Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[S:3]([CH2:6][CH2:7][CH2:8]Cl)(=[O:5])=[O:4].[CH3:11][NH:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC#N.O>[CH3:1][N:2]([CH3:10])[S:3]([CH2:6][CH2:7][CH2:8][N:12]([CH3:13])[CH3:11])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)CCCCl
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C)CCCS(=O)(=O)N(C)C
Temperature: 65 °C
Yield: 68.6 %

Procedure:
A solution of 3-chloro-propane-1-sulfonic acid dimethylamide (0.55 g, 3.00 mmol) in MeCN (5 mL) was treated with dimethylamine (2 M in THF; 10 mL, 20 mmol), potassium carbonate (455 mg, 3.30 mmol) and a catalytic amount of potassium iodide (50 mg, 0.03 mmol). This mixture was heated in a sealed tube at 65° C. for 18 hours, then cooled and diluted with water and extracted into EtOAc. The organic extract was washed with brine then dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a pale brown oil (0.40 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[C:4]=1[NH:5][CH2:6][C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH3:2].[Cl:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:19][CH2:20][C:21]([N:5]([CH2:6][C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[C:4]1[C:13]([CH2:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:3]=1[CH2:1][CH3:2])=[O:22]
Reactant: O=C(Cl)CCl
Reactant: C=CCOC(=O)CNc1c(CC)cccc1CC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CCOC(=O)CN(C(=O)CCl)c1c(CC)cccc1CC
Reaction time: 2 h

Procedure:
24.7 Grams of allyl 2,6-diethylanilinoacetate and 11.3 g of monochloroacetic acid chloride were dissolved in 100 ml of benzene, 11.0 g of triethylamine was then added dropwise thereto with stirring maintaining the reaction temperature at 10°-20° C., and, thereafter, stirring was continued for further 2 hours at a room temperature. The reaction solution was washed with successive, 5% sodium hydroxide aqueous solution, 5% hydrochloric acid aqueous solution, and water. Then, the benzene layer was dried over anhydrous sodium sulfate. Thereafter, benzene was removed under reduced pressure to obtain the end product, allyl N-chloroacetyl-2,6-diethylanilinoacetate. nD21.5 : 1.5288.
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[CH2:15]([N:22]1[CH2:27]CC(=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N>CO>[CH2:15]([N:22]1[CH2:23][CH2:24][C:3]2[N:2]=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=2[CH2:27]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)CN(Cc1ccccc1)CC2
Yield: 49.7 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (1.2 g, 6.0 mmol), 1-benzyl-4-piperidone (1.12 g, 5.9 mmol) and ammonia solution in methanol (2.0 M, 60 mL) was refluxed for 3 h. The solvent was removed in vacua and the residue was dissolved in ethyl acetate. The soluble portion was flash chromatographed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane) to give a yellow solid (0.79 g, 49.7% yield).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.C(OC(=O)[N:32]([C:44]1[CH:49]=[CH:48][C:47]([C:50](=[O:52])[CH3:51])=[CH:46][N:45]=1)[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1)(C)(C)C>O1CCCC1>[F:43][C:40]([F:41])([F:42])[C:37]1[CH:38]=[CH:39][C:34]([CH2:33][NH:32][C:44]2[N:45]=[CH:46][C:47]([C:50]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=3)([OH:52])[CH3:51])=[CH:48][CH:49]=2)=[CH:35][CH:36]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: CC(=O)c1ccc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(C)(O)c2ccc(NCc3ccc(C(F)(F)F)cc3)nc2)c2cccnc21
