Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:3][CH2:4][CH2:5]O.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.O>ClCCl>[CH3:13][S:14]([CH2:5][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)=CCC[C@@H](C)CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)=CCC[C@@H](C)CCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(R)-methyl-8-methylnon-7-enyl alcohol (3.25 g, 19.1 mmol) in dichloromethane (50 ml) at 0° C. was added methanesulfonyl chloride (2.29 g, 20.0 mmol) followed by triethylamine (3.04 g, 30.0 mmol). After stirring for 10 min at 0° C., the reaction was allowed to warm to 25° C. and stirred for 3 hr. The reaction was poured into water (50 ml), separated and washed with dichloromethane (50 ml). The organic portions were combined, dried (magnesium sulfate), and evaporated to give the 1-methanesulfonyl-4-(R)-methyl-8-methylnon-7-ene as a yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.P(Cl)(Cl)Cl.[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>N1C=CC=CC=1>[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:25]([C:27]([N:14]2[CH2:15][CH2:16][N:11]([CH2:1][C:2]3[CH:10]=[CH:9][C:8]4[O:7][CH2:6][O:5][C:4]=4[CH:3]=3)[CH2:12][CH2:13]2)=[O:28])[N:26]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: Nc1nc(C(=O)O)c(-c2ccncc2)s1
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: Nc1nc(C(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
To a mixture of 1-piperonylpiperazine (2.72 g) and phosphorus trichloride (0.49 ml) in pyridine (20 ml) was added 2-amino-5-(4-pyridyl)-4-thiazolecarboxylic acid (1.24 g) and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The resultant mixture was adjusted to pH 8.0 with saturated aqueous potassium carbonate. The organic extract was dried over magnesium sulfate. The solvent was evaporated in vacuo to give a crystalline residue, which was recrystallized from ethyl acetate to afford 2-amino-5-(4-pyridyl)-4-[(4-piperonyl-1-piperazinyl)carbonyl]thiazole (0.45 g). mp 216°-217° C.
Reaction SMILES: [CH:1](=[CH:8]/[C:9](=[O:11])[CH3:10])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.O.O1CCO[CH2:19][CH2:18]1>CCCCCC>[C:2]1([CH:1]([CH2:18][CH3:19])[CH2:8][C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: C1COCCO1
Agent: C[Al](C)C
Solvent: O
Solvent: CCCCCC
Product: CCC(CC(C)=O)c1ccccc1
Temperature: 22 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
143 mg of CuBr is added to 1.46 g (10 mmol) of cis/trans-benzylideneacetone (3-phenyl-but-3-en-2-one) in 20 ml of absolute dioxane. 11 ml (11 mmol) of a 1 molar solution of trimethyl aluminum in hexane is added to the reaction at room temperature under nitrogen atmosphere and, after completion of the addition, stirred for 10 minutes at 22° C. For hydrolysis of the reaction solution, 1 ml of water dissolved in 5 ml of dioxane is carefully added to the reaction. It is stirred for 10 minutes more and the inorganic precipitate filtered off with dioxane is washed again. The dioxane solution is concentrated by evaporation on a rotary evaporator and the residue is chromatographed on silica gel with ethyl acetate/hexane as eluent. After concentration by evaporation of the fractions, 1.37 g of 4-phenyl-hexan-2-one (78% of theory) is obtained a colorless liquid.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]1=[O:22].[H-].[Na+].[CH2:32]([SH:35])[CH2:33][CH3:34]>C1COCC1>[ClH:2].[C:16]1([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][S:35][CH2:32][CH2:33][CH3:34])([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:8]2=[O:22])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCS
Reactant: O=C1N(c2ccccc2)c2ccccc2C1(CCCCCl)Cc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCSCCCCC1(Cc2ccncc2)C(=O)N(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(4-Chlorobutyl)-1,3-dihydro-1-phenyl-(4-pyridinylmethyl)-2H-indol-2-one hydrochloride (6.0 g, 14.04 mmol) in 75 ml dry THF was treated with NaH (0.75 g, 31.25 mmol) and stirred for 10 min. under dry nitrogen. The mixture was then treated with propanethiol (1.2 g, 15.4 mmol) and stirred at room temperature for 16 h. The mixture was concentrated in vacuo, and the residue was partitioned between 150 ml CH2Cl2 and 100 ml water. The organic layer was washed with water and brine, dried over MgSO4, filtered, treated with 20 ml 1N HCl/ether, and evaporated to dryness. The residue was triturated with 100 ml hot EtOAc, cooled to room temperature, and filtered to collect the solid. The solid was dried in vacuo to give the product in 81% (5.3 g) yield; mp 149°-150° C.; IR(KBr): C=O 1717 cm-1 ; NMR(DMSOd6TMS): δ0.90 (t, 3H, CH3), 1.02, 1.18 (2m, 2H, SCCCH2), 1.45 (m, 4H, CH2CSCCH2), 2.1 (SCCCCH2), 2.37 (2t, 4H, CH2SCH2), [3.42 (d, 1H), 3.59 (d, 1H), CH2 -Pyr], [6.53 (m, 1H), 7.19 (m, 2H), 7.44 (d, 3H), 7.53 (m, 2H), 7.65 (m, 1H) Ar], 7.10, 8.66 (2d, 4H, 4-Pyr]; mass spec m/e 431 (M+1)-HCl.
