Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH:20][C:21](OCC)=[O:22])[C:14]=1[NH:26][C:27](=[O:43])[CH2:28][CH:29]1[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:36][C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)([CH3:12])[CH3:11].[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)C(C(C(O)=O)O)O>C(Cl)Cl>[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH:20][CH2:21][OH:22])[C:14]=1[NH:26][C:27](=[O:43])[CH2:28][CH:29]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=2[O:36][C:37]2[C:42]1=[CH:41][CH:40]=[CH:39][CH:38]=2)([CH3:12])[CH3:11]
Reactant: CCOC(=O)C=Cc1cccc(C(C)C)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: FB(F)F
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)c1cccc(C=CCO)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
68 μl (0.60 mmol) of boron trifluoride etherate were added at -78° C. to a solution of 228 mg (0.5 mmol) of N-[2-isopropyl-6-(2-ethoxycarbonylethenyl)phenyl]-2-(9H-xanthen-9-yl)acetamide [prepared as described in step (i) above] in 6 ml of methylene chloride. The resulting mixture was stirred for 30 minutes, after which 2.0 ml of a 1.0M solution of diisobutylaluminum hydride were added dropwise over a period of 5 minutes. The temperature of the mixture was allowed to rise to room temperature, and then 10 ml of a 10% w/v aqueous solution of tartaric acid were added to the reaction mixture in order to stop the reaction. The reaction mixture was then diluted with methylene chloride. The diluted mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was triturated with a mixture of diethyl ether and hexane to cause crystallization. The crystals were collected by filtration to give 185 mg (yield 85%) of the title alcohol derivative, melting at 225°-227° C. (after recrystallization from a mixture of acetonitrile and diisopropyl ether).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-:3])=[O:2].Br[CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:17][CH:16]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Nc1ccc(O)cc1
Reactant: CCOC(=O)C=C(OC)C(C)Br
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
Following the procedure of Example 1, 4-(2-nitro-4-trifluoromethylphenylamino)phenol is reacted with ethyl 4-bromo-3-methoxy-2-pentenoate to give ethyl 4-[4-(2-nitro-4-trifluoromethylphenylamino)phenoxy]-3-methoxy-2-pentenoate
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][C:9]1([CH3:22])[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2].CCO>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][C:9]1([CH3:22])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(CNC(=O)OC(C)(C)C)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1(CNC(=O)OC(C)(C)C)CCNCC1
Reaction time: 16 h
Yield: 103.1 %

Procedure:
20% palladium hydroxide on carbon (283 mg) was added to an EtOH (100 ml) solution of tert-butyl[(1-benzyl-4-methylpiperidin-4-yl)methyl]carbamate (2.57 g), and stirring was performed at 70° C. under a hydrogen atmosphere of medium pressure of 3 kgf/cm2 for 16 hours. After argon purge the reaction liquid was filtered through Celite and concentrated under reduced pressure to obtain tert-butyl[(4-methylpiperidin-4-yl)methyl]carbamate (1.90 g).
Reaction SMILES: ClC1C=C(C2C=[C:10]([C:20]([N:22]3[CH2:27][CH2:26]NC(=O)C3)=O)[O:11]C=2C2C=CC(F)=CC=2)C=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[CH:38]=[C:39]([C:50](O)=[O:51])[O:40][C:41]=2[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[N:49])[CH:43]=2)[CH:33]=[C:34]([F:36])[CH:35]=1.N1CC[C@@H](O)C1>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[CH:38]=[C:39]([C:50]([N:22]3[CH2:27][CH2:26][C@@H:10]([OH:11])[CH2:20]3)=[O:51])[O:40][C:41]=2[C:42]2[CH:43]=[C:44]([C:48]#[N:49])[CH:45]=[CH:46][CH:47]=2)[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccc(F)cc3)o2)CCN1
Reactant: N#Cc1cccc(-c2oc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)c1
Agent: O[C@@H]1CCNC1
Product: N#Cc1cccc(-c2oc(C(=O)N3CC[C@@H](O)C3)cc2-c2cc(F)cc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 6 starting with the compound from Example 20A. 1.1 equivalents of (3R)-pyrrolidin-3-ol are used. 51.0 mg (85% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:2].[CH3:11]I>C(#N)C>[CH2:1]([S:3][CH2:4][C:5]1[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH:10]=1)[CH3:2]
Reactant: CCSCc1ccncc1
Reactant: CI
Solvent: CC#N
Product: CCSCC1=CCN(C)CC1
Yield: 47.6 %

