Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=C(C23CCC(CCOCC(OC(C)(C)C)=O)(CC2)CO3)C=CC=1.O1CCCCC1OC1C=C(C23CCC(CCOCC(OC(C)(C)C)=O)(CC2)CO3)C=CC=1.O1CCCCC1[O:65][C:66]1[CH:67]=[C:68]([C:72]23[CH2:79][CH2:78][C:75]([CH2:80][CH2:81]/[CH:82]=[CH:83]/[C:84]([O:86][CH3:87])=[O:85])([CH2:76][CH2:77]2)[CH2:74][O:73]3)[CH:69]=[CH:70][CH:71]=1>>[OH:65][C:66]1[CH:67]=[C:68]([C:72]23[CH2:77][CH2:76][C:75]([CH2:80][CH2:81]/[CH:82]=[CH:83]/[C:84]([O:86][CH3:87])=[O:85])([CH2:78][CH2:79]2)[CH2:74][O:73]3)[CH:69]=[CH:70][CH:71]=1
Reactant: COC(=O)/C=C/CCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(O)c3)(CC1)OC2
Agent: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Product: COC(=O)/C=C/CCC12CCC(c3cccc(O)c3)(CC1)OC2

Procedure:
(E)-Methyl 5-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)pent-2-enoate was prepared using a procedure analogous to tert-butyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate except that tert-butyl 2-(2-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate was replaced with (E)-methyl 5-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)pent-2-enoate. The title compound was obtained (210 mg, 0.66 mmol, 89% yield) as a white solid. LCMS, [M−H]+=315.2. 1H NMR (500 MHz, CDCl3) δ 7.17 (t, J=8.0 Hz, 1H), 7.03-6.89 (m, 3H), 6.70 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 5.87 (dt, J=15.7, 1.5 Hz, 1H), 5.71 (s, 1H), 3.85 (s, 2H), 3.76 (s, 3H), 2.23-2.15 (m, 2H), 2.03 (dd, J=9.1, 4.7 Hz, 4H), 1.74-1.62 (m, 4H), 1.37-1.30 (m, 2H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:11][CH2:12][OH:13])[C:3]=1[F:14].[ClH:15].N([O-])=O.[Na+]>C(O)(=O)C>[Cl:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:11][CH2:12][OH:13])[C:3]=1[F:14]
Reactant: Nc1ccc([N+](=O)[O-])c(CCO)c1F
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Cl)c(F)c1CCO
Reaction time: 0.5 h
Yield: 83 %

Procedure:
7.33 g (37 mmol) of the compound (124) obtained in Reference Example 6 was added to 60 ml of 6N hydrochloric acid, and while cooling on ice, 15 ml of aqueous solution containing 2.95 g (43 mmol) of sodium nitrite was dropped to the solution through 5 minutes. The solution was stirred for 30 minutes as was. Then, 20 ml of concentrated hydrochloric acid and 20 ml of acetic acid were added to the solution, and the solution was stirred for 1 hour. While cooling on ice, 35 ml of concentrated hydrochloric acid solution containing 6.20 g (63 mmol) of cuprous chloride was dropped to the solution through 40 minutes, and the solution was stirred for 3 hours as was. The solution was extracted with 300 ml of ethyl acetate, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by the column chromatography (silica gel 100 g, eluent solvent; chloroform: methanol=50:1) to obtain 6.69 g of the subject compound (125) in a 83% yield.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)=[N:4][OH:5]>C(O)C.[Pt]>[NH2:12][C:8]1[CH:7]=[C:6]([C:3](=[N:4][OH:5])[C:2]([F:16])([F:15])[F:1])[CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(C(=NO)C(F)(F)F)c1
Agent: [Pt]
Solvent: CCO
Product: Nc1cccc(C(=NO)C(F)(F)F)c1
Reaction time: 2 h
Yield: 98 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(3-nitrophenyl)ethanone oxime (2.34 g) and 5% Pt(S)/C (2340 mg) in ethanol (530 mL) was hydrogenated at 50 psi for 2 hours. The crude reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (2 g) as an oil which was used in the next step without purification.
Reaction SMILES: [CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:48][C@@H:49]([C:53]1[CH:54]=[N:55][C:56]([CH3:59])=[CH:57][CH:58]=1)[CH2:50][CH2:51][OH:52].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:52][CH2:51][CH2:50][C@@H:49]([NH:48][C:21]([C:10]1[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=[C:8]([C:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH3:24])=[O:7])[CH:9]=1)=[O:22])[C:53]1[CH:54]=[N:55][C:56]([CH3:59])=[CH:57][CH:58]=1
Reactant: Cc1ccc([C@H](N)CCO)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](CCO)c3ccc(C)nc3)cc(C(=O)N(C)CC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylic acid (15 mg, 0.046 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (18 mg, 0.092 mmol), 1-hydroxybenzotriazole hydrate (7.0 mg, 0.046 mmol), and CH2Cl2 (2 mL) were added (R)-3-amino-3-(6-methylpyridin-3-yl)propan-1-ol (11 mg, 0.069 mmol) (WO 2008/130481) and N,N-diisopropylethylamine (12 μL, 0.069 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 40-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:19])[NH:10]2.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].[ClH:26].Cl.C(O)C>CO>[ClH:26].[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:20][NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:11]=1[NH:10][C:9](=[O:19])[CH2:8][CH2:7]2)[C:17]#[CH:18]
Reactant: CC(C)(C)N
Reactant: C#CCOc1ccc(OCC2CO2)c2c1NC(=O)CC2
Agent: Cl
Solvent: CO
Solvent: CCO
Product: C#CCOc1ccc(OCC(O)CNC(C)(C)C)c2c1NC(=O)CC2
Reaction time: 12 h

