Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:13][C:14]([C:16]1[S:20][C:19]2[CH:21]=[CH:22][C:23](Br)=[CH:24][C:18]=2[CH:17]=1)=[O:15].B(O)(O)[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:13][C:14]([C:16]1[S:20][C:19]2[CH:21]=[CH:22][C:23]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:24][C:18]=2[CH:17]=1)=[O:15]
Reactant: Nc1ccc(-c2cccs2)cc1NC(=O)c1cc2cc(Br)ccc2s1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1cc2cc(-c3cccnc3)ccc2s1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a stirred solution of 261a (120 mg, 0.26 mmol) and pyridin-3-yl-3-boronic acid (123 mg, 0.34 mmol) in a 2:1 mixture of DME-water (9 mL), was added Pd(PPh3)4 (22 mg, 0.018 mmol), tri-o-toly phosphine (6 mg, 0.018 mmol) and potassium carbonate (109 mg, 0.79 mmol). The solution was degassed with N2 for 5 minutes and then heated at 80° C. for 15 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2×40 mL). The organic layer was separated, dried with sodium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluent ethyl acetate. A subsequent trituration was performed with DCM for 15 minutes to yield 262 as a white solid (80 mg, 67% yield). 1H NMR: (DMSO) δ 10.09 (s, 1H), 8.99 (dd, J=2.3, 0.8 Hz, 1H), 8.58 (dd, J=4.7, 1.6 Hz, 1H), 8.38 (s, 1H), 8.33 (d, J=1.4 Hz, 1H), 8.17 (ddd, J=9.6, 3.9, 1.8 Hz, 1H), 7.83 (dd, J=8.5, 1.8 Hz, 1H), 7.53-7.50 (m, 2H), 7.46 (d, J=2.2 Hz, 1H), 7.34 (dd, J=5.1, 1.2 Hz, 1H), 7.31 (dd, J=8.2, 2.2 Hz, 1H), 7.25 (dd, J=3.5, 1.2 Hz, 1H), 7.03 (dd, J=5.1, 3.7 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 5.74 (s, 2H).
Reaction SMILES: [CH2:1]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][CH2:3][NH:2]1.B.C1COCC1.FC(F)(F)C(O)=O>O1CCCC1>[CH2:1]1[CH:7]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2c(c1)cc1n2CCCNC1
Agent: B
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: c1ccc2c(c1)CC1CNCCCN21
Yield: 75 %

Procedure:
In an operation carried out in a manner similar to that described in Example I but employing 22 grams of 2,3,4,5-tetrahydro-1H-[1,4]-diazepino[1,2-a]indole, milliliters of 1 M BH3.THF in tetrahydrofuran and milliliters of trifluoroacetic acid, a 75 percent yield of 2,3,4,5,11,11a-hexahydro-1H-[1,4]-diazepino[1,2-a]indole was obtained as determined by GLC on the isolated product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][S:10](Cl)(=[O:12])=[O:11])=[C:4]([O:14][CH3:15])[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[S:24]([NH2:27])(=[O:26])=[O:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][S:10]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[S:24]([NH2:27])(=[O:25])=[O:26])(=[O:12])=[O:11])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: COc1cc(Cl)ccc1C=CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(Cl)ccc1C=CS(=O)(=O)Nc1ccc(C)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
2-(4-Chloro-2-methoxy-phenyl)-ethenesulfonyl chloride (0.50 g, 1.87 mmol) was added slowly to a solution of 2-amino-5-methyl-benzenesulfonamide (0.38 g, 2.05 mmol) in anhydrous pyridine (10 mL) and the reaction mixture was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL). The organic phase was washed with 1 M hydrochloric acid and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography gave 0.42 g (54% yield) of the title compound.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(OCC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2OCC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2-(2,2-dimethylpropoxy)-2′-fluoro-5′-methoxybiphenyl-4-yl)oxy)methyl)phenyl)propanoate (114 mg) in ethanol (3.0 mL) was added 2N aqueous sodium hydroxide solution (0.22 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (97 mg) as a white solid.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1>[N+](C1C=CC=CC=1)([O-])=O>[F:15][C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][C:21]=1[C:10]([C:9]1[CH:13]=[CH:14][C:6]([F:5])=[CH:7][CH:8]=1)=[O:11]
Reactant: COc1cccc(F)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(F)cc2)c(F)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 24.5 %

