Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10](Cl)[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[CH3:16][C:17](=O)[CH2:18][C:19](=O)[CH3:20]>C(O)(=O)C>[OH:15][C:5]1[C:6]([OH:14])=[N:7][C:8]2[CH:9]=[CH:10][C:11]3[NH:12][C:17]([CH3:16])=[CH:18][C:19]([CH3:20])=[N:1][C:2]=3[C:3]=2[N:4]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Solvent: CC(=O)O
Product: CC1=CC(C)=Nc2c(ccc3nc(O)c(O)nc23)N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.9 %

Procedure:
A mixture of 0,5 g (2,24 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline and 1,0 g (10 mmol) 2,4-pentanedione in 15 ml glacial acetic acid was stirred at 25° C. for 20 h. The precipitate was filtered off and washed with ethanol and ether to give 0,43 g (67%) 2,3-dihydroxy-8,10-dimethyl-7H-pyrazino(2,3-g)(1,5)benzodiazepine, m.p.>300° C. NMR (DMSO-D6): 7.07 (2H,s), 2.33 (3H,s), 2.27(3H,s).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1CCCCCCC(=O)CC(O)(C(OC)=O)CC(OC)=O.ClC1C=C(Cl)C=CC=1[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49](=[O:62])[CH2:50][C:51]([OH:61])([C:57]([O:59]C)=O)[CH2:52][C:53]([O:55]C)=[O:54]>>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C@@H:49]1[O:62][C:57](=[O:59])[C@@:51]([CH2:52][C:53]([OH:55])=[O:54])([OH:61])[CH2:50]1
Reactant: COC(=O)CC(O)(CC(=O)CCCCCCc1ccc(C(F)(F)F)cc1C(F)(F)F)C(=O)OC
Reactant: COC(=O)CC(O)(CC(=O)CCCCCCc1ccc(Cl)cc1Cl)C(=O)OC
Product: O=C(O)C[C@]1(O)C[C@H](CCCCCCc2ccc(C(F)(F)F)cc2C(F)(F)F)OC1=O

Procedure:
Following the procedures described in examples 1 (g) and 2, substituting ±methyl 11-[2,4-Bis (trifluoromethyl)phenyl]-3-hydroxy-3-methoxycarbonyl-5-oxo-undecanoate for ± methyl 11(2,4-dichlorophenyl )-3-hydroxy-3-methoxycarbonyl-5-oxo-undecanoate, gave the title compound as a solid, m.p. 70°-73° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([Cl:28])[C:24]([Cl:27])=[C:25]([Br:26])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].CCO.Cl>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[C:23]([Cl:28])[C:24]([Cl:27])=[C:25]([Br:26])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3c(Br)c(Cl)c(Cl)cc3n2COCCOC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3c(Br)c(Cl)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a mixture of 1-[4-bromo-5,6-dichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.132 g, 0.27 mmol) and EtOH (2 mL) was added 4M HCl in dioxane (2 mL). The mixture was stirred for 18 h at 23° C. The resulting white precipitate was filtered and washed with EtOH to yield the titled compound (0.088 g, 81%). MS (ESI/CI): mass calcd. for C13H9BrCl2N4O4, 402.9; m/z found, 403.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 14.22-13.94 (m, 1H), 8.98 (s, 1H), 8.40 (s, 1H), 7.74 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:11][Si](C)(C)C)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.F[B-](F)(F)F.[C:21]1([N+:27]#[N:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1.C(OCC)C>[C:5]1([C:4](=[N:28][NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]([O:2][CH3:1])=[O:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=Cc1ccccc1)O[Si](C)(C)C
Reactant: N#[N+]c1ccccc1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)C(=NNc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
1.0 mmol of (1-methoxy-2-phenylethenyl)oxytrimethylsilane was placed in a 20-ml flask, followed by the addition of 3 ml of pyridine as a solvent. 1.3 mmol of benzenediazonium tetrafluoroborate was added to the flask. The obtained mixture was stirred at 0° C. in a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with diethyl ether and washed with 1.5N hydrochloric acid, water and a saturated aqueous solution of common salt successively. The obtained organic phase was dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The obtained oily mixture was subjected to silica gel thin-layer chromatography to obtain 0.84 mmol of methyl 2-phenyl-2-phenylhydrazonoacetate.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:10]([N:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCN(Cc1ccccc1)Cc1ccccc1
