Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[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.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[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>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([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:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(OC(F)(F)F)cc4)cc3CC[C@@H]12
Yield: 54.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-trifluoromethoxyphenylboronic acid (161 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 137 mg (56%) of the title compound as a waxy solid. FDMS: m/e=389. α[D]589 =+48.95 (c=0.96, chloroform).
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([O:11][C@@:12]1([CH2:44][CH3:45])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:43])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:38])([CH3:37])[CH2:33][CH2:34][CH2:35][NH3+:36])=[C:23]2[CH:39]=[CH:40][CH:41]=[CH:42][C:22]2=[N:21][C:20]3=1)(=[O:10])[CH3:9].[CH3:46][N:47]([CH3:51])[C:48](Cl)=[O:49]>>[CH3:46][N:47]([CH3:51])[C:48](=[O:49])[NH:36][CH2:35][CH2:34][CH2:33][Si:32]([CH3:37])([CH3:38])[CH2:31][CH2:30][C:24]1[C:25]2[CH2:26][N:27]3[C:19](=[CH:18][C:17]4[C@@:12]([O:11][C:8](=[O:10])[CH3:9])([CH2:44][CH3:45])[C:13](=[O:43])[O:14][CH2:15][C:16]=4[C:28]3=[O:29])[C:20]=2[N:21]=[C:22]2[CH:42]=[CH:41][CH:40]=[CH:39][C:23]=12
Reactant: CN(C)C(=O)Cl
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCC[NH3+]
Agent: O=C([O-])C(F)(F)F
Product: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCNC(=O)N(C)C

Procedure:
The required product was prepared according to Procedure E, above, using Compound 21 and dimethylcarbamyl chloride. The required product was obtained in 72% yield.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.C(=O)(O)[O-:28].[Na+].I([O-])(=O)(=O)=O.[Na+]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[Si:1]([O:8][CH:9]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: C=CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc2ccccc2c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(CCCCC=O)c1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of alkene 182 (1.05 g, 3.23 mmol) in t-butyl alcohol (50 mL) were successively added water (10 mL), solid sodium bicarbonate (2.71 g, 32.3 mmol), sodium periodate (4.15 g, 19.38 mmol), and osmium tetroxide (8 mg, 0.032 mmol). The mixture turned light brown and a precipitate formed in large amount, making magnetic stirring impossible so the mixture was shaken by hand every 10 minutes for 3.5 hours and the brownish color almost disappeared. The reaction was quenched with a 10% aqueous solution of sodium thiosulfate. After 30 minutes, the white precipitate was filtered off and rinsed with diethyl ether. The filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether and water. The aqueous layer was extracted (2×50 mL) with diethyl ether. The combined organic layers were washed successively with a 10% aqueous solution of sodium thiosulfate, water and brine, dried (MgSO4), and concentrated in vacuo, yielding the title compound 183 as a crude oil in 91% yield (1.05 g). 1H NMR: (300 MHz, CDCl3) δ: 9.73 (t, J=1.9 Hz, 1H), 7.83-7.78 (m, 3H), 7.69 (s, 1H), 7.49-7.43 (m, 3H), 4.80 (t, J=6.9 Hz, 1H), 2.39 (td, J=7.1, 1.6 Hz, 2H), 1.81-1.55 (m, 4H), 1.43-1.25 (m, 2H) 0.90 (s, 9H), 0.04 (s, 3H), −0.15 (s, 3H). MS (ESI) 225 (M+1-TBSO).
Reaction SMILES: C[N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17](=[O:21])[O:18]3)=[CH:13][CH:12]=2)[CH2:4][C:3]1([CH3:23])[CH3:22].CCOC(/N=N/C(OCC)=O)=O.[ClH:36]>C1(C)C=CC=CC=1>[ClH:36].[CH3:8][C:7]1([CH3:9])[CH2:6][CH:5]([O:10][C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17](=[O:21])[O:18]3)=[CH:13][CH:12]=2)[CH2:4][C:3]([CH3:23])([CH3:22])[NH:2]1
Reactant: CN1C(C)(C)CC(Oc2ccc3ccc(=O)oc3c2)CC1(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1(C)CC(Oc2ccc3ccc(=O)oc3c2)CC(C)(C)N1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
A mixture of 7-(1,2,2,6,6-pentamethyl-piperidin-4-yloxy)-chromen-2-one (0.69 g, 2.2 mmol), diethylazodicarboxylate (1.0 ml, 6.6 ml) and toluene (50 ml) was stirred at 115° C. for 15 h. Hydrochloric acid (10 ml, 2 N) was added to the mixture and was refluxed for 1 h. The mixture was cooled and the product precipitated as the hydrochloric acid salt. Yield 0.26 g (37%). Mp>300° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([C:18]3([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+].O>CO>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH:16]([C:18]3([C:22]4[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=4)[CH2:21][CH2:20][CH2:19]3)[OH:17])[CH2:10]2)=[CH:32][CH:33]=1
Reactant: O=C(CN1CCCC(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc(C(F)(F)F)cc2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(CN1CCCC(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc(C(F)(F)F)cc2)CCC1
Yield: 69.7 %

