Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[S:18]C(S(C)(=O)=O)=[N:20][N:21]=3)[CH:15]=2)[N:10](S(C2C=CC(C)=CC=2)(=O)=O)[CH:9]=1.[NH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=O)OC(C)(C)C>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[S:18][C:41]([NH:40][CH2:39][CH2:38][CH2:37][NH2:36])=[N:20][N:21]=3)[CH:15]=2)[NH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3F)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: C1COCCO1
Product: NCCCNc1nnc(-c2ccc3[nH]cc(-c4ccccc4F)c3c2)s1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of 2-(3-(2-fluorophenyl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (0.053 g, 0.10 mmol) in p-dioxane (1 mL) was added tert-butyl 3-aminopropylcarbamate (88 mg, 0.50 mmol, Aldrich), and the reaction was heated at 90° C. for 8 h. The residue was then purified with RP-HPLC. The purified material was dissolved in dioxane (1 mL) and aq. NaOH (1M, 0.1 mL) was added. The solution was heated in a microwave at 120° C. for 10 min. The solution was concentrated under reduced pressure and the resulting oil was stirred with 4M HCl/dioxane for 30 min, then evaporated under reduced pressure. The residue was purified by preparative HPLC to give N-(5-(3-(2-fluorophenyl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-yl)-1,3-propanediamine (32 mg, 61.4%). MS (ESI, pos. ion) m/z: 368 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 8.10 (1H, s), 7.66-7.72 (1H, m), 7.62-7.66 (1H, m), 7.59 (1H, d, J=1.6 Hz), 7.53-7.57 (1H, m), 7.17-7.35 (3H, m), 3.57 (2H, t, J=6.7 Hz), 3.03-3.10 (2H, m), 2.04-2.11 (2H, m).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][C@@H:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[CH2:11]=O>CO.O.[Pd]>[CH3:11][N:5]1[CH2:6][CH2:7][C@@H:2]([CH3:1])[CH2:3][C@@H:4]1[C:8]([OH:10])=[O:9]
Reactant: C=O
Reactant: C[C@@H]1CCN[C@@H](C(=O)O)C1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: C[C@@H]1CCN(C)[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a solution of (2R,4R)-4-methylpiperidine-2-carboxylic acid (2 g, 13.97 mmol) in MeOH (40 mL) and water (40.0 mL) was added paraformaldehyde (2.52 g, 27.94 mmol) and Pd/C (10%) (0.8 g, 7.52 mmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature overnight. From TLC, the reaction was not completed. Another one equivalent of paraformaldehyde (2.52 g, 27.94 mmol) was added and the reaction mixture was stirred another 24 hours. TLC indicated the reaction was completed and reaction mixture was filtered, washed the catalyst with MeOH (2×30 mL). The filtrate was concentrated in vacuo to give crude product as a white solid, which was washed with ether (3×30 mL), dried in high vacuum overnight to yield (2R,4R)-1,4-dimethylpiperidine-2-carboxylic acid (1) (1.870 g, 85%) as a white solid. LC-MS: 158 (M+1); 1H NMR (400 MHz, D2O) δ ppm 0.97 (d, J=5.52 Hz, 3H), 1.54 (br. s, 1H), 1.71-1.87 (m, 3H), 1.91-2.07 (m, 1H), 2.84 (s, 3H), 3.13 (td, J=8.41, 3.76 Hz, 1H), 3.35 (m, 1H), 3.65 (m, 1H).
