Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1([F:55])[C:53](=O)[NH:52][C:26]2([C:39]3[CH:38]=[C:37]([O:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=[CH:35][C:34]=3[O:33][C:32]3[C:27]2=[CH:28][C:29]([C:46]2[CH:47]=[N:48][CH:49]=[N:50][CH:51]=2)=[CH:30][CH:31]=3)[CH2:25]1>C1(C)C=CC=CC=1>[F:23][C:24]1([F:55])[C:53](=[S:10])[NH:52][C:26]2([C:39]3[CH:38]=[C:37]([O:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=[CH:35][C:34]=3[O:33][C:32]3[C:27]2=[CH:28][C:29]([C:46]2[CH:47]=[N:48][CH:49]=[N:50][CH:51]=2)=[CH:30][CH:31]=3)[CH2:25]1
Reactant: CC(C)(C)COc1ccc2c(c1)C1(CC(F)(F)C(=O)N1)c1cc(-c3cncnc3)ccc1O2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)COc1ccc2c(c1)C1(CC(F)(F)C(=S)N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 90 °C

Procedure:
Lawesson's reagent (6.72 mg, 0.017 mmol) was added to a solution of 4,4-difluoro-2′-(neopentyloxy)-7′-(pyrimidin-5-yl)spiro[pyrrolidine-2,9′-xanthen]-5-one (0.015 g, 0.033 mmol) in toluene (0.665 mL) and the reaction was heated at 90° C. for 2.5 hours before being concentrated. The crude material was purified by dissolving in a minimal amount of CH2Cl2 and filtering through a pad of silica gel eluting with 1:4 EtOAc in hexane followed by 1:1 EtOAc in hexane, to provide 4,4-difluoro-2′-(neopentyloxy)-7′-(pyrimidin-5-yl)spiro[pyrrolidine-2,9′-xanthene]-5-thione. M=468.1 [M+H].
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[ClH:25].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][C:28]=1[O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([NH:43][C:44]2[S:45][CH:46]=[C:47]([CH3:49])[N:48]=2)[CH:38]=1.[NH2:50][CH2:51][CH2:52][N:53]1[CH2:57][CH2:56][CH2:55][CH2:54]1.CN(C=O)C>O>[ClH:25].[ClH:25].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:50][CH2:51][CH2:52][N:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)=[O:33])=[CH:29][C:28]=1[O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([NH:43][C:44]2[S:45][CH:46]=[C:47]([CH3:49])[N:48]=2)[CH:38]=1
Reactant: Cc1csc(Nc2cc(Oc3cc(C(=O)O)ccc3F)ccn2)n1
Reactant: NCCN1CCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2cc(Oc3cc(C(=O)NCCN4CCCC4)ccc3F)ccn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A 3 dram vial was charged with bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.488 g, 1.05 mmol), 4-fluoro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid hydrochloride (Example 107; 0.200 g, 0.524 mmol), N-(2-aminoethyl)pyrrolidine (0.179 g, 1.57 mmol) and DMF (3 mL). The reaction was stirred for 1 hour at ambient temperature. Water was added and the reaction was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography. 2M HCl in ether was added to the isolated material and the collected solids were dried over high vacuum to give the title compound (0.078 g, 28.9% yield) as a white solid. 1H NMR (d6-DMSO) δ 11.21 (bs, 1H), 9.75 (bs, 1H), 8.86 (t, 1H), 8.23 (m, 1H), 7.92 (m, 2H), 7.64 (dd, 1H), 6.62 (m, 2H), 6.58 (d, 1H), 3.60 (m, 4H), 3.32 (quart, 2H), 3.03 (m, 2H), 2.21 (d, 3H), 2.00 (d, 2H), 1.85 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[CH2:14][C@@H:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[CH2:14][C@@H:9]1[CH2:10][N:11]2[C:20]([C:19]1[CH:18]=[N:17][C:16]([NH2:15])=[CH:24][CH:23]=1)=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1CN2
Product: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1CN2C(=O)c1ccc(N)nc1
Yield: 31 %