Procedure:
2-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-1-[1-(4-trifluoromethyl-phenyl)-cyclobutyl]-ethanone (30 mg) was dissolved in 3 mL of dry methanol and solid sodium borohydride (10 equiv.) was added in portions. Water (10 mL) was added and the mixture was extracted with ether and the ether extracts were concentrated in vacuo and purified on silica gel to give the desired 2-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-1-[1-(4-trifluoromethyl-phenyl)-cyclobutyl]-ethanol (21 mg, 67%). Data for this mixture of diastereomeric amino alcohols: MS 502 (M+1); 1H NMR (300 MHz, CDCl3): δ 7.5–7.6 (m, 4H), 7.29–7.35 (m, 2H), 6.89–6.96 (overlapping doublets, total 2 H), 3.8–4.0 (m, 4H, 1 of which is exchanged upon exposure to D2O), 1.1–3.1 9 (various overlapping multiplets totaling 17 H); 13C NMR (75 MHz, CDCl3): δ 207 peak in starting ketone is absent. Most peaks are doubled (adjacent equal intensity peaks) due to diastereoisomerism: δ 161.7, 151.0, 128.6 & 128.5, 128.0 & 127.8, 127.15 & 127.10, 126.45, 124.91 & 124.87, 123.30, 122.86, 114.63, 71.2 & 71.1, 59.7 & 59.5, 58.99 & 58.97, 55.96, 49.31 & 49.28, 36.8 & 36.6, 31.0, 29.5 & 29.4, 27.33 & 27.26, 25.24 & 25.03, 16.42.
Reaction SMILES: CC1C=CC(N2C3C(=CC=CC=3)C=C2)=CC=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]4[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:37][CH:38]=4)[CH2:29][CH2:28]3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.[F:45][C:46]1[CH:51]=[CH:50][C:49](I)=[CH:48][CH:47]=1>>[F:45][C:46]1[CH:51]=[CH:50][C:49]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([C:33]5[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:42])[CH3:43])[CH:36]=[CH:37][CH:38]=5)[CH2:29][CH2:28]4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[CH:48][CH:47]=1
Reactant: Fc1ccc(I)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Agent: Cc1ccc(-n2ccc3ccccc32)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4ccc(F)cc4)c3)CC2)c1
Yield: 44.7 %

Procedure:
According to the procedure used for the synthesis of 1-(4-methylphenyl)1H-indole, N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide (37.5 mg, 0.100 mmol) and 1-fluoro-4-iodobenzene (44.4 mg, 0.200 mmol) gave the desired product (21 mg, 45%). 1H NMR (400 MHz, CDCl3) δ 7.71–6.60 (m, 14H), 3.69 (s, 2H), 3.19–2.99 (m, 2H), 2.62–2.41 (m, 2H), 2.22–2.07 (m, 2H), 1.94–1.70 (m, 4H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 470.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH3:22].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CO>[CH3:22][O:21][CH2:20][C:7]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=1
Reactant: O=Cc1cccnc1
Reactant: COCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCc1nc2c(N)nc3ccccc3c2n1CCCCNCc1cccnc1
Reaction time: 0.08 h
Yield: 15.3 %

