Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][S:23]2(=[O:29])=[O:28])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12]CC1C=CC=CC=1)=[O:5])[CH3:2].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][S:23]2(=[O:28])=[O:29])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[OH:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1O
Yield: 82.6 %

Procedure:
A solution of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-5-benzyloxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (4.05 g, 9.61 mmol) in a mixture of ethanol (250 ml) and ethyl acetate (250 ml) was hydrogenated over 10% palladium on activated carbon (0.9 g) and under 1 atmosphere of hydrogen for 1 h. The catalyst was then filtered and the solvent was evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate gave 2.63 g (82% yield) of the title ester as white crystals; mp 186–189° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.42 (3H, t, J=7.0 Hz, CH3), 1.6–1.63 (1H, m, CH), 2.3–2.6 (3H, m, CH2 and CH), 3.2 (1H, m, CH), 3.55–3.75 (2H, m, CH2), 3.65 (3H, s, NCH3), 3.95–4.05 (1H, m, CH), 4.44 (2H, q, J=7.0 Hz, OCH2). HRMS (FAB POS) calculated for C12H18N3O6S [M+H+]: 332.091632. found: 332.092342.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8]3)(=[O:18])=[O:17])=[CH:27][CH:26]=2)=[N:31][CH:32]=1
Reactant: NCc1ccc(F)cn1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cn1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add to a stirring mixture of 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid (5.0 g, 13.25 mmol) and 2-aminomethyl-5-fluoropyridine (dihydrochloride) (2.9 g, 14.57 mmol) in anhydrous methylene chloride (60 mL), EDCI (3.8 g, 19.82 mmol) and 4-DMAP (6.0 g, 49.10 mmol). Stir the resulting solution overnight at room temperature, concentrate to a paste, and partition between ethyl acetate (100 mL), water (100 mL), and brine (100 mL). Dry the organic layer over sodium sulfate and concentrate to an oil. Dissolve the oil in methylene chloride and add to a biotage 65 cartridge. Elute with 1:1 ethyl acetate/hexanes to provide isolation of the pure 3 (N-(5-Fluoro-pyridin-2-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide as a solid, 5.7 g (89%): 1H NMR (DMSO-d6) δ 9.32 (t, J=5.9 Hz, 1H), 8.46 (d, J=2.9 Hz, 1H), 8.20 (d, J=8.3 Hz, 2H), 8.12 (s, 1H), 8.03 (m, 3H), 7.82 (d, J=7.8 Hz, 1H), 7.72 (d, J=6.8 Hz, 2H), 7.62 (dt, J=2.9, 8.8 Hz, 1H), 7.50 (t, J=7.3 Hz, 2H), 7.39 (m, 4H), 4.50 (d, J=5.9 Hz, 2H); MS (ESI) m/z 486 (m+H).
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:13]=[CH:12][C:10]([OH:11])=[C:7]([O:8][CH3:9])[CH:6]=1)=[O:4].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>C(O)C>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][C:10]1[CH:12]=[CH:13][C:5]([C:3](=[O:4])[CH3:2])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: BrCCCCBr
Reactant: COc1cc(C(C)=O)ccc1O
Agent: [Na]
Solvent: CCO
Product: COc1cc(C(C)=O)ccc1OCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
to a warm solution of 12.7 g (0.55 mole) of sodium metal in 500 ml of absolute ethanol was added a slurry of 83.1 g (0.5 mole) of acetovanillone in 250 ml of absolute ethanol. All solids dissolved and then a solid precipitated. The mixture was stirred at ambient temperature for 1 hr and then added over a 3-hr period to a solution at reflux of 177 g (0.82 mole) of 1,4-dibromobutane in 500 ml of absolute ethanol. After addition was complete, the mixture was heated at reflux overnight. The mixture was concentrated under reduced pressure and the residue was partitioned between 1.5 liter of benzene and 1 liter of water. The mixture was filtered to remove undesirable insoluble material. The filtrate layers were separated and the organic layer was washed with four 300 ml portions of a 5% sodium hydroxide solution once with water and once with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 138 g of gummy solid as residue. This solid was purified by column chromatography on 1 kg of silica gel, eluting with 2% ethylacetate in benzene to yield 69.6 g (46%) of title compound as an off-white solid. The solid was recrystallized from isopropyl ether, m.p. 52°-54° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][N:6]=1.[CH3:15][N:16](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:17].F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.CNC>CN(C)C=O>[CH3:15][N:16]([CH3:17])[C:9]([C:8]1[CH:12]=[CH:13][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])=[N:6][CH:7]=1)=[O:10]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)Cc1ccc(C(=O)O)cn1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(C(=O)N(C)C)cn1
Reaction time: 8 h

