Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.O1CCCC1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C:2]2[C:15]3[NH:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[S:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: Nc1cccc2c1Nc1ccccc1S2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cccc3c2Nc2ccccc2S3)cc1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
107 mg (0.5 mmol) of 1-amino-10H-phenothiazine was dissolved in 4 ml of pyridine. Then 2 ml of a solution of 115 mg (0.55 mmol) of 4-methoxybenzenesulfonyl chloride in tetrahydrofuran was added thereto under stirring at room temperature. After stirring at room temperature overnight, the reaction mixture was concentrated. Then ethyl acetate and water were added to the residue and the organic layer was separated, washed with water and dried over magnesium sulfate. After concentrating, the residue was purified by silica gel column chromatography and recrystallized from ethanol. Thus 115 mg of the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[N:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1.O1CCCC1.[OH-].[Li+]>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[N:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)nc3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridine-2-carboxylic acid (395 mg), ethyl 3-(methylamino)propanoate (157 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg), hydroxybenzotriazole monohydrate (184 mg) and triethylamine (168 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give ethyl 3-[{[5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate (155 mg). Ethyl 3-[{[5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.6 mL) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (100 mg, 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:66][Si](C(C)(C)C)(C)C)[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]3[CH:35]=[C:36]([S:40]([C:43]4[CH:44]=[C:45]5[C:50](=[C:51]([CH3:53])[CH:52]=4)[N:49]=[CH:48][C:47]([C:54]([NH2:56])=[O:55])=[C:46]5[NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH3:65])[CH:59]=4)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=3)=[O:33])=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(O)(=O)C>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:66])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]3[CH:35]=[C:36]([S:40]([C:43]4[CH:44]=[C:45]5[C:50](=[C:51]([CH3:53])[CH:52]=4)[N:49]=[CH:48][C:47]([C:54]([NH2:56])=[O:55])=[C:46]5[NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH3:65])[CH:59]=4)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=3)=[O:33])=[CH:29][CH:30]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC[C@H](O)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Intermediate 140 (135 mg, 0.133 mmol) was combined with TBAF (1M/THF, 0.4 mL) and acetic acid (23 μL) in anhydrous acetonitrile (0.2 mL) and allowed to stir at rt. After 18 h, the reaction was concentrated in vacuo to a brown oil, which was suspended in H2O. The solid was filtered and washed with H2O and hexane, then dried to give the title compound as a yellow solid, 124 mg, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.46 (s, 1H), 9.09 (s, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 8.30 (br s, 1H), 8.16-8.24 (m, 2H), 8.03 (s, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.77 (br s, 1H), 7.76 (dd, J=7.6, 15.6 Hz, 1H), 7.66 (d, J=8.3 Hz, 2H), 7.55 (d, J=7.6 Hz, 2H), 7.32-7.41 (m, 2H), 7.26-7.32 (m, 1H), 7.07-7.23 (m, 5H), 6.61-6.69 (m, 2H), 6.49-6.59 (m, 2H), 5.28 (s, 2H), 5.03 (t, J=6.1 Hz, 1H), 3.60 (s, 3H), 3.15-3.19 (m, 2H), 2.70 (s, 3H), 2.62-2.81 (m, 7H). ES/MS calcd. for C51H47N6O8S+ 903.3. Found m/z=903.3 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: OB(O)c1cccnc1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2cccnc2)nc(N2CCOCC2)n1
Yield: 61 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) and 3-pyridinylboronic acid, as in Example 47, gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(3-pyridinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole in 61% yield: mp (CH2Cl2/MeOH) 208-210° C.; 1H NMR (DMSO-d6) δ 9.59 (dd, J=2.2, 0.7 Hz, 1H), 8.85 (dd, J=4.8, 1.7 Hz, 1H), 8.75 (dt, J=8.0, 1.9 Hz, 1H), 8.35 (dd, J=8.4, 0.4 Hz, 1H), 7.83 (t, Jjw=52.6 Hz, 1H), 7.66 (ddd, J=8.0, 4.8, 0.8 Hz, 1H), 7.50 (t, J=8.3 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.09 (t, J=7.8 Hz, 2H), 4.00 (s, 3H), 3.94 (m, 2H), 3.78 (m, 4H); Anal. Calcd. for C21H19F2N7O40.3H2O: C, 56.7; H, 4.4; N, 22.0. Found: C, 56.6; H, 4.0; N, 22.1%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[NH:28]1[CH:32]=[N:31][N:30]=[N:29]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]3[CH:32]=[N:31][N:30]=[N:29]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: c1nnn[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCn3cnnn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=444.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-tetrazole.
Reaction SMILES: [O:1]=[C:2]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C@@H:24]([C:35]([OH:37])=O)[CH2:25][C:26]3[CH:31]=[C:30]([CH3:32])[C:29]([OH:33])=[C:28]([CH3:34])[CH:27]=3)=[O:22])[CH2:17][CH2:16]2)[C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:67]1[CH2:72][CH2:71][CH:70]([N:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH2:69][CH2:68]1>CN(C=O)C>[O:1]=[C:2]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C@H:24]([CH2:25][C:26]3[CH:31]=[C:30]([CH3:32])[C:29]([OH:33])=[C:28]([CH3:34])[CH:27]=3)[C:35](=[O:37])[N:76]3[CH2:75][CH2:74][N:73]([CH:70]4[CH2:71][CH2:72][O:67][CH2:68][CH2:69]4)[CH2:78][CH2:77]3)=[O:22])[CH2:17][CH2:16]2)[C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[NH:3]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)O)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Reaction time: 2 h

