Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](Cl)[C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][N:37]([CH3:43])[CH2:38][CH2:39][CH2:40][NH:41][CH3:42]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:41]([CH2:40][CH2:39][CH2:38][N:37]([CH3:43])[CH3:36])[CH3:42])[C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: CNCCCN(C)C
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(N(C)CCCN(C)C)c1[N+](=O)[O-]

Procedure:
In an analogous procedure to that described in the fifth paragraph of the portion of Note a) which is concerned with the preparation of starting materials, N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3-chloro-2-nitrobenzamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 1.44-1.58 (m, 2H), 2.06 (s, 6H), 2.15 (t, 2H), 2.21 (s, 3H), 2.69 (s, 3H), 3.02 (t, 2H), 3.48-3.53 (m, 4H) 3.69-3.73 (m, 4H), 7.1 (d, 1H) 7.19-7.25 (m, 2H), 7.44-7.62 (m, 3H), 7.74-7.64 (m, 1H), 7.94 (d, 1H), 8.26 (d, 1H), 10.13 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H+ 576.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[O:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C)o1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(CBr)oc1C
Temperature: 76 °C
Reaction time: 3 h
Yield: 7.8 %

Procedure:
A mixture of 2,4,5-trimethyloxazole (0.50 mL, 4.3 mmol), N-bromosuccinimide (0.77 g, 4.3 mmol) and benzoyl peroxide (0.21 g, 0.86 mmol) in carbon tetrachloride (4 mL) was heated at 76° C. under nitrogen atm. for 3 hrs. After cooling to rt, the solid was removed by filtration. The filtrate solution was washed with saturated aqueous NaHCO3 (20 mL) and concentrated. The residue was purified by flash column chromatography (SiO2; hexanes:ethyl acetate/4:1) to afford 2-(bromomethyl)-4,5-dimethyloxazole (64 mg) as an yellow oil.
Reaction SMILES: C(OCC([NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:14]=1[NH:25][C:26](=O)[CH2:27][O:28]CC1C=CC=CC=1)=O)C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.N>C1(C)C(C)=CC=CC=1>[OH:28][CH2:27][C:26]1[NH:25][C:14]2[C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[N:12]=1
Reactant: COc1cc(NC(=O)COCc2ccccc2)c(NC(=O)COCc2ccccc2)c(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CO
Product: COc1cc2nc(CO)[nH]c2c(OC)c1OC
Reaction time: 3 h

Procedure:
1,2-Di(benzyloxyacetamido)-3,4,5-trimethoxybenzene (1.9 g) was dissolved in xylene (30 mL), p-toluenesulfonic acid monohydrate (2.0 g) was added to the solution, and the mixture was stirred for 3 hours under reflux. After cooling, methanol saturated with ammonia was added to the reaction mixture into a uniform solution. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=15:1 to 10:1) to obtain the title compound.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([CH3:19])[CH:15]=[C:14]([OH:20])[CH:13]=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:27][CH2:28][CH2:29]Br>C(#N)C.O>[Br:27][CH2:28][CH2:29][O:20][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[NH:11]2)=[C:16]([CH3:19])[CH:15]=1
Reactant: BrCCBr
Reactant: Cc1cc(O)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(OCCBr)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 20.5 %

Procedure:
To a stirred solution of N-cyclohexyl-6-hydroxy-4-methyl-1H-indole-2-carboxamide (I-9A-b: 0.7 g, 2.57 mmol) in acetonitrile (20 mL) was added Cs2CO3 (1.67 g, 5.14 mmol) cooled to 0° C. followed by 1,2-dibromoethane (1.1 mL, 12.86 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 h, diluted with water (20 mL) and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient of 50% ethyl acetate in petroleum ether as eluent to afford 200 mg (21%) of 6-(2-bromoethoxy)-N-cyclohexyl-4-methyl-1H-indole-2-carboxamide (I-9A-c) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1>C(O)CCC>[Cl:9][C:10]1[N:11]=[CH:12][N:13]=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=2)[CH:15]=1
Reactant: Nc1cccc(N)n1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Cl)ncn2)n1
Temperature: 100 °C
Yield: 32.7 %