Reaction SMILES: ClC1C=CC(C2OC(NC3C4CC(OCC)=CCC=4C=CC=3)=NC=2)=CC=1.C([O:29][C:30]1[CH2:39][C:38]2[C:37]([NH:40][C:41]3[O:42][C:43]([C:46]4[CH:51]=[CH:50][C:49]([N:52]5[CH2:56][CH2:55][CH2:54][CH2:53]5)=[CH:48][CH:47]=4)=[CH:44][N:45]=3)=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:32][CH:31]=1)C.C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[N:52]1([C:49]2[CH:48]=[CH:47][C:46]([C:43]3[O:42][C:41]([NH:40][C:37]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:38]=4[CH2:39][C:30](=[O:29])[CH2:31][CH2:32]5)=[N:45][CH:44]=3)=[CH:51][CH:50]=2)[CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(N5CCCC5)cc4)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(Cl)cc4)o3)c2C1
Product: O=C1CCc2cccc(Nc3ncc(-c4ccc(N5CCCC5)cc4)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 1I, substituting the product of Example 7B for the product of Example 1H.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Br)s1

Procedure:
Following the procedure of Preparation A, 2.07 g (10.0 mmoles) of commercially available 5-bromo-2-thiophenecarboxylic acid was reacted with 10 ml of thionyl chloride to give 2.35 g of crude 5-bromo-2-thiophenecarbonyl chloride as a red oil. The total crude acid chloride was coupled to 1.76 g (8.33 mmoles) of 5-chloro-2,3-dihydro-2-oxo-1H-indole-1-carboxamide by the procedure in Preparation A using 3.05 g (25.0 mmoles) of 4-(N,N-dimethylamino)pyridine and 50 ml of N,N-dimethylformamide. Acidic workup gave a solid which was recrystallized to give 1.77 g (4.43 moles, 53% yield) of title compound as reddish-brown crystals, m.p. 228°-229° C. (tetrahydrofuran).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[C:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)=[CH:6]1)(=O)C.[OH-].[Na+]>OP([O-])(O)=O.[K+].OP(O)(O)=O>[OH:4][C@@H:5]1[CH2:9][C:8](=[O:10])[C:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)=[CH:6]1
Reactant: CC(=O)O[C@H]1C=C(Cc2cccc(OCc3ccccc3)c2)C(=O)C1
Agent: O=P(O)(O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Product: O=C1C[C@@H](O)C=C1Cc1cccc(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 83 %

Procedure:
(R)-3-(3-Benzyloxybenzyl)-4-oxocyclopent-2-enyl acetate (1.8 kg, 5.35 mol) was added to KH2PO4—H3PO4 buffer solution (20 L). The mixture was added Lipase derived from Pseudomonas cepacia and 1N NaOH was slowly added to the solution at room temperature to keep the ph=7˜7.5. After 8 hours, (R)-3-(3-Benzyloxybenzyl)-4-oxocycl opent-2-enyl acetate remained about 10%, The reaction mixture was filtered to remove Lipase and the filtrate was extracted with EtOAc, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the (R)-4-hydroxy-2-(3-benzyloxybenzyl)cyclopent-2-enone as yellow oil: 1.3 kg (yield: 83%, >99% ee by HPLC using a chiral column)
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][N:11]2[C:16](=[O:17])[CH2:15][CH2:14][CH:13]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:27][NH:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([Cl:39])[CH:33]=5)=[O:30])[CH:24]=4)[C:19]3=[O:40])[C:12]2=[O:41])=[O:8])[CH2:3][CH2:2]1.Cl>CCOCC>[ClH:39].[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][N:11]2[C:16](=[O:17])[CH2:15][CH2:14][CH:13]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:27][NH:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([Cl:39])[CH:33]=5)=[O:30])[CH:24]=4)[C:19]3=[O:40])[C:12]2=[O:41])=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)N(COC(=O)C4CCN(C(=O)OC(C)(C)C)CC4)C2=O)C3=O)cc1Cl