Yield: 97 %

Procedure:
Heat a solution of ethyl 3-aminopropanoate hydrochloride (80.0 g, 0.52 mol), benzylbromide (186.7 g, 1.1 mol) and K2CO3 (179.4 g, 1.3 mol) in acetonitrile (1 L) at 40° C. overnight. Concentrate the mixture to dryness, treat with water, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (Pet Ether/EtOAc, 50:1) to afford the title compound (150 g, 97% yield). 1H NMR (400 MHz, CDCl3): δ 7.35-7.21 (m, 10H), 4.09 (q, J=7.2 Hz, 2H), 3.58 (s, 4H), 2.82 (t, J=7.2 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: O.[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([O-:34])=[O:33].Cl.C(O)C>O>[OH2:15].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([OH:34])=[O:33]
Reactant: Cn1c(C(=O)[O-])cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 8 h
Yield: 169.1 %

Procedure:
1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid sodium salt hydrate (0.62 g), from the previous alternative, and aqueous hydrochloric acid (2 molar) were combined in refluxing ethanol (13 mL) and water (1.3 mL). The mixture was cooled, granulating overnight, chilled in ice and the resulting slurry was filtered. The product solids were dried, yielding the title compound, 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid hydrate (0.5 g, 83%, containing 2% water by weight). Anhydrous Mol wt (calc) 438.41, MS: 439.35 (MH+), 437.20 (M−). 1H NMR (DMSO-d6): δ 3.97 (s, 3H), 7.13 (s, 1H), 7.30-7.75 (complex, 10H), 7.92 (s, 1H), 10.21 (s, 1H). HPLC retention time 9.29 minutes.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH:16]=O)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23][N:24]([CH3:26])[CH3:25].C(N(CC)CC)C>>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][NH:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23][N:24]([CH3:26])[CH3:25])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C=O)c1
Reactant: CN(C)C/C=C/CN
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)C/C=C/CNCc1cc(CO[Si](C)(C)C(C)(C)C)ccn1

Procedure:
By General Procedure A from 4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carbaldehyde (1.0 equiv.), [(2E)-4-aminobut-2-en-1-yl]dimethylamine hydrochloride (1.0 equiv.), and triethylamine (1.0 equiv.). Purification by column chromatography (0-10% MeOH in DCM) gave the title product as yellow oil. 1H NMR (300 MHz, chloroform-d): δ ppm 8.45 (d, 1H), 7.20 (s, 1H), 7.11 (d, 1H), 5.67 (m, 2H), 4.68 (s, 2H), 3.85 (s, 2H), 2.89 (s, 2H), 2.19 (s, 6H), 0.89 (m, 9H), 0.07 (m, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[N+](C1C=CC([C:30]([O-])=[O:31])=CC=1)([O-])=O>ClCCl>[CH:30]([NH:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[C:4]=1[C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)=[O:31]
Reactant: O=C([O-])c1ccc([N+](=O)[O-])cc1
Reactant: NCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Solvent: ClCCl
Product: O=CNCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 5-aminomethyl-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (Example C-1) (8.04 g, 30 mmol) in 120 mL dichloromethane was added p-nitrophenylformate (6.01 g, 36 mmol) as a solid. The suspension was stirred for 24 h at room temperature and the solvents removed under reduced pressure. The residue was triturated with ether and filtered to obtain the desired 5-(N-formylaminomethyl)-4-(4-pyridyl)-3-(4-fluorophenyl)pyrazole derivative as a white solid: MS (M+H): 297 (base peak).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][C:34]1([CH3:40])[CH2:39][O:38][CH2:37][CH2:36][NH:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:35]3[CH2:36][CH2:37][O:38][CH2:39][C:34]3([CH3:40])[CH3:33])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CC1(C)COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Solvent: ClCCCl
