Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8](CC2C=CC=CC=2)CC2C=CC=CC=2)[C:5]2[N:23]=[C:24]([CH3:31])[N:25]([CH2:26][CH2:27][O:28][CH2:29][CH3:30])[C:4]=2[C:3]=1[CH3:32].Cl>CO.[OH-].[OH-].[Pd+2]>[CH2:29]([O:28][CH2:27][CH2:26][N:25]1[C:4]2[C:3]([CH3:32])=[CH:2][N:7]=[C:6]([NH2:8])[C:5]=2[N:23]=[C:24]1[CH3:31])[CH3:30]
Reactant: CCOCCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(Cl)c(C)c21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CCOCCn1c(C)nc2c(N)ncc(C)c21
Reaction time: 4 h
Yield: 49.2 %

Procedure:
6-Chloro-1-(2-ethoxyethyl)-2,7-dimethyl-N4,N4 -bis(phenylmethyl)-1H-imidazo[4,5-c]pyridin-4-amine (0.7 g, 1.56 mmole) was taken up in methanol saturated with anhydrous hydrochloric acid (100 mL), combined with palladium hydroxide on carbon and then hydrogenated on a Paar apparatus for four hours. The reaction mixture was filtered to remove the catalyst then concentrated under vacuum. The residue was partitioned between methylene chloride/water/sodium bicarbonate. The methylene chloride layer was separated, dried over magnesium sulfate then concentrated under vacuum to provide an off white solid. This material was recrystallized from ethyl acetate/hexane to provide 0.18 g of the desired product as a solid, m.p. 129°-130° C. Analysis: Calculated for: C12H18N4O+1/4H2O: % C, 60.35; % H, 7.81; % N, 23.46; Found: % C, 60.64; % H, 7.50; N, 23.39.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][N:8]2[CH:13]=[C:12]([C:14]([OH:16])=O)[C:11](=[O:17])[N:10]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[O:25])[CH2:4][O:3]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:60][O:61][C:62]1[CH:63]=[C:64]2[C:69](=[CH:70][C:71]=1[O:72][CH3:73])[N:68]=[CH:67][CH:66]=[C:65]2[O:74][C:75]1[CH:80]=[CH:79][C:78]([NH2:81])=[CH:77][C:76]=1[F:82].O1CCOCC1>CN(C)C=O.CCOC(C)=O.Cl>[CH3:60][O:61][C:62]1[CH:63]=[C:64]2[C:69](=[CH:70][C:71]=1[O:72][CH3:73])[N:68]=[CH:67][CH:66]=[C:65]2[O:74][C:75]1[CH:80]=[CH:79][C:78]([NH:81][C:14]([C:12]2[C:11](=[O:17])[N:10]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9](=[O:25])[N:8]([CH2:7][C@H:5]([OH:6])[CH2:4][OH:3])[CH:13]=2)=[O:16])=[CH:77][C:76]=1[F:82]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CC1(C)OC[C@H](Cn2cc(C(=O)O)c(=O)n(-c3ccc(F)cc3)c2=O)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cn(C[C@H](O)CO)c(=O)n(-c5ccc(F)cc5)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-((S)-2,2-Dimethyl-1,3-dioxolan-4-ylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.0446 g, 0.122 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.0466 g, 0.122 mmol) in N,N-dimethylformamide (2.00 mL) was added N,N-diisopropylethylamine (0.0388 mL, 0.223 mmol) and stirred at rt for 15 min. 4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenylamine (0.035 g, 0.11 mmol) was added and stirred overnight. The solution was diluted with EtOAc, washed with 1N Na2CO3, water and brine then dried over MgSO4 and concentrated. MeOH was added (1 mL) and a solid separated. This material was dissolved in 4 M of hydrogen chloride in 1,4-dioxane (2 mL, 8 mmol), stirred for 2 h and then concentrated. To this product was added MeOH and the precipitate collected to give a white solid. mp=165-6° C.; LCMS m/z=621 (M+1); 1H NMR (DMSO) δ: 11.0 (s, 1H), 8.72 (s, 1H), 8.48 9d, 1H, J=5.4 Hz), 8.01, 7.98 (dd, 1H, J=2.4, 13.5 Hz), 7.52-7.55 (j, 1H), 7.34-7.46 (m, 6H), 6.47 (d, 1H, J=5.4 Hz), 6.17 (d, 1H, J=5 Hz), 4.78 (t, 1H, J=5.7 Hz), 4.22 (d, 1H, J=10 Hz), 3.94 (d, 6H), 3.75-3.78 (m, 2H), 3.3 (m, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:16][C:15]2[CH:17]=[C:18]([CH:21]=[C:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])[CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]1.O>COCCOC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:16][C:15]2[CH:17]=[C:18]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])[CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(c2)CN(c2nc4ccccc4o2)CCO3)S1
Solvent: O
Solvent: COCCOC
Product: O=C1NC(=O)C(Cc2ccc3c(c2)CN(c2nc4ccccc4o2)CCO3)S1
Temperature: 8.5 °C
Reaction time: 4 h

Procedure:
5-(4-Benzooxazol-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethylene)-thiazolidine-2,4-dione [compound of Example 6] (0.118 g, 0.3 mmol) was taken in 1,2-dimethoxyethane (40 mL) under nitrogen. The mixture was cooled to 7-10° C. by using dry ice-acetone bath, freshly prepared Al-amalgam strips and water (0.54 mL, 30 mmol) were added and the reaction mixture was stirred for 4 hours. The reaction mixture was then filtered through a celite bed and washed with 1,2-dimethoxyethane. The organic layer was concentrated under high vacuum and purified using silica gel column in 50% ethyl acetate in petroleum ether. The product obtained after concentration was washed with 2% ethyl acetate in petroleum ether, to give 5-(4-benzooxazol-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethyl)-thiazolidine-2,4-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:15][CH2:14]1)([O-:3])=[O:2].Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:17][CH2:18]1)([O-:3])=[O:2]
Reactant: Brc1ccccn1
Reactant: COc1ccccc1N1CCN(CCNc2ccccc2[N+](=O)[O-])CC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1N1CCN(CCN(c2ccccn2)c2ccccc2[N+](=O)[O-])CC1
Temperature: 160 °C
Yield: 48 %

Procedure:
A mixture of 0.43 g of 1-[N-(2-nitrophenyl)-2-aminoethyl]-4-(2-methoxyphenyl)piperazine (prepared as described in U.S. Pat. No. 3,472,854), 0.19 g of 2-bromopyridine, 0.17 g of anhydrous potassium carbonate and 0.01 g of powdered copper was heated to 100° C., and maintained at that temperature for 3 h, followed by the addition of another 0.138 g of 2-bromopyridine, and the heating of the mixture to 160° C. for 24 h. After cooling the mixture to room temperature and extraction with ethyl acetate (2×20 mL), the combined organic phases were then washed with water, dried on sodium sulphate, and evaporated to dryness in vacuo. The obtained crude was next purified by flash chromatography (ethyl acetate-petroleum ether 7:3). The recovered fractions, after evaporation to dryness, afforded 0.25 g of the compound of Example 11 (52%).
