Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[C:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])#[CH:31]>C(N(CC)CC)C.C(OC(=O)C)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.[Cu]I>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:31]#[C:30][Si:32]([CH3:35])([CH3:34])[CH3:33])=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: C#C[Si](C)(C)C
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 80 °C
Yield: 53 %

Procedure:
A mixture of (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone, Example 9 (100 mg, 0.186 mmol), Pd(PPh3)4 (10 mg, 0.0093 mmol), CuI (1.8 mg, 0.0093 mmol) and Ethynyltrimethylsilane (32 ul, 0.223 mmol) in triethylamine (0.4 ml) was heated to 80° C. for 4 hours. The mixture was cooled to room temperature, diluted with ethylacetate, filtered and the solvent was removed in vacuo. The crude brown oil was purified on SiO2 (Heptane/AcOEt 0%-40%,15 minutes) to provide the title compound (50 mg, 53%, yellow foam); M+H=590.2.
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].[CH2:7]([O:14][CH2:15][CH:16]1CC(=O)C1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH2:1]=[C:2]1[CH2:4][CH:16]([CH2:15][O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1
Reactant: O=C1CC(COCc2ccccc2)C1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=C1CC(COCc2ccccc2)C1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In a 50 mL three-neck flask with t-BuOK (0.54 g, 4.8 mmol) and methyltriphenylphosphonium bromide (1.72 g, 4.8 mmol) inside, dry 1,4-dioxane was added under argon to give a yellow emulsion. This was heated to 40° C. for 30 min, after which time the mixture was cooled to 10° C. and a 1,4-dioxane solution of 3-(benzyloxymethyl)cyclobutanone (0.76 g, 4 mmol) was added drop by drop. The mixture was left stirring at 10° C. for 3 hr. Then the solvent was removed by rotary evaporator and the residue was dissolved in Et2O and H2O. The organic phase was separated and the aqueous phase was extracted with Et2O. The combined organic phase was dried over MgSO4 and the solvent was evaporated to dryness to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=20:1) to give a colorless oil (0.48 g, 63%, Rf=0.79 (Hexane: EtOAc=3:1)). 1H NMR (CDCl3, 400 MHz): δ 2.36-2.48 (m, 2H), 2.52-2.64 (m, 1H), 2.72-2.84 (m, 2H), 3.48-3.50 (d, J=7.2, 2H), 4.53 (s, 1H), 4.74-4.77 (m, 2H), 7.2-7.4 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 29.82, 35.06, 73.26, 74.60, 106.52, 127.77, 127.88, 128.60, 147.34. MS (FAB): expected for C13H160 (M+H)+ 189.27. Found 189.12748. IR (neat) νmax 2921, 2853, 1720, 1676, 1453, 1272, 1113, 1071, 1027, 875, 737, 713, 698.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Na].[Cl:11][C:12]([Cl:16])([Cl:15])[C:13]#[N:14]>>[C:3](/[C:2](=[C:13](/[NH2:14])\[C:12]([Cl:16])([Cl:15])[Cl:11])/[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#CC(Cl)(Cl)Cl
Agent: [Na]
Product: CCOC(=O)/C(C(C)=O)=C(\N)C(Cl)(Cl)Cl
Temperature: 50 °C