Product: CC[C@@H](CN1CCOCC1(C)C)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (70 mg, 0.151 mmol; Example 210, Step A) in DCE (3 mL) was added 45.9 mg (0.303 mmol) of 3,3-dimethylmorpholine hydrochloride (Cottle, D.; Jeltsch, A.; Stoudt, T.; Walters, D. Journal of Organic Chemistry. 1946, 11(3), 286-91.; Note: reference is for the free base) and sodium triacetoxyborohydride (64.2 mg, 0.303 mmol). After stirring overnight, the mixture was diluted with sat. aq. NH4Cl solution. The mixture was extracted with DCM (2×). The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography on silica gel (eluent: 50% ethyl acetate/hexanes). The product containing fractions were pooled, concentrated and repurified by preparative thin layer chromatography on silica gel (eluent: 10% MeOH/DCM) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[OH:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:23])[C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COCN(c1cc(Cl)cnc1C(O)c1c(F)cccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)c1c(F)cccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
To a solution of 4-chloro-N-{5-chloro-2-[(2-chloro-6-fluoro-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (144 mg, 0.252 mmol) in CH2Cl2 (5 mL) was added Dess-Martin periodinane (213.5 mg, 0.5 mmol) and stirred for 3 h at room temperature. 10% aqueous Na2S2O3 (5 mL) and saturated aqueous NaHCO3 solution (5 mL) were added to the reaction mixture and stirred for 30 min. The aqueous layer was then extracted with EtOAc (2×25 mL). The combined organic extracts were subsequently washed with saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL), dried (Na2SO4), and concentrated to obtain 4-chloro-N-[5-chloro-2-(2-chloro-6-fluoro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (107 mg) in 75% yield which was used without further purification. MS m/z: 539 (M-MeOH+H), 593 (M+Na).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[CH:19]=[C:18]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[CH:29]([F:31])[F:30])[N:17]=[C:16]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[N:15]=3)[CH2:9][CH2:8]2)[C:3]1=[O:38].C(N(CC)CC)C.[CH3:46][O:47][C:48](Cl)=[O:49].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:46][O:47][C:48](=[O:49])[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[CH:19]=[C:18]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[CH:29]([F:31])[F:30])[N:17]=[C:16]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[N:15]=3)[CH2:9][CH2:8]2)[C:3]1=[O:38]
Reactant: COC(=O)Cl
Reactant: N[C@H]1CCN([C@H]2CC[C@H](Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)CC2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H]1CCN([C@H]2CC[C@H](Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3S)-3-amino-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]pyrrolidin-2-one (75 mg), triethylamine (22 μL), and dichloromethane (750 μL) was added methylchlorocarbonate (12 μL), followed by stirring at room temperature for 1 hour. After the completion of the reaction, a saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain methyl{(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate (55 mg) as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:44])[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[C:18]([O:21][C@@H:22]4[CH2:27][O:26][C@@H](C5C=CC=CC=5)[O:24][CH2:23]4)[CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=2)=[O:35])=[O:10])[CH2:5][CH2:4]1.Cl.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:1][N:2]([CH3:44])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[C:18]([O:21][CH:22]([CH2:27][OH:26])[CH2:23][OH:24])[CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=2)=[O:35])=[O:10])[CH2:5][CH2:4]1
