Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][O:38][C:39](=[O:56])[C:40]1[CH:45]=[CH:44][C:43](B2OC(C)(C)C(C)(C)O2)=[C:42]([F:55])[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:37][O:38][C:39](=[O:56])[C:40]1[CH:45]=[CH:44][C:43]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:42]([F:55])[CH:41]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c(F)c1
Yield: 51.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.55 g, 1 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (1.0 g, 3 mmol) and dichlorobis(triphenylphosphine)palladium (II) (70 mg, 0.1 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 1.5 mL). The mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-3-fluoro-benzoic acid methyl ester (260 mg, 49%) as a white solid: LC/MS m/e calcd for C28H25FN2O4S [M+H]+ 505.58, observed 505.0.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].[OH-].[Na+].Cl>C(Cl)(Cl)Cl.O>[C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: NCCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCCCCCCCCNC(=O)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 81.8 %

Procedure:
Compound I (50 g, 0.204 mol), prepared according to the general method described in Example 1, was dissolved in 2500 ml of chloroform, followed by the addition of a solution of 43.1 g (0.214 mol) of 11-aminoundecanoic acid and 60.0 g (1.5 mmol) of sodium hydroxide in 1500 ml of water. The mixture was stirred vigorously for one hour in a 5 liter Morton flask to insure thorough mixing of the two layers. The mixture was acidified with 250 ml of concentrated hydrochloric acid and stirred an additional 30 minutes. The organic layer was separated and the aqueous was extracted with 3×500 ml of chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give a solid. The product was recrystallized from toluene to give 68.37 g (82%) of 11-(4-benzoylbenzamido)undecanoic acid with a melting point of 107-109° C. Analysis on an NMR spectrometer was consistent with the desired product: 1H NMR (CDCl3) aromatic protons 7.20-7.80 (m, 9H), amide NH 6.30 (broad t, 1H), methylene adjacent to amide N 3.35 (in, 2H), methylene adjacent to carbonyl 2.25 (t, 2H), and remaining methylenes 1.00-1.80 (m, 16H).
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[C:21]1([NH:27][CH2:28][CH2:29][OH:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)([N:27]([CH2:28][CH2:29][OH:30])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: OCCNc1ccccc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)N(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.9 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (370 mg, 1 mmol), N-phenylethanolamine (165 mg, 1.2 mmol) and K2CO3 (276 mg, 2 mmol) in DMF (2 mL) was stirred at room temperature for 3 h. The mixture was poured into water (30 mL), extracted with ethyl acetate (10 mL×3). The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 51 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-[(2-hydroxy-ethyl)-phenyl-amino]-1,3-dihydro-indol-2-one as a white solid. MS: [M+H]+=427.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:23]([O:25][CH3:26])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1CCCCC1>[C].[Rh].O1CCCC1>[CH2:1]([O:19][CH:20]1[CH:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:28]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH2:27][CH:22]([C:23]([O:25][CH3:26])=[O:24])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Agent: [Rh]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)OC)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Yield: 8.2 %

Procedure:
To methyl 3,4,5-tris(octadecyloxy)benzoate (1 g, 10.6 mmol) was added cyclohexane, 5% rhodium-carbon (0.8 g) was added, and hydrogenation was performed at 80° C., 10 atm. Tetrahydrofuran (10 ml) was added, and the catalyst was filtered off. The filtrate was concentrated, methanol (8 ml) was added, and the mixture was stirred. The precipitate was collected by filtration and dried to give methyl 3,4,5-tris(octadecyloxy)cyclohexylcarboxylate (820 mg, 0.87 mmol, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([CH3:28])=[CH2:27])=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:19])=[O:5].[CH2:29](OC(OCC)OCC)C.C(O)(=O)C>C(O)C>[CH:16]1([NH:15][C:13](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([CH3:19])=[C:7]([N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:23][CH:22]=[C:21]([O:24][CH2:25][C:26]([CH3:28])=[CH2:27])[CH:20]=4)[N:1]=[CH:29]3)[CH:12]=2)[CH2:17][CH2:18]1
Reactant: C=C(C)COc1ccc(N)c(C(=O)Nc2cc(C(=O)NC3CC3)ccc2C)c1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Solvent: CC(=O)O
Product: C=C(C)COc1ccc2ncn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1
Temperature: 25 °C

