Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[NH:18][C:19]5[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl-].[NH4+].C(Cl)CCl.C1C=CC2N(O)N=[N:43]C=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[NH:18][C:19]5[CH:25]=[C:24]([C:26]([NH2:43])=[O:27])[CH:23]=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)[nH]c2c1
Reactant: On1nnc2ccccc21
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: NC(=O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)[nH]c2c1
Temperature: 25 °C
Yield: 38 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-3H-benzoimidazole-5-carboxylic acid (44-0.8 mg, 0.11 mmol), ammonium chloride (11.8 mg, 0.22 mmol), EDC (32.6 mg, 0.17 mmol) and HOBt (23.0 mg, 0.17 mmol) in DMF 3.0 mL was added DIPEA (0.03 ml 0.17 mmol). After stirring at room temperature, the mixture was partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=6:1) to give 2-(4-adamantan-1-yl phenoxymethyl)-3H benzoimidazole-5-carboxylic acid amide as a white solid (16.8 mg, 37.5% yield).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[N:17][C:16]([N:19]3[CH2:23][CH2:22][NH:21][C:20]3=[O:24])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6].[H-].[Na+].I[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37].O>CN(C=O)C>[CH3:37][CH:36]([CH3:38])[CH2:35][CH2:34][N:21]1[CH2:22][CH2:23][N:19]([C:16]2[N:17]=[N:18][C:13]([N:10]3[CH2:9][CH2:8][N:7]([C:5](=[O:6])[C:4]4[CH:25]=[CH:26][CH:27]=[CH:28][C:3]=4[C:2]([F:1])([F:29])[F:30])[CH2:12][CH2:11]3)=[CH:14][CH:15]=2)[C:20]1=[O:24]
Reactant: CC(C)CCI
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(N3CCNC3=O)nn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCN1CCN(c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A mixture of 1-{6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazin-3-yl}imidazolidin-2-one (0.080 g, 0.180 mmol), sodium hydride in 60% mineral oil (0.0035 g, 0.150 mmol) in DMF (10 mL) was stirred at room temperature for 30 minutes. 1-Iodo-3-methylbutane (0.0376 g, 0.190 mmol) was added and the mixture was stirred at 60° C. for 24 hours, followed by the dilution with 50 mL of water, and then extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The title compound was obtained as a pale yellow solid in 32% yield (0.028 mg) after column chromatography purification. 1H NMR (300 MHz, CDCl3) δ 8.45 (d, J=9.9 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.48-7.65 (m, 2H), 7.32 (d, J=7.5 Hz, 1H), 6.98 (d, J=9.9 Hz, 1H), 3.82-4.12 (m, 4H), 3.42-3.64 (m, 6H), 3.24-3.34 (m, 4H), 1.38-1.66 (m, 3H), 0.92 (d, J=6.5 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 167.8, 157.3, 150.5, 134.8, 132.6, 129.7, 127.5, 127.1, 125.8, 122.1, 120.4, 116.6, 46.8, 46.3, 45.9, 42.5, 42.1, 41.5, 36.5, 26.1, 22.8. MS (ES+) m/z 491 (M+1).
Reaction SMILES: [CH2:1]1[O:14][C:4]2([CH2:11][CH2:10][CH:9]3[CH2:12][CH:5]2[CH2:6][CH2:7][C:8]3=O)[O:3][CH2:2]1.[BH4-].[Na+].[NH3:17]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:1]1[O:14][C:4]2([CH2:11][CH2:10][CH:9]3[CH2:12][CH:5]2[CH2:6][CH2:7][CH:8]3[NH2:17])[O:3][CH2:2]1
Reactant: N
Reactant: O=C1CCC2CC1CCC21OCCO1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: NC1CCC2CC1CCC21OCCO1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4.2 g of bicyclo[3.3.1]nonan-2,6-dione-monoethylene ketal (97) were dissolved in 54 mL of 2M ammonia in ethanol and 12.6 mL of titanium(IV) isopropoxide were added. The mixture is stirred at 60° C. overnight. Heating was continued until no further conversion was observed, another 22 mL of ammonia in ethanol was added portionwise over the course of the reaction. The mixture was cooled to room temperature and 1.21 g of sodium borohydride were added portionwise. The mixture was stirred for 2 h and then poured into 100 mL of 2M aqueous ammonia. The formed precipitate was filtered over celite and washed with ethyl acetate. The aqueous layer was extracted with ethyl acetate, the combined organic layer was dried over sodium sulfate and evaporated to dryness. The crude product was taken up in water and lyophilized to give 1.97 g of the desired product. Rt=0.52 min (Method C). Detected mass: 198.3 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[SH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N+:22]=1[O-:27]>>[O-:27][N+:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:20][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1
Reactant: [O-][n+]1ccccc1S
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3cccc[n+]3[O-])cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 2-mercapto-pyridine-1-oxide.
Reaction SMILES: Cl.[Si]([O:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[C:18]3[C:23](=[N:24][C:25]=2[CH:26](OC)[O:27]C)[N:22]([C:31]([NH:33][C:34]2[CH:39]=[C:38]([NH:40][CH2:41][CH2:42][O:43][CH3:44])[C:37]([C:45]#[N:46])=[CH:36][N:35]=2)=[O:32])[CH2:21][CH2:20][CH2:19]3)[C:11]1=[O:47])(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1.O.CCCCCCC.C(Cl)Cl>[C:45]([C:37]1[C:38]([NH:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:39][C:34]([NH:33][C:31]([N:22]2[C:23]3[C:18](=[CH:17][C:16]([CH2:15][N:12]4[CH2:13][CH2:14][C@H:10]([OH:9])[C:11]4=[O:47])=[C:25]([CH:26]=[O:27])[N:24]=3)[CH2:19][CH2:20][CH2:21]2)=[O:32])=[N:35][CH:36]=1)#[N:46]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CC[C@H](O[Si](C)(C)C(C)(C)C)C4=O)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CC[C@H](O)C4=O)c(C=O)nc32)ncc1C#N

