Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)=[C:4]([F:14])[CH:3]=1.O=S(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]2[C:5]([CH2:9][CH2:10][C:11]2=[O:13])=[C:4]([F:14])[CH:3]=1
Reactant: Cc1cc(CCC(=O)O)c(F)cc1Br
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(Br)cc(F)c2c1C(=O)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-bromo-2-fluoro-5-methylphenyl)propanoic acid (EP1795524 A1; 8.4 g) in DCM (200 mL) was added SOCl2 (19.1 g) dropwise at r.t. The mixture was stirred for 2 hours at r.t. The solvent was removed under reduced pressure. AlCl3 (21.4 g) was added to the residue. The brown slurry was heated to 130° C. for 1.5 hours and then cooled to r.t. The residue was dissolved in EA (300 mL) and then washed with water and brine. The organic phase was dried over Na2SO4. The residue obtained after filtration and evaporation was purified by SGC (PE/EA 400:1) to provide the title compound. MS ESI+: m/z=243 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[CH3:49][NH2:50]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][NH:50][CH3:49])=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2ccccc2)cc1
Solvent: C1CCOC1
Product: CNCCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.476 g, 0.777 mmol) in 2.0 M methylamine in THF (8.0 mL, 16 mmol) was stirred at 70° C. in a sealed tube for 3 hours. After cooling to ambient temperature and concentrating, the residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80° C. in vacuo for 20 minutes gave {2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-methyl-amine as a clear, dark yellow gum (0.324 g, 88.5%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried at 81° C. in vacuo for 13 hours. The hydrochloride as a light orange foam (0.330 g) resulted; Mass Spectrum (+EI, [M+H]+) m/z 472. 1HNMR (500 MHz, DMSO-d6): δ8.86 (s, 2H), 8.74-8.77 (m, 1H), 8.54-8.56 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.79 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.58-7.65 (m, 2H), 7.27 (d, 1H, J=3.30 Hz), 7.09-7.18 (m, 6H), 5.70 (s, 2H), 4.24-4.27 (m, 2H), 2.59 ppm (s, 3H). Elemental Analysis for C27H25N3O3S2.1.00 HCl.0.55 mol H2O: Calcd: C, 62.61; H, 5.27; N, 8.11; Found: C, 62.23; H, 5.45; N, 7.72.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:11][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]2=[CH:10][CH:9]=1
Reactant: Cc1nccn2cccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1nccn2c(Br)ccc12
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
5.0 g of 1-methylpyrrolo[1,2-a]pyrazine prepared in Preparation Example 2 was dissolved in 60 ml of chloroform; and 6.7 g of N-bromosuccinimide was added thereto at 0° C. The reaction mixture was stirred for 30 minutes at the same temperature; and the resulting solution was concentrated. The residue was chromatographed over silica gel to obtain 6.3 g of title compound (yield: 80%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[C:14]([Cl:27])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:27][C:14]1[CH:13]=[N:12][C:11]2[NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:5]=3)[CH2:3][CH2:2][O:26][C:22]3[CH:21]=[C:20]([CH2:19][CH2:18][NH:17][C:15]=1[N:16]=2)[CH:25]=[CH:24][CH:23]=3
Reactant: Oc1cccc(CCNc2nc(Nc3cccc(CCBr)c3)ncc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cnc2nc1NCCc1cccc(c1)OCCc1cccc(c1)N2
Yield: 20.7 %

Procedure:
To a solution of 3-{2-[(2-{[3-(2-bromoethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]ethyl}phenol (50.0 mg, 0.112 mmol) in tetrahydrofuran (1.09 mL) was added a solution of sodium hydroxide in water (0.893 mL, 0.50 M). The resultant solution was stirred at rt for 2 days until the reaction was complete. The reaction was neutralized with HCl (3 M, aqueous solution) to pH 7. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude, which was purified by silica gel column chromatography to give the desired product as a white powder (8.5 mg, 21%). LCMS for C20H20ClN4O (M+H)+: m/z=367.0. 1H NMR (400 MHz, CD3OD): δ 7.81 (s, 1H), 7.70 (s, 1H), 7.57 (m, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.08 (m, 2H), 6.69 (s, 1H), 6.67 (m, 2H), 5.73 (dd, J=6.8, 0.8 Hz, 2H), 5.14 (dd, J=7.2, 1.2 Hz, 2H), 3.72 (t, J=7.6 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.CCN(CC)CC.Cl[C:24]1[C:25]2[C:30]([N:31]=[C:32]3[C:37]=1[CH:36]=[CH:35][CH:34]=[CH:33]3)=[CH:29][CH:28]=[CH:27][CH:26]=2>CO>[CH:26]1[C:25]2[C:30](=[N:31][C:32]3[C:37]([C:24]=2[NH:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:15][CH:14]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[CH:28][CH:27]=1
Reactant: Clc1c2ccccc2nc2ccccc12
Reactant: Nc1ccc(CCCCCCCO)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: OCCCCCCCc1ccc(Nc2c3ccccc3nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 91.4 %