Procedure:
Using amide formation method 1, (R,R)-2,5-Diaza-bicyclo[2.2.1]heptane-2-c arboxylic acid tert-butyl ester (1.0 g, 4.26 mmol, 1.0 eq) was combined with 6-Amino-nicotinic acid (588 mg, 4.26 mmol, 1.0 eq) to give 5-(6-Amino-pyridine-3-carbonyl)-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (420 mg, 31% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35-1.40 (m, 3H) 1.40-1.51 (m, 9H) 1.89 (br. s., 2H) 3.31-3.50 (m, 2H) 3.55 (d, J=9.09 Hz, 1H) 3.67 (dd, J=13.14, 6.57 Hz, 1H) 4.50 (br. s., 1H) 4.64 (br. s., 1H) 4.91 (br. s., 1H) 6.51 (d, J=6.57 Hz, 1H) 7.64 (br. s., 1H) 8.24 (br. s., 1H); MS m/z 637.0 (M+H)+.
Reaction SMILES: [C:1](=[N:14][NH:15][C:16](=[O:29])[CH2:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:19][OH:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.ClCCl>[C:1](=[N:14][NH:15][C:16]([CH2:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:19][O:20][S:31]([CH3:30])(=[O:33])=[O:32])=[O:29])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(C(CO)CC(=O)NN=C(c2ccccc2)c2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(C(COS(C)(=O)=O)CC(=O)NN=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-hydroxy-3-(3-methoxy-phenyl)-butyric acid benzhydrylidene-hydrazide and (1.7 g, 4.38 mmol) and 4-dimethylaminopyridine (26 mg, 0.22 mmol) in pyridine (15 mL) is cooled to 0° C. treated with methanesulfonyl chloride (0.4 mL, 5.25 mmol) and stirred 18 h at room temperature. The mixture is diluted with dichloromethane (30 mL) and washed with 1 N hydrochloric acid (30 mL), a saturated solution of sodium bicarbonate and brine. The mixture is dried over magnesium sulfate, filtered, concentrated in vacuo and chromatographed on SiO2 (2% methanol/dichloromethane) to yield the title compound, 1.64 g (80%), as yellow foam.
Reaction SMILES: OC1CC[N:5]([C:8]([NH:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]5)=[CH:26][CH:25]=4)(=[O:23])=[O:22])=[CH:19][C:13]=3[N:12]=2)=[O:9])[CH2:4][CH2:3]1.NC[CH:39]1[O:44][CH2:43][CH2:42][NH:41][CH2:40]1>O1CCCC1.CN1CCCC1=O>[N:41]1([CH2:3][CH2:4][NH:5][C:8](=[O:9])[NH:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][S:21]([C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]5)=[CH:28][CH:29]=4)(=[O:23])=[O:22])=[CH:19][C:13]=3[N:12]=2)[CH2:42][CH2:43][O:44][CH2:39][CH2:40]1
Reactant: NCC1CNCCO1
Reactant: O=C(Nc1nc2cc(OS(=O)(=O)c3ccc(N4CCC(O)CC4)cc3)ccc2[nH]1)N1CCC(O)CC1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=C(NCCN1CCOCC1)Nc1nc2cc(OS(=O)(=O)c3ccc(N4CCC(O)CC4)cc3)ccc2[nH]1
Yield: 33.1 %

Procedure:
A solution of 4-(4-hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[(4-hydroxy-piperidine-1-carbonyl)-amino]-1H-benzoimidazol-5-yl ester (example 79, 20 mg) and 2-(aminomethyl)-morpholine (50 mg) in tetrahydrofuran (1 ml) and N-methylpyrrolidinone (0.2 ml) was heated at 95° C. for 22 hours. The reaction mixture was then evaporated and purified by triggered LC/MS to give 4-(4-hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester as an off-white solid (7 mg). Mass spectrum: 545 [M+H]+; retention time=5.47 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:13]([F:12])([F:24])[F:25])=[O:23]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccccc1OC(F)(F)F
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1OC(F)(F)F
Yield: 59.6 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromethoxy phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.69 g, 60%). EI-MS m/z 358(M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[NH2:20])=[O:14]>C(Cl)Cl>[CH3:11][O:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[NH:20][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:14]
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1sccc1N
Solvent: ClCCl
Product: COC(=O)c1sccc1NCc1ccc(OC)cc1
Temperature: 85 °C
Yield: 91.6 %