Procedure:
Concentrated hydrochloric acid (0.66 ml) was added to a solution of (S)-6-((3-((tert-butyldimethylsilyl)oxy)-2-oxopyrrolidin-1-yl)methyl)-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 80C, 525 mg, 0.803 mmol) in THF (10 ml) and water (2 ml) at room temperature. After stirring for 15 h at room temperature saturated aqueous NaHCO3 was added, the mixture extracted with DCM (3×), the organic layers dried over Na2SO4 and evaporated. The residue was sonicated with EtOAc (6 ml) and pentane (6 ml) and then filtered. The white solid obtained was then heated and stirred with EtOAc (7 ml) and DCM (3 ml) for 30 minutes. The mixture was cooled, heptane (10 ml) added and the suspension filtered to give the title compound as a white solid.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[Cl:30][C:31]([F:39])([F:38])[C:32]([C:34]([F:37])([F:36])[Cl:35])=[O:33]>O>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:32]([C:31]([Cl:30])([F:39])[F:38])([C:34]([Cl:35])([F:37])[F:36])[OH:33])=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C(F)(F)Cl)C(F)(F)Cl
Reactant: c1ccc(C(c2ccccc2)N2CCc3ccccc32)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: OC(c1ccc2c(c1)CCN2C(c1ccccc1)c1ccccc1)(C(F)(F)Cl)C(F)(F)Cl
Reaction time: 13 h

Procedure:
A mixture of 14.5 g (0.05 mole) of 1-benzhydryl-indoline, 100 ml of toluene, 2 ml of water, and 10.9 g (0.055 mole) of 1,3-dichlorotetrafluoroacetone is refluxed for 3 hrs. Another 10.9 g portion of 1,3-dichlorotetrafluoroacetone is added, and refluxing is continued for 13 hrs. The moisture is then removed azeotropically, and the solvent is evaporated to give a crude, viscous residue of 1-benzhydryl-α,α-bis(chlorodifluoromethyl)-2,3-dihydro-1H-indole-5-methanol. This crude material is tedious to purify and is more conveniently used without further purification for conversion to the desired product.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])C>OS(O)(=O)=O>[O:12]=[C:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: O=S(=O)(O)O
Product: O=C1CCC(C(=O)O)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
20 mmol (3.4 g) of 4-oxocyclohexanecarboxylic acid ethyl ester is suspended in 40 ml of 2% H2SO4 and stirred for 2 hours at 90° C. Then, it is extracted 4 times with ethyl acetate, dried with Na2SO4, and solvent is removed. Recrystallization is carried out from ether/hexane and yields 2.9 g of white solid 3.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[NH:14][CH:15]([CH3:17])[CH3:16])([CH3:3])[CH3:2].[H-].[Na+].[CH3:20]I>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[N:14]([CH:15]([CH3:17])[CH3:16])[CH3:20])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1cc([N+](=O)[O-])ccc1OC(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1N(C)C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
2-Isopropoxy-N-isopropyl-5-nitrobenzenamine 29 (218 mg, 0.915 mmol, 1 equiv) in DMF (4 mL) under nitrogen gas, was cooled to 0° C. Sodium hydride (60% oil, 168 mg, 3.84 mmol, 4.2 equiv) was added in one portion, and the reaction mixture was stirred for 10 minutes at 0° C. Methyl iodide (525 uL, 7.68 mmol, 8.4 equiv) was added at 0° C., then the reaction mixture was stirred at ambient temperature for 2 hours, and heated at 80° C. overnight. The reaction mixture was concentrated to dryness and directly loaded into a silica gel flash column and eluted with dichloromethane to provide 2-isopropoxy-N-isopropyl-N-methyl-5-nitrobenzenamine 30 (205 mg, 89%) as a solid.
Reaction SMILES: S(=O)(=O)(O)O.B(O)(O)O.[Na+].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.OCC(CO)O.[O:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([NH2:40])[C:34]=2[O:33][CH2:32][CH2:31]1>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].O>[O:33]1[C:34]2[C:39]3[N:40]=[CH:15][CH:14]=[CH:19][C:38]=3[CH:37]=[CH:36][C:35]=2[O:30][CH2:31][CH2:32]1
Reactant: Nc1cccc2c1OCCO2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: OCC(O)CO
Solvent: O
Product: c1cnc2c3c(ccc2c1)OCCO3
Temperature: 140 °C
Reaction time: 4 h
Yield: 64.4 %

