Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)OCC[C:9]1[CH:14]=[C:13]([C:15]([C:17]2[C:22]([N:23](COC)[S:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=3)(=[O:26])=[O:25])=[CH:21][C:20]([Cl:41])=[CH:19][N:18]=2)=[O:16])[CH:12]=[CH:11][N:10]=1)(C)(C)C.O.[O:45]1CC[O:48][CH2:47][CH2:46]1>Cl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([NH:23][C:22]2[C:17]([C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([O:45][CH2:46][CH2:47][OH:48])[CH:14]=3)=[O:16])=[N:18][CH:19]=[C:20]([Cl:41])[CH:21]=2)(=[O:25])=[O:26])=[CH:28][C:29]=1[C:34]([F:37])([F:36])[F:35]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccnc(CCO[Si](C)(C)C(C)(C)C)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: O=C(c1ccnc(OCCO)c1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of N-(2-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-pyridine-4-carbonyl}-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide in 4N HCl in dioxane (4 mL) and water (1 mL) was stirred at 100° C. for overnight. The reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The crude product was purified by HPLC. 1H NMR (400 MHz, CDCl3) δ 10.82 (s, 1H), 8.35 (m, 1H), 8.24 (m, 1H), 8.15-8.18 (m, 2H), 7.96 (m, 1H), 7.63 (m, 1H), 7.17 (m, 1H), 7.09 (m, 1H), 4.51 (m, 2H), 3.97 (m, 2H), 3.09 (m, 1H); MS: (M+H)/z=535.9.
Reaction SMILES: [CH2:1]([S:8]([NH:11][CH2:12][CH2:13][C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:17]=2[O:16][CH:15]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C=O)C>[CH2:1]([S:8]([N:11]([CH2:12][CH2:13][C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:17]=2[O:16][CH:15]=1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cccc2c(CCNS(=O)(=O)Cc3ccccc3)coc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c(CCN(Cc3ccccc3)S(=O)(=O)Cc3ccccc3)coc12
Temperature: 25 °C
Reaction time: 27 h
Yield: 57 %

Procedure:
Methyl (3-(2-(benzylsulfonylamino)ethyl)benzofuran-7-yloxy)acetate (143 mg) was dissolved in DMF (3 ml), and potassium carbonate (49 mg) and benzyl bromide (0.13 ml) were added to the obtained solution, followed by stirring the resulting mixture at room temperature for 27 hours and then at 50° C. for 14.5 hours. The reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with 1N hydrochloric acid and with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1-1/1) using silica gel to obtain the desired compound (100 mg, yield: 57%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:67]=[N:68][C:69]([O:72][CH3:73])=[CH:70][CH:71]=1>C(Cl)Cl>[CH3:73][O:72][C:69]1[N:68]=[CH:67][C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:71][CH:70]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COc1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.217 mmol) in methylene chloride (10 mL), HATU (Aldrich, 118 mg, 0.31 mmol) was added followed by the addition of DIPEA (0.15 mL, 0.86 mmol) and 3-amino-6-methoxy-pyridine (Aldrich, 43 mg, 0.34 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 0-5% MeOH/methylene chloride) to give a white solid. 73 mg.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13](Br)=[C:12]([CH3:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:46]([O:50][CH3:51])(=[O:49])[CH:47]=[CH2:48]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[N:11]=[C:12]([CH3:20])[C:13](/[CH:48]=[CH:47]/[C:46]([O:50][CH3:51])=[O:49])=[CH:14][C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(cc1Br)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cc2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2nc1C
Temperature: 120 °C
Yield: 24.3 %

Procedure:
To a suspension of 2-anilino-6-bromo-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (41 mg, 0.1 mmol) in DMF (2.0 mL) were successively added Pd(OAc)2 (0.70 mg, 0.003 mmol), Ph3P (5.2 mg, 0.02 mmol), TEA (0.03 mL) and methyl acrylate (17.2 mg, 0.2 mmol). The suspension was heated at 120° C. in a sealed tube for 64 h. The residue obtained after concentration in vacuo was washed with water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by prep-HPLC provided methyl (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)-2-propenoate (10.0 mg, 24%): LCMS RT: 2.61 min, MH+: 412.3, Rf=0.26 (1:1 EtOAc:Hex).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[O:10]1[CH:16]2[CH:11]1[C:12]([CH3:29])([CH3:28])[O:13][C:14]1[CH:20]=[CH:19][C:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[CH:17][C:15]=12.O>CS(C)=O>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C@@H:16]1[C:15]2[CH:17]=[C:18]([S:21]([C:24]([F:25])([F:27])[F:26])(=[O:23])=[O:22])[CH:19]=[CH:20][C:14]=2[O:13][C:12]([CH3:28])([CH3:29])[C@H:11]1[OH:10]
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2C2OC21
Reactant: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](n2ccccc2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.5 %

