Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:16][C@@H:11]([O:12][CH:13]=[CH:14][CH3:15])[C@@H:10]1[NH:39][C:40](=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:57][CH2:58][C:59](Cl)=[O:60].Cl>O.C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]1[C@H:18]([O:19][C:59](=[O:60])[CH2:58][Cl:57])[C@@H:17]([CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:16][C@@H:11]([O:12][CH:13]=[CH:14][CH3:15])[C@@H:10]1[NH:39][C:40](=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: CC=CO[C@@H]1O[C@H](COC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC=CO[C@@H]1O[C@H](COC(=O)CCCCCCCCCCCCCCC)[C@@H](OC(=O)CCl)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Temperature: 0 °C

Procedure:
To 0.4 g. of Compound 7 in 15 ml. of CH2Cl2 was added 0.4 ml. of pyridine. The reaction mixture was cooled to about 0° C. and 0.4 ml. chloroacetyl chloride in 5 ml. of CH2Cl2 was added dropwise with stirring. After stirring at room temperature for 30 minutes, thin layer chromatography showed the reaction was complete. Next water was added, then 5% HCl followed by a wash with water and NaHCO3. The dried chloroform layer was evaporated and the residue taken up in hot methanol and the solid material filtered off. Thin layer chromatography showed the solid material to be Compound 8 of high purity.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:16][CH2:15][C@H:14]([CH2:17][NH2:18])[O:13][C:9]3=2)[N:4]=1.[F:19][C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]1[CH2:27][CH:26]([C:33](O)=[O:34])[CH2:25][CH2:24][C:23]2=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.C(N(CC)CC)C>[F:19][C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]1[CH2:27][CH:26]([C:33]([NH:18][CH2:17][C@@H:14]3[O:13][C:9]4=[C:10]5[C:5](=[CH:6][CH:7]=[C:8]4[O:16][CH2:15]3)[N:4]=[C:3]([CH3:2])[CH:12]=[CH:11]5)=[O:34])[CH2:25][CH2:24][C:23]2=1
Reactant: O=C(O)C1CCc2c([nH]c3ccc(F)cc23)C1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CN)O3
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CNC(=O)C1CCc2c([nH]c4ccc(F)cc24)C1)O3
Reaction time: 0.25 h

Procedure:
[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methylamine hydrochloride (360 mg, 1.35 mmol) and compound I were suspended in anhydrous tetrahydrofuran (THF) containing triethylamine (1.8 mL) and HOBT (54 mg) with stirring for 15 min. The coupling reagent, DCC (300 mg) was added and stirring was continued overnight. The reaction mixture was filtered and the filtrate was diluted with water and extracted with ether. The ether layers were combined, dried (MgSO4), and evaporated under reduced pressure to give a residue which was purified by flash chromatography on silica gel eluting with 1-2% methanol in methylene chloride to give the intermediate II (240 mg) as a white solid. mp 262-267° C.; MS (ES) m/z 444.3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:41])[C:13](=O)[CH:14](Br)[CH:15]([CH3:38])[CH:16]2[CH:19]([CH:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])[C:18](=[O:30])[N:17]2[Si](C(C)(C)C)(C)C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[SH:42][C@H:43]1[CH2:47][O:46][C@@H:45]([CH2:48][OH:49])[CH2:44]1.O1CCCC1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([C:13]2[N:17]3[CH:16]([CH:15]([CH3:38])[C:14]=2[S:42][CH:43]2[CH2:44][CH:45]([CH2:48][OH:49])[O:46][CH2:47]2)[CH:19]([CH:20]([OH:22])[CH3:21])[C:18]3=[O:30])=[O:41])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C1C(=O)N([Si](C)(C)C(C)(C)C)C1C(C)C(Br)C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: OC[C@H]1C[C@@H](S)CO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CO)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 104 using 0.166 g of product from Example 103, 0.0396 g of product from Example 77, 2.3 ml of dry tetrahydrofuran and 0.0413 ml of triethylamine to obtain the crude β-lactam. The subsequent cyclization uses the above product, 1.48 ml of 1M solution in methylene chloride of titanium tetrachloride and 1.6 ml of dry tetrahydrofuran to give 0.053 g of the desired product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[CH:19]=CC2N(O)N=[N:24][C:22]=2[CH:23]=1.N1CCCC1.CCN(CC)CC>C(Cl)Cl>[CH3:16][C:10]1([CH3:17])[C@@H:11]([C:13]([N:24]2[CH2:19][CH2:18][CH2:23][CH2:22]2)=[O:15])[CH2:12][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Solvent: CCN(CC)CC
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N2CCCC2)C1(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.9 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.700 g, 2.88 mmol) in DCM (20 ml) EDCI (0.660 g, 3.456 mmol) and HOBt (0.529 g, 3.456 mmol) were added at about 0° C. and after 10 minutes, pyrrolidine (0.47 ml, 5.761 mmol) and Et3N (1.42 ml, 14.403 mmol) were added drop wise and the reaction mass was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water and saturated NaHCO3 solution, then washed with aqueous 1N HCl, then water and saturated brine, and the organic layer was concentrated under reduced pressure, the resulting crude residue was stirred in hexane and the resulting solid was obtained which was filtered and dried under vacuum. Wt: 0.400 g; Yield: 46.9%; 1H NMR (300 MHz, CDCl3): δ 5.00 (d, 1H, J=7.5 Hz), 3.89-3.77 (m, 1H), 3.57-3.29 (m, 4H), 2.78-2.68 (m, 1H), 2.31-2.22 (m, 2H), 1.98-1.78 (m, 4H), 1.43 (s, 9H), 1.35 (s, 3H), 0.89 (s, 31-1); Mass: [M+1]+ 297 (40%), [M+Na]+ 319 (100%); 1R (KBr, cm−1): 3312, 2977, 2956, 1709, 1621, 1606, 1526, 1442, 1365, 1348, 1283, 1267, 1176, 1106, 1046, 1009, 912, 877; M.R: 164.8° C.-165.5° C.
Reaction SMILES: [C:1](OC)(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[CH2:15]([OH:20])[CH2:16][CH2:17][CH2:18][OH:19].CCOP(SCSP(OCC)(OCC)=S)(OCC)=S>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:10]1[O:8][CH2:6][CH2:5]1.[C:1]1(=[O:12])[O:20][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]1=[CH:3][CH:4]=2
Reactant: OCCCCO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CCOP(=S)(OCC)SCSP(=S)(OCC)OCC
Product: C1COC1
Product: O=C1OCCCCOC(=O)c2ccc1cc2