Reactant: CN(C)C1CCC(C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(O[C@H]4CO[C@H](c5ccccc5)OC4)cc23)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(OC(CO)CO)cc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-5-(2-phenyl-[1,3]dioxan-5-yloxy)-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide (200 mg) obtained in Example 35 is dissolved in tetrahydrofuran (5 ml), and thereto is added 2N hydrochloric acid (5 ml), and the mixture is stirred at room temperature for 3 hours. The reaction solution is basified with a saturated aqueous sodium hydrogen carbonate solution and potassium carbonate, and extracted with chloroform. The organic layer is washed with a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: methanol/ethyl acetate=1/20→methanol/ethyl acetate=1/5) to give trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-5-(2-hydroxy-1-hydroxymethylethoxy)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (162 mg). This product is dissolved in methanol, and thereto is added 4N hydrogen chloride in ethyl acetate (1 ml). The solvent is evaporated under reduced pressure, and the resulting residue is suspended in diethyl ether, and the precipitates are collected by filtration to give the title compound (141 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:9]=[C:10]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=3)[C:5]=2[O:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1oc2ccc(C(C)(C)C)c(O)c2c1C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1oc2c(C(=O)c3ccc(Cl)cc3)cc(C(C)(C)C)c(O)c2c1C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 3-methyl-4-hydroxy-5-tert-butylbenzofuran-2-carboxylate, compound 12a (1.00 g, 3.62 mmol) and p-chlorobenzoyl chloride (0.793 g, 4.53 mmol) in 1,2-dichloroethane (40 mL) at 0° C. was added aluminum chloride (0.604 g, 4.53 mmol) and the mixture heated to reflux for two hours. Additional portions of 4-chlorobenzoyl chloride (0.475 g, 2.71 mmol) and aluminum chloride (0.362 g, 2.71 mmol) were added and the reflux continued for an additional 1.5 hours. The reaction mixture was poured into 2N HCl (100 mL) and extracted with methylene chloride (4×25 mL). The combined extracts were washed with water (25 mL), dried (Na2SO4), and concentrated. Flash chromatography using 25% ethyl acetate in hexane as eluant afforded ethyl 3-methyl-4-hydroxy-5-tert-butyl-7-p-chlorobenzoylbenzofuran-2-carboxylate, compound 17 as an oil sufficiently pure for further chemistry. 1H NMR d 1.34 (3H, t, J=6 Hz), 1.50 (9H, s), 2.88 (3H, s), 4.54 (2H, q, J=6 Hz), 7.47 (2H, d, J=8 Hz), 7.78 (2H, d, J=8 Hz), 7.87 (1H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:21])[CH:3]=1.BrC1C=CC(C(O)=O)=C(C)C=1.N1(C2CCNCC2)CCCC1.BrC1C(C)=C(C(N2CCC(N3CCCC3)CC2)=O)C=CC=1.[F:65][C:66]([F:78])([F:77])[O:67][C:68]1[CH:69]=[C:70](B(O)O)[CH:71]=[CH:72][CH:73]=1>>[CH3:21][C:4]1[CH:3]=[C:2]([C:70]2[CH:71]=[CH:72][CH:73]=[C:68]([O:67][C:66]([F:65])([F:77])[F:78])[CH:69]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cc(Br)ccc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: C1CCN(C2CCNCC2)C1
Agent: Cc1c(Br)cccc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)ccc1C(=O)O
Product: Cc1cc(-c2cccc(OC(F)(F)F)c2)ccc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2-methyl-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (prepared from 4-bromo-2-methyl-benzoic acid and 4-pyrrolidin-1-yl-piperidine in analogy to the procedure described for the preparation of intermediate 2) was reacted with 3-trifluoromethoxy-phenyl boronic acid to give the title compound as light yellow solid. MS: 433.3 (MH+).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:36])([F:35])[CH2:30][S:31]([NH2:34])(=[O:33])=[O:32]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:34][S:31]([CH2:30][C:29]([F:36])([F:35])[F:28])(=[O:33])=[O:32])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)CC(F)(F)F
