Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].[CH2:16]=[C:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18](O)=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:18](=[O:19])[C:17](=[CH2:16])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:10]
Reactant: C=C(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(Cc1ccccc1)C(=O)NCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (3.10 mL, 0.022 mol, 1.2 eq) was added to a suspension of glycine ethyl ester hydrochloride (2.84 g, 0.020 mol, 1.1 eq) in anhydrous dichloromethane (100 mL) (see FIG. 6). The mixture was stirred for 15 min at room temperature and then cooled to 0° C. (ice bath). Compound 17 (3 g, 0.018 mol, 1 eq) and dicyclohexylcarbodiimide (4.19 g, 0.020 mol, 1.1 eq) were added successively to the reaction mixture which was stirred at room temperature for 17 h. The precipitate (dicyclohexylurea and triethylamine hydrochloride) was collected by filtration. The filtrate was washed successively with a saturated aqueous solution of sodium bicarbonate (100 mL), 1N aqueous solution of HCl (100 mL), brine (100 mL) and was then dried over sodium sulfate. Evaporation of the solvent afforded an oil which was purified by column chromatography (eluent:hexane/EtOAc=8:2). The desired product 18 was obtained as a solid (3.79 g, 83%). Rf=0.14 (hexane/EtOAc=7:3). m.p. 51° C. 1H NMR δ (CDCl3) 1.25 (t, 3H), 3.65 (s, 2H), 4.05 (d, 2H), 4.20 (q, 2H), 5.30 (s, 1H), 5.85 (s, 1H), 6.30 (s, 1H), 7.15–7.35 (m, 5H). [M+H]+ 248.0, tR=3.03 min; purity: 99.5%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][N+:11]([O-:13])=[O:12].[O:14]1[CH2:19][CH2:18][N:17]([CH:20]=[CH:21][C:22]#[N:23])[CH2:16][CH2:15]1.O1CCCC1>C(Cl)(Cl)Cl>[O:14]1[CH2:19][CH2:18][N:17]([CH:20]=[C:21]([C:22]#[N:23])[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[CH2:10][N+:11]([O-:13])=[O:12])[CH2:16][CH2:15]1
Reactant: N#CC=CN1CCOCC1
Reactant: O=[N+]([O-])C=Cc1cccc(Cl)c1Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: N#CC(=CN1CCOCC1)C(C[N+](=O)[O-])c1cccc(Cl)c1Cl

Procedure:
5.0 g of 1-(2',3'-dichlorophenyl)-2-nitroethylene, 3.18 g of 3-morpholinoacrylonitrile and 30 ml of tetrahydrofuran (abs.) are refluxed for 24 hours, and the reaction solution is subsequently concentrated by evaporation. The resulting residue, dissolved in toluene/ethyl acetate (2:1 V/V), is chromatographed through silica gel, and from the eluate is thus obtained the finished product, m.p. 74°-77° C. IR (CHCl3) in cm-1 ; 2200 (CN), 1630 (C=C), 1560 (NO2). NMR (CDCl3) in ppm: 4.5 (m, 4H); 4.7 (m, 4H); 4.8 (ABX, 3H); 6.60 (s, 1H); 7.2-7.5 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([O:14][CH2:15][CH2:16]Br)[CH2:12]Br.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][O:14][CH2:11][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: BrCCOCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(Br)cc1)N1CCOCC1
Yield: 58.9 %

Procedure:
(1S)-(−)-1-(4-Bromophenyl)ethylamine (2.4 g), 2,2′-dibromodiethylether (3.25 g) and N,N-diisopropylethylamine (6 ml) were heated to 100° C. in dimethylformamide (40 ml) for 18 h, allowed to cool and partitioned between water and ethyl acetate. The organic phase was dried (MgSO4), evaporated under vacuum and purified by column chromatography using a 0-40% ethyl acetate/iso-hexane gradient. The product was obtained as a yellow oil (1.91 g).
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][CH2:8][CH:9]1[CH2:13][CH:12]([OH:14])[C:11](=[O:15])[NH:10]1)(C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O>[OH:14][CH:12]1[C:11](=[O:15])[NH:10][CH:9]([CH2:8][CH2:7][C:6]([OH:16])=[O:5])[CH2:13]1
Reactant: CC(C)(C)OC(=O)CCC1CC(O)C(=O)N1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC1CC(O)C(=O)N1