Temperature: -20 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 485.9 mg, 1.21 mmol) was dissolved in tetrahydrofuran (8 mL) at −20° C. under an atmosphere of nitrogen. 2.0 M isopropylmagnesium chloride in tetrahydrofuran (0.655 mL) was added. The reaction was stirred at −20° C. for 1 hour. Into the reaction was added (5-acetyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (621, 300.0 mg, 0.76 mmol) in tetrahydrofuran (6 mL) The reaction was allowed to warm to room temperature overnight. The mixture was extracted with ethyl acetate and saturated sodium bicarbonate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography on the (ethyl acetate:hexanes), to provide the desired compound as an oil (622, 125 mg, 29%), consistent with the compound structure by 1H-NMR.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:19])=[CH:5][C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:7][C:8]=1[O:9][CH3:10])#[N:2]>CC(O)=O.C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1[C:4]([CH3:19])=[CH:5][C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1C#N
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1CN
Yield: 68.9 %

Procedure:
A clear solution of tert-butyl (5-cyano-6-methoxy-4-methylpyridin-2-yl)carbamate (0.60 g, 2.279 mmol) in HOAc (5 mL) and ethanol (20 mL) was treated on an H-Cube apparatus (50 psi, 40° C., 1 mL/min., Raney Nickel cartridge) for 18 hr. LCMS showed that the reaction was complete (86% pure). The reaction was evaporated to dryness under vacuum. Purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 12% (5% NH4OH/MeOH) in CH2Cl2). The pure fractions were combined and evaporated to dryness under vacuum to give the product tert-butyl (5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)carbamate (0.42 g, 1.571 mmol, 68.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.16 (s, 1H), 3.80 (s, 3H), 3.57 (s, 2H), 2.28 (s, 3H), 1.46 (s, 9H). MS(ES)+ m/e 268.1 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH:59]1[CH2:64][CH2:63][N:62]([CH2:65][C:66]([N:68]([CH3:70])[CH3:69])=[O:67])[CH2:61][CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH:59]5[CH2:60][CH2:61][N:62]([CH2:65][C:66]([N:68]([CH3:70])[CH3:69])=[O:67])[CH2:63][CH2:64]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:5][CH2:6]1
Reactant: CN(C)C(=O)CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(CC(=O)N(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for the synthesis of the compound 16 using HATU except that 2-(4-aminopiperidin-1-yl)-N,N-dimethylacetamide was used. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-2.17 (m, 14H) 2.94 (d, J=10.61 Hz, 6H) 3.01-3.20 (m, 2H) 3.33 (s, 3H) 4.06 (t, J=13.89 Hz, 5H) 4.24 (d, J=4.55 Hz, 2H) 4.78 (t, J=7.45 Hz, 1H) 7.43-7.62 (m, 2H) 8.06 (br. s., 1H) 8.27 (s, 2H) 8.36 (d, J=7.07 Hz, 1H) 9.52 (br. s., 1H) [M+H] calc'd for C30H40F2N8O4, 614. found 614.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][C:32](O)=[O:33]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:32](=[O:33])[CH2:31][CH:27]5[CH2:28][CH2:29][CH2:30][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)CC1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1CCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (9 mg, 25%), MS (ISP) m/z=443.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 2-(tetrahydrofuran-2-yl)acetic acid.