Procedure:
A mixture of 2,6-diaminopyridine (1.530 g, 14.020 mmol) and 4,6-dichloropyrimidine (2.610 g, 17.519 mmol) in 15 mL of n-butanol in a sealed vial was heated at 100° C. for 72 h. The dark brown sample was cooled and was concentrated at reduced pressure to remove most of the n-butanol. The residue was then partitioned between EtOAc and saturated. NaHCO3 solution. An emulsion formed, the sample was filtered through a pad of Celite and the layers were separated. The organic extract was washed with sat. KH2PO4 and brine solutions, dried (MgSO4), filtered and concentrated to brown oily-solid. The sample was suspended into ˜50 mL of CH2Cl2, cooled and filtered to give 1.017 g (36%) of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine as yellow-orange solid. MS: m/z 222/224 (M+1, 100/63%). To a solution of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine (100 mg, 0.45 mmol) in DMF (1 mL) was added 3-methylphenol (88 mg, 0.8 mmol) and anhydrous K2CO3 (93 mg, 0.6 mmol). The reaction mixture was heated at 145° C. for 16 h. It was then cooled and DMF was removed under reduced pressure to get a yellow gummy residue. The residue was taken in EtOAc (20 mL), was washed sequentially with water (5 mL) and brine (5 mL) and was dried over Na2SO4. Filtration followed by concentration under reduced pressure afforded a yellow gum which was further purified by column chromatography (SiO2, 60-120, EtOAc/hexane, 5/5) to give 100 mg of 2-[6-(3-methylphenoxy)-pyrimidin-4-yl]amino-6-aminopyridine (IR-12) as a pale yellow solid. MS: m/z 294 (M+H)
Reaction SMILES: [C:1]1([NH:7]C(N)=S)C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=S)=[C:14]([OH:29])[C:13]=1[S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31].[Si](Cl)(C(C)(C)C)(C)C.[NH:44]1C=CN=C1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([C:1]#[N:7])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[NH:44])=[C:14]([OH:29])[C:13]=1[S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2Cl)c1O
Reactant: NC(=S)Nc1ccccc1
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[Si](C)(C)Cl
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N(C#N)C(=N)Nc2ccccc2Cl)c1O
Yield: 49 %

Procedure:
Following the general procedure for protected phenyl thiourea formation outlined in example 12, N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-chlorophenyl)thiourea (500 mg, 1.19 mmol), tert-butyldimethylsilyl chloride (897 mg, 5.95 mmol) and imidazole (162 mg, 2.38 mmol) were reacted to form the desired product (311 mg, 49%). EI-MS m/z 535.32 (M+).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl>CO.O>[NH:23]1[CH2:24][CH2:25][CH2:26][C@@H:21]([NH:20][C:19]2[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=4)(=[O:3])=[O:2])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:22]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CCCNC4)ncnc32)cc1
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of (R)-tert-butyl 3-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (20 g, 42.5 mmol) in MeOH (100 mL) was added conc. HCl (100 mL) at 0° C. and the reaction mixture was stirred for 1.5 h. The solvent was removed in vacuo to give a residue which was dissolved in water (50 mL). The aqueous phase was washed with ether and the aqueous phase was adjusted to a pH 10. The aqueous layer was then extracted with EtOAc (3×30 mL), combined, dried (Na2SO4) and concentrated in vacuo to give the titled compound (15 g, 95%). 1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H), 8.03 (d, J=8.8 Hz, 2H), 7.42 (d, J=3.6 Hz, 1H), 7.28 (d, J=m 8.8 Hz, 2H), 6.77 (d, J=3.6 Hz, 1H), 6.43 (bs, 1H), 4.51 (bs, 1H), 3.18-3.09 (m, 3H), 2.95-2.84 (m, 2H), 2.37 (s, 3H), 1.95-1.88 (m, 2H), 1.81-1.78 (m, 1H), 1.66-1.63 (m, 1H). LCMS [M+1]: 372.
Reaction SMILES: [OH2:1].[C:2]1([P:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)Cl)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:18]=1[CH:19]=[O:20].C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[OH:20][CH:19]([P:8](=[O:1])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]1[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:17]=1[CH3:16]
Reactant: Cc1cc(C)c(C=O)c(C)c1
Reactant: O
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C(O)P(=O)(c2ccccc2)c2ccccc2)c(C)c1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a mixture of 9 g (0.5 mol) of water and 200 mL of toluene there were added 110 g (0.5 mol) of diphenyl chlorophosphine in 200 mL of toluene. The reaction mixture was extracted with 90 mL of 20 wt % strength caustic soda solution following a period of 1 h, and to the the organic phase of there were added 74 g (0.5 mol) of 2,4,6-trimethylbenzaldehyde and also 0.5 g of 30% strength sodium methylate solution in methanol. The product began to crystallize after 10 minutes, after which it was isolated in the usual manner. Yield 95%, top: 152°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH2:20])=[O:19])[CH2:13][CH2:12]1.CO.CN(C)C=O>[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH2:20])=[O:19])[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: NC(=O)CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)CN1CCN(c2ccc(N)cc2F)CC1
Yield: 97.1 %