Procedure:
A mixture of concentrated sulphuric acid (30 ml), boric acid (2.29 g; 47.20 mmol) iron (II) sulphate heptahydrate (1.09 g; 3.93 mmol) and 3-nitrobenzene sulphonic acid sodium salt (9.5 g; 42.36 mmol) was cooled to 0° C. before addition of glycerol (11 ml; 151.31 mmol) and 2,3-dihydro-1,4-benzodioxin-5-amine (4.6 g; 30.26 mmol) followed by water (30 ml). The mixture was then heated to 140° C. and stirred for 4 hours. The reaction was then cooled to rt before being poured onto ice water (150 ml) and filtered. The resulting mixture was then basified to pH 8 with 6N NaOH and stirred with EtOAc for 30 mins. The organics were separated and the aqueous layer extracted with EtOAc×3. The combined organic layers were filtered through kieselguhr, washed with brine and dried with MgSO4. The solvents were removed to afford the desired product (3.65 g; 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[N+:22]#[C-:23])/[C:11](/[N+:20]#[C-:21])=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[C:24](=O)([O-])[O-].[K+].[K+].CBr>CN(C=O)C>[CH3:24][O:19][C:16]1[CH:15]=[CH:14][C:13](/[CH:12]=[C:11](/[C:10](/[N+:22]#[C-:23])=[CH:9]/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[N+:20]#[C-:21])=[CH:18][CH:17]=1
Reactant: [C-]#[N+]C(=C\c1ccc(O)cc1)/C(=C/c1ccc(OC)cc1)[N+]#[C-]
Reactant: O=C([O-])[O-]
Agent: CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: [C-]#[N+]C(=C\c1ccc(OC)cc1)/C(=C/c1ccc(OC)cc1)[N+]#[C-]
Yield: 110.3 %

Procedure:
13 mg of xanthocillin X monomethyl ether is dissolved in 2 ml of DMF and 40 mg of potassium carbonate is added thereto. Further, 50 μl of methyl bromide is added thereto and the mixture thus formed is extracted with 30 ml portions of ethyl acetate thrice. The extracts are combined, successively washed with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The sodium sulfate is filtered off, and the solvent is distilled from the filtrate. Thus, approximately 15 mg of xanthocillin X dimethylether is obtained in the form of a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([CH3:21])[N:17]=[C:18]([CH2:19][OH:20])[C:13]=3[CH2:12][CH2:11][C:10]2=[O:22])=[CH:4][CH:3]=1.[C:23]([N:27]1[C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2B(O)O)=[N:30][N:29]=[N:28]1)([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+].CCO>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.O>[OH:20][CH2:19][C:18]1[C:13]2[CH2:12][CH2:11][C:10](=[O:22])[N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[C:31]4[N:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:28]=[N:29][N:30]=4)=[CH:3][CH:4]=3)[C:14]=2[N:15]=[C:16]([CH3:21])[N:17]=1
Reactant: Cc1nc(CO)c2c(n1)N(Cc1ccc(Br)cc1)C(=O)CC2
Reactant: CC(C)(C)n1nnnc1-c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1nc(CO)c2c(n1)N(Cc1ccc(-c3ccccc3-c3nnnn3C(C)(C)C)cc1)C(=O)CC2
Yield: 90.4 %