Procedure:
4-Methoxybenzyl chloride (22.8 mL, 167.42 mmol) was added to a solution of methyl-3-amino-thiophene-2-carboxylate (17.55 g, 111 mmol) in dry CH2Cl2 (20 mL). The solution was mixed well. Excess CH2Cl2 was evaporated and the mixture was heated overnight at 85° C. under vacuum (3 torr). The mixture was cooled to room temperature. Hexane was added to the mixture, which was refluxed for 30 min, and cooled to 0° C. The solids formed were filtered, washed by hexane, and dried to yield 28.19 g (91%) of 3-(4-methoxybenzylamino)-thiophene-2-carboxylic acid methyl ester as red solids. 1H NMR (400 MHz, DMSO-d6) δ 3.71 (s, 6H), 4.42 (s, 2H), 6.77 (d, J=5.6 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.63 (d, J=5.6 Hz, 1H), ppm; MS m/z=278 amu (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:25])[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: CC(Br)c1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(C(C)c3ccccc3)C(C)(C)C2=O)cn1

Procedure:
Prepared as in Example 16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 16a) and (1-bromoethyl)benzene. MS 408 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.15 μm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.O.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([F:17])[F:16])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
4-bromo-2-chlorophenol (1.0 g, 4.8 mmol) was dissolved in DMF (35 ml) and water (5 ml) was added followed by sodium chloro(difluoro)acetate (2.0 g, 12 mmol) and cesium carbonate (3.1 g, 9.6 mmol). The mixture was stirred for 15 minutes at room temperature and then heated to 100° C. for 2 hours under nitrogen. The mixture was partitioned between water (50 ml) and tBuOMe (50 ml). The organic phase was separated, washed brine, dried over sodium sulphate, filtered, and concentrated in vacuo to give a crude product. The crude product was purified by silica gel chromatography eluting with 0-30% EtOAc in heptanes to give a title compound (0.83 g, 67% yield) as colourless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[N:13](OCCC(C)C)=[O:14].C(OCC)C.[ClH:26]>C(O)CC>[ClH:26].[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([N:13]=[O:14])=[C:6]([OH:10])[CH:5]=1)[CH3:12]
Reactant: CC(C)CCON=O
Reactant: CCN(CC)c1cccc(O)c1
Agent: Cl
Solvent: CCCO
Solvent: CCOCC
Product: CCN(CC)c1ccc(N=O)c(O)c1

Procedure:
0.1 mol of 3-diethylaminophenol are dissolved in 50 ml of n-propanol saturated with gaseous hydrogen chloride and, at 0° C., admixed dropwise and with stirring with 0.1 mol of isoamyl nitrite. Stirring is continued for another hour and the reaction solution is then admixed with diethyl ether, and the product which is formed is isolated by filtration with suction.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[Na].[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([NH:16][NH2:17])=O>CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[N:2]=[C:14]([C:13]2[CH:18]=[CH:19][CH:20]=[C:11]([Cl:10])[CH:12]=2)[NH:16][N:17]=1
Reactant: NNC(=O)c1cccc(Cl)c1
Reactant: N#Cc1ccccn1
Agent: [Na]
Solvent: CO
Product: Clc1cccc(-c2nc(-c3ccccn3)n[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.3 %