Procedure:
2-[4-(2-Fluoro-4-nitro-phenyl)-piperazin-1-yl]-acetamide (0.558 g, 0.00198 mol) was combined with Methanol (60 mL, 1 mol) and N,N-Dimethylformamide (10 mL, 0.1 mol). The solution was passed through a 10% Pd/C CatCart (55×4 mm) in an H-cube hydrogenator at 10 bar, 30° C. for 3.5 hours. The reaction was concentrated to yield a yellow solid, 2-[4-(4-Amino-2-fluoro-phenyl)-piperazin-1-yl]-acetamide (485 mg, 97%). LCMS: m/z=253.06 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, 2H), 6.76 (m, 1H), 6.31 (m, 2H), 4.97 (br s, 2H), 2.87 (m, 6H), 2.52 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH3:11])[C:5]#[N:6].[NH2:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=2[N:17]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:11][N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[C:27]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:26])([F:24])[F:25])[CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CNc1ccc(C#N)cc1N
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: ClCCCl
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C#N)ccc21
Yield: 72.9 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonitrile (2.12 g) was prepared by following General Procedure D starting from 3-amino-4-methylamino-benzonitrile (1.1 g), 2-amino-6-(trifluoromethoxy)-benzothiazole (1.75 g), 1,1′-thiocarbonyldiimidazole (1.78 g), and EDC (1.9 g). LC/MS: m/z 391. 1H NMR (DMSO-d6, 400 MHz): δ 7.97 (s, 1H), 7.89 (s, 1H), 7.78 (br, 1H), 7.60 (d, 2H), 7.55 (br, 1H), 7.39 (d, 1H), and 3.72 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH:12]2[CH2:18][OH:19].C(N(CC)CC)C>ClCCl>[CH:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH:12]2[CH:18]=[O:19]
Reactant: OCC1CC2CCC1C2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC1CC2CCC1C2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 103.1 %

Procedure:
In a flask under argon was placed dichloromethane (25 mL) and to this was added a 2M solution of oxalyl chloride in dichloromethane (4.0 mL, 8.0 mmol). The mixture was then cooled to −78° C. and then slowly treated with dimethyl sulfoxide (846 μL, 11.92 mmol) and gas evolution occurred. The mixture was stirred at −78° C. for 20 min. After this time, a solution of bicyclo[2.2.1]hept-2-yl-methanol (505 mg, 4.0 mmol) in dichloromethane (15 mL) was added dropwise. The mixture was stirred at −78° C. for another 15 min and then triethylamine (2.2 mL, 15.6 mmol) was added and the reaction was slowly warmed to 0° C. The mixture was then quenched with a 1M aqueous sodium bisulfate solution (50 mL) and extracted with dichloromethane (3×20 mL). The organic layers were combined and dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (12 g column, 3% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded slightly impure bicyclo[2.2.1]heptane-2-carbaldehyde (512 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:4].N[CH:20]([CH3:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(#[N:32])C>>[CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH:13]([NH2:32])[CH:14]([OH:16])[CH2:15][CH:20]([CH3:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(N)CCc1ccccc1
Reactant: CC#N
Reactant: COC(=O)NC=Cc1ccc(OCC2CO2)cc1
Product: COC(=O)NC=Cc1ccc(OC(N)C(O)CC(C)CCc2ccccc2)cc1
Reaction time: 20 h

