Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH:6]3[CH2:17][CH:8]([C:9]4[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=4[C:4]=2[CH:3]=1)[CH2:7]3.[C:20]([C@:22]1([OH:29])[CH2:26][CH2:25][N:24]([CH3:27])[C:23]1=[O:28])#[CH:21]>>[OH:29][C@@:22]1([C:20]#[C:21][C:2]2[CH:19]=[CH:18][C:5]3[CH:6]4[CH2:17][CH:8]([C:9]5[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=5[C:4]=3[CH:3]=2)[CH2:7]4)[CH2:26][CH2:25][N:24]([CH3:27])[C:23]1=[O:28]
Reactant: NC(=O)c1nc2c(s1)C1CC(C1)c1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)sc2C2CC3C2)C1=O
Yield: 59 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-5,6-dihydro-4H-4,6-methanobenzo[6,7]cyclohepta[1,2-d]thiazole-2-carboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give the titled compound as an off-white solid (14.4 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[F:18][C:19]([F:24])([F:23])[C:20](O)=[O:21].C(=O)([O-])O.[Na+]>ClCCl>[Cl:17][C:14]1[CH:15]=[CH:16][C:2]([NH:1][C:20](=[O:21])[C:19]([F:24])([F:23])[F:18])=[C:3]([CH:13]=1)[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11]
Reactant: Nc1ccc(Cl)cc1C(O)c1ccccc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1C(O)c1ccccc1Cl)C(F)(F)F
Yield: 95.7 %

Procedure:
To a solution of 1.0 g of 2-amino-5-chloro-α-(2-chlorophenyl)benzyl alcohol in 12 ml of dichloromethane, a solution of 0.8 g of anhydrous trifluoroacetic acid in 2 ml of dichloromethane was added. After reaction, an aqueous solution of sodium hydrogen carbonate was added, and the organic layer was dried, after which the solvent was removed and the residue was recrystallized from hexane to yield 1.3 g of a crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:16][CH:17]([C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=1[Cl:27])[CH3:18].[CH3:28][P:29](Cl)([CH3:31])=[O:30].C(N(CC)CC)C>ClCCl>[Cl:27][C:20]1[C:21]([F:26])=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[CH:17]([O:16][C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][P:29]([CH3:31])([CH3:28])=[O:30])=[CH:12][CH:13]=2)[CH:4]=1)[CH3:18]
Reactant: CP(C)(=O)Cl
Reactant: CC(Oc1cc(-c2ccc(CO)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1cc(-c2ccc(COP(C)(C)=O)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.2 %

Procedure:
a mixture of [4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]phenyl]methanol (15 mg, 0.037 mmol), dimethylphosphoryl chloride (50 mg, 0.45 mmol), and triethylamine (0.5 mL) in dichloromethane (10 mL) was stirred at room temperature for 1.5 hours. The solvent was removed and the residue was purified by HPLC (water/methanol, 10˜100%) to give the title compound (2 mg, 11%). ESMS: m/z 483 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[NH:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]([N:57]1[CH2:56][CH2:55][CH:54]([NH:53][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[Cl:46])[CH2:59][CH2:58]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC(Nc2ccccc2Cl)CC1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a stirred mixture of glycine (30 g, 0.3996 mole) in 1N aqueous NaOH (39.96 g, 0.999 mole) was added tert-butanol (270 mL). The mixture was cooled to 0° C. and di-tert-butyl dicarbonate (96.42 g, 0.4395 mole) was added dropwise. The mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was acidified with citric acid. The product was extracted with ethyl acetate. the organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 49 g (70%) of tert-butoxycarbonylamino-acetic acid. 1H NMR (DMSO-d6): δ 12.8-12.0 (bs, 1H), 7.1 (t, 1H), 3.6 (d, 2H), 1.4 (s 9H). To a stirred solution of tert-butoxycarbonylamino-acetic acid (0.2 g, 0.00114 mol) in DMF (5 mL) was added DIPEA (0.59 g, 0.00457 mol), HOBt (0.193 g, 0.001427 mol) and EDCI.HCl (0.274 g, 0.00143 mol) at ambient temperature. After 5 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.283 g, 0.00114 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and purified by column chromatography using basic aluminium oxide (60% ethyl acetate in hexane) to afford 0.41 g (98%) of {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester. LCMS: 368.18 (M+1)+, 93.53%. A solution of {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (0.41 g, 0.00111 mole) in methanol (10 mL) was added dioxane.HCl (5 mL) and the resulting mixture was stirred at ambient temperature for 10 minutes. The mixture was then concentrated under reduced and the resulting residue was washed with ether to afford 0.34 g (98%) of 2-amino-1-[4-(2-chloro-phenylamino)-piperidin-1-yl]-ethanone hydrochloride. LCMS: 268.11 (M+1)+, 84.63%.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH3:22])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=1.[CH3:24][C:25]1([CH3:32])[O:29][CH:28]([CH2:30]O)[CH2:27][O:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH2:30][CH:28]2[CH2:27][O:26][C:25]([CH3:32])([CH3:24])[O:29]2)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH3:22])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Reactant: CC1(C)OCC(CO)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC3COC(C)(C)O3)c(Cl)c1Cl)C2
Reaction time: 8 h