Procedure:
2 g of 5-(2,3-epoxypropoxy)-8-(2-propynyloxy)-3,4-dihydrocarbostyril was dissolved in 15 ml of methanol, and 2.6 g of t-butylamine was added to the solution, followed by allowing the mixture to stand at 15°-20° C. for 12 hours. After completion of the reaction, the methanol and the t-butylamine were evaporated under reduced pressure, and the resulting crude oil was converted into the hydrochloride thereof using hydrochloric acid and ethanol. The solvent was evaporated under reduced pressure, and the resulting crystals were dissolved in water and washed with chloroform to remove impurities. The aqueous layer was made alkaline with sodium hydroxide and then extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure to obtain colorless crystals, which were converted into the hydrochloride thereof with hydrochloric acid-ethanol. The solvent was evaporated under reduced pressure, and the residue was recrystallized from isopropanol to obtain 1.6 g of 8-(2-propynyloxy)-5-[3-(t-butylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril hydrochloride having a melting point of 182°-183° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].I[CH2:34][C:35]([NH2:37])=[O:36].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([O:26][CH2:34][C:35]([NH2:37])=[O:36])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)CI
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(O)ccc2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(OCC(N)=O)ccc2c1=O
Yield: 48.2 %

Procedure:
A solution of tert-butyl[4-(4-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.44 g, 1 mmol), 2-iodoacetamide (0.37 g, 2 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.30 mL, 2 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(2-amino-2-oxoethoxy)-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.24 g, 49.0%) as crystals.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:8]([O:15][CH2:16][CH:17]([O:24]C(=O)C)[CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:9]([O:13][CH3:14])[C:10]=2[OH:12])[N:5]=[C:4]([F:35])[N:3]=1.N>CO>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([NH:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:8]([O:15][CH2:16][CH:17]([OH:24])[CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:9]([O:13][CH3:14])[C:10]=2[OH:12])[N:5]=[C:4]([F:35])[N:3]=1
Reactant: COc1c(OCC(CN2CCCC2)OC(C)=O)c(Nc2ccccc2)c2nc(F)nc(Br)c2c1O
Agent: N
Solvent: CO
Product: COc1c(OCC(O)CN2CCCC2)c(Nc2ccccc2)c2nc(F)nc(Br)c2c1O
Yield: 69.5 %