Procedure:
Poly(trimethylene ether-tetramethylene terephthalate) was prepared as described for Example 1, with the exception that the number average molecular weight of the polytrimethylene ether glycol used was 2,390. The amounts of ingredients used were: dimethyl terephthalate, 12.52 kg; 1,4-butanediol, 14.90 kg; polytrimethylene ether glycol, 13.0 kg; tetraisopropyl titanate, 43.3 g; and ETHANOX, 80.8 g. The properties of the elastomer are reported in Table 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[C:16]([CH3:34])=[CH:17][N:18]([CH:31]([CH3:33])[CH3:32])[C:19]=2[CH:20]=[C:21]([C:23]2[CH:24]=[N:25][C:26]([CH:29]=O)=[CH:27][CH:28]=2)[CH:22]=1)=[O:13].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[C:16]([CH3:34])=[CH:17][N:18]([CH:31]([CH3:33])[CH3:32])[C:19]=2[CH:20]=[C:21]([C:23]2[CH:24]=[N:25][C:26]([CH2:29][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:27][CH:28]=2)[CH:22]=1)=[O:13]
Reactant: C1CCNC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCCC4)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6-formylpyridin-3-yl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (100 mg, 0.219 mmol), in DCM (10 mL) and methanol (2 mL) was added pyrrolidine (0.035 mL, 0.438 mmol), followed by sodium sulfate (31.1 mg, 0.219 mmol). The reaction stirred at rt for 12 h, at which time sodium borohydride (16.57 mg, 0.438 mmol) was added and the reaction stirred rt for 2 h and 45° C. for 2 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was evaporated. Purification by reverse phase Gilson HPLC (10-60% acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column 7 minutes), followed by isolation and extraction with EtOAc/0.1 N NaOH provided N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-6-(6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indole-4-carboxamide, which was evaporated from the organic layer as a yellow foam solid (68 mg, 0.125 mmol, 57.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (br. s., 1H) 9.06 (d, J=2.02 Hz, 1H) 8.30 (dd, J=8.08, 2.27 Hz, 1H) 8.20 (t, J=5.18 Hz, 1H) 7.94 (d, J=1.26 Hz, 1H) 7.60 (d, J=8.08 Hz, 1H) 7.40 (s, 1H) 7.32 (s, 1H) 5.88 (s, 1H) 4.92-4.89 (m, 1H) 4.59 (d, J=5.56 Hz, 2H) 4.36 (d, J=5.05 Hz, 2H) 3.34 (br. s., 4H) 2.25 (s, 3H) 2.17 (d, J=1.01 Hz, 3H) 2.11 (s, 3H) 1.99 (br.s., 4H) 1.45 (d, J=6.57 Hz, 6H). LCMS: [M+H]+=512.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:29])([CH3:28])[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](F)=[C:16]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2].ClC1C=C(C(C)(C)COCC2C=CC(F)=C(OC3C=CC=CC=3)C=2)C=CC=1OCC>C1C=CC=CC=1>[O:21]([C:16]1[CH:15]=[C:14]([CH3:13])[CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1.[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:28])([CH3:29])[CH2:11][OH:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(C)(C)COCc2ccc(F)c(Oc3ccccc3)c2)cc1
Agent: CCOc1ccc(C(C)(C)COCc2ccc(F)c(Oc3ccccc3)c2)cc1Cl
Solvent: c1ccccc1
Product: CCOc1ccc(C(C)(C)CO)cc1
Product: Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C