Procedure:
4-Hydroxy-5-oxo-2-pyrrolidinepropanoic acid t-butyl ester (1.87 g) and trifluoracetic acid (1.2 g) in 10 ml of N,N-dimethylformamide was heated at 100° C. until disappearance of starting material by thin layer chromatography. After concentration under reduced pressure, the resulting solid is washed with acetone and filtered to give 4-hydroxy-5-oxo-2-pyrrolidinepropanoic acid with mp 129°-132° C. NMR (DMSOD6) and 12.14 (s, 1H), 7.96 (d, J=5 Hz, 1H), 5.37 (m, 1H), 4.00 (m, 1H), 2.60-1.09 (m, 6H). IR (cm-1) 3420, 3080, 2030, 2920, 1698, 1494, 1387, 1284.
Reaction SMILES: [H-].[Na+].[CH:3]1([O:7][CH2:8][C@H:9]([OH:20])[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:29]=[CH:30][C:23]=12>C1COCC1.C(OCC)(=O)C>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[N:28]1[C:24]2=[N:25][CH:26]=[N:27][C:22]([O:20][C@@H:9]([CH2:8][O:7][CH:3]3[CH2:6][CH2:5][CH2:4]3)[C:10]([NH:12][C:13]3[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=3)=[O:11])=[C:23]2[CH:30]=[N:29]1
Reactant: Cc1cnc(NC(=O)[C@@H](O)COC2CCC2)cn1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cnc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2ccccc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
Sodium hydride (44.4 mg, 1.11 mmol) was added to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (186 mg, 0.74 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting mixture was stirred for 10 minutes at 0° C. and 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (255 mg, 0.96 mmol) was added and the reaction was allowed to warm up to room temperature and stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (262 mg, 73.8%). 1H NMR (400 MHz, DMSO) δ 1.39-1.52 (m, 1H), 1.56-1.67 (m, 1H), 1.77-1.91 (m, 2H), 2.13-2.24 (m, 2H), 2.44 (s, 3H), 3.88-4.02 (m, 2H), 4.06-4.15 (m, 1H), 5.89-5.94 (m, 1H), 7.56-7.70 (m, 3H), 7.73-7.78 (m, 1H), 8.31-8.33 (m, 1H), 8.54 (s, 1H), 8.63 (s, 1H), 9.10 (s, 1H), 11.17 (s, 1H). m/z (ESI+) (M+H)+=480.33; HPLC tR=2.45 min.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.CS(O)(=O)=O.[NH2:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O.C1(C)C=CC=CC=1.[OH-].[Na+]>O>[CH:1]1([C:4]2[C:5]([C:6]#[N:7])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:16]3[C:15](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: N#CCC(=O)C1CC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Into a glass flask having an internal volume of 300 mL, equipped with a stirring apparatus, a thermometer, a reflux condenser and a Dean-Stark apparatus, 11.6 g (106.6 mmol) of 3-cyclopropyl-3-oxopropanenitrile, 31.0 g (96.9 mmol) of 2-amino-4′-fluorobenzophenone methanesulfonate having a purity of 97.3% and 121 mL of toluene were put in an atmosphere of nitrogen, and reaction was carried out under 0.04 MPa at 80° C. for 2 hours while distilling off the formed water. After completion of the reaction, the reaction liquid was cooled to room temperature, 60 mL of water and 13.3 mL (106.4 mmol) of a 8 mol/L sodium hydroxide aqueous solution were added thereto to make the reaction liquid basic, followed by liquid separation, and the obtained organic layer was analyzed by high performance liquid chromatography (absolute quantitative analysis), whereupon 27.9 g (yield: 99%) of 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile was formed.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](=O)[CH3:30])=[CH:24][CH:23]=1>CO>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([NH:5][CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH3:30])=[CH:24][CH:23]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C)NCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 82.5 %