Procedure:
to 130.14 g (1.00 mole) of ethyl acetoacetate was added 1.5 g of sodium. The reaction temperature increased spontaneously to 50° C. The reaction mixture was cooled with an ice bath. To the cooled reaction mixture was added, with vigorous stirring at 30°-50° C., 144.3 g (1.00 mole) of trichloroacetonitrile in 30 minutes. After complete addition of the trichloroacetonitrile, the reaction mixture was cooled with a dry ice bath. No precipitate of the ethyl 2-acetyl-3-amino-4,4,4-trichlorocrotonate formed. Part of the above product was stirred with 100 ml. of concentrated 28-30% ammonium hydroxide for 2 hours. The reaction mixture was then extracted with ether. The ether solution was dried (CaSO4) and concentrated to give 180 g (82.5%) of crude ethyl 3-amino-4,4,4-trichlorocrotonate. Part of this crude material (20 g) was distilled at 0.5 mm Hg to give 11.7 g of pure product, m.p. 91°-95° C. To a cold (10° C.) solution of 21.8 g (0.0937 mole) of crude ethyl 3-amino-4,4,4-trichlorocrotonate in 15 ml. of chlorobenzene was added 13.5 g (0.103 mole) of chlorocarbonylsulfenyl chloride. The reaction temperature rose spontaneously to 35° C. after the ice water bath was removed. The reaction mixture was stirred at 65° C. for 1 hour, cooled and triturated with petroleum ether to give 10.3 g (38%) of ethyl 2,3-dihydro-2-oxo-4 -trichloromethyl-5-thiazolecarboxylate, m.p. 109°-110° C. A mixture of 14.5 g (0.05 mole) of ethyl 2,3-dihydro-2-oxo-4-trichloromethyl-5-thiazolecarboxylate, 10.4 g ) 0.05 mole) of phosphorus pentachloride, and 100 ml. of phosphorus oxychloride was held at reflux for 7 days. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with ice water and the aqueous mixture was extracted with ether. The ether solution was extracted with 10% sodium hyroxide, dried (CaSO4) and concentrated under reduced pressure to give 3.2 g of oil which was chromatographed on silica gel using 5% ethyl acetate-petroleum ether as eluant. The first 1.2 l. of eluant gave 2.27 g of solid which was recrystallized from petroleum ether at low temperature to give 2.13 g (13.8%) of ethyl 2-chloro-4-trichloromethyl-5-thiazolecarboxylate, m.p. 42.5°-43.5° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]1[CH2:29][CH2:28][O:27][CH:26]1[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[CH3:36][C:37]1[CH:42]=[C:41]([C:43]([N:45]2[CH2:54][C:53]3[CH:52]=[N:51][N:50]([CH3:55])[C:49]=3[NH:48][C:47]3[CH:56]=[CH:57][CH:58]=[CH:59][C:46]2=3)=[O:44])[CH:40]=[CH:39][C:38]=1[CH2:60][CH2:61][C:62](O)=[O:63].CCN(C(C)C)C(C)C>ClCCl>[O:25]1[CH2:29][CH2:28][O:27][CH:26]1[CH:30]1[CH2:35][CH2:34][N:33]([C:62](=[O:63])[CH2:61][CH2:60][C:38]2[CH:39]=[CH:40][C:41]([C:43]([N:45]3[CH2:54][C:53]4[CH:52]=[N:51][N:50]([CH3:55])[C:49]=4[NH:48][C:47]4[CH:56]=[CH:57][CH:58]=[CH:59][C:46]3=4)=[O:44])=[CH:42][C:37]=2[CH3:36])[CH2:32][CH2:31]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)O
Reactant: C1CC(C2OCCO2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(C2OCCO2)CC1
Yield: 83 %

Procedure:
HBTU (327 mg, 0.86 mmol) was added to a solution of 4-[1,3]dioxolan-2-yl-piperidine from Example E33 (143 mg, 0.91 mmol) and 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (320 mg, 0.82 mmol) in dichloromethane (20 ml) and DIEA (0.7 ml, 4.02 mmol) and the mixture was stirred for 20 h at room temperature. Dichloromethane was added and the solution was washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 4% methanol:96% dichloro-methane to 8% methanol:92% dichloromethane) to give a white solid identified as the title compound (359 mg, 83%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH3:11])=[N:8][C:7]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:6]=2[C:5]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH2:24]([O:26][C:27](=[O:32])[CH2:28][C:29](O)=[O:30])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:15]([N:12]1[C:7]2=[N:8][C:9]([CH2:10][CH3:11])=[C:4]([CH2:3][NH:2][C:29](=[O:30])[CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:32])[C:5]([NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:6]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CCOC(=O)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)NCc1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (400 mg, 1.18 mmol), 3-(ethyloxy)-3-oxopropanoic acid (171 mg, 1.30 mmol), HBTU (535 mg, 1.41 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (8 mL) was stirred at room temperature over the weekend. It was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layer was dried over sodium sulfate, filtered, concentrated and purified with CombiFlash eluting with 90% ethyl acetate in hexane. The product fractions were combined and concentrated to give ethyl 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoate as an oil (270 mg, 55%). LC-MS m/z 418 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 95 °C
Yield: 84.7 %