Procedure:
A solution of 100 mg (0.15 mmol) (R)-1-carboxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylate, 53 mg (0.16 mmol) TBTU and 26 μL (0.19 mmol) triethylamine in 1 mL DMF was stirred for 15 min at RT. Then 28 mg (0.16 mmol) 1-(tetrahydropyran-4-yl)-piperazine was added and the reaction solution was stirred for 2 h. The reaction solution was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[C:7](C(=O)CS(C)(=O)=O)[NH:8]2)=[CH:4][C:3]=1Cl.[BH4-].[Na+].C(O)(=O)C.C>C(O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:6]1[C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: CS(=O)(=O)CC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(-c2c[nH]c3ccccc23)nc1

Procedure:
To 6-bromo-5-chloro-2[(methylsulfonyl)acetyl]-3-(2-pyridyl)indole (2.2 g) in 75 ml of ethanol add 0.175 g of sodium borohydride. After a solution is obtained (about 10 minutes) stir the mixture of another 30 minutes, then slowly add 2 ml of acetic acid. Treat with charcoal, filter and add 100 ml of water to the filtrate to obtain 6-bromo-5-chloro-2[1-hydroxy-2-methylsulfonyl)ethyl]-3-(2-pyridyl)indole.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH2:31][CH3:32])[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3.CCN=C=NCCCN(C)C.Cl.O>CN(C)C=O>[C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH2:31][CH3:32])[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:16])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(NC(=O)CCCCCNC(=O)OC(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 74.2 %

Procedure:
N-Boc-6-aminocaproic acid (7.58 g) prepared by the method described in a Journal of Medicinal Chemistry (J. Med. Chem., 35, p.272 (1993)) and 7.58 g of 3-amino-9-ethylcarbazole were dissolved in 75 mL of dimethylformamide, and the solution was added with 10.4 g WSC hydrochloride and stirred at room temperature for 3.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with 1 N aqueous sodium hydroxide, 10% aqueous citric acid and saturated brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/1) to obtain 10.3 g of 3-(N-Boc-6-aminocaproyl)amino-9-ethylcarbazole.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][C:9]2([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=4[NH2:31])[CH2:20][CH:19]3[OH:32])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[C:35](Cl)(=[O:44])[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH:31][C:35](=[O:44])[CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:20][C:19]3=[O:32])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[CH:33][CH:34]=1
Reactant: Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccc(F)cc3)CCCCC2)C(O)C1
Reactant: O=C(Cl)CCc1ccccc1
Product: O=C(CCc1ccccc1)Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3ccc(F)cc3)CCCCC2)C(=O)C1