Procedure:
A solution of sodium cyanoborohydride (1.07 grams, 17 mmole), 4-aminomethyl-1-(tert-butoxycarbonyl)piperidine (3.0 grams, 14.3 mole) and 1-(4-methoxyphenyl)propan-2-one (2.35 grams, 14.31 mmole) in methanol (50 ml) was stirred at 22° C. for 17 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The dried (anhydrous magnesium sulfate) organic phase was concentrated under reduced pressure to leave N-[2-(4-methoxyphenyl)-1-methylethyl]-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]amine as an oil (4.28 grams, 82%); hydrochloride, m.p. 198-199° C. (methanol/ethyl ether), M+H 391.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][C:23]1[S:24][C:25]([Cl:30])=[C:26]([CH2:28]Cl)[N:27]=1>CC#N>[Cl:22][C:23]1[S:24][C:25]([Cl:30])=[C:26]([CH2:28][O:1][N:2]=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:27]=1
Reactant: Cn1nnnc1C(=NO)c1ccccc1
Reactant: ClCc1nc(Cl)sc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1nnnc1C(=NOCc1nc(Cl)sc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.2 %

Procedure:
To a stirred solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (2.15 g, 10.58 mmol, 1.0 eq.) in 20 ml of MeCN was added Cs2CO3 (4.12 g, 12.69 mmol, 1.2 eq.) followed by KI (0.17 g, 1.05 mmol, 0.1 eq.) in one portion. The resulting suspension was stirred for 5 mins before addition of 2,5-dichloro-4-(chloromethyl)-1,3-thiazole (2.35 g, 11.63 mmol, 1.1 eq.) in one portion. The reaction was stirred for 24 hrs at room temperature. The solvent was evaporated and the residue was dissolved in EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give N-[(2,5-dichloro-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (1.65 g, 42% yield, 86:14 mixture of stereoisomers) as a yellow viscous oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([NH:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([O:16][C:17]2[CH:22]=[CH:21][C:20](C=O)=[CH:19][CH:18]=2)=[CH:8][C:7]=1[N+:25]([O-])=O)=O.[CH:30]([O:37][CH2:38][CH3:39])([O:34]CC)OCC.C(O)CO>C(OCC)(=O)C>[O:37]1[CH2:38][CH2:39][O:34][CH:30]1[C:20]1[CH:21]=[CH:22][C:17]([O:16][C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]3[NH:5][C:3]([C:2]([F:29])([F:28])[F:1])=[N:25][C:7]=3[CH:8]=2)=[CH:18][CH:19]=1
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1ccc(Oc2cc([N+](=O)[O-])c(NC(=O)C(F)(F)F)c(C(F)(F)F)c2)cc1
Solvent: CCOC(C)=O
Solvent: OCCO
Product: FC(F)(F)c1nc2cc(Oc3ccc(C4OCCO4)cc3)cc(C(F)(F)F)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,2,2-trifluoro-N-[4-[(4-formylphenyl)oxy]-2-nitro-6-(trifluoromethyl)phenyl]acetamide (0.65 g, 1.54 mmol), triethyl orthoformate (0.282 mL, 1.69 mmol), and ethylene glycol (0.343 mL, 6.16 mmol) was added (butyl)4NBr3 (0.007 g, 0.015 mmol). The reaction was stirred at ambient temperature for 1 hour and then diluted with ethyl acetate. The organics were washed 1×NaHCO3, 1× brine and then dried (Na2SO4), filtered and concentrated. The residue was dissolved in ethyl acetate (5 mL) and hydrogenated over 10% Palladium on carbon (0.13 g) under an atmosphere of hydrogen for 3 hours. The catalyst was removed by filtration through Celite and the filtrate concentrated. The residue was purified by silica gel column chromatography on using a gradient of 20-40% ethyl acetate:hexanes to give 5-{[4-(1,3-dioxolan-2-yl)phenyl]oxy}-2,7-bis(trifluoromethyl)-1H-benzimidazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N:10]=[C:11]=[S:12].[CH2:13]([NH:15][CH2:16][C:17](O)=[O:18])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([N:15]1[CH2:16][C:17](=[O:18])[N:10]([C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:11]1=[S:12])[CH3:14]
Reactant: CCNCC(=O)O
Reactant: Cc1cc(C)c(N=C=S)cc1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2cc(C)c(C)cc2C)C1=S
Yield: 58.4 %