Procedure:
Using an analogous procedure to that described in Example 10, 4-bromo-2-fluoro-5-hydroxyphenylamino-7-[2-acetoxy-3-(pyrrolidin-1-yl)propoxy]-6-methoxyquinazoline (106 mg) was treated with methanol saturated with ammonia to give 4-bromo-2-fluoro-5-hydroxyphenylamino-7-[2-hydroxy-3-(pyrrolidin-1-yl)propoxy]-6-methoxyquinazoline (68 mg)
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].C([Li])CCC.Cl[C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH3:25])[N:17]=[C:16]2[N:26]([CH3:29])[CH:27]=[N:28][C:15]=12.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.C1C=CC=CC=1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH3:25])[N:17]=[C:16]2[N:26]([CH3:29])[CH:27]=[N:28][C:15]=12
Reactant: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl
Reactant: CN(C)CCCO
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)c1c(C)nc2c(ncn2C)c1OCCCN(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.1 g. of 3-dimethylaminopropan-1-ol in 100 ml. of dry benzene are added 4 ml. of a 20% solution of butyl lithium in hexane. The mixture is stirred at room temperature for 15 minutes. After this time, 2.5 g. of 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester are added and the solution is heated at reflux temperature with stirring for 12 hours. After cooling, the solution is shaken with 50 ml. of a saturated aqueous sodium carbonate solution. The benzene layer is separated, dried with calcium chloride and evaporated to dryness. The remaining oily residue, 7-[3-(dimethylamino)propoxy]-3,5 -dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester, is purified by distillation, yield 2.2 g. (85%); b.p. 175°-180° /0.01 mm.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18]CC3C=CC=CC=3)=[CH:15][CH:16]=2)[C:11]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]2[CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:10]1[CH3:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd]>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]2[CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:10]1[CH3:41])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(CCN2CCCCC2CC2CCCCC2)c2cc(OCc3ccccc3)ccc2n1C(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: Cc1c(CCN2CCCCC2CC2CCCCC2)c2cc(O)ccc2n1C(=O)c1ccccc1

Procedure:
Catalytic reduction of the 1-benzoyl-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-benzyloxy-2-methylindole described above in Example 53 with hydrogen over a palladium-on-charcoal catalyst at about 50 pounds p.s.i.g. pressure affords 1-benzoyl-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-hydroxy-2-methylindole.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][C:14](Cl)=[C:13]([CH:17]=[O:18])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(O)C.C(N(CC)CC)C.[Pd].C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc(C=O)c(Cl)s1
Reactant: [H][H]
Agent: [Mn+4]
Agent: [Pd]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCc1cc(C=O)cs1

Procedure:
5-(2-(tert-butyldimethylsilyloxy)ethyl)-2-chlorothiophene-3-carbaldehyde (0.8 g) (example 278, step b) in a mixture of ethanol (50 mL) and triethylamine (0.91 mL) with 10% palladium on carbon catalyst (0.28 g) was stirred vigorously under 4 bar pressure of hydrogen for 18 hours. The mixture was filtered through celite and the filter pad washed with ethanol (50 mL). The combined filtrate and washings were evaporated and azeotroped with toluene (20 mL) to give a yellow oil. The oil was dissolved in DCM (100 mL), manganese dioxide (2.3 g) was added and the resulting suspension refluxed overnight. The mixture was filtered through celite and the filter pad washed with DCM (50 mL). The combined filtrate and washings were evaporated in vacuo to give the subtitled compound as a yellow oil. Yield 0.6 g.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](#[N:24])[CH3:23]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]([OH:18])[CH2:23][C:22]#[N:24])[CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: O=Cc1cccc(OCCCCOCc2ccccc2)c1
Product: N#CCC(O)c1cccc(OCCCCOCc2ccccc2)c1

Procedure:
Addition of acetonitrile to 3-(4-benzyloxybutoxy)benzaldehyde gave 3-[3-(4-benzyloxy-butoxy)-phenyl]-3-hydroxypropionitrile as yellow oil. Yield (0.3 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.33-7.37 (m, 4H), 7.27-7.32 (m, 2H), 6.93-6.96 (m, 2H), 6.86 (d, J=8.0 Hz, 1H), 5.0 (t, J=6.4 Hz, 2H), 4.52 (s, 2H), 4.01 (t, J=6.2 Hz, 2H), 3.55 (t, J=6.0 Hz, 2H), 2.75 (d, J=6.4 Hz, 2H), 1.87-1.94 (m, 2H), 1.77-1.85 (m, 2H).
Reaction SMILES: S1C=CC(C(Cl)=[O:7])=C1.C([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][C:25](C4SC=CC=4C([O-])=O)=[CH:26][CH:27]=3)[O:22][C:21]=2[C:39]2[CH:43]=[CH:42][S:41][CH:40]=2)=[CH:16][CH:15]=1)=[O:13])C>>[OH:7][C:25]1[CH:24]=[C:23]2[C:28]([C:29](=[O:30])[C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:12]([OH:11])=[O:13])=[CH:15][CH:16]=3)=[C:21]([C:39]3[CH:43]=[CH:42][S:41][CH:40]=3)[O:22]2)=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccsc1
Reactant: CCOC(=O)c1ccc(-c2c(-c3ccsc3)oc3cc(-c4sccc4C(=O)[O-])ccc3c2=O)cc1
Product: O=C(O)c1ccc(-c2c(-c3ccsc3)oc3cc(O)ccc3c2=O)cc1