Procedure:
A solution of 6-(2-methoxy-2-oxoethyl)nicotinic acid (37 mg, 0.19 mmol), HATU (72.6 mg, 0.19 mmol), and N-ethyl-N-isopropylpropan-2-amine (26.5 mg, 0.20 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 15 min, then, dimethyl amine (0.05 mL, 1 mol solution in THF) was added and continued to stir overnight. The reaction is quenched with water, extracted with EtOAc and purified by a standard method to give the desired compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][C:14]1[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:15]=1[S:25](Cl)(=[O:27])=[O:26]>>[CH3:13][C:14]1[CH:19]=[C:18]([O:20][C:21]([F:22])([F:23])[F:24])[CH:17]=[CH:16][C:15]=1[S:25]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:27])=[O:26]
Reactant: Cc1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2C)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-methyl-4-trifluoromethoxybenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (41.7 mg) with purity >90%. MS (pos) m/z 425.3.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:30]([CH3:32])[CH3:31])=[O:28])[C:22]3[CH:40]=[CH:41][CH:42]=[CH:43][C:21]=3[N:20]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:19]2=[O:50])=[N:9]1)=O)(C)(C)C.Cl.CCOCC>O1CCOCC1>[F:39][C:36]1[CH:37]=[CH:38][C:33]([N:29]([CH:30]([CH3:32])[CH3:31])[C:27](=[O:28])[CH2:26][N:23]2[C:24](=[O:25])[CH:18]([CH2:17][C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][N:9]=3)[C:19](=[O:50])[N:20]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:21]3[CH:43]=[CH:42][CH:41]=[CH:40][C:22]2=3)=[CH:34][CH:35]=1
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc(F)cc1
Reaction time: 4 h
Yield: 11.6 %

Procedure:
To 890 mg (1.3 mmol) of crude 2-[3-(1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-(4-fluoro-phenyl)-N-isopropyl-acetamide, prepared as in Intermediate 58, is added 10 mL of 4N HCl in dioxane at RT. The resulting solution is stirred 4 h and 100 mL of Et2O is added. The precipitate is filtered and purified by RP-HPLC (50-60% acetonitrile/ H2O over 30 min) to afford 86.7 mg of the title compound: 1H NMR (CDCl3, 300 MHz) δ7.85 (d, 1H, J=8.2), 7.43-7.09 (m, 15H), 6.96 (d, 1H, J=8.3), 5.01 (m, 1H), 4.98 (m, 2H), 3.82 (m, 2H), 1.05 (m, 6H); low resolution MS (FAB) m/e 576 (MH+); RP-HPLC Tr =5.5 min (40-60% acetonitrile/ H2O).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:15]=[C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[CH:17]=2)[CH:13]=[CH:12][N:11]=1>CN1C(=O)CCC1>[CH3:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:1][C@H:2]3[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]3)[N:15]=2)=[CH:17]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Solvent: CN1CCCC1=O
Product: Cn1cc(-c2ccnc(N[C@H]3CC[C@H](O)CC3)n2)c2ccccc21
Temperature: 120 °C