Procedure:
The title compound was prepared by the procedure described in Example 9 using 17.7 g of 2,4,5-trimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (15.3 g) as an off-white solid, m.p. 162°-164° C. Anal. Calcd. for. C14H18N2OS: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.21; H, 6.93; N, 10.80. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1I.C(N(CC)CC)C.[CH3:17][C:18]([CH3:22])([CH3:21])[C:19]#[CH:20]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1COCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:20]#[C:19][C:18]([CH3:22])([CH3:21])[CH3:17]
Reactant: Cc1cccc(I)c1Br
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(C#CC(C)(C)C)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with bis(triphenylphosphine)palladium(II)chloride (0.042 g, 0.060 mmol) and copper(I) iodide (0.023 g, 0.120 mmol) under nitrogen atmosphere. THF (4.6 mL) was added, followed by 2-bromo-1-iodo-3-methylbenzene (0.594 g, 2 mmol), triethylamine (2.3 mL, 16.50 mmol) and 3,3-dimethylbutyne (0.251 mL, 2.040 mmol). The reaction mixture was allowed to stir at RT overnight. The reaction mixture was filtered through a plug of silica gel and the plug was rinsed with Et2O. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (0-2% EtOAc/hexanes). 2-Bromo-1-(3,3-dimethylbut-1-ynyl)-3-methylbenzene was obtained as a light-yellow clear oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12.[OH-].[Na+].[C:13](Cl)(=[O:25])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>C1COCC1.O>[N+:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:13]([NH:1][CH2:2][C:3]2[N:4]=[CH:5][N:6]3[CH:10]=[CH:9][S:8][C:7]=23)=[O:25])=[CH:21][CH:20]=1)([O-:24])=[O:23]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: NCc1ncn2ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ncn2ccsc12)OCc1ccc([N+](=O)[O-])cc1
Yield: 68.1 %

Procedure:
7-Aminomethylimidazo[5,1-b]thiazole (1.53 g) was dissolved in 50 ml of THF and 30 ml of water. A 1 N aqueous sodium hydroxide solution (12 ml) and 2.59 g of 4-nitrobenzyl chlorocarbonate were added under ice cooling to the solution. The mixture was allowed to react at the same temperature for 30 min. The reaction solution was extracted with 200 ml of ethyl acetate, followed by washing with 15% brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under the reduced pressure to about 20 ml. The resultant crystal was collected by filtration, washed with 20 ml of ethyl acetate, and dried under the reduced pressure to give 2.26 g of 7-(4-nitrobenzyloxycarbonylamino)methylimidazo-[5,1-b]thiazole.
Reaction SMILES: [OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].[C:9]([C:13]1[S:17][C:16]([NH:18][C:19](=[O:25])[CH:20]([NH2:24])[CH2:21][CH2:22][CH3:23])=[N:15][N:14]=1)([CH3:12])([CH3:11])[CH3:10].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C(Cl)Cl>[C:9]([C:13]1[S:17][C:16]([NH:18][C:19](=[O:25])[CH:20]([NH:24][C:3](=[O:4])[CH:2]([OH:1])[CH:6]([CH3:8])[CH3:7])[CH2:21][CH2:22][CH3:23])=[N:15][N:14]=1)([CH3:11])([CH3:10])[CH3:12]
Reactant: CCCC(N)C(=O)Nc1nnc(C(C)(C)C)s1
Reactant: CC(C)[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(NC(=O)C(O)C(C)C)C(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C

Procedure:
A mixture of 2-(S)hydroxyl-3-methyl-butyric acid (35.4 mg, 0.3 mmol), 2-amino-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide (88 mg, 0.3 mmol), HBOT (43 mg, 0.21 mmol), EDC HCl (69 mg, 0.36 mmol.) and triethylamine (0.17 ml) in 2 ml of methylene chloride was stirred at room temperature until product formation or disappearance of starting material. The mixture was quenched with water and extracted with methylene chloride. The organic layer was separated, washed with dilute HCl, brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide the title compound as a cude oil. The oil was purified by Shimadzu HPLC to provide the title compound as a light yellow solid (44 mg), LC-MS M+1=357.1
Reaction SMILES: [H-].[Na+].O.[F:4][C:5]1[CH:6]=[C:7]([CH2:11][OH:12])[CH:8]=[CH:9][CH:10]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=1
Reactant: OCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 1.4 g, 33.5 mmol) is suspended in dry DMF (10 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice:water. To above suspension is added dropwise over 15 minutes (3-Fluoro-phenyl)-methanol (2.90 ml, 27 mmol). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2-chloro-1-fluoro-4-nitro-benzene (4.2 g, 24 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 4 hours. The reaction mixture is poured into 300 ml of ice:water. The resultant solid is isolated by suction filtration, washed with water (500 ml), and air dried to yield 5.5 g (20 mmol, 83%) of the clean desired material as an yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[NH2:26][CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:26][CH2:27][CH2:28][C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncnc(NCCc3c[nH]c4ccccc34)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and Tryptamine (18 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:22][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccccc1-c1ccc(CBr)cc1
Yield: 61.3 %