Procedure:
To a solution of 636.9 mg (3.07 mmol) of 4-(7-hydroxyheptyl)-aniline 30 and 428 μL (3.07 mmol) of Et3N in 20 mL of MeOH were added 656.4 mg (3.07 mmol) of 9-chloroacridine. After stirring for 7 hr at room temperature, the solvent was evaporated. Purification by column chromatography on silica gel with 5% MeOH in CH2Cl2 gave 1.079 g (91%) of N-(9-acridinyl)-4-(7-hydroxyheptyl)-aniline 31: 1H NMR (300 MHz, CDCl3, TMS) δ 8.0-7.9 (m, 4H), 7.63 (t, J=7 Hz, 2H), 7.3-7.2 (m, 2H), 7.07 (d, J=8.3 Hz, 2H), 6.85 (d, J=8.3 Hz, 2H), 3.64 (t, J=6.6 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 1.7-1.5 (m, 4H), 1.4-1.3 (m, 6H).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[O-:2].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O+]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:30]([C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].NC1C=CC=CC=1>C(O)C>[S:1](=[O:3])(=[O:2])([OH:5])[O-:4].[CH2:30]([C:44]1[CH:45]=[CH:46][C:47]([N+:48]2[C:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:14]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:49][CH:50]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Reactant: CCCCCCCCCCCCCCc1ccc(N)cc1
Agent: O=S(=O)([O-])O
Solvent: Nc1ccccc1
Solvent: CCO
Product: CCCCCCCCCCCCCCc1ccc(-[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)cc1
Temperature: 90 °C
Yield: 21 %

Procedure:
In a 500-ml round-bottom flask is placed 2.03 g (0.005 mole) of 2,4,6-triphenylpyrylium bisulfate. To this is added 150 ml of ethanol followed by 2.90 g (0.01 mole) of p-tetradecylaniline. This mixture is heated at 90° C. for about 8 hours and then allowed to cool. Upon cooling some of the starting aniline separates and is removed by filtration. The ethanol is then removed to give a yellow waxy substance which is rinsed with ether to remove any excess pyrylium. The resulting product is then dissolved in acetonitrile to remove any aniline still present. The acetonitrile is then stripped and the product is rinsed a final time with ether. The final product is a yellow crystal which turns a pale yellow color upon grinding. The yield is 0.71 g (0.00105 mole) of N-(p-tetradecylphenyl)-2,4,6-triphenylpyridinium bisulfate (yield 21 percent).
Reaction SMILES: [CH2:1]([C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9]C)=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4].C1(C(CCC)(CCC)C(OC)=O)C=CC=CC=1>>[CH2:1]([C:6]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[C:7]([OH:9])=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)C(CCC(C)C)(CCC(C)C)c1ccccc1
Agent: CCCC(CCC)(C(=O)OC)c1ccccc1
Product: CC(C)CCC(CCC(C)C)(C(=O)O)c1ccccc1