Reaction SMILES: [Si:1]([N:8]1[C:11](=[O:12])[CH2:10][C@H:9]1[C:13]([OH:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:17]C([N-]C(C)C)C.CI>C1COCC1>[Si:1]([N:8]1[C:11](=[O:12])[C@H:10]([CH3:17])[C@H:9]1[C:13]([OH:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C(=O)O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylic acid 4 (2.00 g, 8.73 mmol.) in THF (30 ml) at −78° C. was added LDA (19 ml, 2.0 eq.). After the solution was stirred for 20 min. at −78° C., it was warmed to 0° C. for 5 min. The solution was re-cooled to −78° C. and methyl iodide (3.10 g, 2.5 eq.) in THF (5 ml) was added. The reaction solution was warmed up to room temperature, quenched with aqueous KHSO4 solution (10%, 30 ml), extracted with ethyl acetate (3×). The combined organic layers were washed with brine twice and dried with MgSO4. After concentrating in vacuo, 47 was obtained. H1NMR (CDCl3): 0.15, 0.35 (s, 6H), 1.14 (s, 9H), 1.35 (d, 3H), 3.71 (d, 1H), 4.14 (m, 1H). C11H21NO3Si, Mol. Wt.: 243.37. Found: 244 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[C:23]([CH3:29])[NH:24]2.C(N(C(C)C)C(C)C)C>C(O)CCC>[CH3:29][C:23]1[NH:24][C:25]2[C:21]([N:22]=1)=[C:20]([NH:18][C@H:16]([C:8]1[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=1)[CH3:17])[N:28]=[CH:27][N:26]=2
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Reactant: Cc1nc2c(Cl)ncnc2[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(N[C@@H](C)c3nc4ccccc4n3-c3ccccc3)ncnc2[nH]1
Yield: 32.7 %

Procedure:
A solution of (1S)-1-(1-phenyl-1H-1,3-benzodiazol-2-yl)ethan-1-amine from Example 4 (150 mg, 0.62 mmol, 1.00 equiv, 98%), 6-chloro-8-methyl-9H-purine (150 mg, 0.87 mmol, 1.41 equiv) and ethylbis(propan-2-yl)amine (0.3 mL, 98%) in butan-1-ol (6 mL) was stirred overnight at 130° C. The resulting mixture was concentrated under vacuum. The residue was purified on a C18 column eluted with water/acetonitrile to give 75 mg (30%) of 158 as a white solid. LC-MS (ES, m/z) 370 [M+H]+. H-NMR (300 MHz CD3OD, ppm) δ 8.04 (s, 1H), 7.69 (d, 1H), 7.55 (m, 5H), 7.30 (m, 2H), 7.11 (d, 1H), 5.63 (s, 1H), 2.55 (s, 3H), 1.71 (d, 3H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:14])[CH3:13])=[O:9])[CH:5]=[CH:4][C:3]=1[S:23](Cl)(=[O:25])=[O:24].[S:27]1[C:31]([NH2:32])=[N:30][CH:29]=[N:28]1.[OH-].[Na+].O1CCOCC1.O>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[S:23]([NH:32][C:31]1[S:27][N:28]=[CH:29][N:30]=1)(=[O:25])=[O:24])[C:8]([NH:10][CH2:11][C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH3:13])=[O:9]
Reactant: CC(C)(CNC(=O)c1ccc(S(=O)(=O)Cl)c(F)c1)Oc1ccc(F)cc1
Reactant: Nc1ncns1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(CNC(=O)c1ccc(S(=O)(=O)Nc2ncns2)c(F)c1)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
2-Fluoro-4-({[2-(4-fluorophenoxy)-2-methylpropyl]amino}carbonyl)benzenesulfonyl chloride (Preparation 95, 242 mg, 0.599 mmol) was added portion-wise to a solution of 1,2,4-thiadiazol-5-amine (182 mg, 1.80 mmol) and sodium hydroxide (71.9 mg, 1.80 mmol) in 1,4-dioxane (1.9 mL, 24 mmol) and water (0.37 mL, 21 mmol). After stirring 30 min at ambient temperature, the reaction was quenched with 2 N HCl. The mixture was partitioned with methylene chloride. The aqueous layer was washed with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated onto Celite. The residue was purified via automated flash chromatography (12 g SiO2, chloroform to 20% MeOH in chloroform). The product containing fractions were concentrated in vacuo, and the residue was dissolved in 1 mL of DMSO, filtered, and purified via reverse-phase HPLC (Prep: Phenomenex 250×30.0 mm 15 micron C18 column. 40 mL/min. Gradient 15% B to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). The product containing fractions were lyophilized to afford the product as a white powder (48 mg, 16%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:9]2[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])=[C:6]([CH3:8])[N:7]=1)[CH3:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(OC(=O)C)C>[CH2:1]([C:3]1[NH:4][C:5]([C:9]2[CH:14]=[C:13]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C)c(-c2cc(F)ccc2[N+](=O)[O-])[nH]1