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:14][C:13](=[O:15])[NH:12][C:11]1([CH3:17])[CH3:16])C1C=CC=CC=1>CCO.[Pd]>[OH:8][CH2:9][CH:10]1[O:14][C:13](=[O:15])[NH:12][C:11]1([CH3:17])[CH3:16]
Reactant: CC1(C)NC(=O)OC1COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)NC(=O)OC1CO
Reaction time: 24 h

Procedure:
To a solution of 5-((benzyloxy)methyl)-4,4-dimethyloxazolidin-2-one (2.6 g, 11 mmol) in EtOH (40 ml) was added 500 mg of 10% Pd/C (wet, Degussa type E101). The vessel was pressurized with H2 (450 psi) and the suspension stirred for 24 h. An additional 500 mg of 10% Pd/C was added and the reaction was stirred under 450 PSI H2 for 5 days. The mixture was filtered through celite, concentrated in vacuo, and purified by column chromatography (1 to 10% methanol in dichloromethane) to give a clear liquid which solidified to a white solid upon standing (1.8 g, 12 mmol, 100%). 1H NMR (CDCl3, 400 MHz) δ 1.30 (s, 3H), 1.41 (s, 3H), 2.45 (br s, 1H), 3.76-3.81 (m, 1H), 3.87-3.92 (m, 1H), 4.30-4.32 (dd, J=4.4, 7.2 Hz, 1H) 5.59 (br s, H). LRMS (ESI/APCI) m/z 146 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]>C(Cl)Cl.CCOCC>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OCc1ccccc1I
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccccc1I

Procedure:
Commercially available 2-iodobenzyl alcohol (10.0 g, 42.7 mmol) was dissolved in 200 mL CH2Cl2. Upon completion, the reaction was diluted with 250 mL Et2O. The product was recovered as a brown liquid (10.3 g, 104%). TLC: Rf 0.57 (3:1 hexanes/EtOAc). IR (neat): 3061, 2853, 2745, 1696, 1580, 1561. 1H-NMR (400 MHz, CDCl3): δ 10.07 (s, 1H, C1-H), 7.95 (dd, 1H, J=7.9, 1.0, C4-H), 7.88 (dd, 1H, J=7.7, 1.8, C7-H), 7.47 (td, 1H, J=7.5 0.8, C6-H), 7.29 (td, 1H, J=7.6, 1.8, C5-H). 13C-NMR (100 MHz, CDCl3): δ 195.1, 140.2, 135.1, 134.7, 129.9, 128.4, 100.5. EI-MS m/z (rel int): 232 (M+, 100), 231 ([M−H]+, 40), 203 ([M−CHO]+, 15), 105 ([M−I]+, 3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:23])([CH2:20][CH:21]=[CH2:22])[CH2:9][CH2:10][NH:11][N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:24](Cl)(Cl)=[O:25]>C(N(CC)CC)C.C1(C)C=CC=CC=1.C(Cl)(Cl)=O>[CH2:20]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:23][C:24](=[O:25])[N:11]([N:12]([CH3:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)[CH:21]=[CH2:22]
Reactant: C=CCC(O)(CCNN(C)c1ccccc1)c1ccc(F)cc1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCC1(c2ccc(F)cc2)CCN(N(C)c2ccccc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(4-fluorophenyl)-1-(2-methyl-2-phenylhydrazinyl)hex-5-en-3-ol (14 mg, 0.04 mmol) and triethylamine (3 drops) was dissolved in toluene (1 mL). The solution was cooled to 0° C. and phosgene (3 drops, 20% toluene solution) was added. After 1 h, more phosgene was added (3 drops, 20% toluene solution) and the reaction was allowed to warm to rt overnight. The solvent was evaporated and the residue was redissolved in toluene. DBU (5 drops) was added and the solution heated to reflux for 4 h. The solvent was evaporated and the residue was purified by preparative HPLC to afford 6-allyl-6-(4-fluorophenyl)-3-(methyl(phenyl)amino)-1,3-oxazinan-2-one (8.8 mg). LC-MS Method 1 m/z=341 (M+1). 1H NMR (CDCl3) δ 7.43-7.37 (br m), 7.25-7.26 (m), 7.19-7.12 (m), 6.99 (t), 6.85 (m), 6.72-6.66 (m), 6.07 (d), 6.73 (m), 5.15-5.05 (m), 3.42 (m), 3.33 (m), 3.14 (s), 2.85 (s), 2.65-2.55 (m), 2.50-2.34 (m).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:9]=[CH:8][O:7][C:6]=1[CH2:10][C:11](O)=[O:12])(O)=[O:2]>C1COCC1>[OH:2][CH2:1][CH2:4][C:5]1[CH:9]=[CH:8][O:7][C:6]=1[CH2:10][CH2:11][OH:12]