Procedure:
trans-4-Aminocyclohexanol (0.45 g, 4 mmol) was added to 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (0.23 g, 1 mmol) in NMP (8 mL), and the resulting mixture heated to 120° C. for 3 h. A second aliquot of trans-4-aminocyclohexanol (0.16 g, 1 mmol) was added, and the resulting mixture was heated to 130° C. The reaction mixture was cooled and partitioned between water and EtOAc, the organic layer separated, washed twice with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was recrystallized from DCM/EtOAc/hexanes to give trans-4-[4-(1-methyl-1H-indol-3-yl)-pyrimidin-2-ylamino]-cyclo-hexanol (148 mg, 46% yield) as a light-yellow solid. MS=323 [M+H]+; MP=194.5-195.3° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:10]2[C:15]([N:16]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:18])[N:11]=2.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)[N:13]=[C:12]([CH3:18])[N:11]=2
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Br)n(C3CCOCC3)c2n1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Br)n(C3CCOCC3)c2n1
Yield: 65.5 %

Procedure:
Heat a solution of 8-(2-bromophenyl)-6-chloro-2-methyl-9-(tetrahydro-2H-pyran-4-yl)-9H-purine (0.0023 mol, 1.0 g), 1-methyl piperazine (0.0025 mol, 0.25 g, 1.1 equiv.) and triethylamine (0.0025 mol, 0.25 g, 1.1 equiv.) in ethanol (10.0 mL) at 90° C. for 16 h. Concentrate the reaction mixture under reduce pressure. Dissolve the residue in dry dichloromethane and wash with saturated sodium bicarbonate solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give the residue. Purify the residue by silica gel chromatography eluting with dichloromethane:methanol 97:3 to give 8-(2-Bromo-phenyl)-2-methyl-6-(4-methyl-piperazin-1-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine (0.71 g). Used as such for the next step.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28]>C(OC(=O)C)(=O)C>[CH3:28][C:27]([O:11][C@@H:10]1[C@@:2]2([CH3:1])[CH2:3][CH2:4][C@@H:5]3[C@@H:20]4[C:14](=[CH:15][C:16]([CH2:18][CH2:19]4)=[O:17])[CH2:13][CH2:12][C@H:6]3[C@@H:7]2[CH2:8][CH2:9]1)=[O:29]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C

Procedure:
In an apparatus supplied with a drierite drying tube, a solution of 19-nor-testosterone (10 (100 g; 0.365 mole) in acetic anhydride (200 ml), pyridine (32 ml) and acetylchloride (320 ml) was heated at reflux under magnetic stirring, for 3 h and then concentrated to dryness under vacuum. The dry residue was triturated in absolute ethanol, filtered and washed with little portions of absolute ethanol. After drying, 19-nor-testosterone acetate 3-enolacetate was obtained as a white powder (121.4 g, yield 93%) mp. 176-177° C. The structure was confirmed by spectroscopic means.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]1[CH2:17][CH:12]2[CH2:11][CH2:10]1.[B:18](OC)([O:21]C)[O:19]C.Cl>C1COCC1.C(OC)(C)(C)C>[CH:12]12[CH2:17][CH:9]([C:8]3[C:7]([B:18]([OH:21])[OH:19])=[CH:16][CH:15]=[CH:14][C:13]=31)[CH2:10][CH2:11]2
Reactant: COB(OC)OC
Reactant: Brc1cccc2c1C1CCC2C1
Agent: Cl
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1C1CCC2C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
100 ml (250 mmol) of n-butyllithium (2.5M in hexane) are added dropwise to a solution, cooled to −78° C., of 44.6 g (200 mmol) of 5-bromo-1,2,3,4-tetrahydro-1,4-methanonaphthalene in 500 ml of THF. The reaction mixture is stirred at −78° C. for 1 h, and a mixture of 33.5 ml (300 mmol) of trimethyl borate in 50 ml of THF is then added rapidly. After warming to −10° C., the mixture is hydrolysed using 10 ml of 2.5M hydrochloric acid, and 500 ml of methyl tert-butyl ether are then added. The organic phase is separated off, washed with water, dried over sodium sulfate and evaporated to dryness. The residue is taken up in 200 ml of n-heptane, and the colourless solid is filtered off with suction, washed with n-heptane and dried under reduced pressure. Yield: 24.1 g (128 mmol), 64.1% of theory; purity: 98% according to 1H-NMR.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[S:12]1[CH:16]=[CH:15][N:14]2[CH:17]=[N:18][CH:19]=[C:13]12>C(=S)=S.ClCCl>[C:5]([C:19]1[N:18]=[CH:17][N:14]2[CH:15]=[CH:16][S:12][C:13]=12)(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: c1cn2cncc2s1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: S=C=S
Product: CC(C)(C)C(=O)c1ncn2ccsc12