Procedure:
Prepared following General Scheme 1, starting from Intermediate A-1a and thiophene-3-carbonyl chloride in step 1 using condition b) to 3-(4-(ethoxycarbonyl)phenyl)-4-oxo-2-(thiophen-3-yl)-4H-chromen-7-ylthiophene-3-carboxylate. Step 2 followed d) conditions. See Example 3 for detailed example.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].O.[CH3:8][C:9]1[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=1[NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1B1OC(C)(C)C(C)(C)O1.Br[C:37]1[N:42]=[C:41]([CH2:43][NH:44][C:45]2[C:50]([CH:51]([CH2:54][CH3:55])[CH2:52][CH3:53])=[CH:49][CH:48]=[CH:47][C:46]=2[CH:56]([CH2:59][CH3:60])[CH2:57][CH3:58])[CH:40]=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.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.CO>[CH2:57]([CH:56]([C:46]1[CH:47]=[CH:48][CH:49]=[C:50]([CH:51]([CH2:54][CH3:55])[CH2:52][CH3:53])[C:45]=1[NH:44][CH2:43][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][C:13]=2[CH2:12][NH:11][C:10]2[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=2[CH3:8])[N:42]=1)[CH2:59][CH3:60])[CH3:58]
Reactant: CCC(CC)c1cccc(C(CC)CC)c1NCc1cccc(Br)n1
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC(CC)c1cccc(C(CC)CC)c1NCc1cccc(-c2c(CNc3ccccc3C)ccc3ccccc23)n1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of 2.50 g (6.7 mmol) of Na2CO3×10H2O, 69 ml of water and 22 ml of methanol was purged with argon for 30 min. The obtained solution was added to a mixture of 2.50 g (6.7 mmol) of 2-methyl-N-{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}aniline, 2.70 g (6.7 mmol) of N-[(6-bromopyridin-2-yl)methyl]-2,6-bis(1-ethylpropyl)aniline, and 0.39 g (0.34 mmol) of Pd(PPh3)4 in 90 ml of toluene. This mixture was stirred for 12 h at 70° C., then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×50 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was re-crystallized from 5 ml of diethyl ether. Yield 2.20 g (58%) of white crystalline powder. Anal. calc. for C39H45FN3: C, 84.31; H, 8.31; N, 7.37. Found: C, 84.28; H, 8.26; N, 7.19. 1H NMR (CDCl3): δ 7.90 (d, J=8.5 Hz, 1H), 7.88 (m, 1H), 7.83 (m, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.60 (m, 1H), 7.35-7.49 (m, 4H), 6.96-7.07 (m, 5H), 6.61 (m, 1H), 6.53 (m, 1H), 4.17-4.32 (m, 4H), 3.92 (br.m, 1H), 3.85 (br.s, 1H), 2.88 (m, 2H), 2.08 (s, 3H), 1.62 (m, 4H), 1.49 (m, 4H), 0.73 (t, J=7.1 Hz, 6H), 0.71 (t, J=7.1 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.OO.C([O-])([O-])=O.[K+].[K+].O=P(Cl)(Cl)[Cl:23]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[Cl:23]
Reactant: COC(=O)c1nc(Cl)ccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(Cl)cc(Cl)c1Cl
Temperature: 60 °C
Yield: 30.3 %