Procedure:
Using the procedures of Browne et al., Aust. J. Chem., (1975) 28:2543-2546, a solution of 2-cyanopyridine (0.1 mL, 1.00 mmol) in methanol (5 mL) was treated with sodium metal (6.9 mg, 0.30 mmol) and stirred for at ambient temperature for 1 hour. After this time, a solution of 3-chlorobenzhyrazide (0.17 g, 1.0 mmol) in methanol (5 mL) was added and the resulting solution heated at reflux for 3 hours. The reaction mixture was concentrated in vacuo, and the resulting yellow solid (100 mg) dissolved in toluene (2 mL). The mixture was heated at 175° C. for 3 hours and then stirred overnight at ambient temperature. Evaporation of the solvent in vacuo and silica gel chromatography using 1% methanol in dichloromethane afforded 29 mg (11%) of 3-(2-pyridyl)-5-(3-chlorophenyl)-1,2,4-triazole as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:34]4[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(-c4ccc(C(F)(F)F)cc4)ccc3C2=O)cc1
Reaction time: 0.33 h
Yield: 47 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 4-(trifluoromethyl)phenyl boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (47%).
Reaction SMILES: Br.Br[CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH:9]=[CH2:10].[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=1.C(N(CC)CC)C>C(O)C>[CH:9]([C:5]1[N:6]=[CH:7][S:8][C:4]=1[CH2:3][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[N:13]=1)=[CH2:10]
Reactant: C=Cc1ncsc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=Cc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To a 0° C. mixture of 5-(bromomethyl)-4-ethenyl-1,3-thiazole hydrobromide (2.6 mmol) and 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (275 mg, 1.4 mmol) in absolute ethanol (15 mL) was added triethylamine (1.5 mL, 10.8 mmol). The mixture was stirred at room temperature overnight. The solution was evaporated, and the residue was treated with diethyl ether (100 mL). The solid material was removed by filtration. The filtrate was evaporated, and the crude product was purified by flash chromatography (0-5% MeOH/DCM), affording 2-{[(4-ethenyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (270 mg, 60%); 1H NMR (500 MHz, DMSO-d6): δ 4.75 (s, 2H), 5.42 (dd, 1H, J=2.3 Hz, 10.8 Hz), 6.06 (dd, 1H, J=2.3 Hz, 16.9 Hz), 6.68 (s, 1H), 8.95 (s, 1H); M+320.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:23][C:24]([C:26]2[N:27]=[N:28][NH:29][CH:30]=2)=[O:25])[CH2:9][C@@:10]([CH3:22])([CH2:14][O:15]C2CCCCO2)[C:11](O)=[O:12])=[CH:3][CH:2]=1.[CH2:37]([OH:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].Cl.O1CCOCC1>>[CH2:37]([O:44][C:11](=[O:12])[C@@:10]([CH2:14][OH:15])([CH3:22])[CH2:9][C@H:8]([NH:23][C:24]([C:26]1[N:27]=[N:28][NH:29][CH:30]=1)=[O:25])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:2][CH:3]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCO
Reactant: C[C@@](COC1CCCCO1)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-methyl-2-(tetrahydropyran-2-yloxymethyl)-4-[(1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (100 mg, 0.2 mmol) was combined with 1-heptanol (0.3 mL, 2 mmol) and 4 M HCl in 1,4-dioxane (0.3 mL, 1 mmol). The mixture was stirred for 2 hours at 60° C. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography to yield the title compound (60 mg). MS m/z [M+H]+ calc'd for C29H38N4O4, 507.29. found 507.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[N:19][C:18]([I:21])=[CH:17][N:16]=1>C(O)(C)(C)C>[I:21][C:18]1[N:19]=[CH:20][C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cnc(I)cn1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(I)cn2)CC1
Temperature: 100 °C
Yield: 51.5 %

Procedure:
In a 5 mL round bottomed flask were mixed: 1,1-dimethylethyl 1-piperazinecarboxylate (110 mg, 0.590 mmol, available from Fluke), 2-bromo-5-iodopyrazine (140 mg, 0.491 mmol, available from Apollo) and Dipea (0.112 mL, 0.639 mmol) in Tert-Butanol (2 mL). The reaction was stirred and heated under reflux at 100° C. for 40 hr. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the organic layer washed with brine (20 mL) before being dried through an hydrophobic frit and concentrated. The samples were dissolved in 1:1 MeOH:DMSO 2×1 mL and purified by MDAP. The solvent was evaporated in vacuo to give the required product 1,1-dimethylethyl 4-(5-iodo-2-pyrazinyl)-1-piperazinecarboxylate (98.6 mg) LCMS (Method C): Rt=1.20, MH+=391
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:27](O)=[O:28]>>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH:27]=[O:28])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: CCCCCCCCc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 29 %