Procedure:
105 mg of 2-hydroxypyridine were added to a suspension of 48 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in anhydrous dimethyl sulfoxide, and the resulting mixture was stirred at room temperature for 15 minutes. At the end of this time, 309 mg of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl-2H-1-benzopyran (prepared as described in Preparation 8) were added under an atmosphere of nitrogen and at room temperature to the mixture. The mixture was then stirred at room temperature for 24 hours, after which it was poured into water and extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order; it was then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of ethyl acetate and cyclohexane as the eluent, to afford 95 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].[CH3:16][C:17]1[N:22]=[C:21]([SH:23])[N:20]=[C:19]([OH:24])[CH:18]=1.C(N(CC)CC)C>C(O)C>[Cl:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:3]=1[CH2:2][S:23][C:21]1[N:20]=[C:19]([OH:24])[CH:18]=[C:17]([CH3:16])[N:22]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCN(CC)Cc1cccc(Cl)c1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN(CC)Cc1cccc(Cl)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of {[2-(bromomethyl)-3-chlorophenyl]methyl}diethylamine (13.2 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (1.07 g, 7.5 mmol), and triethylamine (8 mL, 57.4 mmol) in absolute ethanol (50 mL) was stirred at room temperature overnight. The mixture was evaporated and then co-evaporated with EtOAc (20 mL). The solid residue was treated with water (100 mL), and the solution was extracted with dichloromethane (5×100 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-15% MeOH/CH2Cl2), affording 2-[({2-chloro-6-[(diethylamino)methyl]phenyl}methyl)sulfanyl]-6-methylpyrimidin-4-ol (932 mg, 39% yield); 1H NMR (400 MHz, DMSO-d6): δ 0.96 (t, 6H, J=6.8 Hz), 2.21 (s, 3H), 2.86 (m, 4H), 4.69 (s, 2H), 6.01 (s 1H), 7.35 (m, 1H), 7.42 (m, 1H); M+ 352.
Reaction SMILES: C(O[C:4]([C:6]1[NH:10][CH:9]=[N:8][C:7]=1[CH3:11])=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>>[F:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4]([C:6]1[N:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)c1[nH]cnc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1[nH]cnc1C(=O)Nc1ccccc1F
Temperature: 25 °C

Procedure:
To ethyl-4-methyl-5-imidazolecarboxylate (5 g, 32.4 mmol) was added 20 mL of 2-fluoroaniline and potassium carbonate (8.9 g, 64.8 mmol). The reaction mixture was heated to reflux for 18 h then cooled to room temperature and concentrated in vacuo. Water and hexane were added and the precipitate filtered to give the crude product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH2:10].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[C:11]([NH:19][C:20]([NH:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([NH:10][C:20](=[S:21])[NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:5]=1[CH3:9])=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1cc(N)c(C)cc1N
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=S)NC(=O)c2ccccc2)c(C)cc1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
2,5-Dimethyl-p-phenylenediamine (0.340 g, 2.5 mM) was dissolved in 30 ml of ethyl acetate, and 2 equivalents of benzoylisothiocyanate (0.816 g, 5 mM) were added. The mixture was stirred at room temperature for 10 minutes. After cooling, the reaction mixture was filtered, and washed with ethyl acetate/n-hexane to obtain 1.14 g (98.6% yield) of a colorless crystal of compound A-26.
Reaction SMILES: O.S([O-])([O-])=O.[Na+].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C(#N)C>[CH3:33][O:32][C:30](=[O:31])[CH2:29][S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:19]=1)(=[O:26])=[O:25]
Reactant: COC(=O)CCl
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)c2ccc(Br)cc2)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)CS(=O)(=O)c1cccc(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To 150 ml of water was added 85 g of sodium sulfite and then 54 g of 3-(4-bromophenylsulfonyl)benzenesulfonyl chloride was added thereto. After stirring the mixture for 2 hours at 50° C., the reaction mixture thus obtained was ice-cooled and crystals thus formed were collected by filtration. To the crystals thus obtained were added 40 ml of water, 40 ml of acetonitrile and 15 ml of methyl chloroacetate followed by refluxing for 2 hours. The reaction mixture thus formed was extracted with chloroform and then chloroform was distilled off from the extract to provide 32.7 g of oily 3-(4-bromophenylsulfonyl)phenylsulfonylacetic acid methyl ester. Then, the oily product thus obtained was added to a mixture of 60 ml of water, 60 ml of methanol, and 8.1 g of potassium hydroxide and the resultant mixture was stirred for one hour at room temperature. After adding 20 ml of 35% hydrochloric acid to the reaction mixture, the mixture was ice-cooled and crystals thus deposited were collected by filtration to provide 25.4 g of 3-(4-bromophenylsulfonyl)phenylsulfonylacetic acid. By neutralizing 21 g of the crystals thus obtained with 4.5 g of guanidine carbonate as in Synthesis Example 3 22.3 g of Base Precursor (123) was obtained. The melting point was 85° C. and the decomposition point was 95° C.
Reaction SMILES: [Cl:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:21].O>CN(C=O)C>[Cl:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[N:9]([CH3:21])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(Cl)cc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)Oc2cc([N+](=O)[O-])c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-2,2-dimethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (2.29 g, 8.9 mmol) was stirred in DMF at 0° C. under an atmosphere of nitrogen then sodium hydride (60% dispersion in oil) (392 mg, 9.79 mmol) was added. The reaction was allowed to stir at room temperature for 30 min then iodomethane (1.89 g, 13.4 mmol) was added and the reaction was stirred at room temperature for 18 h. Analysis by LCMS indicated that the reaction was complete. Water (10 mL) was added carefully then the DMF was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The organic portions were combined then passed through a phase separation cartridge. The solvents were evaporated to afford an orange solid (2.4 g, quant.) which was taken through to the next step with no further purification.
Reaction SMILES: NC(=O)[C@@H](N[C:6]([C@@H:8]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9]1)=[O:7])C.[OH:17]S(O)(=O)=O>O1CCOCC1>[C@@H:8]1([C:6]([OH:7])=[O:17])[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9]1
Reactant: O=S(=O)(O)O
Reactant: C[C@H](NC(=O)[C@H]1CC12CCCCC2)C(N)=O
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC12CCCCC2