Procedure:
In accordance with the same procedure as in Example 87, except that 4-[N-[1-[N-(4-fluorobenzoyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol and hydrocinnamoyl chloride was used instead of methoxyacetyl chloride in Step 3 thereof, 671 mg of the titled compound was prepared.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[S:16])[NH2:15])=[CH:4]1)[CH3:2].CO[CH:19](OC)[CH2:20]Br>C(COC)OC>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[S:16][CH:19]=[CH:20][N:15]=2)=[CH:4]1)[CH3:2]
Reactant: COC(CBr)OC
Reactant: CCn1cc(C(N)=S)c2ccc(OC)cc21
Solvent: COCCOC
Product: CCn1cc(-c2nccs2)c2ccc(OC)cc21
Temperature: 80 °C
Yield: 47.3 %

Procedure:
1-Ethyl-6-methoxy-1H-indole-3-thiocarboxamide (83 mg, 0.36 mmol), glyme (3.6 mL) and bromoacetaldehyde dimethyl acetal (220 μL, 1.86 mmol) are heated at 80° C. for 16 h. More bromoacetaldehyde dimethyl acetal (250 μL is added. This is heated at 80° C. for 2 h. Addition of 250 μL more bromoacetaldehyde dimethyl acetal is followed by heating for another 2 hours. The reaction mixture is cooled to room temperature, absorbed onto silica and purified by silica gel chromatography (hexanes/EtOAc, 7/3) to afford 1-ethyl-6-methoxy-3-thiazol-2-yl-1H-indole as a brown oil (44 mg, 47%).
Reaction SMILES: C([O:8][CH2:9][C:10]([NH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][C:20]=2[N:22]2[CH2:27][CH2:26][N:25](CC3C=CC=CC=3)[CH2:24][CH2:23]2)[NH:15][CH:14]=1)=[O:11])C1C=CC=CC=1.CCN(C(C)C)C(C)C>CO.Cl.[Pd]>[OH:8][CH2:9][C:10]([NH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][C:20]=2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[NH:15][CH:14]=1)=[O:11]
Reactant: O=C(COCc1ccccc1)Nc1c[nH]c2nccc(N3CCN(Cc4ccccc4)CC3)c12
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CO)Nc1c[nH]c2nccc(N3CCNCC3)c12
Yield: 99.5 %

Procedure:
2-(Benzyloxy)-N-(4-(4-benzylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.100 g, 0.219 mmol) was placed in MeOH (2 mL). Pd/C (0.0467 g, 0.0220 mmol) was then added, followed by the addition of 3 drops of concentrated HCl. The reaction was next placed under an H2 filled balloon for 3 hours. Additional Pd/C (0.0467 g, 0.0219 mmol) was then added, and the reaction was placed under an H2 filled balloon for an additional 3 hours to drive the reaction to completion. DIEA was added to achieve solubility. The reaction was then filtered, washed with MeOH, and concentrated to give the crude product 2-hydroxy-N-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.060 g, 99.2% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O=[C:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]#[N:16].[Cl-].[Ca+2].[Cl-]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]#[N:16])[CH:6]=[CH:7][CH:8]=1
Reactant: N#CC1CCCC1=O
Reactant: Nc1cccc(F)c1
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2cccc(F)c2)CCC1