Procedure:
25.0 g (151.3 mmol) of (L)-phenylalanine and 66.67 g (482.4 mmol) of potassium carbonate were dissolved in 100 ml of water, and then 57.51 g (454.3 mmol) of benzyl chloride was added thereto and stirred under heat at 95° C. for 19 hours. After having been cooled to room temperature, this was subjected to phase separation with 67 ml of n-heptane and 50 ml of water. The organic layer thus separated was washed two times with 50 ml of a solution of methanol/water (=1/2) and then dried with anhydrous sodium sulfate. This was filtered and concentrated to obtain 61.64 g (90.5 wt. %, 121.8 mmol) of the above-entitled compound. The yield was 84.7%.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14]CC)=[O:13])(OCC)=O)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.[OH-].[Na+]>O.C(O)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:27]=[CH:28][C:29](/[CH:32]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:30][CH:31]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2ccc(/C=C/C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.36 g) was added to an ethanol (30 ml) solution of ethyl diethylphosphonoacetate (1.4 g) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, to which was added 4-[(4-methoxyphenyl)oxy]benzenecarboaldehyde (1.2 g). The reaction mixture was stirred at room temperature for 2 hours, which was further stirred at 50° C. for 30 minutes. The reaction mixture was cooled, to which were added water (20 ml) and sodium hydroxide (0.5 g). The reaction mixture was stirred at room temperature for 2 hours, and concentrated. 2N Hydrochloric acid was added to the residue to become acidic, which was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound (1.2 g).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]1([O-:24])[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[N+:25]([C:12]1[CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N+:8]([O-:24])[CH:13]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc[n+]([O-])c1C(=O)OCC
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c[n+]([O-])c1C(=O)OCC
Temperature: 0 °C
Yield: 78 %

Procedure:
255 ml of acetic anhydride were added to a mixture of 203.2 g (0.85 mol) of diethyl pyridine-2,3-dicarboxylate-N-oxide in 1.2 l of glacial acetic acid. 68.3 g (1.06 mol) of 98% strength nitric acid were then added in the course of 40 minutes at from 20° to 28° C. with gentle cooling and stirring and the mixture was stirred at 30° C. for 12 hours. The reaction solution was poured into 3.5 l of ice-water and extracted with methylene chloride. The organic phase was extracted in succession with water, saturated sodium hydrogencarbonate solution and sodium chloride solution, dried over magnesium sulfate and filtered off with suction through silica gel. After concentration, 177.6 g (78% of theory) of diethyl 5-nitropyridine-2,3-dicarboxylate-N-oxide were obtained of nD25 =1.5290. A sample crystallized after relatively long standing; m.p. 84°-86° C.
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:53](I)[CH3:54].O>CN(C)C=O>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:53][CH3:54])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: CCI
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 50 mg (0.077 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, in 1.0 ml of N,N-dimethylformamide, 75 mg (0.23 mmol) of cesium carbonate and 12 μl (0.15 mmol) of ethyl iodide were added, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [n-hexane/ethyl acetate=70/30 (V/V)] to provide 45 mg of the title compound as a white solid (yield: 85%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:2][C:3]2[CH:4]=[N:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1cnc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cnc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
3-(bromomethyl)quinoline, 6-methyl-2-sulfanylpyrimidin-4-ol (853 mg, 6 mmol) and triethylamine (1 mL, 7 mmol) were mixed in ethanol (50 mL). The mixture was stirred at room temperature for 2 hours. After evaporation, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide pure titled product (1.7 g, 99% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.54 (s, 2H), 6.01 (s, 1H), 7.58 (m, 1H), 7.70 (m, 1H), 7.94 (m, 2H), 8.35 (s, 1H), 8.96 (s, 1H); M+284.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][C:17]#[N:18]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:16][C:17]#[N:18])[CH2:11][CH2:10]1
Reactant: N#CCBr
Reactant: c1ccc(CCN2CCNCC2)nc1
Product: N#CCN1CCN(CCc2ccccn2)CC1