Procedure:
A mixture of 2 gm. of [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]-acetic acid, 3 ml. of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane and 0.5 g. of p-toluenesulfonic acid hydrate are heated on the steam bath for 3 hours. The dark reaction mixture then is chromatographed on 300 g of silica, and eluted with acetic acid-acetone-toluene (5:5:90). Fractions containing a single component (Rf~0.4) are pooled and concentrated to a yellow oil. On standing overnight, a mixture of crystalline solid and yellow oil resulted. The mixture is filtered and the solid recrystallized from tetrahydrofuran-ether-petroleum ether (5:15:25). The yield of pure product is 0.3 g., m.p. 143°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1[I:12].[N+:18]([O-])([OH:20])=[O:19].C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:16]=[C:15]([N+:18]([O-:20])=[O:19])[C:14]([F:17])=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1[I:12]
Reactant: Nc1nccc(Oc2cc(F)ccc2F)c1I
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1nccc(Oc2cc(F)c([N+](=O)[O-])cc2F)c1I
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
A chilled (−10° C.) mixture of 4-(2,5-difluorophenoxy)-3-iodopyridin-2-amine (2.31 g, 6.64 mmol) in sulfuric acid (15 ml) was treated with nitric acid (0.35 ml, 7.96 mmol) while maintaining the temperature below 0° C. After stirring for 20 minutes, the mixture was poured into ice-cold 2 N aq. NaOH solution (100 mL of 2 N NaOH in ice) with stirring. The pH of the resultant solution was then made basic by careful addition or NaHCO3. After stirring for 30 min, the suspension was filtered, washed with water (3×10 mL) and dried to afford 4-(2,5-difluoro-4-nitrophenoxy)-3-iodopyridin-2-amine as light red solid (2.05 g, 79% yield). MS (ESI) m/z: 393.9 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18](=[O:30])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][C:18]([OH:30])=[O:17])=[CH:22][C:23]=3[O:28][CH3:29])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: CCOC(=O)CCc1ccc(O)c(OC)c1
Product: COc1cc(CCC(=O)O)ccc1OCc1cccnc1SC1CCCC1
Yield: 58.1 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (40 mg, 0.16 mmol) obtained in Step C of Preparation Example 8 and 3-(4-hydroxy-3-methoxy-phenyl]-propionic acid ethyl ester (48 mg, 0.21 mmol) obtained in Step C of Preparation Example 38 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (36 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:22])[N:5]([CH2:13][C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:6]2=[O:12].[N:23]1[S:27][N:26]=[C:25]2[C:28]([S:32](Cl)(=[O:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:24]=12>CCOC(C)=O>[Br:11][C:9]1[CH:8]=[C:7]2[C:3]([C:4](=[O:22])[N:5]([CH2:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:6]2=[O:12])=[C:2]([NH:1][S:32]([C:28]2[C:25]3=[N:26][S:27][N:23]=[C:24]3[CH:31]=[CH:30][CH:29]=2)(=[O:34])=[O:33])[CH:10]=1
Reactant: C[C@H](CN1C(=O)c2cc(Br)cc(N)c2C1=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Solvent: CCOC(C)=O
Product: C[C@H](CN1C(=O)c2cc(Br)cc(NS(=O)(=O)c3cccc4nsnc34)c2C1=O)c1ccccc1
Temperature: 170 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
A mixture of (S)-4-amino-6-bromo-2-(2-phenyl-propyl)-isoindole-1,3-dione (30 mg, 0.08 mmol) and benzo[1,2,5]thiadiazole-4-sulfonyl chloride (150 mg, 0.64 mmol) was heated to 170° C. forming a melt and stirred for 2 h. The mixture was allowed to cool, and the solidified residue was dissolved in EtOAc, and the solution was washed with satd. aq. NaHCO3, dried (Na2SO4), and concentrated. Purification by flash chromatography (EtOAc/hexanes) gave the desired sulfonamide as a tan solid (30 mg, 64%). HPLC: RT=11.01 min. MS (ESI−): mass calcd. for C23H17BrN4O4S2, 555.99; m/z found, 555/557 [M−H]−. 1H NMR (400 MHz, CDCl3): 9.59 (br s, 1H), 8.39 (dd, J=7.0, 1.0, 1H), 8.27 (dd, J=8.8, 1.0, 1H), 8.08 (d, J=1.4, 1H), 7.75 (dd, J=8.8, 7.1, 1H), 7.47 (d, J=1.3, 1H), 7.27-7.22 (m, 2H), 7.21-7.17 (m, 3H), 3.78 (dd, J=13.6, 8.1, 1H), 3.68 (dd, J=13.6, 7.81, 1H), 3.26 (sextet, J=7.4, 1H), 1.26 (d, J=7.0, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([C:12](=[O:14])[CH3:13])[CH3:11])=[CH:6][CH:5]=1)[CH3:2].[O:16]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH:26]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:16]([C:23]1[CH:24]=[C:25]([CH:26]=[CH:13][C:12](=[O:14])[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)([CH3:11])[CH3:15])[CH:28]=[CH:29][C:30]=1[F:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: CCOc1ccc(C(C)(C)C(C)=O)cc1
Product: CCOc1ccc(C(C)(C)C(=O)C=Cc2ccc(F)c(Oc3ccccc3)c2)cc1
Yield: 47.7 %