Procedure:
3-Fluoro-aniline (Aldrich Chemicals) (4.6 g, 41 mmol), cyano-ketone (Example 11) (4.4 g, 40 mmol), calcium chloride (5.0 g, 45 mmol) and T.H.F. (60 ml) were heated under reflux for 17 hours. After being allowed to cool, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (125° C., 0.02 mm Hg) gave the product as a pale yellow powder.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Cl:19])=[CH:12][C:13]([C:17]#[N:18])=[N:14]2)=[CH:9][CH:8]=1.O>CCO>[N:1]([CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Cl:19])=[CH:12][C:13]([C:17]#[N:18])=[N:14]2)=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: N#Cc1cc(Cl)c2ccc(CBr)cc2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc(Cl)c2ccc(CN=[N+]=[N-])cc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
Sodium azide (1.690 g, 26.0 mmol, 1.3 equiv.) was added to a stirred solution of 7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4, 5.63 g, 20.00 mmol) in 100 ml of EtOH, and the resulting slurry mixture was refluxed for 1 h. The mixture was cooled to rt, water (100 ml) was added, and the slurry was stirred at rt for 30 min. The resulting solid was collected by filtration and air dried to afford 7-(azidomethyl)-4-chloroquinoline-2-carbonitrile (3-12, 4.75 g, 97%) as a white solid. LRMS m/z (M+H)+ 244.1 found, 244.65 required.
Reaction SMILES: [C:1](=[NH:26])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[C:8]([F:25])[CH:7]=1)[NH2:2].[OH:27]/[CH:28]=[C:29](/[CH2:35][C:36]1[CH:37]=[N:38][C:39]([O:42][CH3:43])=[N:40][CH:41]=1)\[C:30](OCC)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:9]2[C:10]([F:12])=[CH:11][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:30]=[C:29]([CH2:35][C:36]4[CH:37]=[N:38][C:39]([O:42][CH3:43])=[N:40][CH:41]=4)[C:28](=[O:27])[N:26]=3)=[CH:7][C:8]=2[F:25])=[CH:15][C:16]=1[C:21]([F:22])([F:24])[F:23]
Reactant: CCOC(=O)/C(=C\O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc(Cc2c[nH]c(OCCc3cc(F)c(Oc4ccc(Cl)c(C(F)(F)F)c4)c(F)c3)nc2=O)cn1
Yield: 14.9 %

Procedure:
The same procedure as E125 from 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3,5-difluorophenyl)ethyl imidocarbamate (143 mg, 0.362 mmol), ethyl (2Z)-3-hydroxy-2-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-propenoate (129 mg, 0.543 mmol) and K2CO3 (125 mg, 0.906 mmol) in DMF (3 mL), except that the reaction temperature was 130° C., to afford the title compound (31 mg, 0.054 mmol, 15.04% yield) as white solid. LCMS: rt=3.61 min, [M+H+]=569
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH2:28][CH:29]([O:35][CH2:36][CH3:37])[C:30]([O:32]CC)=[O:31])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[CH2:1]([C:8]1[CH:9]=[C:10]([CH2:28][CH:29]([O:35][CH2:36][CH3:37])[C:30]([OH:32])=[O:31])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(Cc2ccccc2)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(Cc2ccccc2)c1)C(=O)O
Yield: 70 %

Procedure:
Ethyl 3-[3-benzyl-4-({4-[(methylsulfonyl)oxy]phenethyl}oxy)phenyl]-2-ethoxypropanoate—Example 5 (0.23 g; 0.42 mmole) was dissolved in THF and water (2:1), lithium hydroxide (0.014 g; 0.59 mmole) was added and the reaction mixture was stirred over night. Water was added and the THF evaporated. The remaining water was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate. Evaporation gave 0.15 g (70% yield) of the product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][C:23]([F:22])([F:33])[F:34])=[CH:26][CH:27]=2)[N:13]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: FC(F)(F)Oc1ccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.16 ml of 4-trifluoromethoxy-benzaldehyde and 0.2 ml of acetic acid are mixed together, the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. The solvent is evaporated off, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 129 mg of expected product is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:24]2[CH:28]=[C:27]([C:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=3)[S:26][C:25]=2[C:35]([O:37][CH3:38])=[O:36])[C:15]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:38][O:37][C:35]([C:25]1[S:26][C:27]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:28][C:24]=1[N:14]([C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]1)=[O:16])[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:36]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1

Procedure:
A solution of 4-[(5-cyclohex-1-enyl-2-methoxycarbonyl-thiophen-3-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (2.3 g, 4.22 mmol) in dichloromethane (15 mL) and trifluoroacetic acid (15 mL) was stirred at room temperature under N2 atmosphere for 4 h. Solvents were removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using methanol, chloroform and triethyl amine (10:89:1) as eluent to obtain 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (1.5 g, 80%) as a solid.