Procedure:
To a cold (5° C.) mixture of aluminium trichloride (144 g, 1.08 mol, 1.13 eq.) in nitrobenzene (450 mL) was slowly added a solution of 4-fluorobenzoyl chloride (120 mL, 1 mol, 1.05 eq.) in nitrobenzene (200 mL). 3-fluoroanisole (108.5 mL, 0.95 mol) was slowly added to the reaction mixture. The cooling bath was removed and the reaction mixture was stirred 3 h at 20° C., and poured into ice-water. The aqueous layer was extracted with dichloromethane (2 times). The combined organic layers were dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The crude mixture was crystallized in cyclohexane, filtered and the solid was washed with cyclohexane. The solid was dried in vacuo, affording the title compound (57.78 g, 25%) as a white solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][O:28][C:29](=[O:65])[CH2:30][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][O:45]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:25])C=CC=CC=1>C(O)(=O)C>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][O:28][C:29](=[O:65])[CH2:30][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][OH:45])=[O:25]
Reactant: O=C(CCCCCCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1)OCOC(=O)CCCCCCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: O=C(CCCCCCCCCCCCCCCO)OCOC(=O)CCCCCCCCCCCCCCCO
Temperature: 55 °C

Procedure:
Methylene bis(16-triphenylmethoxyhexadecanoate) (0.07 g, 0.07 mmol) is dissolved in glacial acetic acid (8 ml) and heated at 55° C. The reaction is monitored by TLC. After 10 hours the reaction mixture is poured onto ice, and the crude product is filtered, washed with aqueous sodium bicarbonate and water, and dried under reduced pressure. The product is purified by flash chromatography on a silica column with chloroform/methanol (20:1) as eluant to yield the title compound as a white solid. 1H-NMR (300 MHz, CDCl3): δ 1.2-1.4(m, 44H), 1.5-1.6(m, 8H), 2.35(t, 4H), 3.64(t, 4H), 5.75(s, 2H).
Reaction SMILES: C(OC([N:7]1[CH2:11][C@@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH:20]=[C:21]([C:23]1[CH2:29][C@H:28]2[N:25]([C:26](=[O:40])[C@@H:27]2[C@H:30]([O:32][Si](C(C)(C)C)(C)C)[CH3:31])[C:24]=1[C:41]([O:43]CC=C)=[O:42])[CH3:22])=O)C=C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.C(OCC)(=O)C>[OH:32][C@@H:30]([C@H:27]1[C:26](=[O:40])[N:25]2[C@@H:28]1[CH2:29][C:23]([C:21]([CH3:22])=[CH:20][C@@H:8]1[CH2:9][C@H:10]([OH:12])[CH2:11][NH:7]1)=[C:24]2[C:41]([OH:43])=[O:42])[CH3:31]
Reactant: C=CCOC(=O)C1=C(C(C)=C[C@@H]2C[C@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=C[C@@H]1C[C@H](O)CN1)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 9 h
Yield: 11.4 %