Reactant: O=C(O)Cc1ccoc1CC(=O)O
Solvent: C1CCOC1
Product: OCCc1ccoc1CCO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
A solution of the product from step c.) (6.4 g, 35 mmol) in dry THF (400 ml) was cooled to 0° C. and a 1.0 M solution of BH3 in THF (174 ml, 174 mmol) was added dropwise over 10 minutes. After the addition was complete the mixture was stirred for an additional 20 minutes at 0° C. and then warmed to 22° C. for 2 hours. Next, the mixture was poured into ice cold sat. NaHCO3 (300 ml) and extracted with EtOAc (2×200 ml). The organic layer was dried (MgSO4) and concentrated providing 3.58 g (65%) of the subtitle compound. MS: ESI (positive): 157 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:11].[OH-].[Na+].Cl[O-].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.CO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=2[NH:9][C:10]1=[O:11]
Reactant: COc1ccccc1NC(=O)Nc1ccccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1ccccc1-n1c(=O)[nH]c2c(OC)cccc21

Procedure:
A mixture of N,N'-di-(2-methoxyphenyl)-urea (6.81 g, 25 mmol) and tetra-n-butyl-ammoniumbromide (0.4 g, 1.3 mmol) in methylene chloride/methanol (1:1 , 200 ml) was at room temperature under vigorous stirring added a solution of sodium hydroxide (2 g in 10 ml water) followed by a solution of sodiumhypochlorite(55 ml, Aldrich). The mixture was stirred for 4 hours and 30 ml water was added The organic phase was washed with 10 ml 1M hydrogen chloride sol., dried and concentrated in vacuo. Upon trituration with diethyl ether dark grey crystals separated The crude product was recrystallized twice, first from ethanol and then from ethyl acetate yielding the title compound as white crystals, M.p. 246°-247° C.
Reaction SMILES: [F:1][CH:2]([F:43])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1>C(O)(C(F)(F)F)=O.CS(C)=O>[F:43][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cccc(OC(F)F)c3)n2)cc1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cccnc2Nc2cccc(OC(F)F)c2)n1
Yield: 3.4 %

Procedure:
A solution of 4-(2-(3-(difluoromethoxy)phenylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.121 g, 0.207 mmol) in TFA (8.0 mL) (Aldrich) was heated at 80° C. overnight using a hotplate and a metal heating block. The crude product was dissolved in 2.5 mL of DMSO, and was purified by reversed phase chromatography (Gilson; 10-90% CH3CN in water with TFA additive: 0.1% v/v in each solvent). The fractions were combined and the CH3CN was removed. DCM was added and the whole was washed with a saturated solution of NaHCO3 (1×), brine (1×), dried over MgSO4, filtered and concentrated to give 4-(2-(3-(difluoromethoxy)phenylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (24 mg, 6.97 μmol, 3.37% yield) as a yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ 12.17 (br. s., 1H); 8.80 (d, J=8.2 Hz, 1H); 8.41 (br. s., 1H); 7.97 (br. s., 1H); 7.83-7.90 (m, 1H); 7.78 (br. s., 1H); 7.62 (d, J=8.6 Hz, 1H); 7.31-7.40 (m, 1H); 6.93-7.01 (m, 1H); 6.78 (d, J=8.2 Hz, 1H); 2.45 (br. s., 3H). m/z (ESI, +ve ion) 345.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[OH:11].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15]>>[OH:11][C@@H:6]1[C:7]2[C:3](=[C:2]([O:1][C:19]3[CH:20]=[CH:21][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][CH:18]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Oc1cccc2c1CC[C@@H]2O