Procedure:
The title compound is synthesized by coupling of 1-(2-Pyridin-2-yl-ethyl)-piperazine (commercially available from ABCR GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=231.2: CtRet=2.17.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:18][OH:19])[CH2:16][OH:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1C=CC(S(O)(=O)=O)=C[CH:26]=1>C1(C)C=CC=CC=1.CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:18][O:19][C:21]([CH3:26])([CH3:20])[O:17][CH2:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(CO)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)OCC(c2ccc(OCc3ccccc3)cc2)CO1
Temperature: 30 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
To a suspension of 2-(4-(benzyloxy)phenyl)propane-1,3-diol (2.0 gm, 0.00775 moles) in dry toluene (500 ml), dry acetone (20 ml) and PTSA (1.2 gm, 0.0062 mole) were added and the reaction mixture was stirred for 18 hours at 30° C. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The organic extract was washed successively with water & brine, dried over sodium sulfate and evaporated under reduced pressure to yield 1.47 gm product as white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.II.Br[C:17]1[C:22](Br)=[C:21](Br)[C:20](Br)=[C:19](Br)[C:18]=1Br>C1COCC1>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:17]1[CH:22]=[C:21]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[C:20]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:19][C:18]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: Brc1c(Br)c(Br)c(Br)c(Br)c1Br
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: II
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2-c2cc(-c3ccccc3-c3ccccc3)c(-c3ccccc3-c3ccccc3)cc2-c2ccccc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dry Mg turnings (3.9 g, 0.16 mol) and 30 mL of anhydrous THF were added to a 1 L 3-necked round-bottomed flask equipped with a condenser, a nitrogen inlet, an additional funnel and a magnetic stirring bar. 4-Bromobiphenyl (37.2 g, 0.16 mol) was dissolved in 150 mL of THF and placed in an additional funnel. The reaction flask was placed in a 50° C. oil bath and one crystal of iodine was added. Once the reaction started 4-bromobiphenyl was added dropwise to the reaction. After addition, the brownish reaction was heated at reflux for another hour and then cooled to room temperature. A suspension of hexabromobenzene (11.0 g, 0.02 mol) in 150 mL of THF was added dropwise from an additional funnel to the reaction and the mixture was stirred at room temperature overnight. The reaction was quenched with ice and 8% hydrochloric acid and extracted with 400 mL of methylene chloride. The organic layer was washed with saturated sodium chloride solution and dried over magnesium sulfate. Solvent was evaporated and the crude product was washed with hexane and filtered to give pure product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[CH2:45][CH3:46]>CN1C(=O)CCC1>[CH:30]1([N:27]2[CH2:28][CH2:29][CH:24]([C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:10]4[C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=[C:8]([N:4]5[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:44](=[O:47])[CH2:45][CH3:46])[CH2:3]5)[N:9]=4)=[CH:23][CH:22]=3)[CH2:25][CH2:26]2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: NC(=O)c1ncc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Reactant: CCC(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3ccc(C4CCN(C5CCCC5)CC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-5-(3-Aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (436) (40 mg, 0.075 mmol) was dissolved in 3 mL NMP. To it were added DIEA (80 μL, 0.45 mmol) and then propionyl chloride (20 μL, 0.23 mmol). The mixture was stirred at RT for 30 min, quenched with 0.3 mL TFA, and directly subjected to reverse phase preparative HPLC using 5 mM HCl (aq) and nest MeCN to isolate the title compound, (R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-propionamidopiperidin-1-yl)pyrazine-2-carboxamide (438), as HCl salt (23 mg). LC-MS (ESI): m/z (M+1) 520.6. UV: λ=267, 276, 305, 335, 372 nm. Proton NMR (CD3OD): δ 7.62 (1H, s), 7.59 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 4.19 (1H, m), 4.01 (1H, m), 3.91 (1H, m), 3.72 (2H, d, J=12.0 Hz), 3.55 (1H, m), 3.42 (1H, m), 3.38 (1H, m), 3.12 (2H, m), 2.86 (1H, m), 2.22-1.64 (18H, m), 1.12 (3H, t, J=7.5 Hz) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(-c2nnn[nH]2)ccc1OCc1ccccc1
Yield: 101.9 %

Procedure:
A solution of 436 mg (1.27 mmol) of benzyl 2-benzyloxy-5-cyanobenzoate, 91 mg (1.40 mmol) of sodium azide, and 68 mg (1.27 mmol) of ammonium chloride in 5 mL of DMF is heated at 120° C. for 24 hrs. The DMF was removed by rotoevaporation, the residue is taken up in water, and acidified. The white precipitate is collected by filtration and dried to give 500 mg of unpurified benzyl 2-benzyloxy-5-(1H-tetrazol-5-yl)benzoate, which is treated with 28% aqueous ammonium hydroxide in 5 mL of MeOH at 85° C. for 72 hrs. The reaction mixture was concentrated, taken up in water, and then acidified. Filtration of the precipitate gives 400 mg (1.04 mmol, 82% yield) of 2-benzyloxy-5-(1H-tetrazol-5-yl)benzamide.