Procedure:
In the same manner as described in (a) of (1) of Synthesis Example 2, 12.0 g of the residue was obtained by using 6.2 g of 2-(4-ethoxyphenyl)-2-methyl-3-butanone and 6.5 g of 3-phenoxy-4-fluorobenzaldehyde. The residue was purified by column chromatography on 200 g of silica gel (eluent: benzene) to give 5.8 g of 1-(3-phenoxy-4-fluorophenyl)-4-(4-ethoxyphenyl)-4-methyl-1-penten-3-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[C:18]([O:22][C:23](=[O:29])[N:24]([CH3:28])[CH2:25][CH:26]=O)([CH3:21])([CH3:20])[CH3:19].N1CCCC1>C1(C)C=CC=CC=1>[C:18]([O:22][C:23](=[O:29])[N:24]([CH3:28])[CH2:25][CH:26]1[CH2:16][C:15](=[O:17])[C:3]2[C:2](=[CH:7][C:6]([S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)[O:1]1)([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(=O)c1ccc(Sc2ccccc2)cc1O
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CN(CC1CC(=O)c2ccc(Sc3ccccc3)cc2O1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 33.5 %

Procedure:
To a solution of 1-(2-hydroxy-4-phenylsulfanyl-phenyl)-ethanone (244 mg, 1 mmol) and methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (259 mg, 1.5 mmol) (Tetrahedron 58, 2002, 1719-37) in toluene (25 mL) was added pyrrolidine (71 mg, 1 mmol). The reaction was stirred at room temperature for 60 hours. The mixture was concentrated in vacuo and the residue was purified via flash chromatography (hexane/Et2O, 3/1) to give methyl-(4-oxo-7-phenylsulfanyl-chroman-2-ylmethyl)-carbamic acid tert-butyl ester (134 mg, 34% yield) as clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.[Cl:13]SCl>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([Cl:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cccc(F)c1
Reactant: ClSCl
Product: O=C(Cl)CCc1cccc(F)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(3-fluorophenyl)propanoic acid (2.50 g, 14.9 mmol) and dichlorosulfane (10 mL) under N2 was refluxed for 3 h. The mixture was cooled to rt and concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].[NH2:8][C@@H:9]([CH3:38])[CH2:10][O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[C:25]([Cl:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2>>[Cl:37][C:25]1[CH:24]=[C:23]([NH:22][C:14]2[C:13]3[C:18](=[CH:19][CH:20]=[CH:21][C:12]=3[O:11][CH2:10][C@@H:9]([NH:8][C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH3:38])[N:17]=[CH:16][N:15]=2)[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: C[C@H](N)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CN(C)CC(=O)O
Product: C[C@@H](COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)NC(=O)CN(C)C
Yield: 42 %

