Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O.[CH2:18]([O:20][C:21]([C:23]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([NH2:33])[S:25][C:24]=1[NH2:34])=[O:22])[CH3:19]>C(O)(C)C>[CH2:18]([O:20][C:21]([C:23]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([N:33]=[CH:9][C:7]2[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[S:25][C:24]=1[NH2:34])=[O:22])[CH3:19]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCOC(=O)c1c(N)sc(N=Cc2ccc([N+](=O)[O-])s2)c1C(=O)OCC

Procedure:
In a 50 mL round bottom flask, 30 mg of 2,5-diamino-thiophene-3,4-dicarboxylic acid diethyl ester was dissolved in 20 mL of isopropanol. To this solution, 5-nitro-2-thiophenecarboxaldehyde (91 mg) was added with vigorous stirring, followed by the addition of a catalytic amount of TFA. The reaction was refluxed for 30 minutes. The title compound was isolated as a dark black-purple powder (87%) by flash chromatography (SiO2). M.p.: 194°-196° C. 1H-NMR (300 MHz, [D] acetone): δ=8.21 (s, 1H), 8.00 (d, 1H, 3J=4.4 Hz), 7.74 (s, 2H), 7.50 (d, 1H, 3J=4.4 Hz), 4.37 (q, 2H, 3J=7.1 Hz), 4.22 (q, 2H, 3J=7.1 Hz), 1.40 (t, 3H, 3J=7.1 Hz), 1.27 (t, 3H, 3J=7.1 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9](Br)[CH:10]=1)=[O:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([F:28])[CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:9]2[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:7][CH:6]=[C:5]([CH:10]=2)[C:3]([OH:2])=[O:4])=[C:21]([F:28])[CH:20]=1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1F
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2F)c1

Procedure:
The title compound was synthesized in analogy to Examples BI to BJ using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid methyl ester (CAN 1211589-51-3) and B-(4-chloro-2-fluorophenyl)-boronic acid, (CAN 160591-91-3) as starting materials; LC-MS (UV peak area/ESI) 98.8%, 348.0061 (M−H)−.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N:10]1([C:17](=[O:19])[CH3:18])[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:17]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:12][CH2:11]1)(=[O:19])[CH3:18]
Reactant: CC(=O)N1CCCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCCN(c2ccc(C=O)cc2)CC1
Temperature: 120 °C
Yield: 69.6 %

Procedure:
A mixture of 4-fluorobenzaldehyde (1.56 g, 12.6 mmol), 1-(1,4-diazepan-1-yl)ethanone (1.5 g, 10.5 mmol), and K2CO3 (1.74 g, 12.6 mmol) in DMF (10 mL) were heated at 120° C. for 20 hours. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate and the organic phase washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 50% ethyl acetate/hexanes to 100% ethyl acetate to 10% methanol/ethyl acetate, to afford 4-(4-acetyl-1,4-diazepan-1-yl)benzaldehyde (1.8 g, 70%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1>>[N+:10]([C:4]1[CH:3]=[C:2]([C:23]2[N:19]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[N:20]=[CH:21][CH:22]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:12])=[O:11]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Product: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 4-chloro-2-nitrobenzonitrile (1.50 g) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-1H-pyrazole (2.74 g) using the method of Example 39(a). Yield 1.75 g. 1H-NMR (400 MHz; d6-DMSO): δ 1.57 (m, 3H), 1.84 (m, 1H), 1.97 (m, 1H), 2.38-2.47 (m, 1H), 3.68-3.75 (m, 1H), 4.03 (m, 1H), 5.33 (dd, 1H), 6.84 (d, 1H), 7.69 (d, 1H), 8.13 (dd, 1H), 8.31 (d, 1H), 8.60 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].Cl.[C:17]([O-])(O)=O.[Na+].O>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:17])=[O:7]
Reactant: O=C([O-])O
Reactant: O=C(O)C=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C=Cc1cc([N+](=O)[O-])ccc1Cl

