Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]\[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>O1CCCC1>[C:1]1(/[CH:7]=[CH:8]\[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)/C=C\c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C\c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.9 %

Procedure:
A solution of (z)-3-phenylpropenoic acid, methyl ester (0.8 g, 4.9 mmol) in 20% aqueous tetrahydrofuran (5 mL) was treated with lithium hydroxide hydrate (0.42 g, 9.9 mmol) and the reaction mixture was stirred under argon at room temperature for 20 hours. It was concentrated in vacuo, diluted with water (50 mL) and extracted with dichloromethane (2×50 mL). The organic extracts were discarded and the aqueous layer was acidified to pH~3 with 1N hydrochloric acid and extracted with dichloromethane (3×100 mL). The combined extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title B compound (0.5 g). 1H NMR (CDCl3) δ11.57 (brs, 1H), 7.48 (m, 2H), 7.25 (m, 2H), 6.94 (d, J=12.2 Hz, 1H), 5.84 (d, J=12.3 Hz, 1H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl[C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:14]1([C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[S:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)Cc1ccc(S)cc1
Solvent: ClCCl
Product: O=C(O)Cc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
4-mercaptophenylacetic acid (369.6 mg, 2.2 mmol) was added to the solution of chlorotriphenylmethane (557.6 mg, 2 mmol) in 2.0 mL of anhydrous dichloromethane. The solution was stirred for 2 hrs under nitrogen. The reaction was quenched by 1N NaOH (3 mL). The suspension was extracted with 10 mL of ethyl acetate, and the organic phase was washed with brine (5 mL×3) and dried over anhydrous magnesium sulfate. The solvent was removed and residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/hexane=⅓) to afford 713.4 mg of desired product (87%). 1H NMR (400 MHz, CDCl3) δ 7.43-7.40 (m, 6H), 7.26-7.17 (m, 9H), 6.93 (m, 4H), 3.52 (s, 2H) ESI-MS: observed [M+Na]+: 433.6, calculated: 410.5.
Reaction SMILES: [Br:1][C:2]1[N:6]2[NH:7][C:8](=O)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:39]([O:43][C:44](=[O:51])[N:45]([CH2:47][CH2:48][CH2:49][NH2:50])[CH3:46])([CH3:42])([CH3:41])[CH3:40].N12CCCN=C1CCCCC2>CN(C=O)C.C(#N)C>[C:39]([O:43][C:44](=[O:51])[N:45]([CH2:47][CH2:48][CH2:49][NH:50][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([Br:1])=[CH:3][N:4]=2)[N:7]=1)[CH3:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Reactant: O=c1ccc2ncc(Br)n2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(CCCNc1ccc2ncc(Br)n2n1)C(=O)OC(C)(C)C

Procedure:
Acetonitrile (16.0 mL) was added to a mixture of 3-bromo-imidazo[1,2-b]pyridazin-6-one (344.3 mg, 1.6 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) [56602-33-6], the mixture allowed to stir to effect dissolution. A solution of (3-amino-propyl)-methyl-carbamic acid tert-butyl ester [150349-36-3] (0.8 g, 3.98 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) [6674-22-2] (2.4 mL, 2.4 mmol) in DMF (4.0 mL) was added and the reaction allowed to stir at ambient temperature for 3d. The reaction solution was partitioned between brine and ethyl acetate, dried (MgSO4), and flash chromatographed (silica gel, eluted with 10% (v/v) 2-propanol/ethyl acetate) to provide [3-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-propyl]-methyl-carbamic acid tert-butyl ester as 0.4 g of clear yellow oil. LRMS (ESI) m/z 384.1/386.1 [(M+H)]+, calc'd for C16H22BrN6O2: 384.28.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:13][CH2:14][CH:15]=O)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH3:18][C:19]([S@@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[C:19]([S@@:22]([N:24]=[CH:15][CH2:14][CH2:13][C:2]([CH3:17])([CH3:1])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:23])([CH3:21])([CH3:20])[CH3:18]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(C)(CCC=O)C(=O)OCc1ccccc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(CCC=N[S@@](=O)C(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 22 h

Procedure:
To a mixture of benzyl 2,2-dimethyl-5-oxopentanoate (1.06 g, 4.54 mmol, Step C) and anhydrous CuSO4 (1.59 g, 9.98 mmol) in DCM (10 mL) was added (S)-2-methylpropane-2-sulfinamide (0.550 g, 4.54 mmol). This mixture was stirred for 22 hours, before being filtered through a pad of celite. Additional DCM was used to wash the celite. The combined organics were concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:DCM-0.5:99.5 to 1.5:98.5, to give the title compound. MS: m/z=338 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1ccccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 79.2 %