Reaction SMILES: C[O-].[Na+].[C:4](#[N:7])[CH:5]=[CH2:6].Cl.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[C:19]([F:25])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO.CCOC(C)=O>[NH2:7][C:4]1[NH:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:18][C:19]=2[F:25])[CH2:6][CH:5]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1F
Reactant: C=CC#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1=CCN(c2ccc(OCc3ccccc3)cc2F)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaOMe (25 wt. % solution in MeOH, 7.75 mL) and acrylonitrile (2.1 mL) were added to a solution of 4-benzyloxy-2-fluorophenylhydrazine hydrochloride (4.15 g) in MeOH (40 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes and refluxed overnight. Additional NaOMe (25 wt. % solution in MeOH, 3.9 mL) and acrylonitrile (1.05 ml) were added to the reaction mixture and refluxed for 7.5 hours. The mixture was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was crystallized from CHCl3/hexane to yield 3.86 g of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH3:9].C(Cl)(=O)C(C)(C)C.[S:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[CH2:47][CH2:48][NH2:49]>C(Cl)Cl>[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH:49][CH2:48][CH2:47][C:43]4[S:42][CH:46]=[CH:45][CH:44]=4)=[O:32])=[CH:28][N:27]=3)=[O:25])[CH2:22][CH2:23]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:9])[CH3:10]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: NCCc1cccs1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCc3cccs3)cn2)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Triethylamine (0. 8 ml) was added to 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid (2g) in methylene chloride (30 ml) for dissolution and cooled. With the slow addition of pivaloyl chloride (0. 7 ml) at 0° C.˜5° C., the mixture was stirred at 5° C for 1 hour. With the successive addition of triethylamine (0.9 ml) and 2-thiophenethylamine (0.75 g), the mixture was stirred at 5° C.˜10° C. for 2 hours. The solution was washed with an aqueous sodium bicarbonate and water. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was treated with ether for crystallization. The solid, so obtained, was recrystallized with ethanol and hexane to give a desired compound of 1.92 g (yield: 74%).
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1)=O.C([NH:26][NH2:27])(=O)C1C=CC=CC=1.CC(C)([O-])C.[K+]>C(O)(=O)C.C(O)C>[C:11]([C:9]1[O:10][C:6]([C:4]2[C:3]3[C:2](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:27][N:26]=2)=[CH:7][CH:8]=1)([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2F)o1
Reactant: NNC(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccc(-c2n[nH]c3ccccc23)o1

Procedure:
2.5 g (11 mmol) of 5-(2-fluorobenzoyl)furan-2-carboxylic acid, 3.28 g (24 mmol) of benzhydrazide and 2 drops of glacial acetic acid in 50 ml of ethanol were heated under reflux for 10 h. The mixture was subsequently concentrated using a rotary evaporator and the residue was taken up in water, made alkaline using 2 N NaHCO3 solution and extracted with ethyl acetate. The aqueous phase was made acidic using 2N hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried and concentrated using a rotary evaporator. The residue was dissolved in 25 ml of THF, 2.74 g (24.2 mmol) of potassium tert-butoxide were added and the mixture was stirred at reflux temperature for 1.5 h. After cooling, the mixture was concentrated using a rotary evaporator and the residue was taken up in 1 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The precipitate that resulted when the aqueous phase was acidified was filtered off with suction, washed with water and dried in a vacuum drying cabinet at 40° C. This gave 1.88 g (75%) of the title compound. m.p.: 205° C. (decomp).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:44]([N+:48]1[N:52]=[C:51]([CH3:53])[S:50][C:49]=1[CH3:54])[CH2:45][CH2:46][CH3:47]>>[CH2:44]([N:48]1[N:52]=[C:51]([CH3:53])[S:50]/[C:49]/1=[CH:54]\[C:7]([CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:9])[CH2:45][CH2:46][CH3:47]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)CC1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-cyclopentylacetic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.06-1.16 (m, 2 H) 1.24-1.34 (m, 2 H) 1.43-1.54 (m, 2 H) 1.53-1.61 (m, 2 H) 1.63-1.73 (m, 4 H) 2.14-2.23 (m, 1 H) 2.30-2.34 (m, 2 H) 2.39-2.43 (m, 3 H) 4.03 (t, 2 H) 5.90 (s, 1 H); MS (ESI) m/z 281 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1>O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.P.[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W]>[CH3:1][CH2:5][CH2:1][CH2:5][O:4][C@H:3]([CH2:2][OH:4])[CH2:3][CH3:2]
Reactant: C1CCOC1
Agent: [W]
Agent: P
Solvent: O
Product: CCCCO[C@@H](CC)CO

Procedure:
Polymerization of THF was carried out according to the same procedure as in Example 1 except that phosphotungstic acid was used as a catalyst solution of a specific gravity of 2.05 and the reaction liquid volume V in the reactor 1 was kept constant at 420 ml. First, in order to find the relation between Mw/Mn and V/F, with P/V fixed at 1.9 kW/m3, the Mn and the Mw/Mn of PTMG obtained under conditions 1 to 3 shown in Table 1 were measured. The results obtained are shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:11]Cl)[CH:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH:19][CH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CCl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCc1cc(Cl)ccc1[N+](=O)[O-]
Yield: 99.3 %

Procedure:
A mixture of 4-chloro-2-chloromethyl-1-nitro-benzene (85 g, 0.41 mol), glycine ethyl ester hydrochloride (70 g, 0.50 mol) and triethylamine (121.4 ml, 0.8665 mol) in ethanol (1000 ml) was heated at reflux for 8 h. The solvent was evaporated and the residue was triturated in warm tert-butyl methyl ether. The ammonium salts were removed by filtration and the filtrate was concentrated in vacuo to give the title compound (111 g, 99%) as an amorphous brown solid which was used in the next step without purification. MS m/e: 273 (M+H+).