Procedure:
A mixture of 4′-methyl-2-chloro-biphenyl (1.08 g, 5.33 mmol), NBS (1.14 g, 6.40 mmol) and AIBN (175 mg, 1.06 mmol) in CCl4 (37 mL) was heated at reflux for 3 h. The reaction mixture was diluted with CH2Cl2 and the organic solution was washed sequentially with aqueous saturated NaHCO3 (2×), water (1×), and brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (hexanes to 5% EtOAc-hexanes) to afford the title compound (920 mg). 1H NMR (CDCl3 400 MHz) δ 7.63-7.25 (m, 8H), 4.56 (s, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3ncccc3c2)cc1
Reaction time: 0.08 h
Yield: 92.7 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (159 mg, 0.728 mmol) in dichloromethane (4 mL) was added pyridine (140 μL, 1.74 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-aminoquinoline (100 mg, 0.694 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (210 mg, 93%), single spot at Rf 0.71 (ethyl acetate). mp 180.1-180.7° C., HPLC purity 99+% (tR 2.37 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.83 (1H, dd, J=4.2, 1.7 Hz), 8.05 (1H, d, J=8.4 Hz), 7.97 (1H, d, J=9.2 Hz), 7.70 (2H, d, J=8.2 Hz), 7.57 (1H, d, J=2.5 Hz), 7.40-7.34 (2H, m), 7.22 (2H, m), 6.85 (1H, s, N—H, 2.57 (2H, t, J=7.2 Hz), 1.57 (2H, sextet, J=7.2 Hz), 0.87 (3H, t, J=7.3 Hz). LCMS: 325.23 (M−). FAB-MS (MH+, C18H18N2O2S): calcd 327.1167, found 327.1167.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH:12]=O)=[C:10]([O:14][Si:15]([CH3:23])([CH3:22])[C:16]([CH3:21])([CH3:20])[CH:17]([CH3:19])[CH3:18])[CH:9]=[C:8]([O:24][CH3:25])[C:7]=1[Cl:26])[CH:2]=[CH2:3].[I-:28].[Na+].C[Si](C)(C)Cl.C[SiH2]O[Si](C)(C)C>C(#N)C>[CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH2:12][I:28])=[C:10]([O:14][Si:15]([CH3:23])([CH3:22])[C:16]([CH3:21])([CH3:20])[CH:17]([CH3:19])[CH3:18])[CH:9]=[C:8]([O:24][CH3:25])[C:7]=1[Cl:26])[CH:2]=[CH2:3]
Reactant: [I-]
Reactant: C=CCOC(=O)c1c(Cl)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Agent: C[SiH2]O[Si](C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CC#N
Product: C=CCOC(=O)c1c(Cl)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CI
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 80.8 %

Procedure:
To a solution of 3.3 g of 2-chloro-5-[dimethyl-(1,1,2-trimethylpropyl)-silanyloxy]-6-formyl-3-methoxy-benzoic acid allyl ester in 4 ml of acetonitrile were added 1.8 g of sodium iodide and 1.6 ml of trimethyl-chlorosilane. A white precipitate occurred. The mixture was stirred for 5 min at 20° C. The suspension was cooled to 0° C. and 1.48 ml of tetramethyldisiloxane were added. The mixture was stirred for 2 hours at 0° C. and then partitioned between 20 ml of ethyl acetate and 20 ml of water. The aqueous phase was extracted twice with 20 ml of ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was chromatographed on silica gel using diethyl ether/hexane (3:1, v/v) as eluent to afford 3.39 g of 2-chloro-5-[dimethyl-(1,1,2-trimethylpropyl)-silanyloxy]-6-iodomethyl-3-methoxy-benzoic acid allyl ester as a colorless oil.