Procedure:
1-t-Butoxycarbonyl-4-(2-methoxyphenyl)-1,2,3,6-tetrahydropyridine (150 mg, 0.52 mmol) and 10% palladium-carbon (30 mg) were stirred in methanol for two nights in an atmosphere of hydrogen. The reaction solution was filtered and the thus obtained residue was thoroughly washed with methanol. Then the filtrate and washed solution were combined and evaporated under a reduced pressure to obtain 120 mg of the aforementioned compound of interest (0.42 mmol, 81% in yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][NH:17][C:18](=[O:32])[N:19]3[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)C>Cl.C(O)C>[CH2:25]([N:19]1[C:20]2[C:15](=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:23]([F:24])=[CH:22][CH:21]=2)[CH2:16][NH:17][C:18]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc3c2CNC(=O)N3Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: O=C1NCc2c(ccc(F)c2N2CCNCC2)N1Cc1ccccc1
Temperature: 80 °C

Procedure:
4-(1-Benzyl-6-fluoro-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (141 mg) was dissolved in 4 mL 2 N HCl/ethanol and heated to 80° C. for 20 minutes, then cooled to room temperature. Diethyl ether was added, precipitating 115 mg of 1-benzyl-6-fluoro-5-piperazin-1-yl-3,4-dihydro-1H-quinazolin-2-one hydrochloride. MP: 285.6–290.0° C. MS: 341 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:16](=[C:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[N:18]3)[NH:15][S:14](=[O:24])(=[O:23])[C:13]1[C:8]2=[CH:9][C:10]([C:25](O)=[O:26])=[CH:11][CH:12]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(Cl)Cl>[CH3:1][N:2]([CH3:3])[C:25]([C:10]1[CH:9]=[C:8]2[C:13]([S:14](=[O:24])(=[O:23])[NH:15][C:16]3[C:7]2=[CH:6][C:5]([Cl:4])=[C:22]2[C:17]=3[N:18]=[CH:19][CH:20]=[CH:21]2)=[CH:12][CH:11]=1)=[O:26]
Reactant: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
Dimethyl amine (0.2M in THF, 2.77 ml, 0.69 mmol) was added to a solution of 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 524 (100 mg, 0.27 mmol), EDC.HCl (80 mg, 0.41 mmol), HOBt (56 mg, 0.41 mmol) and TEA (0.12 ml, 0.83 mmol) in DMF (1 ml) and the mixture was stirred at room temperature for 12 h. The mixture was diluted with water and DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with chloroform/MeOH (95:5) as the eluent to give the title compound (45 mg, 42%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11](=[NH:23])[NH:12][C:13]2[CH:14]=[CH:15][C:16]3[S:20][CH:19]=[N:18][C:17]=3[C:21]=2Br)[CH:10]=1)=[O:5])[CH3:2].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.COCCOC>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:23][C:21]3[C:17]4[N:18]=[CH:19][S:20][C:16]=4[CH:15]=[CH:14][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C(=N)Nc2ccc3scnc3c2Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CCOC(=O)c1cnn(-c2nc3ccc4scnc4c3[nH]2)c1
Temperature: 80 °C
Yield: 21 %

Procedure:
The hydrochloride salt of 1-[N-(4-bromo-benzothiazol-5-yl)carbamimidoyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.128 g, 0.297 mmol), 1,10-phenanthroline (10.7 mg, 59.4 μmol), cesium carbonate (0.290 g, 0.891 mmol), and DME (5.5 mL) were combined in a sealable microwave tube. The tube was sparged with dry nitrogen and copper (I) iodide (5.70 mg, 29.7 μmol) was added. The reaction mixture was further sparged and the tube was sealed and heated at 80° C. for 1.75 h. The reaction mixture was partitioned between 1M aq. HCl (15 mL) and EtOAc (25 mL). The aqueous layer was further extracted with EtOAc (2×20 mL) and the combined organic layers were washed with brine (10 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-60% EtOAc/hexanes, dry-loaded), the clean fractions were concentrated and the residue triturated with diethyl ether to yield the titled compound (19.5 mg, 21% yield). MS (ESI/CI): mass calcd. for C14H11N6O2S, 313.1; m/z found, 314.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.75 (s, 1H), 9.45 (s, 1H), 9.05 (s, 1H), 8.37 (s, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.65 (d, J=6.0 Hz, 1H), 4.31 (q, J=7.0 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:18][S:19]([O-:21])=[O:20].[Na+].CN(C)C=O>O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[CH:16]=[CH:17][C:3]([CH2:2][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:4][CH:5]=2)=[O:8])=[CH:10][CH:11]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
4-bromomethyl-4'-chlorobenzophenone (3.1 g) and sodium methanesulfinate (1.5 g) were added to N,N-dimethylformamide (50 ml), and the mixture was stirred for 16 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residual solid was washed with n-hexane to obtain the desired product (2.8 g, melting point: 164° to 166° C., yield: 90%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:37])[C:23](=[O:36])[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[C:26]([O:33][CH2:34][CH3:35])[CH:25]=4)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1>CO>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:37])[C:23](=[O:36])[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[C:26]([O:33][CH2:34][CH3:35])[CH:25]=4)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1
Reactant: CCOc1ccc(C(=O)N(C)Cc2cccc(-c3ccc(C=C4SC(=O)NC4=O)cc3)c2)cc1OCC
Solvent: CO
Product: CCOc1ccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1OCC
Yield: 41.3 %