Reaction SMILES: C(C1[O:5]C1)Cl.[C:6]1([O:16][CH3:17])[C:7](=[CH:9][CH:10]=[C:11]([CH:15]=1)[CH:12]=[CH:13][CH3:14])[OH:8].[OH-].[Na+]>C(O)C>[O:5]1[C:12](=[CH:13][CH3:14])[C:11]2[CH:15]=[C:6]([O:16][CH3:17])[C:7]([OH:8])=[CH:9][C:10]1=2
Reactant: ClCC1CO1
Reactant: CC=Cc1ccc(O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC=C1Oc2cc(O)c(OC)cc21

Procedure:
To manufacture this combination Epichlorohydrin was mixed with isoeugenol and NaOH dissolved in ethanol and boiled to reflux for 2–6 hours. Ethanol was then removed from the resulting mixture and the mixture was passed through silica gel column eluted with n-hexane and ethyl acetate, and dried with reduced pressure, to obtain 4-epoxy isoeugenol.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[N:12][NH:13][C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[CH2:20]([S:23](Cl)(=[O:25])=[O:24])[CH2:21][CH3:22].C(Cl)Cl.CCOC(C)=O>C(Cl)Cl>[CH2:1]([N:5]1[C:10]2[CH:11]=[N:12][N:13]([S:23]([CH2:20][CH2:21][CH3:22])(=[O:25])=[O:24])[C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]ncc2n(CCCC)c1=O
Reactant: CCCS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCn1c(=O)c2c(cnn2S(=O)(=O)CCC)n(CCCC)c1=O
Temperature: 23 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To 500 mg (2.6-2.8 mmol/g resin) of piperidinomethyl polystyrene resin in 25 mL CH2Cl2 was added 280 mg (1.06 mmol) of 4,6-dibutyl-1,4-dihydro-pyrazolo[4,3-d]pyrimidine-5,7-dione followed by 166 mg (1.17 mmol) of propanesulfonyl chloride. The resulting solution was stirred at 23° C. for 3 h after which time TLC showed that all starting material (4/1 CH2Cl2 /EtOAc; Rf =0.15) had been consumed. The reaction mixture was filtered, the filtered cake washed with 3×5 mL CH2Cl2, and the combined organics were evaporated to give crude yellow oil. Flash chromatography on silica gel, eluting with CH2Cl2 /EtOAc (40/1 to 10/1) gave 359 mg (0.97 mmol, a 92% yield) of the title compound as a yellow solid. mp: 44-48° C.; 1H NMR (300 MHz, CDCl3); δ 0.93-1.17 (m, 9H), 1.35-1.44 (m, 4H), 1.61-1.83 (m, 4H), 2.06-2.33 (m, 2H), 3.51-3.68 (m, 2H), 3.85 (t, J=7.5 Hz, 2H), 4.02 (t, J=7.4 Hz, 2H), 7.88 (s, 1H); IR (KBr, cm-1): 3231w, 2960m, 1719m, 1675s, 1620m, 1387m, 1289m, 1171m, 1066m; MS (ES) m/z (relative intensity): 371 (M+ +H, 100). Anal. Calcd. for C16H26N4O4S: C, 51.87; H, 7.07, N, 15.12. Found: C, 46.22; H, 6.65; N, 11.91
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH3:11])[CH2:8][CH2:9][NH2:10].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:6][N:7]([CH3:11])[CH2:8][CH2:9][NH:10][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CN(C)CCN