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Product: CCc1nc(C)c(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])[nH]1

Procedure:
5 g 2-(2-Ethyl-4-methyl-imidazolyl)-4-fluoro-nitrobenzene and 10 g piperidine were heated 30 minutes at 100° C. After cooling 150 ml ethylacetate were added. The solution was extracted three times with 50 ml water. The organic layer was evaporated to dryness. The residue is purified by chromatography (silica gel, dichloromethane/methanol=95/5).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].O=[C:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20]([C:19]1[C:18]([CH3:25])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH:7]=[CH:8][CH:9]=2)=[O:21])[CH3:24]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OC1CCOCC1
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCOCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile (Example 118b) and ethyl 3-oxobutanoate as a pale yellow solid (51%). MS 331 (MH+).
Reaction SMILES: Cl[C@H:2]([CH3:19])[C:3]([O:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[OH:20]/[N:21]=[C:22](/[C:29]1[N:30]=[C:31]([NH:34][C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:32][CH:33]=1)\[C:23]([O:25]CC=C)=[O:24].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:35]([NH:34][C:31]1[S:32][CH:33]=[C:29]([C:22](=[N:21][O:20][C@H:2]([C:3]([O:5][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH3:19])[C:23]([OH:25])=[O:24])[N:30]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@@H](Cl)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](ON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 11 ml of dimethylformamide was dissolved 2.16 g of benzhydryl L-lactate. After cooling the solution to -40° C., 0.8 ml of sulfuryl chloride was added thereto followed by stirring for an hour. Thereafter the reaction solution was extracted with ethyl acetate and a sodium bicarbonate aqueous solution. The organic phase was washed with water, dried and then concentrated to dryness to give 1.8 g of benzhydryl (2R)-2-chloropropionate. This ester was reacted with 3.1 g of allyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate prepared in a manner similar to the description of Published Unexamined Japanese Patent Application No. 149289/80 in 16 ml of dimethylsulfoxide overnight at room temperature in the presence of 1.8 g of potassium carbonate. The reaction solution was partitioned with ice water and ethyl acetate. The organic phase was washed with water, dried and concentrated. The residue was dissolved in 30 ml of methylene chloride. To the solution were added 182 mg of triphenylphosphine and 34 mg of tetrakistriphenylphosphine palladium. The mixture was stirred at room temperature for 30 minutes. Then, a solution of 1.26 g of potassium 2-ethylhexanoate in ethyl acetate. After stirring at room temperature for 2 hours, 45 ml of isopropyl ether was added and the mixture was allowed to stand overnight at 0° C. The obtained precipitates were partitioned in ethyl acetate-acidic water (pH 2.8). The organic phase was washed with water, dried and concentrated to give 2.13 g of 2-(2-tritylamino-thiazol-4-yl)-2-{(1S)-1-diphenylmethoxycarbonylethoxyimino}acetic acid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:25][CH:26]([F:29])[CH2:27]O.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:25][CH:26]([F:29])[CH2:27][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: OCC(F)F