Procedure:
8.2 g (0.054 mol) of 4-[(ethylthio)methyl]pyridine are dissolved in 60 ml of acetonitrile and then 9.1 g of methyliodide are added. After 12 hours the reaction mixture is evaporated down in vacuo. The residue is reacted analogously to Example 1 b) with sodium borohydride in methanol and worked up. The crude product obtained is distilled (5.2 g; 56.3% of theory; b.p. 118°-120° C./20 mbar) and then chromatographed on neutral aluminium oxide using chloroform as eluant. 4.4 g of 4-[(ethylthio)methyl]-1-methyl-1,2,3,6-tetrahydropyridine are obtained, which is converted with one equivalent of maleic acid into the maleate (m.p. 102°-105° C., from ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([NH2:10])[CH:4]=1.C(=O)(O)[O-].[Na+].[Br:16][CH2:17][C:18](Br)=[O:19]>C(Cl)(Cl)Cl>[Br:16][CH2:17][C:18]([NH:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:9])=[O:19]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(O)c(NC(=O)CBr)c1
Temperature: 0 °C
Yield: 76.6 %

Procedure:
4-methoxy-2-aminophenol (3.0 g, 17.1 mmol) was dissolved in 100 mL of chloroform. 62 mL of saturated sodium bicarbonate solution was added and the new bi-phase mixture was stirred vigorously and cooled to 0° C. using an ice bath. Bromoacetylbromide (3.42 mL, 39 mmol) was added drop-wise. Fifteen minutes later the solution was removed from the ice bath and maintained at room temperature for 1.5 hours. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) indicated that all of the starting material was gone and a new peak (Rt=4.9 min) had formed. The organic layer was separated and the aqueous phase was extracted with 100 mL of chloroform. The combined organic phases were dried over Na2SO4, filtered and concentrated to give 2-bromo-N-[2-hydroxy-5-(methyloxy)phenyl]acetamide (3.42 g, 13.1 mmol, 77%) as a brown amorphous solid. MS (ES) m/e 260 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[CH3:13][C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=[O:15].[OH-].[K+].O>C(O)C>[CH3:18][O:17][CH:16]([O:19][CH3:20])[C:14](=[O:15])[CH:13]=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COC(OC)C(C)=O
Reactant: O=Cc1ccc(-c2cccs2)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(OC)C(=O)C=Cc1ccc(-c2cccs2)s1

Procedure:
To a solution of 5-formyl-2,2'-bithiophene (4.0 g) in ethanol (120 ml) was added dimethoxymethyl methyl ketone (3 ml). Potassium hydroxide aqueous solution (50%) was added dropwisely into the solution mixture at 16° C. Color changed from yellowish brown into dark green, then dark brown. Yellow solid was formed during the reaction. Water was added. Solid residue was filtered and washed with water, redissolved in acetone and separated by silica gel chromatography eluted with ethyl acetate/n-hexane (1:9). Yellowish crystals 1.88 g were obtained, melting point 74° C.
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]([NH:9][N:10]=[C:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)N.[OH-].[Na+].CN([CH:23]=[O:24])C>>[CH:23]([C:17]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][NH:9][CH:6]=1)=[O:24]
Reactant: CCOC(=O)C(C)=NNC(N)=O
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1n[nH]cc1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
POCl3 (532 mL) was added drop-wise to DMF (1 L) at 0° C. over 1 h. The solution was stirred at 0° C. for 1 h, and then product (1-B) (200 g, 0.9 mol) was added in small portions while the reaction temperature was maintained below 5° C. After the addition, the reaction was heated to 80° C. and stirred for another 4 hours. The solution was poured into ice water, and the pH was adjusted to 7 with 2 M NaOH, while maintaining the temperature below 5° C. After standing overnight, the solid was filtered, washed with H2O, and dried in vacuo to give crude product (2-B) (46 g, 30%, for two steps) as a yellow solid. 1H NMR (300 MHz, d-DMSO): δ 14.14 (br, 1H), 10.27 (s, 1H), 8.52 (br, 1H), 4.38 (q, 2H), 1.35 (t, 3H). LC-MS (M+H)+=169.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[N:11]([CH3:13])[CH3:12])=[O:4].O[Li].O>C1COCC1.CO.O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:14]([N:10]([C:9]1[CH:8]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])[N:11]([CH3:13])[CH3:12])=[O:23]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)N(C)C
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N(C(=O)c1ccc(Cl)cc1Cl)c1cc(-c2ccccc2)sc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 16.7 %