Procedure:
A mixture of n-octylbenzene (1.2 g; 6.3 mmol) hexamethylenetetramine (0.97 g; 6.93 mmol) in trifluoroacetic acid was refluxed for 4 h, cooled to room temperature and evaporated to dryness under reduced pressure. The residue was neutralized with 5% NaHCO3 and extracted with diethyl ether (3×5 ml). The combined organic phase was washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane) to give the title compound (0.4 g; 29%) as a colourless oil and starting n-octylbenzene (0.8 g; 67%). 1H-NMR (CDCl3) 0.86 (tr, 3H, J=6.9 Hz); 1.26 (m, 10H); 1.6 (m, 2H); 2.67 (tr, 2H, J=7.9 Hz); 7.31 (d, 2H, J=8.1 Hz); 7.77 (d, 2H, J=8.1 Hz); 9.96 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1cccc(CO)n1
Agent: CS(=O)(=O)Cl
Product: Cc1cccc(CN2CCCC2)n1

Procedure:
By reaction of 6-methyl-2-pyridyl methanol [prepared as described in Helv. Chim. Acta, 2429 (1957)], g 7.1 (0.058 moles), with methanesulfonyl chloride and then with pyrrolidine as in Description 1, g 7.5 of yellow oil (b.p. 62°-65° C. 80 mmHg) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:23]=[CH:22][N:21]([C:24]2([CH2:28][C:29]#[N:30])[CH2:27][NH:26][CH2:25]2)[N:20]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:23]=[CH:22][N:21]([C:24]2([CH2:28][C:29]#[N:30])[CH2:27][N:26]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:25]2)[N:20]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3cccc(Cl)c3)n12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CN(S(C)(=O)=O)C5)n4)n3Cc3cccc(Cl)c3)n12
Reaction time: 0.17 h

Procedure:
To (3-{3-[6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl]-1H-pyrazol-1-yl}azetidin-3-yl)acetonitrile (6.0 mg, 0.013 mmol, from Example 106, Step 1) was added methanesulfonyl chloride (1.2 μL, 0.016 mmol, Aldrich) in DCM (0.46 mL), followed by triethylamine (3.7 μL, 0.026 mmol). After 10 minutes, the product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (4.6 mg, 65%).
Reaction SMILES: [Li]CCCC.[CH2:6]([N:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:27][CH:28]([CH3:32])[C:29](Cl)=[O:30]>C1COCC1>[CH2:20]([N:13]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@H:14]([C:29](=[O:30])[CH:28]([CH3:32])[CH3:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C(=O)C(C)C)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 116.1 %

Procedure:
In a round bottomed flask, at −78° C., under argon atmosphere, a solution of DIPA (1.6 ml, 9.3 mmol) in dry THF (40 ml) was treated with n-BuLi (2.5 M in n-hexane, 3.4 ml, 8.5 mmol). After 30 min a solution of ethyl 2-(dibenzylamino)-acetate [prepared as described in Example 47, step 1] (2.2 g, 7.8 mmol) in dry THF (40 ml) was added dropwise via cannula. After 15 min, 2-methyl-propanoyl chloride (2.4 mL, 23.3 mmol) was added dropwise at −78° C. and the mixture stirred for 10 min at rt. The reaction was then quenched with H2O, and Et2O was subsequently added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (98:2) gave a crude compound (3.2 g) as a mixture of two tautomers (ketone:enol=ca. 65:35), as a colorless oil, which was used without further purification in the following step. Ketone isomer: MS (ESI) m/z: 354 [M−H]+; (ESI) m/z: 352 [M−H]−. 1H NMR (DMSO-d6) δ 0.86 (d, J=6.73 Hz, 3H), 0.91 (d, J=7.01 Hz, 3H), 1.22 (t, J=7.11 Hz, 3H), 2.99 (hept, J=6.90 Hz, 1H), 3.78 (d, J=14.11 Hz, 2H), 3.84 (d, J=14.13 Hz, 2H), 4.10-4.24 (m, 2H), 4.29 (s, 1H), 7.17-7.48 (m, 10H). Enol isomer: MS (ESI) m/z: 354 [M−H]+; (ESI) m/z: 352 [M−H]−. 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.50 (s, 3H), 1.43 (t, J=7.09 Hz, 3H), 3.16-3.28 (m, 1H), 3.90 (d, J=12.66 Hz, 2H), 3.96 (d, J=12.66 Hz, 2H), 4.38 (q, J=7.08 Hz, 2H), 7.10-7.46 (m, 10H), 12.32 (s, 1H).