Procedure:
To a round-bottomed flask containing 1-(4-aminobutyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (10.0 g, 33.4 mmol) was added methanol (160 mL) followed by acetic acid (40 mL). The reaction was stirred for 5 minutes and pyridine 3-carboxaldehyde (5.4 g, 50.1 mmol) was added and the reaction was stirred overnight at ambient temperature. Sodium cyanoborohydride (1 M in THF, 33.4 mL, 33.4 mmol) was added to the resultant imine in portions over 10 minutes. After 45 minutes the solvent was evaporated to afford an oil. To the oil was added saturated aqueous sodium bicarbonate (200 mL) and the aqueous layer was washed with ethyl acetate (200 mL) and dichloromethane (200 mL). The product was extracted from the aqueous with 20% methanol (2×100 mL) in dichloromethane. The organic layers were combined and the solvent evaporated to afford crude 2-methoxymethyl-1-{4-[(pyridin-3-ylmethyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-amine (about 2 g). The aqueous layer was again extracted with 20% dimethylformamide (2×100 mL) in dichloromethane. The organic layers were combined and the solvent evaporated to afford crude 2-methoxymethyl-1-{4-[(pyridin-3-ylmethyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-amine (about 2 g).
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.CCCCCC.[Br:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=1.CN([CH:29]=[O:30])C>C1(C)C=CC=CC=1.C1COCC1>[Br:18][C:19]1[N:20]=[CH:21][C:22]([CH:29]=[O:30])=[CH:23][CH:24]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)nc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
40.1 ml of a 2M solution of n-butylmagnesium chloride in THF (80.2 mmol) were added to a solution 100.2 ml of a 1.6M solution of n-butyllithium in hexane (160.41 mmol) in 50 ml of toluene and 50 ml of THF at −10° C. to 0° C. over 0.5 h, and the mixture was stirred at −10° C. for 0.5 h. A solution of 50 g (211 mmol) of 2,5-dibromopyridine in 200 ml of toluene and 200 ml of THF was added dropwise over 1 h while maintaining the temperature of the mixture below −5° C. The resulting suspension was stirred at −10° C. for 2.5 h and then transferred into a cooled (−10° C.) solution of 21.2 ml of DMF (274.3 mmol) in 100 ml of toluene and 100 ml of THF over 0.5 h. The mixture was left at −10° C. to −5° C. for 0.5 h and then quenched with 400 ml of water. After stirring the mixture below 20° C. for 10 min, the organic layer was separated and the aqueous layer was extracted three times with 400 ml each of ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, cyclohexane/ethyl acetate 9:1) to give 23.9 g (60.8%) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:9]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[C@@H:17]([NH:26][C:27]2[N:32]=[C:31]([CH2:33][C:34]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=3)[C:30]([CH2:48]Br)=[CH:29][N:28]=2)[CH2:16][C@H:15]1[CH2:50][CH3:51])=[O:13])[CH3:10].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:9]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[C@@H:17]([NH:26][C:27]2[N:32]=[C:31]([CH2:33][C:34]3[CH:39]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:37]=[C:36]([C:44]([F:45])([F:46])[F:47])[CH:35]=3)[C:30]([CH2:48][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:29][N:28]=2)[CH2:16][C@H:15]1[CH2:50][CH3:51])=[O:13])[CH3:10]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CBr)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CN3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 0.5 h

Procedure:
Morpholine (0.02 ml) is dissolved in N,N-dimethylformamide (2 ml), then thereto is added sodium hydride (9 mg) under ice-cooling, and the mixture is stirred for 30 minutes. (2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(bromomethyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (112 mg) is added to the reaction solution under ice-cooling, and the mixture is stirred at room temperature for 1 hour and 30 minutes. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=3:1→1:1) to give (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[(morpholin-4-yl)methyl]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (33 mg). MS (m/z): 683 [M+H]+
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)=[CH:11]2)([O-:5])=[O:4].[CH3:20][O:21][CH2:22]Cl.O>CN(C)C=O.O1CCCC1>[CH3:20][O:21][CH2:22][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[N+:3]([O-:5])=[O:4])[CH:11]=[C:12]1[C:15]1[S:16][CH:17]=[CH:18][N:19]=1
Reactant: COCCl
Reactant: O=[N+]([O-])c1cccc2cc(-c3nccs3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCn1c(-c2nccs2)cc2cccc([N+](=O)[O-])c21
Reaction time: 0.33 h
Yield: 82 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.47 g) in N,N-dimethylformamide (15 mL) was slowly added 7-nitro-2-(1,3-thiazol-2-yl)-1H-indole (2.21 g) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of chloromethyl methyl ether (0.81 mL) in tetrahydrofuran (2 mL) at 0° C. over 20 min, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (2.14 g, yield 82%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:36][CH2:35][CH:31]([C:32]([NH2:34])=[O:33])[CH2:30][CH2:29]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(COC)OC>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([N:28]3[CH2:36][CH2:35][CH:31]([C:32]([NH2:34])=[O:33])[CH2:30][CH2:29]3)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1CCNCC1
Reactant: FC(F)(F)c1cccc2c(-c3ccc(Cl)cc3)n(Cc3ccccc3)nc12
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: COCCOC
Product: NC(=O)C1CCN(c2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)CC1
Yield: 28.4 %