Procedure:
To a solution of allyl (5R,6S)-3-[2-{(2S,4S)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)pyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.85 g) in tetrahydrofuran (20 ml) were added acetic acid (2.9 ml) and 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (25.3 ml) in turn at ambient temperature. After stirring at ambient temperature for 9 hours, the solution was poured into a mixture of water (230 ml) and ethyl acetate (230 ml). The organic layer was separated, washed 5 times with water (100 ml), washed two times with brine (50 ml) dried over magnesium sulfate, and evaporated. To this residue were added tetrahydrofuran (10 ml), ethanol (3.5 ml) and triphenylphosphine (0.08 g). To this solution were added morpholine (0.28 ml) and tetrakis(triphenylphosphine)palladium(0) (0.11 g) successively at ambient temperature. Stirring at ambient temperature for 1 hour gave a precipitate, which was collected by filtration, washed with dichloromethane and dissolved in water (80 ml). The solution was washed with ethyl acetate (40 ml×3) and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[2-{(2S,4S)-4-hydroxypyrrolidin-2-yl}-1-methylethenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (155 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][N:28]([CH:26]=[O:27])[CH2:29][CH2:30]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: O=CN1CCNCC1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCN(C=O)CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from 2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2yl)ethyl]aminocarbonyl}benzoic acid, 4-formylpiperazine, pentafluorophenyl-N,N′,N′-tetramethyluroniumhexafluorophosphate (PFTU), and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.01 minutes; C22H21Cl2N5O3 (474.35); mass spectrum: (M−H)−=473/475/477 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[O:16]CC2C=CC(OC)=CC=2)[CH:11]=[O:12])=[CH:4][CH:3]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[OH:16])[CH:11]=[O:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(COc2ccc(C=O)cc2OCc2ccc(Cl)cc2)cc1
Solvent: CC(=O)O
Product: O=Cc1ccc(O)c(OCc2ccc(Cl)cc2)c1

Procedure:
A solution of 3-(4-chloro-benzyloxy)-4-(4-methoxy-benzyloxy)-benzaldehyde (41)(108 g) in acetic acid (500 mL) was heated at reflux overnight. Excess acetic acid was removed by rotary evaporation under reduced pressure (hard vacuum) and the resulting residue taken up in ethyl acetate. The organic layer was extracted with aqueous sodium hydroxide solution (1 N; 3×150 mL). The combined inorganic phases were neutralised with conc. hydrochloric acid and back extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulphate. The resulting oil was triturated with 50/50 diethyl ether/hexane, the solid product 42 collected by vacuum filtration and the precipitate washed with hexane (32.6 g, 44%, retention time 3.08 mins, ES− 261.33).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[S:6][C:7]([S:10]([CH2:13][N+:14]([O-:16])=[O:15])(=[O:12])=[O:11])=[CH:8][CH:9]=1>C(O)(=O)C>[Br:1][C:9]1[CH:8]=[C:7]([S:10]([CH2:13][N+:14]([O-:16])=[O:15])(=[O:11])=[O:12])[S:6][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COc1ccc(S(=O)(=O)C[N+](=O)[O-])s1
Solvent: CC(=O)O
Product: COc1sc(S(=O)(=O)C[N+](=O)[O-])cc1Br
Yield: 23.9 %

Procedure:
A solution of bromine (0.254 g) in acetic acid (2 ml) was added to a stirred solution of 2-methoxy-5-(nitromethylsulphonyl)thiophene (0.39 g) in acetic acid (8 ml). After 1hour the mixture was quenched with water (10 ml). The yellow precipitate was collected by filtration and recrystallised from ethanol to give 3-bromo-2-methoxy-5-(nitromethylsulphonyl)thiophene as a white solid (0.12 g) m.p. 120°-121° C.; m/e (electron impact): 315, 317 [mean M+ for Br=80 is 316]; NMR (90 MHz): 4.1 (s,3H), 5.60 (s,2H), 7.22 (s,1H); microanalysis, found: C,23.1; H,1.8; N,4.1%; C6H6BrNO5S2 requires C,22.8; H,1.9; N,4.4%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)C.[H-]>>[OH:3][CH2:4][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(-c3ccccc3)c2c1
Agent: [H-]
Product: N#Cc1cnc2ccc(CO)cc2c1-c1ccccc1