Procedure:
The product from Example 4 (25.0 0.112 mol, 97% diastereomeric excess), 1,4-dioxane (50 mL), and 4M H2SO4 (100 mL) were refluxed for 8 hours. The resulting solution was extracted with heptane (3×150 mL). The combined organic extracts were concentrated to afford the title compound (97% enantiomeric excess). The enantiomeric excess of the carboxylic acid was determined by chiral gas chromatography (GC) performed on a Hewlett-Packard 5890 Series gas chromatograph with a flame ionization detector (250° C.), and split mode capillary injection system (ratio 30:1), using a Chiraldex GTA column (30 m×0.25 mm, lot 06847 Serial # G0112-15); 1.0 μL injection volume, 250° C. injection temperature, helium carrier gas at 20 psi, oven temperature 160° C. isothermal, retention time of 9.02 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[O:4][N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:18]1([CH2:21][C:22]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](S(C)=O)[N:29]=3)=[CH:26][N:25]=[C:24]([NH2:37])[N:23]=2)[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([CH2:21][C:22]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:7][C:5]4[O:4][N:3]=[C:2]([CH3:1])[CH:6]=4)[N:29]=3)=[CH:26][N:25]=[C:24]([NH2:37])[N:23]=2)[CH2:19][CH2:20]1
Reactant: CS(=O)c1nccc(-c2cnc(N)nc2CC2CC2)n1
Reactant: Cc1cc(N)on1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(-c3cnc(N)nc3CC3CC3)n2)on1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-methyl-isoxazol-5-ylamine in THF was added LiHMDS at −78° C., then the solution was stirred for 15 minutes, and 4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine (5-2) in THF was added to the reaction mixture. The reaction was warmed to rt and stirred for 1 hour. The reaction mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to give a crude product which was further purified by reverse-phase HPLC to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)(Cl)Cl)=[CH:6][CH:5]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[OH:25])[C:19]([OH:21])=[O:20]>>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:25][C:24]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=3[N:15]=2)=[CH:6][CH:5]=1)([O:2][CH3:1])=[O:14]
Reactant: Nc1cc(C(=O)O)ccc1O
Reactant: COC(=O)c1ccc(C(Cl)(Cl)Cl)cc1
Product: COC(=O)c1ccc(-c2nc3cc(C(=O)O)ccc3o2)cc1
Temperature: 200 °C