Procedure:
The procedure described in Example 1 was repeated using N,N-dimethylglycine and 5-{[(2S)-2-aminopropyl]oxy}-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine to give the title compound in 42% yield; NMR spectrum (DMSO-d6) 1.21 (d, 3H), 2.05 (s, 6H), 2.60-2.80 (m, 2H), 4.20-4.40 (m, 2H), 4.40-4.60 (m, 1H), 5.30 (s, 2H), 7.15 (m, 1H), 7.22 (m, 1H), 7.35 (m, 2H), 7.54 (m, 2H), 7.70 (t, 1H), 7.90 (t, 1H), 7.98 (m, 2H), 8.48 (s, 1H), 8.59 (d, 1H), 9.76 (s, 1H); Mass spectrum MH+ 521.4.
Reaction SMILES: [C@H]1(C[N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CCC1.[ClH:43].Cl.Cl.NC1CCN([CH2:53][CH2:54][N:55]2[CH2:60][CH2:59][C@H:58]([OH:61])[C@@H:57]([CH3:62])[CH2:56]2)CC1>>[ClH:43].[ClH:43].[OH:61][C@H:58]1[CH2:59][CH2:60][N:55]([CH2:54][CH2:53][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:16][CH2:17]2)[CH2:56][C@@H:57]1[CH3:62]
Reactant: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc2c1
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized from 4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (120, see example 86) and amine 14 analogously to the method described in example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[S:18][C:19]([C:23]([O:25]CC)=[O:24])=[C:20]([CH3:22])[N:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:30])[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[S:18][C:19]([C:23]([OH:25])=[O:24])=[C:20]([CH3:22])[N:21]=3)=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(-c2ccc(C(=O)Nc3ccc(Cl)cc3)cc2)nc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(-c2ccc(C(=O)N(C)c3ccc(Cl)cc3)cc2)sc1C(=O)O
Yield: 72 %

Procedure:
100 mg of Ethyl 2-(4-(4-chlorophenylcarbamoyl)-phenyl)-4-methyl-5-thiazolecarboxylate produced in Example 16 was methylated with sodium hydride and methyl iodide, and hydrolyzed by a conventional process to give 69 mg of 2-(4-(N-(4-chlorophenyl)-N-methylcarbamoyl)phenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 72%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[NH:5][C:6]=1C(O)=O>CC(O)=O.Br>[Br:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[NH:5][CH:6]=1
Reactant: COc1ccc(-c2nc(Br)c(C(=O)O)[nH]2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(-c2nc(Br)c[nH]2)cc1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A suspension of 9 (2.5 g, 0.008 mol) in AcOH (10 ml) and 48% HBr (40 ml) was heated at reflux for 15 hours. The solution was concentrated to dryness and stirred overnight with saturated NaHCO3. The suspension was filtered, the solids chromatographed on silica gel and eluted with 5% CH3OH-CHCl3 to yield 1.4 g (65%) of 11. An analytical sample was prepared by crystallization from CH3CN, m.p. 210°-212° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[O:13][CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(OCC)(=O)C.O>[CH2:21]([N:8]1[C:4]2[C:3]([O:13][CH3:14])=[C:2]([Br:1])[CH:12]=[CH:11][C:5]=2[N:6]([CH3:10])[C:7]1=[O:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COc1c(Br)ccc2c1[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(Br)ccc2c1n(Cc1ccccc1)c(=O)n2C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
A solution of 5-bromo-4-methoxy-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (60.0 mg, 0.233 mmol) in N,N-dimethylformamide (2.31 mL) was treated with cesium carbonate (380 mg, 1.17 mmol) and benzyl bromide (99.8 mg, 0.583 mmol) and stirred at 60° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by flash column chromatography (15% EtOAc/hexanes to 40% EtOAc/hexanes) gave the desired product (73 mg, 90%). LCMS calculated for C16H16BrN2O2 (M+H)+: m/z=347.1, 349.1. found: 347.0, 349.0.
Reaction SMILES: C([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:21])[CH:11]=1)(=O)C1C=CC=CC=1.N1CCCCC1>ClCCl>[OH:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:21])[CH:11]=1
Reactant: Cn1cc(OC(=O)c2ccccc2)c(=O)c2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cn1cc(O)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-methyl-4-oxo-1,4-dihydroquinol-3-yl benzoate (45 g), piperidine (16.9 ml) and dichloromethane (700 ml) was stirred for 3 days at ambient temperature under nitrogen. A further portion of piperidine (3 ml) was added and the stirring continued for 1 day. The solvent was removed by distillation at 50° and the residue was triturated with diethyl ether (300 ml). The resultant solid was collected by filtration and washed with diethyl ether (2×100 ml) to give 3-hydroxy-1-methyl-4-quinolone, m.p. 243°-246°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C@:13]2([CH3:18])[C@H:16]([CH3:17])[C@H:9]1[CH2:10][C:11]1[CH:22]=[CH:21][C:20]([B:23]3[O:27]C(C)(C)C(C)(C)[O:24]3)=[CH:19][C:12]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C@:13]2([CH3:18])[C@H:16]([CH3:17])[C@H:9]1[CH2:10][C:11]1[CH:22]=[CH:21][C:20]([B:23]([OH:27])[OH:24])=[CH:19][C:12]=12)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1[C@H]2Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Solvent: CC(C)=O
Product: C[C@@H]1[C@H]2Cc3ccc(B(O)O)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C