Procedure:
A solution of 34.1 g (150 millimoles) of the product from Example 1 in 300 ml of methanol was saturated with HCl gas, after which further HCl gas was passed in during the reaction time of 5 hours. The solid obtained on cooling was stirred thoroughly with NaHCO3 /water and taken up in methylene chloride. The CH2Cl2 solution was washed with water and dried over MgSO4, and the abovementioned product was obtained by evaporating down the solution and triturating the residue with diethyl ether.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br)#[N:2].[C:14]1([CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[CH:16]=1)[OH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOCC>[OH:15][C:14]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[O:18][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:5]=1[O:4][CH2:3][C:1]#[N:2]
Reactant: Cc1cccc(CBr)c1OCC#N
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cccc(COc2cccc(O)c2)c1OCC#N
Temperature: 60 °C

Procedure:
Heated (60° C.) a mixture of 2-cyanomethoxy-3-methylbenzyl bromide (10.2 g, 42.7 mmoles, example 24), resorcinol (18.8 g, 171 mmoles), and potassium carbonate (47.2 g, 342 mmoles) in acetonitrile (140 mL) for two hours. The reaction is diluted with ether and washed three times with distilled water, once with brine, and dried over MgSO4. The organic layer is isolated and concentrated, and the resulting residue is purified by column chromatography (silica, 5% EtOAc/CH2Cl2) to yield the title compound as a white crystalline solid. MS(EI) 269 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[N:7]=1.CN(C(ON1N=N[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[C:10]([C:11]([N:39]3[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)=[O:13])[CH:14]=[CH:15][CH:16]=2)[N:7]=1
Reactant: Nc1nc(-c2cccc(C(=O)O)c2)cn2nc(-c3ccco3)nc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2cccc(C(=O)N3CCCCC3)c2)cn2nc(-c3ccco3)nc12
Yield: 61.3 %

Procedure:
A solution of 3-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-benzoic acid (20.mg, 0.063 mmol; see Example 5 above), HATU (30 mg, 0.095 mmol), piperdine (0.125 mmol), and diisopropylethylamine (11 μL, 0.063 mmol) in DMF (200 μL) was stirred at room temperature for 30 minutes. The solvent was removed, and the residue was purified by HPLC (C18, H2O:MeCN gradient) to afford the product as a white solid (15 mg, 62%). 1H NMR (300 MHz, DMSO-d6) δ 1.56 (br. s, 6H),3.35 (br. s,2H), 3.65 (br. s, 2H), 6.76 (dd, J=3.4, 1.7 Hz, 1H), 7.18 (dd, J=3.4, 0.8 Hz, 1H), 7.4 (br. dt, J=7.6, 1.4 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.63 (br. s, 2H), 7.96 (dd, J=1.7, 0.8 Hz, 1H), 8.11 (br. s, 1H), 8.14 (dt, J=7.5, 1.5 Hz, 1H),8.9 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.Br[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:16]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCBr
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCCc1cc2ccccc2s1

Procedure:
2-n-Butylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7M, 9.7 mmoles, 5.7 ml), 1-bromobutane (9.7 mmoles, 1.0 ml) and THF (20 ml). 0.65 g (46%) of a yellow liquid was isolated.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][OH:7])[CH2:3][C:4]#[N:5].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].Cl>N1C=CC=CC=1.C(Cl)Cl>[OH:1][C@H:2]([CH2:6][O:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:3][C:4]#[N:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC[C@H](O)CO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CC#N)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 21 %

Procedure:
(3S)-3,4-Dihydroxybutyronitrile (161.8 g, 1.6 mol) was dissolved in pyridine (260 ml). To the resulting solution, a solution of tosyl chloride (396.6 g) in methylene chloride (1.6 liters) was added at 0° C. and stirred at 0° C. for 5 hours. Then, the pH of the mixture was adjusted at 2 with 6N hydrochloric acid, and the mixture was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated off. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain (3S)-3-hydroxy-4-p-toluenesulfonyloxybutyronitrile (85.9 g). Yield, 70 %.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>O>[CH3:20][N:19]1[C:15]([NH:14][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])=[N:16][N:17]=[N:18]1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: Cn1nnnc1N
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cn1nnnc1NC(=O)c1cccc2cccnc12
Temperature: 70 °C