Product: COC(=O)c1ccc(Oc2cccc3c2CC[C@@H]3O)cc1
Yield: 42.7 %

Procedure:
According to the method of (Example 99) <Step 1>, from (1S)-4-hydroxy-2,3-dihydro-1H-inden-1-ol (0.99 g) and (4-(methoxycarbonyl)phenyl)boronic acid (1.31 g) that are commercially available or are obtained according to a known method, the subject compound (0.80 g) was obtained as pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH:11]([CH3:15])[CH2:10][CH2:9][CH:8]([CH3:16])[C:7]=2[CH:6]=1)=O.C(OC([N:24]1[CH2:29][CH2:28][CH:27]([C:30](=[S:32])[NH2:31])[CH2:26][CH2:25]1)=O)(C)(C)C.Br>>[CH3:15][CH:11]1[CH2:10][CH2:9][CH:8]([CH3:16])[C:7]2[CH:6]=[C:5]([C:3]3[N:31]=[C:30]([CH:27]4[CH2:28][CH2:29][NH:24][CH2:25][CH2:26]4)[S:32][CH:2]=3)[CH:14]=[CH:13][C:12]1=2
Reactant: CC1CCC(C)c2cc(C(=O)CBr)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: Br
Product: CC1CCC(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 1.09 g (2.05 mmol) of 2-bromo-1-(5,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone and 500 mg (2.05 mmol) of 4-thiocarbamoylpiperidine-1-carboxylic acid tert-butyl ester. The product is in the form of the hydrobromide.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([OH:9])=[O:8].[C:11](Cl)(=O)[C:12](Cl)=O.CCO>C(Cl)Cl.CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([O:9][CH2:11][CH3:12])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ncc(I)c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1c(I)cnn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
4-Iodo-1-methyl-1H-pyrazole-5-carboxylic acid (301.68 g, 1.2 moles) was slurried in 1.2 L of DCM and DMF (2.3 g, 31 mmol) followed by addition of oxalyl chloride (115 mL, 1.3 moles) over 37 minutes and then stirred at room temperature for 3 h. To the resulting solution was added EtOH (750 mL, 12.9 mol) over 5 min followed by stirring at room temperature for 2 h. The crude product solution was concentrated to dryness in vacuo and then reconstituted in 1.2 L of warm heptane followed by filtration. The filtrate was concentrated by removing 500 mL of heptane, resulting in precipitation of solids. The solids were collected via filtration and dried to afford ethyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylate as a white solid (297.6 g, 89% yield).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].NC(N)=[S:14]>C(O)CCC>[SH:14][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Reactant: NC(N)=S
Solvent: CCCCO
Product: Cc1cc(C)c(C#N)c(S)n1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A mixture of 2-chloro-4,6-dimethylnicotinonitrile (800 mg, 4.83 mmol) and thiourea (1.2 kg, 15.76 mmol) was heated at reflux (118° C.) in n-butanol for 4 h. After cooling to room temperature, the yellow solution turned to a suspension containing light yellow solids. The solids were collected by filtration, rinsed with n-butanol, and dried in vacuo to give 2-mercapto-4,6-dimethylnicotinonitrile (778 mg, 98% yield). C8H8N2S; light yellow powder; mp 219-221° C.; 1H NMR (400 MHz, CDCl3) δ 6.40 (1H, s), 2.45 (3H, s), 2.43 (3H, s); ESI-HRMS (negative mode) calcd for C8H7N2S: 163.0330. found: m/z 163.0332 [M−H]−.