Procedure:
To a stirred solution of methyl 3,6-dichloropyridine-2-carboxylate (0.96 g, 4.66 mmol) in TFA (5 ml) was added hydrogen peroxide (30% w/w aqueous solution, 435 μl, 2.5 mmol) and the reaction mixture was heated at 60° C. for 20 h. The reaction mixture was then cooled and slowly poured onto saturated K2CO3 solution (100 ml), followed by extraction of the aqueous layer with EtOAc (2×200 ml), washing of the combined organic phases with brine (2×50 ml), drying (Na2SO4) and evaporation. The desired 3,6-dichloro-2-(methoxycarbonyl)pyridin-1-ium-1-olate was used crude in the next stage of the synthesis without any further purification. To the crude 3,6-dichloro-2-(methoxycarbonyl)pyridin-1-ium-1-olate (˜70% purity, 2.40 g, 7.7 mmol) was added POCl3 (3.5 ml, 38 mmol) and the solution was heated to 100° C. for 4 h. After cooling the POCl3 was removed in vacuo to give a white solid which was chromatographed over silica gel eluting with 0% to 10% of EtOAc in heptane to afford the title compound as colourless needles (340 mg, 30% over two steps). LC-MS 100%, 2.20 min (3.5 minute LC-MS method), m/z=239.8/241.7, 1H NMR (500 MHz, Chloroform-d) δ 7.51 (1H, s), 3.92 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1>>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)[C:20](=[O:21])[NH:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Nc1cc(Cl)ccc1CO
Product: COc1ccc(-c2cc3ccc(Cl)cc3[nH]c2=O)cc1

Procedure:
2-Amino-4-chlorobenzyl alcohol (4 g, 25.3 mol) and 4-methoxyphenyl acetic acid (14.0 g, 76.4 mmol) were reacted in a similar manner to that described in Example 19 to give 7-chloro-3-(4-methoxyphenyl)-2(1H)-quinolone; mp 256°-257° C. (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]([OH:13])=O.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]([Cl:16])=[O:13]
Reactant: O=C(O)C#Cc1ccc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)C#Cc1ccc(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A reaction mixture of 0.34 g (1.58 mmol) of (2,4-dichlorophenyl)propynoic acid and 0.14 mL (1.9 mmol) of thionyl chloride in 15 mL of absolute toluene is stirred for 3 hours at 70° C. and then evaporated down. The residue is taken up in absolute toluene and the solution is evaporated to dryness. This procedure is then repeated once more and the residue is further reacted in its crude state.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C(O)C>[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1)[CH3:17]
Reactant: CCNCC
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Solvent: CCO
Product: CCN(CC)CCOc1cc(F)cc(S(C)(=O)=O)c1
Yield: 61.7 %

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol) and di-ethylamine (1.39 ml, 13.46 mmol) in ethanol (4 ml). Purification by flash column chromatography (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (300 mg, 61.6%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 172.3° C. MS m/z (relative intensity, 70 eV) 289 (M+, 1), 274 (6), 87 (6), 86 (bp), 58 (5).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27](=[O:30])(=[O:29])[NH2:28])=[CH:23][CH:22]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1)=[O:8].[OH-].[Na+].Cl>CO>[NH2:1][C:2]1[N:3]=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27](=[O:29])(=[O:30])[NH2:28])=[CH:23][CH:22]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:18][CH:19]=1)=[O:8]
Reactant: CCOC(=O)c1ccc(C(=O)c2sc(Nc3ccc(S(N)(=O)=O)cc3)nc2N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)sc1C(=O)c1ccc(C(=O)O)cc1
Reaction time: 4 h
Yield: 70 %

Procedure:
To a suspension of ethyl 4-[4-amino-2-(4-sulfamoyl-phenylamino)-thiazole-5-carbonyl]-benzoate (500 mg, 1.12 mmol; Example C(34)) in MeOH (10 mL) was added 1N aq NaOH (3.4 mL, 3.4 mmol). After 4 hours, the resultant mixture was acidified with 1N aq HCl to pH 3 and filtered. The isolated brown solid crystallized in EtOH to provide 330 mg (70% yield) of light brown crystals, mp 298.5-300° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH2:23][CH2:22][C:21]([C:29]([O:31]C)=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH2:23][CH2:22][C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.45 g). To the solution was added 1N sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature overnight and concentrated, which was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.42 g) as yellow crystals.