Procedure:
The title compound was prepared following the procedure of Example 1C, substituting the product of Example 6B for the product of Example 1B. 1H NMR (300 MHz, CDCl3): δ 7.28 (m, 5 H), 2.01 (m, 4 H), 1.49 (m, 2 H), 0.98 (m, 4 H), 0.87 (m, 12 H).
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:17])=[CH:12][C:13]([Cl:16])=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[C:3]([C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([CH3:18])[CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:17])=[CH:12][C:13]([Cl:16])=[C:14]([Cl:15])[C:8]2=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (150 mg, described in Example 39) and 4-trifluoromethylthiobenzoyl chloride (0.1 mL), the title compound was isolated as a white solid (200 mg, 80%). Rf=0.55 (1:1 EA/heptane). MS (ES): M/Z [M+H]=508. NMR: (400 MHz, DMSO-d6): 1.76 (s, 3H), 5.45 (d, J=13.3 Hz, 1H), 5.61 (d, J=13.3 Hz, 1H), 7.83-7.92 (m, 4H), 7.94 (s, 1H) and 8.91 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: FC(F)(F)Oc1ccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401 (c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 4-(trifluoromethoxy)phenylboronic acid (Lancaster Synthesis Ltd.) (51 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (4:1 hexane:EtOAc), the title compound as an orange glass. MS (ESI, pos. ion) m/z: 389 (M+1).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15](=[O:28])[O:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[C:19]([O:24][C:25](=[O:27])[CH3:26])[CH:18]=2)=O)(C)(C)C.[ClH:29]>C(O)C>[ClH:29].[C:25]([O:24][C:19]1[CH:18]=[C:17]2[C:22]([CH:23]=[C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])[C:15](=[O:28])[O:16]2)=[CH:21][CH:20]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1ccc2cc(NCCCCNC(=O)OC(C)(C)C)c(=O)oc2c1
Agent: Cl
Solvent: CCO
Product: CC(=O)Oc1ccc2cc(NCCCCN)c(=O)oc2c1
Reaction time: 1 h

Procedure:
A mixture of 19.85 g of the product of Step B in 200 ml of ethanol and 38.1 ml of ethanolic 2N hydrogen chloride was refluxed with stirring for one hour and was then evaporated to dryness to obtain 18.67 g of raw product melting at 90° C. The product was crystallized from a refluxing mixture of 95-5 acetonitrile and water and was vacuum filtered. The product was empasted with isopropyl ether to obtain 8.44 g of the desired product melting at 160° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][CH3:12])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: CCc1cc(Br)cc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: CCc1cc(Br)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 10 h
Yield: 92 %

Procedure:
The compound 3-bromo-5-ethylbenzoic acid (0.95 g, 4.14 mmol) was dissolved in MeOH (50 mL), reaction mixture was cooled to 0° C. and SOCl2 (0.5 mL) was added. The reaction mixture was allowed to stir at room temperature for 10 h. The reaction mixture was concentrated under reduced pressure and diluted with CH2Cl2. The organic layer was washed with 10% NaHCO3 solution, water and brine. The organic phase was dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. Methyl 3-bromo-5-ethylbenzoate (0.92 g, yield 92%) was isolated as colorless liquid and carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 7.99 (t, J=1.6 Hz, 1H), 7.81 (d, J=1.4 Hz, 1H), 7.54 (t, J=1.6 Hz, 1H), 3.92 (s, 3H), 2.69 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:17])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[OH:17][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:18])=[CH:5][CH:6]=2)[CH2:15][CH2:14][CH:13]([N:19]2[CH2:22][CH:21]([NH:23][C:24](=[O:25])[CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=3)[CH2:20]2)[CH2:12][CH2:11]1
Reactant: COC(=O)c1ccc(C2(O)CCC(=O)CC2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(C(=O)O)cc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(1-hydroxy-4-oxo-cyclohexyl)-benzoic acid methyl ester (as prepared in Example 9, Step B) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4 followed by base catalyzed hydrolysis of the ester using the procedure described in Example 10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:34]([NH:33][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[O:16])[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=1)(=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 87 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.44 (s, 1H), 7.41–7.37 (m, 2H), 7.29–7.23 (m, 2H), 7.02–6.97 (m, 2H), 6.93 (d, 1H, J=6.8 Hz), 6.80 (br s, 1H), 3.29 (dd, 2H, J=5.6, 11.6 Hz), 2.92 (d, 2H, J=11.6 Hz), 2.46 (m, 1H), 2.36–2.30 (m, 6H), 1.96–1.30 (m, 18H), 1.01 (t, 3H, J=7.6 Hz), ESMS m/e: 508.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[C:46]1([C:52]#[CH:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.CCN(CC)CC.CN(C=O)C>C(O)=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.[Cu]I.CC#N>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:53]#[C:52][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:40][CH:39]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=CO
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(C#Cc2ccccc2)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Yield: 22.3 %