Reaction SMILES: [B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(CC)C(C)C)(C)C.[F:32][C:33]([F:74])([F:73])[C:34]1([C:69]([F:72])([F:71])[F:70])[C:38](=[O:39])[N:37]([C@@H:40]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:41](O)=[O:42])[C:36](=[O:48])[N:35]1[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:57]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[CH3:66])=[O:58])=[C:52]([O:67][CH3:68])[CH:51]=1.[NH2:75][C@H:76]([C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)[CH2:77][C:78]([O:80][CH2:81][CH3:82])=[O:79]>CN(C=O)C>[F:72][C:69]([F:70])([F:71])[C:34]1([C:33]([F:74])([F:73])[F:32])[C:38](=[O:39])[N:37]([C@@H:40]([CH2:44][CH:45]([CH3:46])[CH3:47])[C:41]([NH:75][C@H:76]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[CH2:77][C:78]([O:80][CH2:81][CH3:82])=[O:79])=[O:42])[C:36](=[O:48])[N:35]1[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:57]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[CH3:66])=[O:58])=[C:52]([O:67][CH3:68])[CH:51]=1
Reactant: COc1cc(CN2C(=O)N([C@@H](CC(C)C)C(=O)O)C(=O)C2(C(F)(F)F)C(F)(F)F)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)C[C@H](N)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@H](NC(=O)[C@H](CC(C)C)N1C(=O)N(Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)C(C(F)(F)F)(C(F)(F)F)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
1.89 g (5.77 mmol) of TOTU and 932 μL of N,N-diisopropylethylamine were added at 0° C. to a solution of 3.57 g (5.77 mmol) of (S)-2-(4,4-bis(trifluoromethyl)-3-(4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl)-2, 5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetic acid (prepared from (S)-2-(4,4-bis(trifluoromethyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetic acid and 4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl chloride as described in Example 18f) and 1.11 g (5.77 mmol) of ethyl (S)-3-amino-3-phenylpropionate in 30 mL of absolute DMF. After stirring at room temperature for 1 hour, DMF was removed in vacuo, the residue was taken up in ethyl acetate and the ethyl acetate solution was washed successively with an aqueous KHSO4K2SO4 solution, a saturated NaHCO3 solution and water. After drying the organic phase over sodium sulfate and filtering, the solvent was removed in vacuo and the residue was chromatographed over silica gel using ethyl acetate/heptane (2/3). After concentration of the product fractions, 3.26 g (71%) of the title compound were obtained.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:20][S:21]([CH:24]2[CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH2:4]1)[CH3:2].[OH-].[K+].S([C:39]#[N:40])(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[C:39]([N:20]([C@@H:5]1[CH2:6][C@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[C@H:3]([CH2:1][CH3:2])[CH2:4]1)[S:21]([CH:24]1[CH2:26][CH2:25]1)(=[O:23])=[O:22])#[N:40]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](N(C#N)S(=O)(=O)C2CC2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 4.7 %

Procedure:
To the solution of N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.05 g, 0.134 mmol, WO2009152133) in DMF (4 mL), KOH (0.022 g, 0.401 mmol) was added and the mixture was stirred at rt for about 5 min. Tosyl cyanide (0.024 g, 0.134 mmol) was added and stirring was continued for about 2 h. The solvent was removed under reduced pressure and the residue purified by preparative HPLC (Table 1, Method q) to yield N-cyano-N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.0025 g, 5%) as an off-white solid: LC/MS (Table 1, Method a) Rt=1.84 min; MS m/z: 400 (M+H)+.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].C(N(C(C)C)CC)(C)C.Cl.[NH2:24][C:25]1[N:30]=[C:29]([OH:31])[C:28]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][OH:43])=[CH:35][C:34]=2[O:44][CH3:45])=[C:27]([CH3:46])[N:26]=1>C1COCC1.O>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:31][C:29]1[C:28]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][OH:43])=[CH:35][C:34]=2[O:44][CH3:45])=[C:27]([CH3:46])[N:26]=[C:25]([NH2:24])[N:30]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COc1cc(OCCCO)ccc1Cc1c(C)nc(N)nc1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OCCCO)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 88.1 %

Procedure:
2-Mesitylenesulfonyl chloride (2.7 g) was added to a suspension of diisopropylethylamine (4.6 mL) and the product from step (vi) (2.9 g) in THF (200 mL) and the mixture was stirred under reflux for 18 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (3.6 g) as a white solid; 1H NMR (300 MHz, CDCl3); 6.92 (2H, s), 6.71 (1H, d), 6.40 (1H, d), 6.32 (1H, dd), 4.70 (2H, br s), 4.07 (2H, t), 3.88-3.82 (2H, m), 3.76 (3H, s), 3.73 (2H, s), 2.57 (6H, s), 2.29 (3H, s), 2.24 (3H, s), 2.06-1.98 (2H, m); LC-MS: m/z 502.