH3:29])[CH3:28])[CH:20]=1
Reactant: NCCC(=O)NCC(=O)O
Reactant: COC(=O)CNc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Product: CC(C)c1cc(Oc2c(Cl)c(F)nc(NCCC(=O)NCC(=O)O)c2Cl)ccc1O

Procedure:
By use of β-alanyl-glycine in place of glycine methyl ester for the preparation of Compound 1e followed by deprotection as described for example 2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CC(C)=O.ClCCl>[CH3:24][S:25]([O:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:7][CH:6]=2)=[CH:12][CH:13]=1)(=[O:27])=[O:26]
Reactant: Oc1ccc(SCSc2ccc(O)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(SCSc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
In 200 g of acetone was dissolved 23 g (0.1 mol) of the bis(4-hydroxyphenylthio)methane crude product in Synthesis Example 1. To this were added 35 g (0.25 mol) of potassium carbonate and 28 g (0.24 mol) of methanesulfonylchloride. While refluxing in an oil bath at 70° C., the solution was ripened for 4 hours. After cooling, the inorganic salt was filtered and washed with 50 g of acetone. The filtrate and wash liquid combined was concentrated, yielding an oily product, which was dissolved in 150 g of dichloromethane. This solution was washed with 100 g of water, and concentrated again. There was yielded 38 g of a concentrated oily residue, which was used in the subsequent reaction without further purification. It is noted that this oily matter crystallized when kept at room temperature.