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)N(COC(=O)C4CCNCC4)C2=O)C3=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 209.4 %

Procedure:
To 1-tert-butyl 4-(3-(5-((3-(3-chloro-4-methylphenyl)ureido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl piperidine-1,4-dicarboxylate (300 mg, 0.44 mmol, obtained as described in previous example) was added 2 N HCl in Et2O (15 mL). The slurry was vigorously stirred for 2 h at rt. The solid was filtered, washed with copious Et2O, and dried in a vacuum oven overnight to give (3-(5-((3-(3-chloro-4-methylphenyl)ureido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl piperidine-4-carboxylate Hydrochloride as a white solid (285 mg, 105% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 3.26 min (98.2%); mp: 234-236° C.; 1H NMR (DMSO-d6) δ 1.62-1.81 (m, 2H, CHH, CHH), 1.87-2.01 (m, 2H, CHH, CHH), 2.02-2.16 (m, 1H, CHH), 2.16-2.29 (m, 3H, CH3), 2.32-2.47 (m, 1H, CHH), 2.59-2.76 (m, 1H, CHH), 2.77-2.99 (m, 3H, CHH, CHH, CHH), 3.00-3.28 (m, 3H, CHH, CHH, CHH), 4.15-4.66 (m, 4H, CH2, CH2), 5.26 (dd, J=4.9, 13.2 Hz, 1H, CH), 5.55-5.80 (m, 2H, CH2O), 7.02 (t, J=5.9 Hz, 1H, NH), 7.09-7.29 (m, 2H, Ar), 7.45 (d, J=7.9 Hz, 1H, Ar), 7.53 (s, 1H, Ar), 7.62-7.82 (m, 2H, Ar), 8.41-8.96 (m, 2H, NH, NH), 9.09 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.73, 21.46, 24.31, 31.24, 37.30, 42.00, 42.73, 47.20, 52.09, 63.40, 116.31, 117.50, 121.91, 122.99, 126.97, 127.27, 130.09, 130.99, 132.96, 139.69, 142.38, 144.94, 155.21, 167.96, 170.19, 171.29, 172.20; LCMS: MH=582, 584; Anal Calcd for C29H33Cl2N5O6+1.6 H2O+0.6 HCl+0.2 Et2O+0.4 tBuCl: C, 53.35; H, 6.05; N, 9.91; Cl, 13.04. Found: C, 53.13; H, 6.06; N, 9.70; Cl, 13.25.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([N:18]([CH2:20][CH3:21])[OH:19])[CH3:17].[OH-].[Na+]>C1COCC1>[CH:10]1([NH:9][C:8](=[N:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[O:19][N:18]([CH2:20][CH3:21])[CH2:16][CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCN(O)CC
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CC)OC(=NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 50 h
Yield: 89.6 %

Procedure:
To a solution of dicyclohexylcarbodiimide (10.3 g, 50 mmol) and N,N-diethylhydroxylamine (6.7 g, 75 mmol) in THF (30 ml) is added finely powdered NaOH (0.2 g) and the mixture is stirred at room temperature for 50 hours. The reaction mixture is then filtered and the filtrate is evaporated on the rotary evaporator below 45° C. to afford 13.24 g of the title compound as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([Sn](C)(C)C)=[CH:16][CH:15]=1.O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: Brc1ccccc1-c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccccc2-c2nccs2)cc1
Temperature: 150 °C
Yield: 30.8 %

Procedure:
A solution of 1.18 g (4.92 mmol) of 1-bromo-2-(thiazol-2-yl)benzene and 1.67 g (6.55 mmol) of 4-metylphenyltrimethylstannane in 20 mL of dimethylformamide was treated with 621 mg of bis(triphenylphosphine)palladium(II) chloride. The reaction mixture was heated at 150° C. for 6 hours, cooled and poured into 300 mL of water. The resultant mixture was extracted with ether (3×100 mL). The combined ether extracts were washed with water (4×), dried over magnesium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel, eluting with hexane/ether (100:10) to give 381 mg of the product. EI-MS: calculated for C16H13NS 251; found 250. 1H NMR (200 MHz, CDCl3): 2.36 (s, 3H), 7.14 (s, 4H), 7.24 (d, 1H), 7.40 (m, 1H), 7.42 (m, 2H), 7.73 (d, 1H), 8.20 (dt, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:12])([F:11])[C:8]([OH:10])=[O:9].