Procedure:
Aluminum chloride (6.0 g) was added to a solution of 6.1 ml of pivaloyl chloride in 50 ml of carbon disulfide. The mixture was stirred. A solution of 1.2 g of imidazo[5,1-b]thiazole in 20 ml of dichloromethane was added thereto, and the mixture was stirred at room temperature for 48 hr. Dichloromethane (200 ml) was added to the reaction mixture. The mixture was washed with water and a saturated aqueous sodium hydrogencarbonate solution in that order, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 0.92 g of 7-pivaloylimidazo[5,1-b]thiazole.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][C:16]1([CH3:26])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1.C(O)(C)C.O>CC(C)=O>[CH3:26][C:16]1([C:15]([OH:3])=[O:14])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1
Reactant: CC1(CO)COc2ccccc2O1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CC1(C(=O)O)COc2ccccc2O1

Procedure:
Jones' reagent (33.3 ml.) was added dropwise to a stirred solution of 2-hydroxymethyl-2-methyl-1,4-benzodioxan (5 g.) in acetone (300 ml.) at 5° C., then the reaction was allowed to attain room temperature. Isopropanol (10 ml.) was then added followed by water (200 ml.), the solution extracted with chloroform and the extracts evaporated in vacuo. The residual oil was taken up in chloroform (200 ml.) then extracted with dilute sodium bicarbonate solution and the aqueous phase further washed with chloroform. The aqueous phase was then acidified with hydrochloric acid, extracted with chloroform, the combined extracts washed with water, dried (MgSO4) and evaporated in vacuo ti give 2-methyl-1,4-benzodioxan-2-carboxylic acid (1.7 g.). A sample was recrystallized from toluene, m.p. 133°-134° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23](Br)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[O:36][CH3:35])[O:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3OC)c(-c3ccc(OC)cc3)c12
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Add 0.45 ml of a 2 M aqueous sodium carbonate solution to a mixture of 200 mg (0.45 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 16 mg (0.02 mmol) bis(triphenylphosphine)palladium(II) chloride in 10 ml dimethylsulphoxide. Next, add 85 mg (0.56 mmol) (2-methoxyphenyl)boronic acid and stir the mixture for 15 h at 80° C. Filter the reaction mixture and purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 63 mg (42% of theor.) of the desired product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].Cl[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=O)[C:17](=O)N2>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:16]([C:17]1[CH:4]=[CH:3][CH:2]=[CH:10][CH:6]=1)[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:14]=1)[C:8](=[O:11])[C:7]2=[O:12]
Reactant: O=C1Nc2c(Cl)cccc2C1=O
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(Cl)cccc21