Procedure:
The reaction mixture was cooled to room temperature and the gas was released. 100 ml of benzene was charged in the autoclave to dissolve an oil. An insoluble matter was filtered out. After washing with 20 ml of benzene, a resulting mother wash solution was shaken well and then left to stand to obtain a benzene layer. The benzene layer was washed with 100 ml of water three times. Benzene was distilled off under reduced pressure to obtain an oily product. According to gas chromatographic analysis by the internal standard method, the oily product contained 97.2% of 3-phenoxy-4-fluorobenzyl 2-(4-ethoxyphenyl)-2-methylpropyl ether and 1.0% of starting material 3-phenoxy-4-fluorobenzyl 2-(3-chloro-4-ethoxyphenyl)-2-methylpropyl ether. The amounts of 3-phenoxytoluene and 4-ethoxyneophyl alcohol formed by ether bond cleavage were each less than 0.1%. The amount of 3-phenoxybenzyl 2-(4-ethoxyphenyl)-2-methylpropyl ether formed probably due to the replacement of fluorine atom with hydrogen atom was only less than 0.5%.
Reaction SMILES: [CH3:1]I.[S:3]=[C:4]1[NH:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[NH:5]1.[OH-].[Na+]>>[CH3:1][S:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[N:5]=1
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: CSc1nc(O)cc(O)n1

Procedure:
Methyl iodide can be added to a solution of 2-thioxo-dihydropyrimidine-4,6(1H,5H)-dione and aqueous sodium hydroxide to provide 2-(methylthio)pyrimidine-4,6-diol. The reaction is typically performed in a solvent such as but not limited to ethanol, and may require the use of heat. Addition of phosphorus oxychloride to 2-(methylthio)pyrimidine-4,6-diol will provide 4,6-dichloro-2-(methylthio)pyrimidine. The reaction is typically done at elevated temperature without an additional solvent. 4,6-Dichloro-2-(methylthio)pyrimidine can be added to a mixture of diisopropylamine and n-butyl lithium, followed by the addition of dry carbon dioxide gas to provide 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid. The reaction is typically performed at reduced temperature in a solvent such as but not limited to tetrahydrofuran. A mixture of 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid and thionyl chloride can be refluxed together and concentrated, followed by the addition of aqueous ammonia at reduced temperature in a solvent such as but not limited to tetrahydrofuran to provide 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxamide. A compound of formula (1A) wherein B, R2, R3, and m are as described herein, can be reacted with 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxamide in the presence of a base such as but not limited to N,N-diisopropylethylamine to provide compounds of formula (4). The reaction typically requires the use of heat and a solvent such as but not limited to 1,4-dioxane. Compounds of formula (5) can be prepared by reacting compounds of formula (4) with hydrazine hydrate. The reaction is typically performed at ambient temperature in a solvent such as but not limited to 1,4-dioxane. Methyl orthoformate can be reacted with compounds of formula (5) to provide compounds of formula (6). The reaction may require the use of heat. Compounds of formula (7), which are representative of the compounds of Formula (I), can be prepared by reacting compounds of formula (6) with an organozinc compound of formula (2A), wherein Z, A, R1, and n are as described herein and XA is a halide. The reaction typically involves the use of heat and a nickel or palladium catalyst such as but not limited to bis(triphenylphosphine)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) in a solvent such as but not limited to N-methylpyrrolidone, tetrahydrofuran, or mixtures thereof.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2=[C:19]3C(=[CH:15][CH:16]=[CH:17]2)C=C[CH2:11][N:10]3[C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H+].[B-](F)(F)(F)F.CC1(C)N([Br:35])C(=O)N(Br)C1=O.[C:38]([O:42]C)([CH3:41])([CH3:40])C>C(#N)C.O>[CH2:1]([N:8]1[C:18]2=[C:19]3[C:40](=[CH:15][CH:16]=[CH:17]2)[CH:38]([OH:42])[CH:41]([Br:35])[CH2:11][N:10]3[C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: O=c1n(Cc2ccccc2)c2cccc3c2n1CC=C3
Reactant: COC(C)(C)C
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: CC#N
Product: O=c1n(Cc2ccccc2)c2cccc3c2n1CC(Br)C3O
Reaction time: 3 h