Procedure:
A solution of 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(2-methylprop-2-en-1-yl)oxy]benzamide (3.6 g), triethylorthoformate (4.6 ml) and acetic acid (0.6 ml) in ethanol (50 ml) was heated at reflux for 18 hours. The reaction was cooled to room temperature and concentrated. The residue was partitioned between aqueous potassium carbonate solution (50 ml) and ethyl acetate (200 ml). The organic extracts were washed with brine (100 ml), dried (magnesium sulfate) and concentrated to give the crude N-cyclopropyl-4-methyl-3-[6-[(2-methylprop-2-en-1-yl)oxy]-4-oxoquinazolin-3(4H)-yl]benzamide as an oil (2.5 g) which was used directly in the next step.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>CN(C)C=O>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:39][CH:36]3[CH2:38][CH2:37]3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: BrCC1CC1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC1CC1)N1CCC(N2CCCCC2)CC1
Yield: 91 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless solid (91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:38])[C:13]3[CH:18]=[CH:17][C:16]([N:19]([CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])C(=O)C(F)(F)F)=[CH:15][C:14]=3[O:36][CH3:37])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:39][C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])[C:6]=2[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:38])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])=[CH:15][C:14]=3[O:36][CH3:37])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:39][C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])[C:6]=2[CH:49]=1
Reactant: COc1cc(N(CCOc2ccccc2C)C(=O)C(F)(F)F)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(NCCOc2ccccc2C)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.9 %

Procedure:
To a solution of 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-[2-methoxy-4-{N-[2-(2-methylphenoxy)ethyl]-N-trifluoroacetylamino}benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.45 g) in methanol (20 ml) is added a solution of potassium carbonate (0.11 g) in water (5 ml), and the mixture is stirred at room temperature for 12 hours. The mixture is evaporated to remove the solvent, and thereto is added water. The mixture is extracted with ethyl acetate, and the extract is dried, evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=80:1→50:1→30:1), and recrystallized from acetone/n-hexane to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-{2-methoxy-4-[2-(2-methylphenoxy)ethylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.12 g) as white powder.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:13][CH:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[CH3:22])[C:11]2[C:10](=[O:23])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>O1CCCC1>[CH3:22][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:14]=1[CH:12]1[C:11]2[C:10](=[O:23])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[C:4](=[O:3])[N:13]1[S:35]([CH3:34])(=[O:37])=[O:36])[C:18]#[N:19]
Reactant: Cc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 15 mg, 0.38 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-methylbenzonitrile (example 55, 60 mg, 0.13 mmol) in tetrahydrofuran (3 mL), and the mixture is stirred at room temperature for 20 min. Methanesulfonyl chloride (22 μL, 0.28 mmol) is added, and the mixture is stirred at room temperature over night. Another portion of sodium hydride (60% in mineral oil, 5 mg, 0.13 mmol) and methanesulfonyl chloride (10 μL, 0.13 mmol) is added, and the mixture is stirred for 1 h and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 28 mg; ESI mass spectrum [M+H]+=504; Retention time HPLC: 0.71 min (X012_S01).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[OH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O.CN(C)C=O>[O:12]=[C:6]1[NH:7][C:8]2[N:9]=[CH:10][CH:11]=[C:2]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17]4)[C:3]=2[CH2:4][CH2:5]1
Reactant: O=C1CCc2c(F)ccnc2N1
Reactant: O=C(O)c1cnc2ccc(O)cc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2c(Oc3ccc4ncc(C(=O)O)cc4c3)ccnc2N1
Temperature: 150 °C