Procedure:
A mixture of 2.4 g. (0.020 mole) of 8-quinolinecarboxylic acid and 3.0 g. (0.030 mole) of 5-amino-1-methyltetrazole is stirred in 30 ml. of pyridine at 20° C. while adding 2.0 ml. of thionyl chloride dropwise. The mixture is heated at 70° C. for one hour. The reaction mixture is evaporated to provide a residue which is diluted with water. The solid is separated by filtration and recrystallized from acetic acid with decolorizing charcoal. The product is recrystallized a second time from acetic acid to provide 8-(1-methyl-1H-tetrazole-5-yl-carbamoyl)quinoline, m.p. 224°-225° C.
Reaction SMILES: Br[C:2]1[S:34][C:5]2[N:6]=[C:7]([CH2:30][CH2:31][CH2:32][CH3:33])[N:8]=[C:9]([NH:10][C@H:11]([C:13]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17](=[O:25])[C:16]4=[C:26]([CH3:29])[CH:27]=[CH:28][N:15]4[N:14]=3)[CH3:12])[C:4]=2[CH:3]=1.[C:35](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>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>[CH2:30]([C:7]1[N:8]=[C:9]([NH:10][C@H:11]([C:13]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17](=[O:25])[C:16]3=[C:26]([CH3:29])[CH:27]=[CH:28][N:15]3[N:14]=2)[CH3:12])[C:4]2[CH:3]=[C:2]([CH3:35])[S:34][C:5]=2[N:6]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1nc(N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c2cc(Br)sc2n1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Product: CCCCc1nc(N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c2cc(C)sc2n1
Yield: 36 %