Reactant: c1nc[nH]n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)Cn1cncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of [1,2,4]triazole (7.3 g, 0.11 mol), triphenylphosphine (33 g, 0.13 mol) and 2,2-difluoroethanol (8.0 ml, 10 g, 0.13 mol) in THF (115 ml) was added diethyl azodicarboxylate (20 ml, 22 g, 0.13 mol) dropwise, maintaining the temperature of the mixture between −5 and 0° C. throughout the addition. The resultant solution was allowed to warm to room temperature and was stirred under nitrogen overnight. The solvent was removed it uacuo, and diethyl ether (220 ml) was added to the residue, precipitating a solid. This was separated by filtration, and the filtrate was concentrated in vacuo. The residual oil was purified by distillation under vacuum, yielding 1-(2,2-difluoroethyl)-1H-[1,2,4]triazole as a yellow oil (7.1 g). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ 4.56 (2H, td, J=13.5, 4.1 Hz), 6.13 (1H, tt, J=55.1, 4.2 Hz), 8.01 (1H, s), 8.18 (1H, s).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][O:4][CH2:3]1.CC([O-])(C)C.[K+].Cl[C:13]1[C:18]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)=[O:20])=[C:17]([CH3:30])[CH:16]=[C:15]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:14]=1.O>C1COCC1>[F:29][C:25]1[CH:24]=[C:23]([CH2:22][NH:21][C:19]([C:18]2[C:13]([O:1][CH:2]3[CH2:5][O:4][CH2:3]3)=[N:14][C:15]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:16][C:17]=2[CH3:30])=[O:20])[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: OC1COC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(N2CCOCC2)nc(OC2COC2)c1C(=O)NCc1cccc(F)c1
Temperature: 50 °C
Yield: 83.9 %

Procedure:
A solution of 209 mg (2.82 mmol) 3-hydroxy-oxetane in THF (6 ml) was treated with 316 mg (2.81 mmol) KOtBu and was heated at 50° C. for 15 min. After cooling to RT a solution of 205 mg (0.56 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 9) in THF (3 ml) was added and the mixture was heated at 80° C. for 8 h. The mixture was then poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 190 mg (0.47 mmol, 84%) N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-(oxetan-3-yloxy)-pyridine-3-carboxylic acid amide (example 317). [M+H]+402.2.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH2:16]>S(=O)(=O)(O)O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2([C:14]([NH2:15])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: N#CC1(Nc2ccc(I)cc2)CCCC1
Reactant: O
Agent: O=S(=O)(O)O
Product: NC(=O)C1(Nc2ccc(I)cc2)CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
4.2 g (13.4 mmol) of 1-(4-iodophenyl-amino)-cyclopentanecarbonitrile are dissolved in 40 ml of concentrated sulfuric acid. The reaction medium is stirred for 48 hrs at ambient temperature, then it is poured gently into water and the pH is adjusted to 7 with soda and [the mixture] extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated and the residue is crystallized in a little dichloromethane and heptane. It is then filtered and dried. 4.2 g of 1-(4-iodophenylamino)-cyclopentanecarboxamide are obtained in the form of a pink solid. (M.Pt.=148° C., Yield=94%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[CH2:16]([O:23][CH2:24][CH2:25][C@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:27](O)=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][CH2:24][CH2:25][C@H:26]([NH:30][C:31](=[O:32])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:27](=[O:28])[NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nn1cccc1C(=O)Nc1ccccc1
Yield: 99.6 %

Procedure:
The title compound was prepared from 1-amino-N-phenyl-1H-pyrrole-2-carboxamide (0.65 g, 3.2 mmol) and (S)-4-(benzyloxy)-2-(tert-butoxycarbonylamino)butanoic acid (1.0 g, 3.2 mmol) following the experimental procedure described in Preparation 73a. 1.57 g (96% yield) of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2](=[CH2:7])[CH2:3][N:4]=[C:5]=[S:6].[CH2:8]([SH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N12CCN(CC1)CC2>C(#N)C.C1(C)C=CC=CC=1>[CH2:8]([S:15][C:5](=[S:6])[NH:4][CH2:3][C:2]([Cl:1])=[CH2:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(Cl)CN=C=S
Reactant: SCc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C=C(Cl)CNC(=S)SCc1ccccc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