Procedure:
2.49 g (0.01 mol) of 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane are dissolved in 25 ml of acetonitrile and added dropwise to a boiling stirred solution of 1.42 g (0.0095 mol) of 3-amino-1-phenylbutane in 20 ml of acetonitrile. The mixture is stirred for 20 hours under reflux, the solvent is removed by distillation under reduced pressure and the oil which remains is partitioned between 120 ml of 0.1 N hydrochloric acid and 100 ml of ethyl acetate. The hydrochloric acid extract is separated off, rendered alkaline with sodium carbonate and extracted four times with 50 ml of ethyl acetate at a time. The organic phases are dried over sodium sulphate and evaporated in vacuo. The resulting oil yields 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-(1-methyl-3-phenyl-propyl)-amino propane of melting point 126°-127° C., from ethyl acetate.
Reaction SMILES: [C:1]([N:8](C)[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH2:36][CH3:37])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.[NH2:42][C:43]1[N:48]=[CH:47][C:46](Br)=[CH:45][N:44]=1>>[ClH:27].[ClH:27].[NH2:42][C:43]1[N:48]=[CH:47][C:46]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][CH3:37])=[C:29]([CH:30]=2)[CH2:28][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([NH:8][CH3:1])[CH2:14][CH2:13]2)[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])=[CH:45][N:44]=1
Reactant: CCOc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Nc1ncc(Br)cn1
Product: CCOc1ccc(-c2cnc(N)nc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(NC)CC1
Product: Cl

Procedure:
The title compound is prepared from boronic acid 12 (25 mg, 42 μmol) and 2-amino-5-bromopyrimidine (6.0 mg, 35 μmol) in accordance with Method L2.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=O)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.C[O-].[Na+].Cl.[CH3:19][N:20]([CH3:33])[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=1>CO.O>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](/[CH:13]=[CH:31]/[C:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][N:20]([CH3:19])[CH3:33])=[CH:25][CH:26]=3)=[O:32])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)c1ccc(OCCN(C)C)cc1
Reactant: CON=C1CCc2cc(C=O)ccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CON=C1CCc2cc(/C=C/C(=O)c3ccc(OCCN(C)C)cc3)ccc21
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A solution of the product of Example 1 Step 2 (1.06 g, 5.6 mmol), sodium methoxide (0.750 g, 13.9 mmol) and 1-[4-(2-dimethylaminoethoxy) phenyl]ethanone hydrochloride (1.36 g, 5.6 mmol) (J. H. Short et al., J. Med. Chem. 1965, 8, 223) in methanol (30 ml) and water (1 ml) was heated under reflux for 5 hours. After cooling to room temperature the solid was collected, washed with cold methanol and diethyl ether and dried to give the title compound (1.74 g, 83%); MS(ES+) m/e 378 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Na+].Br[C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[CH2:23][CH:24]4[NH:28][CH:27]([C:16]=3[C:15]=2[C:14]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]4>>[CH3:1][C:2]1[CH:3]=[C:4]([S:8]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(S(=O)[O-])c1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cc1cccc(S(=O)(=O)c2ccc3c(c2C(=O)OC(C)(C)C)c2c(n3C)CC3CCC2N3)c1
Yield: 50 %