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (Compound 19, 2.6 ml, 34.0 mmol) was added to a mixture of N,N-dimethylethylenediamine (3.7 ml, 34.0 mmol) and diisopropylethylamine (5.93 ml, 34.0 mmol) in tetrahydrofuran (30 ml) at 0° C. After 1.5 hours stirring at 0°, the mixture was quenched with water and extracted thoroughly with ethyl acetate. Evaporation of the dried (magnesium sulfate) extract gave an oil, which was purified by flash chromatography on silica using 20% methanol/chloroform to give the title sulfonamide. 1HNMR(CDCl3): 2.24 (s, 6H), 2.48 (t, 2H, J=5.9 Hz), 2.97 (s, 3H), 3.18 (t, 2H, J=5.6 Hz). 13CNMR(CDCl3): 39.3, 39.9, 44.5 and 57.8.
Reaction SMILES: I[C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=2[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:31][CH:30]=1
Reactant: O=C(NOCc1ccccc1I)c1ccccc1NCc1ccncc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccccc2CONC(=O)c2ccccc2NCc2ccncc2)cc1

Procedure:
Prepared by a similar procedure as described for preparation of example 363. Starting materials: N-(2-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)amino]-benzamide (see example 360) and 4-methoxyphenylboronic acid (Aldrich).
Reaction SMILES: Br.[C:2]([S:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=[NH:4])[NH2:3].[C:16]([O-])(=O)[CH3:17].[NH4+].C([N:23]=[C:24]=[O:25])C.O>CN(C=O)C>[CH2:16]([N:13]([CH2:10][CH3:11])[C:24]([NH2:23])=[O:25])[CH3:17].[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][S:5][C:2](=[NH:3])[NH2:4])=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: CC(=O)[O-]
Reactant: CCN=C=O
Agent: Br
Agent: N=C(N)SCc1ccc([N+](=O)[O-])cc1
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-nitrobenzyl carbamimidothioate hydrobromide (2.5 g, 8.55 mmol) in DMF (10 mL) was added aqueous buffer solution of ammonium acetate (pH ˜7, 4.0 mL) followed by addition of ethyl isocyanate (10 mL. 85.57 mmol) at rt and the mixture stirred at rt for 48 h. After completion of reaction (by TLC), water (10 mL) was added and a white precipitate formed. The reaction mixture was filtered and solid was washed with water to obtain the desired product as white solid (1.40 g, 41%). MS: 354.18 [M+H]+
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:7]([CH3:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][C:5](=[S:15])[N:4]1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([N:38]=[C:39]=[O:40])[CH:34]=[CH:35][C:36]=1[Cl:37]>O1CCCC1>[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][C:39]([O:1][N:2]=[C:3]2[C:7]([CH3:14])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:6][C:5](=[S:15])[N:4]2[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:40])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=NO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=NOC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-hydroxyimino-5-methyl-5-phenyl-3-phenylamino-thiazolidine-2-thione (0.19 g), triethylamine (0.06 g) and 3,4-dichlorophenylisocyanate in tetrahydrofuran (3 ml) was stirred for 2 days at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (chloroform) to yield 4-(3,4-Dichlorophenylcarbamoyl)oxyimino-5-methyl-5-phenyl-3-phenylaminothiazolidine-2-thione (0.13 g) having a melting point of 95-96° C.