Procedure:
(S)-2-(1-((6-Bromo-2-butylthieno[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (obtained as by-product in Preparation 82, 53 mg, 0.10 mmol) was treated with potassium carbonate (273 mg, 1.97 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.01 mmol) and trimethylboroxine (124 μl, 0.89 mmol) according to the method described in Example 56. The residue was purified using SP1® Purification System (0% to 35%, hexane-ethyl acetate) to obtain 17 mg (37% yield) of the title compound as a white solid. Purity 86%.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[OH:17]O.[OH-].[Na+]>C(O)C>[NH2:2][C:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:17]
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 4-cyanophenoxy phenyl methane (10.45g.; 0.05 mole), 30% hydrogen peroxide (20 ml) and 6N NaOH (20ml) and ethanol (30ml) was maintained at 40°-50° for 3 hrs., cooled and neutralised. The product was filtered off and recrystallised from ethanol M.p. 186°-7°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[C:5]2[Cl:24].C1(C)C=CC=CC=1.[CH3:32][O-:33].[Na+].[Al]>CCCCCC.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:33][CH3:32])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[C:5]2[Cl:24]
Reactant: C[O-]
Reactant: FC(F)(F)c1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Agent: [Al]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
To a 1 L flask containing 6-bromo-2,4-dichloro-3-(4-(trifluoromethyl)benzyl)quinoline (32.5 g, 74.7 mmol, Intermediate 12: step c) was added toluene (550 mL) followed by solid sodium methoxide (40 g, 740 mmol, 97% purity) at room temperature. The suspension was stirred at reflux (˜118° C.) in an aluminum mantle. TLC (50% hexane-DCM) and HPLC after 5.5 hours showed the reaction to be complete. The reaction mixture was filtered through Celite® while still warm (˜80° C.) and rinsed with warm toluene (˜70° C., 500 mL). The colorless filtrate was concentrated and the resulting residue solidified to provide the title compound as an off white solid.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].Cl[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[N:8]=1>O1CCCC1>[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([S:3][CH2:1][CH3:2])[N:8]=1)#[N:14]
Reactant: CCS
Reactant: N#Cc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
Ethyl mercaptan (0.49 g, 7.9 mmol) was dissolved in tetrahydrofuran (100 ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7 mmol). The reaction mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure to give the titled compound (1.02 g, 86%) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH2:34]([O:36][C:37](=[O:42])[C:38](Br)([CH3:40])[CH3:39])[CH3:35]>>[CH3:39][C:38]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:6]=[C:5]([N:24]2[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[C:25]2[CH3:33])[N:4]=3)[CH2:13][CH2:14]1)([CH3:40])[C:37]([O:36][CH2:34][CH3:35])=[O:42]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)N1CCC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine was alkylated with 2-bromo-2-methyl-propanoic acid ethyl ester to give 456. LCMS m/z: 561.3 (MH+)
Reaction SMILES: C1(CBr)CC1.Br[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:16][C:17]1[N:18]=[C:19]([N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])[S:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:16][C:17]1[N:18]=[C:19]([N:27]2[CH2:31][CH2:30][N:29]([CH2:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:28]2=[O:32])[S:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CCCc3ccccc3)C2=O)nc1C
Yield: 61 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with 1-bromo-3-phenylpropane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 61% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.27-7.13 (m, 5H), 4.27 (q, J=7.2 Hz, 2H), 4.02-3.96 (m, 2H), 3.52-3.46 (m, 2H), 3.37 (t, J=7.2 Hz, 2H), 2.63 (t, J=7.5 Hz, 2H), 2.59 (s, 3H), 1.95-1.88 (m, 2H), 1.23 (t, J=7.2 Hz, 3H); MS (ES+) m/z 374.2 (M+1).
Reaction SMILES: [CH2:1]([CH:5](C(O)=O)[N:6](C(OCC1C=CC=CC=1)=O)[CH2:7][P:8]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:9])[CH2:2][CH2:3]C.Br.C(OCC)C.[C:41]([OH:44])(=[O:43])[CH3:42]>>[CH2:5]([N:6]([CH2:7][P:8]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:9])[CH2:42][C:41]([OH:44])=[O:43])[CH2:1][CH2:2][CH3:3]
Reactant: CC(=O)O
Reactant: CCCCCSP(=O)(CN(C(=O)OCc1ccccc1)C(CCCC)C(=O)O)SCCCCC
Agent: Br
Solvent: CCOCC
Product: CCCCCSP(=O)(CN(CCCC)CC(=O)O)SCCCCC

Procedure:
n-Butyl N-carbobenzoxy-N-[bis(pentylthio)phosphinylmethyl]glycine (5.5 g., 0.01 mole) was reacted with 32% hydrogen bromide (15 ml) in glacial acetic acid at 0° C. Diethyl ether was added and the oily precipitate isolated by decantation of the ether layer. The oil was washed twice with ether, suspended in benzene and then treated with propylene oxide. The resulting solution was concentrated in vacuo to yield n-butyl N-[bis(pentylthio)phosphinylmethyl]-glycine (0.7 g., 0.002 mole) as an oil, ND27 =1.4905.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][CH:54]([O:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=2)[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[O:10]=[C:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:17]=[CH:18][C:19]([C:20]([NH:47][CH2:48][C:49](=[O:50])[N:51]2[CH2:52][CH2:53][CH:54]([O:57][C:58]3[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:65])([F:66])[F:67])[CH:59]=3)[CH2:55][CH2:56]2)=[O:22])=[CH:23][CH:24]=1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1ccc(N2CCCC2=O)cc1
Reaction time: 0.03 h
Yield: 56.62 %