Procedure:
5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one (Int-28, 120 mg, 0.72 mmol), 6-hydroxyquinoline-3-carboxylic acid (1.5 mg, 0.794 mmol), and cesium carbonate (706 mg, 2.17 mmol) were weighed into a microwave vial. N,N-Dimethylformamide (3.5 mL) was added and the vial was sealed and heated in a microwave at 150° C. for 4 h. The vial was opened and water was added (5 mL). The resulting clear solution was neutralized by the addition of 1N HCl and washed with ethyl acetate. The washed aqueous phase was acidified to pH 3 and pure product was collected by suction filtration. LC-MS: (FA) ES+ 336; 1H NMR (400 MHz, d6-DMSO) δ ppm 13.55 (s, 1H), 10.60 (s, 1H), 9.27 (d, J=2.1 Hz, 1H), 8.94 (d, J=1.9 Hz, 1H), 8.17 (d, J=9.1 Hz, 1H), 8.07-8.02 (m, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.74 (dd, J=9.1, 2.8 Hz, 1H), 6.52 (d, J=5.7 Hz, 1H), 2.92 (t, J=7.7, 7.7 Hz, 2H), 2.54 (dd, J=8.3, 7.1 Hz, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)[C:20]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:66]([CH2:68][NH2:69])[OH:67]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][CH2:27][C:28]([NH:69][CH2:68][CH2:66][OH:67])=[O:30])[C:20]([C:31]([CH3:32])([CH3:34])[CH3:33])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCCC(=O)O
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCCC(=O)NCCO
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
To a solution of 4-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indol-1-yl)butanoic acid (10 mg) in anhydrous DMF (0.25 mL) were successively added Et3N (9.5 mL, 0.069 mmol) and HBTU (8.2 mg, 0.022 mmol). After stirring for 10 min at 60° C., ethanolamine (1.3 μL, 0.022 mmol) was added, and the mixture was stirred for another 4 h at 60° C. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(4-(2-hydroxyethyl-amino)-4-oxobutyl)-1H-indol-5-yl)cyclopropanecarboxamide (5.8 mg, 64%) was obtained after purification by preparative HPLC. MS (ESI) m/e (M+H+) 506.0.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]3[NH:16][N:15]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:13]=3)=[CH:9][S:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>[Pd].CO.C(O)(=O)C>[CH:1]1([C:7]2[C:8]([C:12]3[NH:16][N:15]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:13]=3)=[CH:9][S:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: C1=C(c2cscc2-c2cc(Nc3ccccc3)n[nH]2)CCCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(Nc2cc(-c3cscc3C3CCCCC3)[nH]n2)cc1
Reaction time: 16 h
Yield: 57.5 %

Procedure:
Hydrogenation of [5-(4-cyclohex-1-enyl-thiophen-3-yl)-1-H-pyrazol-3-yl]-phenylamine (50 mg, 0.156 mmol) was carried out using 10% palladium on activated carbon (˜20 mg) in methanol (5 mL) and acetic acid (0.5 mL) under a balloon of hydrogen. After stirring for 16 h, the reaction was filtered through Celite. The filtrate was diluted with ether (50 mL), washed with saturated NaHCO3 solution (2×25 mL) and brine (25 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 29 mg (58%) of [5-(4-cyclohexyl-thiophen-3-yl)-1-H-pyrazol-3-yl]-phenylamine as a white solid.
Reaction SMILES: C([Li:5])CCC.[CH3:6][Si:7]([CH3:20])([CH3:19])[CH:8]1[C:17]2[N:16]=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1>CCCCCC.C1COCC1>[Li:5][C:8]1([Si:7]([CH3:19])([CH3:20])[CH3:6])[C:17]2[N:16]=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1
Reactant: Cc1cnc2c(c1)CCCC2[Si](C)(C)C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]C1([Si](C)(C)C)CCCc2cc(C)cnc21