Procedure:
In a manner similar to that of Example 1(g), starting with 360 mg (0.7 mmol) of N-[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]-3,4-diethoxy-N-methylbenzamide in 15 ml of methanol, 150 mg (40%) of the desired product, with a melting point of 66° C., are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]([CH3:33])[C:17](=[O:32])[CH2:18][N:19]2[C:24]3[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:23]=3[O:22][CH2:21][C:20]2=[O:31])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:34][C:35]([O:38][C:39]([NH:41][C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)=[O:40])([CH3:37])[CH3:36].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:30][C:26]1[C:27]([Cl:29])=[CH:28][C:23]2[O:22][CH2:21][C:20](=[O:31])[N:19]([CH2:18][C:17]([N:16]([CH3:33])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:46]4[CH:45]=[CH:44][CH:43]=[C:42]([NH:41][C:39](=[O:40])[O:38][C:35]([CH3:36])([CH3:34])[CH3:37])[CH:47]=4)=[CH:3][CH:4]=3)[CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:32])[C:24]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(B(O)O)c1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(NC(=O)OC(C)(C)C)c2)cc1
Yield: 39.9 %

Procedure:
To a solution of N-[1-(4-bromophenyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (3.28 g, 5.8 mmol) and [3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)phenyl]boronic acid (2.00 g, 8.4 mmol) in DMF (15 mL) was added Pd(dppf)Cl2 (0.24 g, 0.29 mmol) and 2N solution of Na2CO3 (11.6 mL, 23.2 mmol). The resultant mixture was stirred at 80° C. for 16 h. The mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with 5% NaHCO3 (100 mL) and brine (100 mL). The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in methanol, and water was added to precipitate a tan solid. The solid was collected by filtration and air dried to give 1.55 g (40%) of the title compound a tan solid. MS (ES) m/e 669 [M+H]+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>CN(C)C=O.[Cu]>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccccc1I
Reactant: Oc1ccc(F)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1Oc1ccc(F)cc1
Temperature: 160 °C
Yield: 44.5 %

Procedure:
100 g of potassium carbonate are added slowly to a mixture of 120 g of 2-iodobenzoic acid, 1 g of copper powder and 54.4 g of 4-fluorophenol in 200 ml of N,N-dimethylformamide. The mixture is heated at 160° C. for 4 hours and is then allowed to cool before evaporating. The residue is taken up in distilled water, acidified with aqueous 1N hydrochloric acid solution and then extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The desired product crystallizes from a diethyl ether/pentane mixture. 50 g of a white solid are obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([CH2:8][CH2:9][C:10]1([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[O:14][CH2:13][CH2:12][O:11]1)=[O:7])#[N:2].C(O)(=O)C>[Pt]=O.C(O)C>[NH2:2][CH2:1][CH2:3][CH2:4][O:5][C:6]([CH2:8][CH2:9][C:10]1([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[O:14][CH2:13][CH2:12][O:11]1)=[O:7]
Reactant: N#CCCOC(=O)CCC1(c2ccc(F)cc2)OCCO1
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: NCCCOC(=O)CCC1(c2ccc(F)cc2)OCCO1

Procedure:
A Parr apparatus is charged with 450 g of the product obtained in Stage B, 900 ml of acetic acid, 3,000 ml of anhydrous ethanol and 20 g of platinum oxide. The mixture is hydrogenated at 5 bars at 45° C. When the theoretical volume has been absorbed, the catalyst is filtered off and the solvent is evaporated off under vacuum. The residue is taken up in 1 liter of water and the mixture is neutralized with sodium hydroxide and extracted with dichloromethane. The oil obtained is purified by chromatography on 70-230 mesh silica, using a mixture of dichloromethane, methanol and ammonia solution (95:5:0.5 V/V/V) as eluant.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>CC#N>[Br:15][C:6]1[CH:7]=[C:8]([O:11][C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(OC(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(=O)Oc1ccc(OC(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of acetic acid 4-isopropoxy-phenyl ester (1.04 g, 5.35 mmol, 1 eq.) in MeCN (22 mL), N-bromsuccinimide (953 mg, 5.35 mmol, 1 eq.) was added. The resulting mixture was stirred at r.t. for 18 hours. The solvent was removed in vacuo. The residue was partitioned between water and Et2O. The org. layer was dried over MgSO4, filtered, and concentrated in vacuo to give acetic acid 3-bromo-4-isopropoxy-phenyl ester as an orange oil. The product was used without further purification.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:10](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH2:11]O)[CH2:6][CH2:7][CH2:8][CH3:9]>C(Cl)(Cl)Cl>[CH2:5]([C:10](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH2:11][Br:2])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(=Cc1ccc(Cl)cc1Cl)CO
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: CCCCCC(=Cc1ccc(Cl)cc1Cl)CBr
Temperature: 0 °C
Yield: 272.6 %