Procedure:
DIPEA (200 mg, 1.55 mmol) was added to a stirred solution of 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid (70 mg, 0.34 mmol) in DMF (5 mL) followed by HOBt (50 mg, 0.37 mmol) and EDCI (163 mg, 0.85 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (127 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the precipitate was filtered off. The solid obtained was purified by column chromatography (using 60-120 silica gel and 70% ethyl acetate in hexane as eluent) to afford 94 mg (56.62% Yield) of 4-(2-oxo-pyrrolidin-1-yl)-N-{2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-benzamide. LC/MS [M+H]+: 490.19, 98.95%. 1H NMR (300 MHz, DMSO-d6): δ 8.6 (t, 1H), 7.94 (d, 2H), 7.8 (d, 2H), 7.6 (t, 1H), 7.38 (t, 3H), 4.8 (m, 1H), 4.2 (d, 1H), 4.0 (t, 3H), 3.8 (d, 1H), 3.5 (d, 1H), 3.3 (bs, 1H), 2.5 (bs, 2H), 2.1 (m, 2H), 2.0 (d, 2H), 1.7 (d, 2H).
Reaction SMILES: [CH3:1][S+:2]([CH3:4])[CH3:3].P(CNC[C:12]([OH:14])=[O:13])(O)(O)=O.S([O-])(O)(=O)=[O:16].C[S+](C)C.[OH-:24].[Na+]>>[C:12](=[O:13])([OH:16])[O-:14].[CH3:1][S+:2]([CH3:4])[CH3:3].[C:12](=[O:13])([O-:24])[O-:14]
Reactant: O=S(=O)([O-])O
Reactant: [OH-]
Reactant: O=C(O)CNCP(=O)(O)O
Agent: C[S+](C)C
Agent: [Na+]
Product: O=C([O-])O
Product: O=C([O-])[O-]

Procedure:
A process for the manufacture of the trimethylsulfonium salt of N-phosphonomethylglycine which comprises (i) treating trimethylsulfonium hydrogen sulfate with sodium hydroxide to precipitate sodium sulfate (ii) bubbling carbon dioxide through the resultant aqueous solution of trimethylsulfonium hydroxide to form trimethylsulfonium bicarbonate or carbonate or a mixture thereof, (iii) removing the precipitated sodium sulfate either after stage (i) or stage (ii), (iv) optionally obtaining the trimethylsulfonium bicarbonate or carbonate or the mixture thereof as a transportable solid or concentrated aqueous solution, and (v) reacting
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[S:18]1(=[O:26])(=[O:25])[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>C1COCC1.O>[O:25]=[S:18]1(=[O:26])[CH2:23][CH2:22][C:21](=[CH:9][C:7]#[N:8])[CH2:20][CH2:19]1
Reactant: O=C1CCS(=O)(=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC=C1CCS(=O)(=O)CC1
Temperature: 0 °C

Procedure:
Potassium tert-butoxide (3.5 mL, 3.5 mmol, 1.0 M in THF) was stirred at 0° C. and THF (8 mL) was added. Diethyl (cyanomethyl)phosphonate (0.56 mL, 3.5 mmol) was added slowly by syringe. The reaction mixture was maintained at 0° C. for 10 minutes, then warmed to ambient temperature and maintained for 1 hour. The mixture was cooled to 0° C. and treated with the dropwise addition of dihydro-2H-thiopyran-4(3H)-one 1,1-dioxide (0.50 g, 3.4 mmol) in THF (5 mL). After addition, the mixture was maintained at 0° C. for 20 minutes, then warmed to ambient temperature and maintained for 18 hours. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified MPLC on silica gel (using a gradient elution of 0-50% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to the title compound.
Reaction SMILES: [CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH2:3]CC.C(S)CC>>[CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH3:3]
Reactant: CCCCCSc1c[nH]nc1C1CN2CCC1CC2
Agent: CCCS
Product: CCCSc1c[nH]nc1C1CN2CCC1CC2
Yield: 25 %

Procedure:
Compound 49E was prepared following the procedure as described for the synthesis of compound 49B (see Scheme 10) using propane-1-thiol as reagent. Subsequent purification by flash chromatography (EtOH to EtOH/triethylamine 99/1) afforded compound 49E.