Procedure:
Similar procedure as described in example 61h was used, starting from 3-cyano-4-phenyl-quinoline-6-carboxylic acid ethyl ester (example 62a), and diisobutylaminum hydride to give 6-hydroxymethyl-4-phenyl-quinoline-3-carbonitrile. LC-MS m/e 261 (MH+).
Reaction SMILES: C([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[C:8]([NH:18]C(=O)C)[CH:9]=[CH:10][C:11]=2[NH:14]C(=O)C)[CH2:6]1)(=O)C.[ClH:22]>C(O)C>[ClH:22].[ClH:22].[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([NH2:18])=[C:7]2[C:12]=1[CH2:13][CH:5]([OH:4])[CH2:6]2
Reactant: CC(=O)Nc1ccc(NC(C)=O)c2c1CC(OC(C)=O)C2
Agent: Cl
Solvent: CCO
Product: Nc1ccc(N)c2c1CC(O)C2
Yield: 73 %

Procedure:
1.59 g of compound (5), 10 ml of ethanol and 10 ml of 37% hydrochloric acid were mixed in a three-necked flask. The reaction medium was refluxed. The reaction was followed by TLC. When the starting product and the monoacetylated product disappeared, the mixture was allowed to return to ambient temperature. The precipitate was then filtered off, washed with water and then with diisopropyl ether, and dried under vacuum. 944 mg of a white powder (yield=73%) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1.[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54][NH2:55].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([NH:55][CH2:54][CH2:53][N:52]([CH3:56])[CH3:51])=[O:28])=[CH:21][CH:20]=[CH:19]2
Reactant: CN(C)CCN
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4c(C(=O)NCCN(C)C)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-(6,7-Dimethoxyquinolin-4-yloxy)-1-naphthoic acid (80 mg, 0.213 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol) and HOAT (29 mg, 0.213 mmol) were added to a reaction tube, then dissolved in DMF (0.6 mL). A solution of N,N-dimethylethylenediamine (23 mg, 0.256 mmol) in DMF (0.6 mL) was added to the reaction, followed by Hunig's base (75 mg, 0.581 mmol). The mixture became yellow and clear within 15 min and was stirred at RT for 16 h. The mixture was concentrated under vacuum. The remaining yellow oil was purified by silica gel chromatography (2% to 3% 7N NH3 in MeOH in CH2Cl2) to afford 6-((6,7-bis(methoxy)-4-quinolinyl)oxy)-N-(2-(dimethylamino)ethyl)-1-naphthalenecarboxamide as a white solid. MS (ESI, pos. ion) m/z: 446.1 (M+1). Calc'd for C226H27N3O4−445.52.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:5][C:4]([CH3:7])([CH3:6])[C:3](=[O:8])[CH2:2][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]([F:9])([F:19])[F:20])=[CH:13][CH:14]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)COc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
With stirring and at room temperature, a solution of 5.5 g (31 mmol) of 1-bromo-3,3-dimethylbutan-2-one in 50 ml of acetonitrile was slowly added dropwise to a mixture of 5.5 g (31 mmol) of 4-trifluoromethoxyphenol and 4.27 g (31 mmol) of potassium carbonate in 100 ml of acetonitrile. After the addition had ended, the reaction mixture was stirred at reflux temperature overnight. The solid was filtered off and the filtrate was concentrated. The residue was taken up in 50 ml of ethyl acetate and the organic phase was washed with ice-cold 1M aqueous sodium hydroxide solution and water. The organic phase was separated off, dried over sodium sulphate, filtered and concentrated. The crude product was then purified by column chromatography. This gave 2.22 g (26%) of the desired product.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:26])[C:14]3[C:19]([Br:20])=[CH:18][N:17]=[C:16]([O:21][CH2:22][C@@H:23]4[CH2:25][O:24]4)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:27][NH2:28]>O1CCOCC1>[C:1]12([CH2:11][NH:12][C:13](=[O:26])[C:14]3[C:19]([Br:20])=[CH:18][N:17]=[C:16]([O:21][CH2:22][C@@H:23]([OH:24])[CH2:25][NH:28][CH3:27])[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OC[C@@H]2CO2)ncc1Br
Solvent: C1COCCO1
Product: CNC[C@H](O)COc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Br)cn1
Reaction time: 4 h