Procedure:
1-Benzyl-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (II, EXAMPLE 1, 240 g), acetonitrile (1.086 kg), water (227 ml) and fluoboric acid (48.5%, 13.4 g) are mixed and cooled to 0 to 5°. Dibromantin (163.5 g) is slurried into acetonitrile and is added to the reaction mixture. The reaction is carried out for about 3 hr at 0 to 5°. After the reaction is complete, methyl t-butyl ether is added over about 45 minutes keeping the reaction temperature in the pot below 10°. The slurry is cooled to −10 to −15°, stirred for an hour and then filtered. The product is washed with precooled methyl t-butyl ether, dried with 40° nitrogen to give the title compound, CMR (CDCl3) δ156.0, 137.8, 130.5, 129.6, 129.3, 129.1, 126.6, 123.6, 122.5, 119.6, 110.4, 69.9, 49.6, 47.7, 46.9 and 43.8.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5]C=1C.Cl.C1C(O)=CC=CC=1C.[N:20]#[C:21][NH2:22].[OH-].[Na+].CCO[CH2:28][CH3:29]>>[CH3:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:28]([CH3:29])[C:3]=1[N:2]([CH3:1])[C:21]([NH2:22])=[NH:20]
Reactant: N#CN
Reactant: CCOCC
Reactant: CNc1c(C)cccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(O)c1
Product: Cc1cccc(C)c1N(C)C(=N)N

Procedure:
To 40.5 g. (0.315 mole) of N-methyl-2,6-dimethylaniline is added 0.4 moles of ethereal HCl and 200 ml. of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 13.3 g. (0.315 mole) of cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml. of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2×1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 1-(2,6-dimethylphenyl)-1-methylguanidine.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:10])[CH2:8]Br)=[CH:3][CH:2]=1.CCO.[N-:20]=[N+]=[N-].[Na+].[BH4-].[Na+]>CO>[NH2:20][CH2:8][CH:7]([C:4]1[CH:5]=[CH:6][C:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:2][CH:3]=1)[OH:10]
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: NCC(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution consisting of 1-biphenyl-4-yl-2-bromo-ethanone (412 mg. 1.5 mmol) and EtOH (6 mL) was added NaN3 (107 mg, 1.6 mmol) at rt. The mixture was stirred at rt for 2 h and then cooled to 0° C. NaBH4 (61 mg, 1.6 mmol) was added and the mixture stirred for 45 min. A mixture (black slurry) of CuSO4.5H2O (37 mg)/NaBH4 (28 mg) in MeOH 2 mL) was prepared by adding the NaBH4 to CuSO4.5H2O in MeOH at 0° C. This slurry was poured into the reaction mixture. The reaction vessel was allowed to gradually warm to rt. An additional amount of NaBH4 (28 mg) was added 30 min after the addition of the slurry. The reaction was stirred at rt for 2 h. The mixture was filtered through a pad of celite, adhered to silica gel (7-8 g) and purified (FCC) to give the title compound (256 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([N:12]3[CH2:17][CH2:16][N:15]4[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]4[CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(NCc1nccnc1Cl)N1CCn2c(nnc2C(F)(F)F)C1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1nnc2n1CCN(c1ncc3c(Cl)nccn13)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a stirred solution of N-((3-chloropyrazin-2-yl)methyl)-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxamide (1.25 g, 3.46 mmol) in Acetonitrile (10 ml) was added pyridine (2.73 g, 34.6 mmol) and finally phosphoryl trichloride (2.65 g, 17.28 mmol). The resulting reaction mixture was then stirred at room temperature for 15 hours overnight. The reaction was quenched by slowly addition of NaHCO3 and extracted with ethyl acetate (3×). The organic layer was dried by MgSO4, filtered and concentrated. The residue was purified by MPLC (24 g silica gel, 20 to 60% ethyl acetate in hexaes, 18 CV) to afford white solid product 7-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (550 mg, 1.600 mmol, 46.3% yield). LC-MS: C12H9ClF3N7,343. found 344.11 [M+H]+, RT=1.22 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[O:9][C:5]=2[CH:4]=1.[C:15](Cl)(=[O:19])C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:25][NH2:26]>>[CH3:25][NH:26][C:15]([C:7]1[C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:9][C:8]=1[CH:10]([CH3:11])[CH3:12])=[O:19]
Reactant: CN
Reactant: COc1ccc2cc(C(C)C)oc2c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CNC(=O)c1c(C(C)C)oc2cc(OC)ccc12
Yield: 60 %