Procedure:
3-[N-(2,4-Dichloro-benzoyl)-N′,N′-dimethyl-hydrazino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.050 g, 0.11 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 10 mL) and then added 1N aqueous solution of LiOH.H2O (0.67 mL, 0.67 mmol). The reaction mixture was stirred at 60° C. for 2 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by preparative TLC using dicholomethane:methanol (9:1) to obtain 3-[N-(2,4-Dichloro-benzoyl)-N′,N′-dimethyl-hydrazino]-5-phenyl-thiophene-2-carboxylic acid (Compound 72) (0.008 g, 17%). 1H NMR (DMSO, 400 MHz): δ 7.81 (d, 2H), 7.69 (d, 2H), 7.54-7.40 (m, 5H), 2.42 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[S:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:26]2[CH2:27][CH2:28][S:24][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: C1CSCN1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCSC2)cn1
Yield: 28 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using thiazolidine instead of 2-aminoethyl isopropylether, to the title compound (68 mg, 28%) which was obtained as a white solid. MS: m/e=382.2 [M+H]′.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([CH:25]=[N:26][OH:27])[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:33][CH:32]=1)=[CH2:30].C(=O)([O-])O.[K+].ClN1C(=O)CCC1=O>C(OCC)(=O)C.O>[F:28][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:30][CH:29]([C:31]5[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][CH:36]=5)[O:27][N:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: C=Cc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C=NO)cs2)CC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C2CC(c3csc(C4CCN(C(=O)Cn5nc(C(F)F)cc5C(F)F)CC4)n3)=NO2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde oxime (1.50 g) and tert-butyl (4-vinylphenyl)carbamate (0.94 g) in ethyl acetate (140 ml) were added, at room temperature, potassium hydrogencarbonate (1.79 g) and N-chlorosuccinimide (0.50 g), and then one drop of water. After the reaction mixture had been stirred at 60° C. for 3 h, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl (4-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl)carbamate (0.90 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21](N1C=CN=C1)([N:23]1[CH:27]=CN=[CH:24]1)=[O:22].Cl.CNC.C(N(CC)CC)C>ClCCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:19]([NH:20][C:21]([N:23]([CH3:27])[CH3:24])=[O:22])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: CNC
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)N(C)C)nc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Following the procedure of Example 11, 3.0 g of 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine and 2.0 g of carbonyldiimidazole are reacted at reflux in 50 ml of 1,2-dichloroethane for 24 hours. The mixture is cooled, treated sequentially with 1.5 g of dimethylamine hydrochloride and 2 ml of triethylamine, and stirred at room temperature for 1.5 hours. It is then washed with water prior to chromatography over 150 g of silica gel. The product is eluted with a 99/1 chloroform/methanol mixture and recrystallized from ethyl acetate to give N-[6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-yl]-N',N'-dimethylurea, mp 177°-181° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.I[C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl>N1C=CC=CC=1.[Cu]>[C:24]1([N:23]2[C:19]([N:13]3[C:12](=[O:15])[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=4)=[N:14]3)=[CH:20][CH:21]=[N:22]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Ic1ccnn1-c1ccccc1
Reactant: O=c1ccc(-c2cccc(C(F)(F)F)c2)n[nH]1
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Product: O=c1ccc(-c2cccc(C(F)(F)F)c2)nn1-c1ccnn1-c1ccccc1
Yield: 14.8 %