Procedure:
A solution of 2-benzyl-3-(4-chlorophenyl)-7-(trifluoromethyl)-2H-indazole (0.1 g, 0.25 mmol), isonipecotamide (0.039 g, 0.3 mmol), tris-(dibenzylidineacetone)dipalladium(0) (14 mg), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (47 mg) and sodium t-butoxide (0.029 g, 0.3 mmol) in 2 mL of dimethoxyethane was heated at 150° C. for 5 minutes in a microwave (Emory's Optimizer, Personal Chemistry). The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2-CH3OH, 19:1) to give the product (0.034 g) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([O:13][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CC[C@H]1CC[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H]1CC[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl trans-2-(3-ethoxy-3-oxopropyl)-5-hydroxypiperidine-1-carboxylate (625 mg, 2.07 mmol, step 3 of Example 5) and triethylamine (252 mg, 2.49 mmol) in dichloromethane (9.0 mL) was added methanesulfonyl chloride (285 g, 2.49 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 2 h and then stirred at room temperature for 20 h. The mixture was quenched with water (30 mL), extracted with dichloromethane (30 mL×4). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 790 mg (quant.) of the title compound as a yellow oil. The resulting residue was used for the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24].P(Cl)(Cl)([Cl:27])=O>N1C=CC=CC=1>[Cl:27][C:7]1[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(Cl)ccc2[nH]c1=O
Solvent: c1ccncc1
Product: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1Cl

Procedure:
A mixture of ethyl 6-chloro-4-(2-chlorophenyl)-1,2-dihydro -2-oxo-3-quinolinecarboxylate (1.0 g), phosphorus oxychloride (5 ml) and pyridine (0.5 ml) was refluxed for 16 hours. The mixture was concentrated under reduced pressure. Water was added to the residue to obtain ethyl 2,6-dichloro-4-(2-chlorophenyl)-3-quinolinecarboxylate (0.7 g). The product was dissolved in methanol (20 ml), to which 28% sodium methoxide-methanol solution (0.5 ml) was added. The mixture was refluxed for 3 hours, and then diluted with water to obtain methyl 6-chloro-4-(2-chlorophenyl) -2-methoxy-3-quinolinecarboxylate as crystals (0.61 g, 61.0%). Recrystallization from methanol gave colorless needles. mp 151°-152° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)C>[Si:21]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:7]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: COC(=O)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.00 g (11.38 mmol) of the crude product from Example 8A (90% pure) are dissolved in 50 ml of dry DMF, and 1.47 g (21.62 mmol) of imidazole and 2.40 g (15.93 mmol) of tert-butyldimethyl-silyl chloride are added. The reaction mixture is stirred at RT for 20 h. 40 ml each of diethyl ether and of saturated aqueous sodium bicarbonate solution are then added to the mixture. After phase separation, the organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The crude product is used in the next reaction without further purification.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:42])[CH:19]([O:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:12][C:11]=1[OH:43])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCOCC1.[H][H]>[Ni].O1CCCC1>[C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:42])[CH:19]([O:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:12][C:11]=1[OH:43])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(Oc1ccc(N)cc1)C(=O)Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl

Procedure:
An amount of 670 g (1.10 mol) of 2-benzamido-4-chloro-5-[2-(p-nitrophenoxy]-myristamido]-phenol in the presence of 2370 ml of tetrahydrofuran, 47.8 g of morpholine, and 22 ml of Raney nickel is reduced in an autoclave at an initial hydrogen pressure of 10 MPa and a temperature of 40° C. After 90 min the theoretical amount of hydrogen is found to be taken up. The catalyst is filtered off. The filtrate is concentrated by evaporation to a volume of 1 l and then poured out in 4 l of ethanol. The precipitate is filtered off and dried.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[C:24]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1)=[O:20]
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COC(=O)c1ccc2c(c1)C(=Cc1cc(C(C)C)c(OC)c(C(C)C)c1)C(=O)N2

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-methoxycarbonyl-2-oxindole to give 0.25 g of 3-(3,5-Diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester as a yellow-orange solid.