Procedure:
Example 15(b) was prepared from 6-methoxy-2-(1-methylethyl)benzofuran 15a (263 mg, 1.36 mmole) by acylation with oxalyl chloride in the presence of AlCl3, followed by treatment with methylamine in a manner as previously described for example 1c to give 200 mg (60%) of an off-white solid. 1H NMR (DMSO-d6) δ7.83 (1H, d, J=4.8 Hz), 7.56 (1H, d, J=8.8 Hz), 7.20 (1H, d, J=2.3 Hz), 6.89 (1H, dd, J=2.3, 8.8 Hz), 3.78 (3H, s), 3.68–3.61 (1H, m), 2.78 (3H, d, J=4.8 Hz), 1.26 (6H, d, J=6.8 Hz).
Reaction SMILES: [Li+].[Cl-].C([Mg]Cl)(C)C.[Cl:8][C:9]1[N:10]=[C:11]([Cl:27])[C:12]2[C:17](I)=[CH:16][N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=2[N:14]=1.S([C:38]#[N:39])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[Cl:8][C:9]1[N:10]=[C:11]([Cl:27])[C:12]2[C:17]([C:38]#[N:39])=[CH:16][N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=2[N:14]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C#N)c2c(Cl)nc(Cl)nc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 776.8 %

Procedure:
To a solution of LiCl (dry, 5.3 g, 126 mmol) in THF (150 mL) was added iPrMgCl (63 mL of 2 M in THF, 126 mmol). After stirring for 15 min, the mixture was cooled to −78° C. and 2,4-dichloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (31 g, 4.5 mmol) was added dropwise as a solution in THF (50 mL). After stirring for 20 min, a solution of tosyl cyanide (19.8 g, 100 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min. The reaction was quenched with HOAc (20 mL) and after stirring at −78° C. for 15 min, water (200 mL) and EtOAc (200 mL) were added. The organic layer was separated, and the aqueous layer was further extracted with EtOAc (two×150 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product. After sitting as a concentrate in EtOAc overnight, crystals formed which were collected to afford 3.8 grams 90% purity by 1H NMR. The filtrate was purified via flash chromatography to afford the title compound (12 g). The combined yield was 15.8 grams (66% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) 0.00 (s, 9H), 0.91-1.01 (m, 2H), 3.53-3.66 (m, 2H), 5.65 (s, 2H), 7.94 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]=[CH2:11].[Li]CCCC.CN(C)[CH:19]=[O:20]>C1COCC1>[CH2:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:19]=[O:20])[CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCc1ccccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCc1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a mixture of 1-bromo-2-(but-3-en-1-yl)benzene (1 g, 4.74 mmol) in THF (10 mL) at −78° C. was added BuLi (2.274 mL, 5.68 mmol) dropwise. It was then stirred at this temperature for 1 h, then N,N-dimethylformamide (0.416 g, 5.68 mmol) was added. The reaction was stirred at 78° C. for 30 min, then warmed to rt and stirred at rt for 1 h. It was then quenched with NH4Cl, extracted with ether. The organic layer was then dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 10% EtOAc/hexane to obtain 2-(but-3-en-1-yl)benzaldehyde (0.7 g, 92%) as an oil. 1H NMR (400 MHz, CDCl3) δ 10.35-10.26 (m, 1H), 7.86 (dd, J=7.6, 1.5 Hz, 1H), 7.54 (td, J=7.5, 1.6 Hz, 1H), 7.44-7.38 (m, 1H), 7.30 (d, J=8.1 Hz, 1H), 5.95-5.83 (m, 1H), 5.09-5.00 (m, 2H),), 3.20-3.12 (m, 2H), 2.44-2.36 (m, 2H).