Procedure:
Compound 36 was prepared according to Method D, using compound 19 (88.4 mg, 0.130 mmol), phenylacetylene (0.0285 mL, 0.260 mmol), Et3N (0.181 mL, 1.30 mmol), Pd(PPh3)2Cl2 (4.49 mg, 0.0064 mmol), CuI (2.46 mg, 0.0129 mmol) and DMF (2.1 mL). RP-LC-MS (35 min gradient of 40-100% CH3CN in 0.05% aqueous formic acid) afforded the title compound (20.4 mg, 22%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:14][NH:15][O:16][CH3:17].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNOC
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 2-(3,4-dichlorophenyl)acetic acid (1 g, 4.9 mmol), N,O-dimethylhydroxylamine hydrochloride (480 mg, 4.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (940 mg, 4.9 mmol), hydroxybenzotriazole (660 mg, 4.9 mmol), and triethylamine (2.5 g, 25 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE: EtOAc=10:1) to afford 2-(3,4-dichlorophenyl)-N-methoxy-N-methylacetamide (880 mg, yield 72.7%).
Reaction SMILES: C1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)CCCCC1.Br[CH2:14][C:15]([NH:17][CH:18]([CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)[CH2:19][NH:20][C:21](=[O:32])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([NH:20][CH2:19][CH:18]([NH:17][C:15](=[O:16])[CH2:14][N:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH:12]1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)=[O:32]
Reactant: COc1ccccc1CCC(=O)NCC(Cc1c[nH]c2ccccc12)NC(=O)CBr
Reactant: C1CCC(N2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccccc1CCC(=O)NCC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCNCC1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 174.7 %

Procedure:
1-Cyclohexylpiperazine (3.65 g, 22.492 mmoles) was added to a stirring solution of 2-[(2-bromo)acetyl]amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (21.369 mmoles) and powdered potassium carbonate (3.56 g, 25.758 mmols) in methylene chloride under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature. The salts were filtered and the solution concentrated to a brown foam on a rotary evaporator. The desired product was purified on a Prep 500 column using a 10 L gradient starting with 100% methylene chloride and ending with 5% methanol/94.5% methylene chloride/0.5% ammonium hydroxide. Impure fractions were combined and purified further by reverse phase preparative high performance liquid chromatography (methanol/acetonitrile/water/ammonium acetate). After combining the material from both chromatographic purifications the title compound (10.43 g, 18.663 mmoles) was isolated (87% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15](C)[CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13]([C:22]#[N:23])=[CH:12]1.COC(OC)(C)CC=O.Cl.CCCCCC.C(OCC)(=O)C>C(O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13]([C:22]#[N:23])=[CH:12]1
Reactant: Cc1cc(C)c2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Agent: COC(C)(CC=O)OC
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Yield: 9.8 %

Procedure:
To a solution of 1.085 g (5.07 mmole) of the product from Example 64 (part B) and 0.80 mL (0.797 g; 6.03 mmole) of acetoacetaldehyde dimethyl acetal in 20 mL of ethanol was added 0.10 mL of conc. hydrochloric acid. The mixture was refluxed for 16 hours, then cooled and evaporated to give a dark, thick oil. TLC on silica gel with 70:30 hexane-ethyl acetate showed two major spots at Rf 0.47 and 0.41. The oil was dissolved in ethyl acetate, 20 mL silica gel powder was added, and the mixture was evaporated to dryness. The powdery residue was loaded on top of a column of 60 mL of silica gel in hexane. The column was eluted in step gradients of 0, 5, 10, 15, 20, and 25% ethyl acetate in hexane. The first fraction to elute was 0.32 g of the desired 1-(2-bromo-4-isopropyl-phenyl)-3-cyano-6-methyl-7-azaindole. Rf 0.47. The material can be crystallized from hexane to give 176 mg of crystals; mp 176.0° C. Mass spec. (m+H)+ =354.0595; calcd., 354.0606.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>>[Br:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1
Reactant: BrCc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3ccccc3Br)c3c2CCNCC3)cc1
Yield: 42 %

Procedure:
The title compound (0.035 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2-bromobenzyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C20H19BrClN3, 415.05; found, m/z 418.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.69 (d, J=7.8 Hz, 1H), 7.53-7.27 (m, 6H), 6.78 (d, J=7.8 Hz, 1H), 5.58 (s, 2H), 3.50-3.48 (br m, 4H), 3.19-3.17 (br m, 4H).