Procedure:
Following the procedure as described in PREPARATION 4A, and making non-critical variations using 7-chloro-1H-indole-2,3-dione to replace 4-chloro-1H-indole-2,3-dione, 7-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione was obtained (38%) as an orange solid: mp 172-173° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 7.71-7.60 (m, 2H), 7.36-7.27 (m, 11H), 7.22-7.17 (m, 1H).
Reaction SMILES: Cl.C([O:4][C:5](=[O:33])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH:14]([C:18](=[O:30])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=2)[O:15][CH2:16][CH3:17])[CH:11]=[CH:10][C:9]=1[O:31][CH3:32])C.O.[OH-].[Na+].Cl>C1COCC1>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:18]([CH:14]([O:15][CH2:16][CH3:17])[C:12]2[CH:11]=[CH:10][C:9]([O:31][CH3:32])=[C:8]([CH:13]=2)[O:7][CH2:6][C:5]([OH:33])=[O:4])=[O:30])=[CH:26][CH:25]=1)(=[NH:28])[NH2:29]
Reactant: CCOC(=O)COc1cc(C(OCC)C(=O)NCc2ccc(C(=N)N)cc2)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)c1ccc(OC)c(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
To a stirred suspension of (RS)-{5-[(4-carbamimidoyl-benzylcarbamoyl)-ethoxy-methyl]-2-methoxy-phenoxy}-acetic acid ethyl ester hydrochloride (example 18.5, 0.045 g) at rt in THF (1 ml) and water (0.5 ml) was added 1.0 N NaOH (0.2 ml). The mixture was then stirred at rt under an argon atmosphere for 3 h. The mixture waa acidified to pH 5–6 by addition of 1.0 N HCl. The THF was removed (rotavapor) and the product precipitated out from the remaining water. It was collected by filtration, washed with water and cyclohexane and dried overnight under high vacuum to give (RS)-{5-[(4-carbamimidoyl-benzylcarbamoyl)-ethoxy-methyl]-2-methoxy-phenoxy}-acetic acid (0.027 g) as a white powder. MS 416.3 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]([CH2:12][OH:13])=[C:10]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1.[CH:23](O)=[O:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[C:11]([CH2:12][OH:13])=[C:10]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][CH:23]=[O:24])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(N)cc2C(n2ccccc2=O)=C1CO
Reactant: O=CO
Solvent: c1ccncc1
Product: CC1(C)Oc2ccc(NC=O)cc2C(n2ccccc2=O)=C1CO

Procedure:
A solution of 1 g of 2,2-dimethyl-3-hydroxymethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)6-amino-3-chromene in 15 ml of formic acid and 1 ml of pyridine is boiled for 24 hours and evaporated. After customary working up, 2,2-dimethyl-3-hydroxymethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-formamido-3-chromene is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[C:4]([CH:17]=[O:18])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].[CH3:23][Mg]Cl>C1COCC1>[Cl:1][C:2]1[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[C:4]([CH:17]([OH:18])[CH3:23])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: C[Mg]Cl
Reactant: CC(C)Oc1c(C=O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1c(C(C)O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-chloro-7-isopropoxy-4-isopropyl-2,2-dimethyl-2H-chromene-6-carbaldehyde, (Compound 135, 0.97 g, 3.0 mmol) in THF (15 mL) at was added methylmagnesium chloride (3M in THF, 1.6 mL, 4.8 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with 1N HCl. The resulting mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound as a yellow foam.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[O:17][C:18]4[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=4[C:20]=3[C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:12]=2)[CH:7]=1.[OH-].[K+]>C1COCC1.CO>[C:21]([C:20]1[C:19]2[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=2[O:17][C:16]=1[C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])[CH:15]=[CH:14]2)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc2cc(-c3oc4ccccc4c3C(=O)c3ccccc3)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc2cc(-c3oc4ccccc4c3C(=O)c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
To a stirred solution of {[6-(3-benzoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetic acid methyl ester (0.128 g, 0.293 mmol) in THF:MeOH (3:2, 10 mL) at 0° C. was added 1 N KOH (0.879 mL, 0.879 mmol) dropwise. The reaction was stirred at this temperature for 0.25 h and then warmed to room temperature for 1 h. After concentration, the residue was diluted with H2O, and this mixture was acidified to pH 1 with 2 N HCl. After stirring at room temperature for 3 h, the solid was filtered and washed with excess H2O and hexane. At this point, the compound was dried under high vacuum to afford the product (0.116 g) as a yellow solid, mp 178-181° C. Mass spectrum (−APCl, [M−H]−) m/z 421. 1HNMR (500 MHz, DMSO-d6): δ11.05-14.15 (br s, 1H), 8.17 (d, J=1.5 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.76-7.81 (m, 3H), 7.70 (d, J=8.8 Hz, 1H), 7.52-7.57 (m, 2H), 7.42-7.51 (m, 2H), 7.31-7.37 (m, 3H), 7.18-7.24 (m, 2H), and 4.77 ppm (s, 2H). Elemental Analysis for C27H18O5.0.5H2O: Calculated: C, 75.17; H, 4.44; N, 0.00 Found: C, 75.03; H, 4.34; N, 0.14