Procedure:
A mixture of N-(1-adamantylmethyl)-5-bromo-2-[(2S)-oxiran-2-ylmethoxy]isonicotinamide (0.12 g) (Example 35(iii)), 40% aqueous methylamine (4 ml) and 1,4-dioxane (4 ml) was stirred for 4 hours. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel eluting with ethyl acetate:ethanol:0.880 ammonia solution (4:1:0.1 to 1.5:1:0.1). The isolated material was dissolved in a solution of hydrogen chloride in 1,4-dioxane (10 ml of a 4M solution) and concentrated to afford the titled compound (0.039 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[O:9][N:8]=2)[CH:2]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([Cl:18])=[O:14])[O:9][N:8]=2)[CH:2]=1
Reactant: O=C(O)c1cc(-c2cccnc2)no1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(-c2cccnc2)no1
Temperature: 25 °C

Procedure:
600 mg (3.16 mmol) of 3-(pyridin-3-yl)-1,2-oxazole-5-carboxylic acid were initially charged in dichloromethane, and three drops of DMF were added. 1.16 g (9.15 mmol) of oxalyl chloride were added dropwise under argon (vigorous evolution of gas). The reaction solution was stirred at room temperature and then the solvent was removed on a rotary evaporator. 30 ml of toluene were added to the residue. After the toluene had been removed on a rotary evaporator, the residue was converted further directly.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:18]=[C:17]([C:19](Cl)=[O:20])[O:16][N:15]=1>CC(C)=O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19]([C:17]2[O:16][N:15]=[C:14]([CH3:13])[CH:18]=2)=[O:20])=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Cc1cc(C(=O)Cl)on1
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)c2cc(C)no2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a stirred solution of 3.3 g of ethyl p-aminobenzoate in 60 ml of acetone was added 1.46 g of 3-methylisoxazole-5-carbonyl chloride. The mixture was stirred at room temperature for 1 hr. and then refluxed for 1 hr. The solvent was removed and the residue was washed with 5% hydrochloric acid, 5% potassium carbonate and water. Recrystallization from a mixture of benzene and n-hexane gave 1.6 g of pure product. Melting point: 160°-163° C. Yield: 58.4%.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[C:5]([C:12]([OH:14])=[O:13])[CH:4]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:10][C:9]([C:7]1[CH:8]=[N:3][CH:4]=[C:5]([CH:6]=1)[C:12]([OH:14])=[O:13])=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cncc(C(=O)O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cncc(C(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
To a suspension of 60% sodium hydride (527 mg) in dimethylformamide (20 mL) was added 3,5-pyridinedicarboxylic acid (2.00 g) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. To the mixture was added (bromomethyl)benzene (2.05 g) and the mixture was stirred at 60° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with ethyl acetate to give 5-[(benzyloxy)carbonyl]nicotinic acid as a pale yellow powder (722 mg).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH:10]1([N:13]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34](O)([CH3:36])[CH3:35])[CH2:29][CH2:28]2)[C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][CH:24]=[N:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:11]1.C([O-])(O)=O.[Na+]>ClCCl>[CH:10]1([N:13]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]([F:7])([CH3:36])[CH3:35])[CH2:29][CH2:28]2)[C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][CH:24]=[N:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:11]1
Reactant: CC(C)(O)CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reaction time: 2 h

Procedure:
Diethylaminosulfur trifluoride (57 μL) is added drop wise to N-cyclopropyl-N-[1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide (83 mg) in dry dichloromethane (12 mL) at −78° C. and the reaction mixture is stirred at this temperature for 2 h. The mixture is poured on aqueous NaHCO3 solution (15 mL) and the aqueous phase is extracted with dichloromethane. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The solid residue is triturated with diisopropyl ether, filtered off, and dried to give the title compound. LC (method 2): tR=1.10 min; Mass spectrum (ESI+): m/z =386 [M+H]+.