Procedure:
Intermediate 10 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude product was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(3-methylphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (130 mg, 50%) as light yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.19 (s, 1H), 7.72-7.78 (m, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.27-7.35 (m, 3H), 5.26 (br s, 1H), 4.72 (br s, 1H), 3.60 (s, 3H), 3.35 (br s, 1H), 2.49 (d, J=15.8 Hz, 1H), 2.38 (s, 3H), 2.13-2.36 (m, 3H), 1.89-2.01 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1B(O)O>>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:19]=1[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Reactant: Nc1nc2cccc(Br)n2n1
Product: COc1ccc(C(F)(F)F)cc1-c1cccc2nc(N)nn12

Procedure:
5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl-amine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl-amine (0.5 g, 2.3 mmol), and 2-methoxy-5-trifluoromethylbenzeneboronic acid (0.76 g, 3.4 mmol) in a manner analogous to Example 2c. Product was isolated as a foam (0.63 g, 87%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.79-7.73 (m, 2H), 7.49-7.44 (m, 2H), 7.15 (d, J=8.9 Hz, 1H), 6.85 (t, J=4.2 Hz, 1H), 4.45 (brs, 2H), 3.85 (s, 3H). MS=309 (MH)+. 239b) To a stirred solution of 5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl-amine (0.076 g, 0.25 mmol) in acetonitrile (5 mL, 100 mmol), was added acetic anhydride (0.015 g, 0.15 mmol), at 0° C. along with pyridine (0.02 mL, 0.2 mmol). The reaction was stirred at RT for one hour. White solid was formed that was taken up in dichloromethane and washed with 1N Hydrochloric acid and brine. Organic layer was dried over sodium sulfate and was purified via chromatography utilizing an ISCO automated purification apparatus (silica gel 40 g 5%→100% ethyl acetate in hexane). Product was isolated as a solid (0.043 g, 84%). MP=260-262° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.83-7.77 (m, 2H), 7.72 (d, J=8.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 3.87 (s, 3H), 1.6 (s, 3H). MS=351 (MH)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:17][CH2:18][O:19][CH3:20])[C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:17][CH2:18][O:19][CH3:20])=[O:16]
Reactant: [H][H]
Reactant: COCCN(CCOC)C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCN(CCOC)C(=O)c1cccc(N)c1
Yield: 98.5 %

Procedure:
A mixture of N,N-bis(2-methoxyethyl)-3-nitrobenzamide (4.11 g) and palladium on charcoal (411 mg) in ethyl acetate (41 ml) was hydrogenated under 1 atmospheric pressure of hydrogen for 1 hour at ambient temperature. The catalyst was removed by filtration and washed with ethyl acetate, and the volatiles were removed in vacuo. The residue was purified with column chromatography eluting with dichloromethane-methanol to give 3-amino-N,N-bis(2-methoxyethyl)benzamide (3.62 g) as an oil.
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([NH:25][CH:26]4[CH2:28][CH2:27]4)=[O:24])[CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:29][N:30](C)[C:31](=O)OC(C)(C)C)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=3)[O:21][CH2:22][C:23]([NH:25][CH:26]3[CH2:27][CH2:28]3)=[O:24])(=[O:13])=[O:14])[CH:10]=[C:9]([CH2:29][NH:30][CH3:31])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN(Cc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(OCC(=O)NC3CC3)c2)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(OCC(=O)NC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl ((5-(cyclohex-1-en-1-yl)-1-((3-(2-(cyclopropylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 7e (97 mg, 0.22 mmol) was dissolved in 8 mL of dichloromethane, and the reaction solution was cooled in an ice bath, followed by dropwise addition of 2 mL of trifluoroacetic acid. After removing the ice bath, the reaction solution was stirred at room temperature for 2 h. A saturated sodium bicarbonate solution was added dropwise until the pH of the reaction solution was 7 to 8, and then it was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography with elution system A to obtain the title product 2-(3-((2-(cyclohex-1-en-1-yl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N-cyclopropylacetamide 7 (67 mg, a light yellow oil) in 85% yield.