Procedure:
A solution of (2R,6R,11S)-6,11-dimethyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (2.50 g) and NaIO4 (5.00 g) in 1 M aqueous NH4OAc solution (34 mL) and acetone (60 mL) is stirred at room temperature overnight. Then, the solution is concentrated, water is added to the residue, and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with water and brine and dried (Na2SO4). The solvent is removed under reduced pressure to give the title compound as a colorless, foam-like solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Br:9][CH:10]([CH2:18][CH3:19])[C:11](=O)[CH2:12][C:13](OC)=[O:14].[OH-].[Na+]>>[Br:9][CH:10]([C:11]1[N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]2[C:13](=[O:14])[CH:12]=1)[CH2:18][CH3:19]
Reactant: Cc1cccc(N)n1
Reactant: CCC(Br)C(=O)CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CCC(Br)c1cc(=O)n2c(C)cccc2n1
Temperature: 110 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
To a manually stirred polyphosphoric acid (80 g, 800 mmol) in a 1000 mL beaker at room temperature was added 6-methyl-2-pyridinamine (15 g, 140 mmol), followed by methyl 4-bromo-3-oxohexanoate (37.3 g, 167 mmol). The mixture was heated with stirring at 110° C. for 5 h. After cooling, the dark slurry was transferred into 300 g of ice. The pH of the mixture was adjust to 6-7 with 10% sodium hydroxide. The precipitate was collected by filtration under reduced pressure, washed with water, and air dried to yield the desired product (25.4 g, 64.8%). LCMS calculated for C12H14BrN2O (M+H)+: m/z=281.0. Found: 281.2. 1H NMR (DMSO-d6, 300 MHz) δ 7.66 (1H, d, J=9.0 and 6.9 Hz), 7.39 (1H, d, J=9.0 Hz), 6.90 (1H, d, J=6.9 Hz), 6.33 (1H, s), 4.91 (1H, t, J=7.5 Hz), 2.91 (3H, s), 2.15 (2H, qd, J=7.5 and 7.5 Hz), 0.93 (3H, t, J=7.5 Hz) ppm.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1)=[O:12])C1C=CC=CC=1.[CH:28]1([CH2:31][O:32][CH2:33][CH2:34][C:35]2[CH:45]=[CH:44][C:38]([O:39][CH2:40][CH:41]3[O:43]C3)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1>C(O)CC>[OH:43][CH:41]([CH:40]([CH2:20][C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)[O:39][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][CH2:33][O:32][CH2:31][CH:28]2[CH2:29][CH2:30]2)=[CH:45][CH:44]=1)[CH2:1][NH:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:18][CH:19]=1)=[O:12]
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCc2ccccc2)cc1
Solvent: CCCO
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCC(O)C(Cc2ccccc2)Oc2ccc(CCOCC3CC3)cc2)cc1

Procedure:
A mixture of 6-[4-(3-benzylaminopropionamido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (1.46 g, 0.004 mol), 1-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-2,3-epoxypropane (2.0 g, 0.008 mol) (British Pat. No. 1,515,978) and n-propanol was stirred and heated under reflux for 22 hours. Evaporation of the solvent under reduced pressure gave an oily residue which was purified by elution from a silica column with chloroform/methanol mixtures to give 6-[4-[3-[2-hydroxy-3-[4-(2-(cyclopropylmethoxy)ethyl]phenoxy]-N-benzylpropylamino]propionamido]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone as a foam, 1.3 g, (38%); δ(CHCl3) 0.18 and 0.53 (2m, 4H, cyclopropylmethylene protons), 1.23 (d, 3H, dihydropyridazinone 5-methyl) ppm.