Procedure:
32.5 g of PBr3 were added dropwise to a solution of 93 g of (II) in 300 ml of CHCl3 at 10° C. The CHCl3 solution was stirred for 15 hours at room temperature and then poured into ice/water. The organic phase was separated off and the aqueous phase was extracted with CHCl3. The combined organic phases were washed several times with aqueous Na2CO3 solution and with water, dried over Na2SO4 and concentrated. Distillation of the residue gave 110 g of (III) of boiling point 140°-148° C./0.1 mbar.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8](OCC)=[O:9].CC([O-])(C)C.[K+:18]>CCOCC>[Cl:1]/[C:2](/[CH:8]=[O:9])=[C:3](\[O:5][CH2:6][CH3:7])/[O-:4].[K+:18]
Reactant: CCOC=O
Reactant: CCOC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCO/C([O-])=C(\Cl)C=O

Procedure:
A cooled (0° C.) suspension of ethyl 2-chloroacetate (17.47 ml, 163 mmol) and ethyl formate (13.18 ml, 163 mmol) in ether (250 ml) was treated slowly (over 3 hrs) with potassium 2-methylpropan-2-olate (18.31 g, 163 mmol) keeping the temperature below 5° C. The mixture was concentrated in vacuo and the resulting solid was washed with ether and dried (47° C. in a vacuum oven) to afford the title compound; 1H NMR (400 MHz, d6-DMSO) δ 8.95 (1H, s), 3.9 (2H, q), 1.1 (3H, t).
Reaction SMILES: FC(F)(F)C(O)=O.CS(O)(=O)=O.C([O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[C:35]([CH3:44])=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)C1C=CC=CC=1>>[CH3:32][O:31][C:30]1[CH:29]=[C:28]2[C:23]([C:24]([O:33][C:34]3[C:35]([CH3:44])=[N:36][C:37]4[C:42]([CH:43]=3)=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:25][CH:26]=[N:27]2)=[CH:22][C:21]=1[OH:20]
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 4.7 %

Procedure:
Trifluoroacetic acid (5 ml) and methanesulfonic acid (0.2 ml) were added to 6-benzyloxy-7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 415) (700 mg), and the mixture was stirred at 100° C. for 2 hr. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with a saturated aqueous sodium hydrogencarbonate solution and water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give 7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-6-ol (26 mg, yield 5%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)[CH:32]=[N:33][CH:34]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncc(Cl)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(Cl)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 54 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (5-chloropyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.61 min, m/z=479.1-481.0 [M+H]+, m/z=477.1-479.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.79 (m, 1H) 1.80-1.91 (m, 1H) 2.89 (d, 1H) 3.18-3.28 (m, 2H) 3.35-3.44 (m, 1H) 4.18-4.24 (m, 1H) 4.87 (d, J=3.42 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.83-7.88 (m, 2H) 8.03 (t, J=1.96 Hz, 1H) 8.08 (d, J=2.20 Hz, 1H) 8.58 (d, J=1.71 Hz, 1H) 8.64 (d, J=2.45 Hz, 1H) 8.78 (d, J=2.45 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=1[Cl:24].[NH+]1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:11][C:7]1[C:5]2[N:6]=[C:2]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=3[Cl:24])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: Clc1cccc2sc(Br)nc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1ccc(Nc2nc3c(Cl)cccc3s2)c(Cl)c1
Yield: 58.2 %

Procedure:
In xylene (7 ml), 2-bromo-4-chlorobenzothiazole (647 mg, 2.60 mmol), methyl 4-amino-3-chlorophenylacetate (520 mg, 2.60 mmol), and pyridinium•p-toluenesulfonate (PPTS) (200 mg, 0.80 mmol) were heated under reflux for 7 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (6:1, v/v) eluate fractions, methyl (4-(4-chloro-2-benzothiazolyl)amino-3-chlorophenyl)acetate (556 mg, 58%) was obtained as a yellow amorphous substance.