Procedure:
In the apparatus described in Example 1, 12.7 g of 4-trichloromethylbenzoic acid methyl ester (0.05 mol) and 7.5 g of 3-amino-4-hydroxybenzoic acid (0.05 mol) were mixed and heated for 6 hours at 200° C. The reaction product after grinding in a mortar was extracted twice with 100 ml of CHCl3 and then, after drying, twice with 100 ml of water. 9.2 g of raw product remained, melting at 275° to 284° C (62% of the theory). After two recrystallizations with dimethyl formamide plus active charcoal and dimethylsulfoxide, the melting point was 291° to 293° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1.C(O[C:34]1(O[Si](C)(C)C)[CH2:36][CH2:35]1)C>>[ClH:2].[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][O:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([CH:34]4[CH2:36][CH2:35]4)[CH2:23][CH2:24]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=C(N[C@@H](COCC1CCNCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Agent: Cl
Product: O=C(N[C@@H](COCC1CCN(C2CC2)CC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1

Procedure:
Using alkylation method A with addition of 3A molecular sieves, 3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)-ethyl]-1H-indole-6-carboxamide hydrochloride (200 mg, 0.44 mmol) and [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.53 mL, 2.7 mmol) afforded, after purification (SiO2: 0 to 5% isopropylamine in 10:2:2:DCM:EtOAc:hexane) and after conversion to the HCl salt by general method B, 80 mg (40%) of the title compound.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:9]=[C:10]([OH:11])[C:5]=2[CH:4]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH:32]([CH3:34])[CH3:33]>CN(C=O)C>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:9]=[C:10]([O:11][CH:32]([CH3:34])[CH3:33])[C:5]=2[CH:4]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:3]1
Reactant: CC(C)Br
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(OC(C)C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a mixture of ethyl 2-(1,4-dihydroxy-6-(tetrahydro-2H-pyran-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (320 mg, 0.95 mmol) and anhydrous K2CO3 (480 mg, 3.48 mmol) in DMF (10 mL) at 0° C. under N2 atmosphere was added 2-bromopropane (400 mg, 3.30 mmol). The reaction mixture was stirred at room temperature overnight and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound (110 mg. Yield: 30.6%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]([NH:23][O:24]C4CCCCO4)=[O:22])[CH:17]=3)[CH2:12]2)=[O:10])[CH:2]=1.[ClH:31]>CO>[ClH:31].[OH:24][NH:23][C:21]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([C:9](=[O:10])[CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:20][CH2:19]2)=[O:22]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)CCc1cccnc1)C2
Agent: Cl
Solvent: CO
Product: O=C(NO)c1ccc2c(c1)CCN(C(=O)CCc1cccnc1)C2
Reaction time: 3 h

Procedure:
A mixture of 140 mg of 2-(3-pyridin-3-ylpropanoyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 1 ml methanol and 1.5 ml of an aqueous, 0.1 M HCl are stirred for 3 h. Additional 2 ml of a 2N aqueous HCl are added and the mixture is stirred overnight. The mixture is lyophilized. 117 mg of the title compound are obtained as colorless oil. MH+=326.1
Reaction SMILES: Br[CH2:2][C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][CH2:2][C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(O)c1
Reactant: O=C(CBr)CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(OCC(=O)CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A dry, DMF (80 mL) solution of the product of Example 63, Step B (5.519 grams) was exposed to 3-methoxyphenol (3.608 grams) followed by cesium carbonate (9.481 grams). After stirring at ambient temperature for 2 hours the reaction was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried (magnesium sulfate) and filtered. Concentration and silica gel chromatography (5:1 hex/ethyl acetate) completed the isolation of the title compound, a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2.N[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)N[C:18]([C:23]([O:25]CC)=O)=[CH:17]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:4]([C:22]1[CH:14]=[CH:15][C:16](/[CH:17]=[CH:18]/[C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]3)=[O:25])=[CH:20][CH:21]=1)([CH3:8])([CH3:5])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: Nc1ccc2[nH]c(CO)cc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3[nH]c(CO)cc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(5-Aminoindol-2-yl)methan-1-ol. Ethyl 5-aminoindole-2-carboxylate, Example 74(a), (1.5 g, 7.3 mmol) was transferred to a round-bottomed flask and treated with lithium aluminum hydride (10 mL, 10 mmol, 1.0 M in THF, Aldrich) under N2. The reaction mixture was magnetically stirred at 25° C. for 1 h, then quenched by the dropwise addition of H2O (0.5 mL) followed by 20% aq. KOH (30 mL). The suspension was filtered and the aqueous phase extracted with EtOAc. The organic extract was concentrated in vacuo. Purification of the crude product by silica gel chromatography (20:80 hexane:EtOAc) provided the title product. MS (ESI, pos. ion) m/z: 163 (M+1).