Procedure:
A mixture of a 1.55 molar solution of butyl lithium in hexane (6.45 ml, 1O mM) and THF (10 ml) maintained below 10° was treated with a solution of 5,6,7,8-tetrahydro-8-trimethylsilyl-3-methylquinoline (2.2 g, 10 mM) in THF (1O ml) to obtain 5,6,7,8-tetrahydro- -8-lithio-8-trimethylsilyl-3-methylquinoline. After 0.5 hour a 22% solution of t-butyldimethylsilyl isothiocyanate in benzene (6.9 g, 1O mM) was added dropwise. After 0.5 hour the reaction mixture was quenched with 2N hydrochloric acid (25 ml) and after 1 hour the aqueous layer was separated, basified (to pH9) and extracted with dichloromethane (2×50 ml). The organic extracts were dried and evaporated to give the title thioamide (2.1 g, c 100%). Recrystallisation from benzene gave analytically pure material (1.9 g, 88%) m.p. 153°, identical to authentic material (Found: C63.7; H,6.9; N,13.4% C11H14N2S requires: C64.0; H,6.8; N,13.6%).
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH:15]=[CH2:16])[CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=O)[CH:2]=[CH2:3].Cl.[NH2:18][OH:19].N1C=CC=CC=1>C(O)C>[CH2:1]([N:4]([CH2:14][CH:15]=[CH2:16])[CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[N:18][OH:19])[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)CC(=O)c1cccnc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C=CCN(CC=C)CC(=NO)c1cccnc1
Temperature: 70 °C
Yield: 77.8 %

Procedure:
2-(Diallylamino)-1-(3-pyridyl)ethanone (4.75 g, 21.96 mmol) is dissolved in ethanol (47 mL) under a nitrogen atmosphere. Hydroxylamine hydrochloride (3.55 g, 50.51 mmol) and pyridine (2.5 mL, 30.75 mmol) are then added. The resulting solution is heated at 70° C. under nitrogen for 140 minutes. The reaction is then cooled to room temperature and the solvent is partially evaporated under reduced pressure. The resulting residue is partitioned between 1 M aqueous sodium hydroxide (50 ml) and dichloromethane (250 mL). The phases are separated and the aqueous phase is re-extracted with ethyl acetate (250 mL). The organic layers are combined and the solvents are evaporated. The crude material is purified by silica gel column chromatography using a 0-10% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (3.95 g, 78%) as a mixture of E/Z isomers. ES/MS (m/e): 232 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C1(C)C=CC=CC=1.[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25](=[O:39])[C:26](=[CH:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=3)[N:27]=2)=[CH:19][CH:18]=1)[CH:13]([CH3:15])[CH3:14]>O>[OH:4][CH2:3][CH2:2][NH:1][C:25](/[C:26](/[NH:27][C:23](=[O:24])[C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:22][CH:21]=1)=[CH:28]\[C:29]1[CH:30]=[CH:31][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:33][CH:34]=1)=[O:39]
Reactant: CC(C)COc1ccc(C2=NC(=Cc3ccc(OC(C)C)cc3)C(=O)O2)cc1
Reactant: NCCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)COc1ccc(C(=O)N/C(=C/c2ccc(OC(C)C)cc2)C(=O)NCCO)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 21 %

Procedure:
2-Aminoethanol (50 μL, 0.828 mmol) was added to a solution of toluene (2.0 mL) containing 2-(4-isobutoxyphenyl)-4-(4-isopropoxybenzylidene)-1,3-oxazol-5(4H)-one (151 mg, 0.398 mmol, a mixture of 4E isomer/4Z isomer=4.6/1) prepared in Example 103 (103a). The mixture was stirred at 50° C. for 15 minutes, and then water was added to this reaction solution. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by thin layer chromatography for separation (ethyl acetate) to give 37 mg of the title compound (white solid, yield: 21%). [In addition, 53 mg of the corresponding Z isomer of the title compound (white solid, yield: 30%) was given.]
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:4].[Br:18]Br>ClCCl>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[C:16]2[CH2:15][CH2:14][CH:13]([Br:18])[C:12](=[O:17])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)COc1cccc2c1CCCC2=O
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)COc1cccc2c1CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methoxycarbonylmethoxy-5-oxo-5,6,7,8-tetrahydronaphthalene (0.5 g) in dry dichloromethane (3 ml) was added bromine (0.14 ml) at 0° C. The mixture was warmed up to room temperature, stirred for 2 hours. The mixture was washed with an aqueous saturated sodium bicarbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (30 ml) using a mixture of dichloromethane-n-hexane. The desired fractions were collected and evaporated in vacuo to give 1-methoxycarbonylmethoxy-5-oxo-6-bromo-5,6,7,8-tetrahydronaphthalene (0.41 g). The crude crystal (50 mg) was recrystallized from ethyl acetate-n-hexane to give 31 mg as a white crystal.