47 g of 2-chloro-allyl isothiocyanate and 40 g of benzyl mercaptan are dissolved in 150 ml of acetonitrile and 150 ml of toluene. Then 1 g of 1,4-diazabicyclo[2.2.2]octane is added and the mixture is heated to 75° C. and stirred for one hour. After cooling to room temperature, the solvent is removed by evaporation and the residue is crystallised from ether/hexane. In that manner the title product having a melting point of 46-48° C. (compound A) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>CN(C)C=O>[CH3:16][C:15]1[C:10]2[N:11]([CH:17]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:29]([CH2:28][CH2:27][CH2:26][Cl:25])(=[O:31])=[O:30])=[CH:7][CH:6]=3)[N:9]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1cccn2cc(-c3ccc(N)cc3)nc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccn2cc(-c3ccc(NS(=O)(=O)CCCCl)cc3)nc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a suspension of the product of Example 27 Step B (195 mg) in N,N-dimethylformamide (2 mL) was added triethylamine (0.12 mL) and the mixture cooled to 0° C. 3-chloropropanesulfonyl chloride (0.11 mL) was added dropwise and the mixture stirred for 1.5 hours before the addition of H20 (2 mL). The reaction mixture was partitioned between H2O (15 mL) and ethyl acetate (15 mL). The aqueous layer was brought to pH=9-10 with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, decanted, and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (210 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[C:4]([CH3:11])[N:3]=1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:16]2[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([C:13]([F:12])([F:28])[F:27])[CH:15]=2)=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1nc(N)c(C#N)nc1Br
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1nc(N)c(C#N)nc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 4, using 1.7 grams (0.008 mole) of 2-amino-3-cyano-5-bromo-6-methylpyrazine, 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0)in 150 mL of toluene, yielding 2-amino-3-cyano-5-[3,5-di(trifluoro-methyl)phenyl]-6-methylpyrazine.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C.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>[Cl:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:25])([F:24])[F:13])[N:3]=[C:4]([CH3:12])[N:5]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
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: c1ccccc1
Product: Cc1nc(Cl)c([N+](=O)[O-])c(-c2ccccc2C(F)(F)F)n1
Yield: 39.9 %

Procedure:
Part A: To a solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (3.12 g, 15 mmol, J. Chem. Soc 3832 (1954); ibid 677 (1944)) and 2-(trifluoromethyl)phenylboronic acid (3.42 g, 18 mmol) in benzene (50 ml) was added 1M aqueous sodium carbonate (20 ml) and 500 mg of tetrakis(triphenylphosphine)palladium. This mixture was refluxed for 4.5 hours, then was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (10% then 20% ethylacetate in hexanes) afforded 4-Chloro-2-methyl-5-nitro-6-(2-(trifluoromethyl)phenyl)-pyrimidine (1.90 g) as a pale yellow solid. CI Mass Spec. (M+H)+ =318.0.
Reaction SMILES: CS(O[CH2:6][C:7]([NH:10][C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[C:13](Cl)[N:12]=1)([CH3:9])[CH3:8])(=O)=O.C(=O)([O-])[O-:20].[K+].[K+]>O1CCOCC1.O>[Cl:17][C:15]1[CH:16]=[C:11]2[NH:10][C:7]([CH3:9])([CH3:8])[CH2:6][N:12]2[C:13](=[O:20])[N:14]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(COS(C)(=O)=O)Nc1cc(Cl)nc(Cl)n1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)Cn2c(cc(Cl)nc2=O)N1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropyl methanesulfonate (3.00 g, 9.55 mmol) in 1,4-dioxane (15 mL) and water (15 mL) was added potassium carbonate (4.62 g, 33.4 mmol). The reaction mixture was stirred at 80° C. for 2 h, filtered, extracted with ethyl acetate (5 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was used into next step without further purification.