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)CC(F)(F)F)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2,2,2-trifluoroethanesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method A described hereinabove. Yield (34%); 1H NMR (d6-DMSO) δ 7.39-7.01 (m, 13H), 6.83 (d, J=8.1 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.85 (s, 1H), 2.69 (s, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H); ESI m/z: 498 (M−H−).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1([CH3:10])[O:9][CH2:8][CH2:7][O:6]1)[CH3:4].C[O-].[Na+].[CH:14](OCC)=[O:15]>CO>[CH:14]([NH:2][CH:3]([C:5]1([CH3:10])[O:9][CH2:8][CH2:7][O:6]1)[CH3:4])=[O:15]
Reactant: CCOC=O
Reactant: CC(N)C1(C)OCCO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(NC=O)C1(C)OCCO1
Reaction time: 4 h

Procedure:
2-(1-Aminoethyl)-2-methyl-1,3-dioxolane hydrochloride (1.3 g, 0.0078 mol) was dissolved in methanol (25 ml). Sodium methoxide (25% w/w in methanol. 1.68 g, 0.0078 mol) was added and the suspension filtered through Celite. The Celite was rinsed with methanol (25 ml) and the combined filtrates had the solvent removed by rotary evaporation (25 Torr, 40° C.). The resulting clear oil was dissolved in ethyl formate (10.36 g. 0.14 mol) and heated to reflux under nitrogen. The reflux was continued for 4 hours. The excess ethyl formate and ethanol byproduct were removed by rotary evaporation (25 Torr, 40° C.) and the resulting solid was dried in vacuo (0.5 Torr, 25° C., 16 hours). The product was
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](F)[C:6]([CH3:12])=[N:7]2.Cl.[CH3:15][C:16]1([NH2:19])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:19][C:16]1([CH3:15])[CH2:18][CH2:17]1)[C:6]([CH3:12])=[N:7]2
Reactant: Cc1nc2cccc(Br)c2nc1F
Reactant: CC1(N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(Br)c2nc1NC1(C)CC1
Yield: 46 %

Procedure:
This compound (0.50 g, 45% yield) as a light yellow crystalline solid was prepared according to Example 174, using 5-bromo-3-fluoro-2-methylquinoxaline (126f; 0.96 g, 3.72 mmol), 1-methylcyclopropanamine hydrochloride (ChemBridge, San Diego, Calif.; 0.6 g, 5.58 mmol), and DIPEA (2.59 mL, 14.87 mmol) as starting materials: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.83 (dd, J=7.6, 1.2 Hz, 1H), 7.71 (dd, J=8.2, 1.2 Hz, 1H), 7.45-7.51 (m, 1H), 7.22 (t, J=7.8 Hz, 1H), 2.47 (s, 3H), 1.54 (s, 3H), 0.78-0.84 (m, 2H), 0.68-0.75 (m, 2H). m/z (ESI, +ve) 292/294 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].Br[C:35]1[C:40]2=[CH:41][CH:42]=[C:43]3[C:52]([CH:51]=[C:50]4[C:45]([CH:46]=[CH:47][CH:48]=[CH:49]4)=[CH:44]3)=[C:39]2[CH:38]=[CH:37][CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[CH:38]1[C:39]2=[C:52]3[C:43](=[CH:42][CH:41]=[C:40]2[C:35]([C:28]2[CH:29]=[CH:30][C:25]([CH:23]=[O:24])=[CH:26][CH:27]=2)=[CH:36][CH:37]=1)[CH:44]=[C:45]1[C:50]([CH:49]=[CH:48][CH:47]=[CH:46]1)=[CH:51]3
Reactant: Brc1cccc2c1ccc1cc3ccccc3cc12
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2cccc3c2ccc2cc4ccccc4cc23)cc1

Procedure:
14 g (7.9 mmol) of tri-o-tolylphosphine and then 300 mg (1.3 mmol) of palladium(II) acetate are added to a well-stirred suspension of 50 g (333 mmol) of 4-formylphenylboronic acid, 81 g (266 mmol) of 4-bromobenz[a]anthracene and 118 g (558 mmol) of tripotassium phosphate in a mixture of 500 ml of toluene, 500 ml of dioxane and 400 ml of water, and the mixture is subsequently heated under reflux for 16 h. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v), three times with 100 ml of ethanol and finally dried. Yield: 49.7 g (149 mmol), 56%.