Procedure:
A suspension of 6-[3-(trifluoromethyl)phenyl]pyridazin-3(2H)-one (240 mg), 5-iodo-1-phenyl-1H-pyrazole (540 mg), copper powder (64 mg) and potassium carbonate (415 mg) in pyridine (5 mL) was heated under reflux for 24 hr. The reaction mixture was poured into 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from hexane/ethyl acetate to give the title compound (56.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: Brc1ccc2ncccc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1cnc2ccc(Nc3cccc4cccnc34)cc2c1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condensor, and nitrogen inlet was added 8-aminoquinoline (4.2 grams, 29.0 mmoles), 6-bromoquinoline (6.0 grams, 29.0 mmoles), tris(dibenzylideneacetone)dipalladium (0) (0.4 grams, 0.48 mmoles), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (0.6 grams, 0.60 mmoles), sodium tert-butoxide (4.7 grams, 49.0 mmoles) and anhydrous toluene (80 mL). The contents of the flask were refluxed for three days; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with dichloromethane (60 mL) and ethyl acetate (60 mL). The combined organic layers were concentrated in vacuo to yield a yellow solid. The solid was chromatographed on silica gel, eluting with a hexane/ethyl acetate gradient to afford 4.4 grams of the desired product as a yellow solid. 1H NMR (CDCl3) δ 8.8 (d, 2H), 8.6 (bs, 1H), 8.0-8.2 (m, 3H), 7.2-7.8 (m, 7H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7](C(O)=O)[C:8](=[O:15])[NH:9]2.Cl>N1C=CC=CC=1>[Br:1][C:7]1[C:8](=[O:15])[NH:9][C:10]2[C:5]([CH:6]=1)=[C:4]([Cl:3])[CH:13]=[C:12]([Cl:14])[CH:11]=2
Reactant: O=C(O)c1cc2c(Cl)cc(Cl)cc2[nH]c1=O
Reactant: BrBr
Agent: Cl
Solvent: c1ccncc1
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2cc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
50.8 mmol of bromine are added dropwise to a suspension containing 25.4 mmol of 5,7-dichloro-2(1H)-quinolone-3-carboxylic acid in 65 ml of pyridine at 0 C. After stirring for 10 minutes at room temperature, the whole mixture is brought to 90 C. for one hour. After cooling, 300 ml of 1N hydrochloric acid are added. The expected product is obtained by filtering the precipitate, then washing the latter with 1N hydrochloric acid and with water and drying.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[CH3:13][O:12][C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[N:1]([CH2:30][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:15]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:14]=3)=[CH:33][CH:32]=1)[CH:2]=[CH:3]2)=[O:11]
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COC(=O)c1cccc2cc[nH]c12
Product: COC(=O)c1cccc2ccn(Cc3ccc(OCc4ccc5ccccc5n4)cc3)c12

Procedure:
This compound was prepared from methyl 7-indole carboxylate and 4-(quinolin-2-ylmethoxy)benzyl chloride (Example 1a) by the method described in Example 1b, part i. The residue was purified by chromatography on flash silica using petroleum spirit 40°-60° C./diethyl ether (2:1, 7:5) as eluent.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1([OH:71])[CH3:70])[CH3:2]>C(#N)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([OH:62])[CH2:5][C:4]1([OH:71])[CH3:70])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1(C)O)C(C)CC2OC
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1(C)O)C(C)CC2OC
Yield: 77 %

Procedure:
A solution of 0.086 g (0.082 mmole) of 17-ethyl-14-t-butyldimethylsilyloxy-1,16-dihydroxy-12-[2'-(4"-t-butyldimethylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-16-methyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10-trione in 2 mL of a solution of 1:9 48% aqueous HF-acetonitrile was stirred at room temperature for 8 h. The reaction was quenched by addition of 2 mL of ethoxytrimethylsilane and the solution was concentrated to dryness under vacuum. The residue was purified by flash chromatography (2×20 cm silica gel) using 25% acetone-hexane to afford 0.051 g (77%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH2:26])[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:13][CH2:12]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>C1COCC1>[CH2:1]([C@H:8]([NH2:26])[CH2:9][N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC(Oc2ccc(F)c(F)c2)CC1
Agent: B
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)CN1CCC(Oc2ccc(F)c(F)c2)CC1
Reaction time: 1 h
Yield: 95.7 %

Procedure:
The product from Example 5, Step (b) (0.1 g) was dissolved in THF (3 ml) and borane [0.84 ml (1M in THF)] was added. The reaction was stirred for 1 hr and then quenched slowly with methanol. The solvents were evaporated and the residue re-dissolved in 50% H2O/50% conc HCl (2 ml) and refluxed for 1 hr. The solvents were evaporated. The free base was liberated by addition of aqueous NaOH (2M) and extraction with ethyl acetate followed by drying, filtration and evaporation of solvent to give the sub-title compound as an oil (0.092 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)Oc2ccc(C#N)cc2C(N2CCN(c3ccc(F)cc3)CC2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 1-(4-fluoro-phenyl)-piperazine as starting material, the title compound was prepared as a white solid.