[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16].[NH:20]1[CH2:23][CH:22]([C:24]2[C:25]([O:44][CH3:45])=[C:26]([CH:32]([NH:34][C:35]3[N:43]=[CH:42][N:41]=[C:40]4[C:36]=3[N:37]=[CH:38][NH:39]4)[CH3:33])[CH:27]=[C:28]([Cl:31])[C:29]=2[CH3:30])[CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:6][C:7]([F:12])([F:11])[C:8]([OH:10])=[O:9].[Cl:31][C:28]1[C:29]([CH3:30])=[C:24]([CH:22]2[CH2:21][N:20]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:23]2)[C:25]([O:44][CH3:45])=[C:26]([CH:32]([NH:34][C:35]2[N:43]=[CH:42][N:41]=[C:40]3[C:36]=2[N:37]=[CH:38][NH:39]3)[CH3:33])[CH:27]=1.[C:15]([OH:17])([C:14]([F:19])([F:18])[F:13])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CNC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (1.6 μL, 0.021 mmol) was added to a solution of N-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine bis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA (0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0° C. and then the reaction was stirred at room temperature for 30 minutes. The crude mixture was purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C19H24ClN6O3S (M+H)+: m/z=451.1. found: 451.0. 1H NMR (300 MHz, DMSO-d6) δ 8.22 (1H, brs), 8.15 (2H, m), 7.48 (1H, s), 5.67 (1H, m), 4.21 (3H, m), 4.05 (1H, m), 3.96 (1H, m), 3.76 (3H, s), 2.96 (3H, s), 2.10 (3H, s), 1.45 (3H, d, J=6.9 Hz) ppm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN1CCCC1=O.[CH:22]([NH2:25])([CH3:24])[CH3:23]>O>[CH:22]([NH:25][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)N
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a mixture of 5.23 g of 4-fluoro-3-nitro-benzo trifluoride and 25 ml of N-methylpyrrolidone was added 3.69 g of isopropylamine under ice cool, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water, the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure to obtain 5.90 g of N-isopropyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.N1C=CC=CC=1.[CH2:15]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([O:29][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:38][CH:37]=1
Reactant: NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a 0° C. solution of 0.674 g 2-(aminomethyl)pyridine, 20 ml methylene chloride and 1.83 ml pyridine is added, dropwise over 20 minutes, 2.0 g of product from Example 3 dissolved in 25 ml of methylene chloride. The reaction is stirred at 0° C. for 2 hours followed by stirring at room temperature for 17 hours. The reaction mixture is partitioned between chloroform and saturated sodium bicarbonate, washed with water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:75% ethyl acetate/hexane) to give 1.51 g of the desired product.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([NH2:12])=[C:7]([CH3:13])[CH:6]=1.[CH2:15]([S:17](Cl)(=[O:19])=[O:18])[CH3:16]>N1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([NH:12][S:17]([CH2:15][CH3:16])(=[O:19])=[O:18])=[C:7]([CH3:13])[CH:6]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CNC(=O)Oc1cc(C)c(N)c(C)c1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1c(C)cc(OC(=O)NC)cc1C
Temperature: 42 °C
Reaction time: 0.33 h

Procedure:
3,5-Dimethyl-4-aminophenyl N-methylcarbamate (1.0g., 0.0052 mole), prepared according to the general directions of A. T. Shulgin, U.S. Pat. No. 3,084,098 was dissolved in 5 ml. of pyridine. To this solution was added ethanesulfonyl chloride (0.68g., and 0.0053 mole) and after being stirred for about 20 minutes the reaction solution was warmed briefly at 42° C. Quenching the reaction solution in excess water yielded brown solids which upon being recrystallized from ethanol/water melted at 171°-73° C. (0.85g.).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].C(=O)([O-])[O-].[K+].[K+]>>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:13][CH2:12][CH2:11][NH2:14])[CH:7]=1)[CH3:10]
Reactant: NCCN
Reactant: CCOc1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccnc(NCCN)c1
Temperature: 140 °C
Yield: 64 %

Procedure:
A mixture of 2-bromo-4-ethoxypyridine (500 mg, 2.475 mmol), ethane-1,2-diamine (9.9 ml, 150 mmol) and potassium carbonate (685 mg, 4.95 mmol) was stirred under microwave heating at 140° C. for 2 hours. The reaction mixture was filtered, the remaining solids were rinsed with ethanol and the combined filtrates were concentrated under reduced pressure and purified by flash column chromatography (silica, gradient of 2%-100% 7N NH3 in MEOH in DCM) to yield 287 mg of a solid (1.584 mmol, 64%). MS(ESI) m/z=182.0 [M+1]+.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C([Li])CCC.[CH3:15][C:16]1[CH:20]([Si:21](Cl)([CH3:23])[CH3:22])[C:19]([CH3:25])=[C:18]([CH3:26])[C:17]=1[CH3:27]>C(OCC)C>[CH2:1]([N:5]([C:20]1([SiH:21]([CH3:23])[CH3:22])[C:19]([CH3:25])=[C:18]([CH3:26])[C:17]([CH3:27])=[C:16]1[CH3:15])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Reactant: CCCCNCCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCN(CCCC)C1([SiH](C)C)C(C)=C(C)C(C)=C1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
A 250 ml roundboftom flask equipped with a condenser, stirrer, thermometer and dropping funnel with nitrogen inlet was charged with 50 ml diethyl ether in which di-n-butylamine (3.8 g, 27 mmol) was dissolved. The solution was cooled to 0° C. and n-butyllithium (26 mmol, 1.6 M in hexane) was added; the solution was stirred for 2 hours at 2° C. and 30 minutes ar room temperature. The solution was then cooled to -90° C. and tetramethylcyclopentadienyl-dimethylsilylchloride (5.7 g, 27 mmol) was added in one portion. The mixture was then stirred for 16 hours allowing the temperature of the reaction mixture to rise to room temperature. A precipitate was filtered off and the solvent was evaporated. The remaining residue was distilled at sub-atmospheric pressure (2.7 mbar) at 130° C. to obtain di-n-butylamino-dimethylsilyl-tetramethylcyclopentadiene (3.4 g). The product was characterized by GC, GC-MS, 13C and 1H NMR.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1
Reactant: Clc1ncccn1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ncccn2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (46 mg, 1.142 mmol, 60% dispersion in mineral oil) in DMF (1.1 mL) was added methyl 1H-indole-3-carboxylate (200 mg, 1.142 mmol) and 2-chloropyrimidine (131 mg, 1.142 mmol). The resulting suspension was stirred at RT for 1 h. The reaction mixture was diluted with DMF, filtered, and purified by HPLC to afford the title compound as a white-pink solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]1([C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:20]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)C(=O)c1csc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)n1

Procedure:
The title compound was prepared from ethyl (2-amino-4-thiazolyl)glyoxylate and 4-phenylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (28.2 mg) with purity >80%. LCMS (pos) m/z 417.0.