Procedure:
A mixture of 8-[(4-bromophenyl)methyl]-4-hydroxymethyl-2-methyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (490 mg, 1.35 mmol), 2-[(1-tert-butyl)-1H-tetrazol-5-yl]phenylboronic acid (367 mg, 1.49 mmol) (prepared according to J. W. Ellingboe, et al. U.S. Pat. No. 5,149,699), Na2CO3 (287 mg, 2.71 mmol), tetrakis(triphenylphosphine)palladium(0) (78 mg, 0.07 mmol), EtOH (1 mL), water (2 mL), and toluene (6 mL) was heated under reflux for 23 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, brine, dried (MgSO4), and concentrated to give a yellow oil. Purification by flash chromatography (5% MeOH/CH2Cl2) gave 590 mg (90%) of product as an off-white foam. An analytical sample (40 mg) was crystallized from ether/acetone, mp 164°-166° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].Cl>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[CH:27][CH:26]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(-c3cc4c(C(=O)O)n[nH]c4cc3Cl)cc2)CC1
Yield: 4.3 %

Procedure:
To 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (75.0 mg, 0.27 mmol) in a 5 mL microwave vial was sequentially added 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]piperazine (82.2 mg, 0.27 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.0 mg, 0.027 mmol), 1,4-dioxane (2 mL) and 2 N aqueous potassium carbonate solution (0.4 mL, 0.81 mmol). The reaction mixture was degassed with argon and subjected to microwave irradiation at 110° C. for 50 minutes. The cooled reaction mixture was acidified to pH 5 with 1 N HCl and diluted with EtOAc (10 mL). The organic layer was washed with brine (6 mL), dried over MgSO4, and concentrated in vacuo. The resulting solid was purified by reversed phase HPLC (Column: Waters Sunfire C18 19×100, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: HOLD at 90.0% H2O/10.0% MeCN for 1.0 min. 90.0% H2O/10.0% MeCN linear to 60.0% H2O/40.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min.) to afford the title compound (4.3 mg, 4% yield). MS (ES+) 371.0 (M+H)+. Retention time=1.83 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(N)c1cccnc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cccnc1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(3-pyridyl)acetate (prepared as described in P. Kolar et al., J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein), the title compound was prepared as a solid (mp.=146-157° C.). The reaction was monitored by tlc (Rf=0.1 in CHCl3/MeOH 98:2) and the product was purified by silica gel chromatography using 959:5 CHCl3/MeOH as the eluent, followed by recrystallization from chlorobutane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH2:7][CH:8]2[CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cccc2c1C=CCC2CN1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc2c1CCCC2CN1CCCCC1

Procedure:
5% Palladium on carbon (3.0 g) is added to a solution of 5-methoxy-1-piperidinylmethyl-1,2-dihydronaphthalene (63 g) in absolute ethanol (600 ml) and placed under H2 at an initial pressure of 47 psi for 30 min. The reaction mixture is filtered and the filtrate evaporated in vacuo yielding the desired product as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)([Cl:16])=O>>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1ncc(C(=O)O)cc1[N+](=O)[O-]
Product: Nc1ncc(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
6-amino-5-nitro-nicotinic acid (2.50 g, 13.7 mmol) was mixed with 50 mL thionyl chloride and refluxed for 2 h. The mixture was concentrated and the residue reacted without further purification.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](O)(=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH:25]([CH3:27])[CH3:26])[C:28](=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(=O)O
Reactant: CC(C)NCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Product: CCCCCCC(=O)N(CCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(C)C
Yield: 90.8 %

Procedure:
Following literature precedent,2 5-(tert-butyldiphenylsilyloxy)-N-isopropylpentan-1-amine (0.90 g, 2.30 mmol) was condensed with heptanoic acid (0.26 g, 2.0 mmol) to give the title amide (0.90 g, 79%) as a viscous oil. TLC:EtOAc/hexanes (3:8), Rf˜0.60; 1H NMR (300 MHz, 1:1 mixture of rotamers) δ 7.65-7.67 (m, 4H), 7.30-7.40 (m, 6H), 4.62-4.72 (m, 0.5 H), 4.00-4.80 (m, 0.5H), 3.62 (t, J=4.8 Hz, 1H), 3.68 (t, J=4.8 Hz, 1H), 3.02 (t, J=5.2 Hz, 1H), 3.16 (t, J=5.2 Hz, 1H), 2.38 (t, J=5.3 Hz, 1H), 2.24 (t, J=5.3 Hz, 1H), 1.50-1.68 (m, 6H), 1.26-1.44 (m, 8H), 1.18 (d, J=7.3 Hz 3H), 1,12, (d, J=7.3 Hz 3H), 1.03 (s, 4.5 H), 1.04 (s, 4.5H), 0.88 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz) δ 173.38, 172.76, 135.80, 135.78, 134.36, 134.12, 129.85, 129.73, 127.88, 127.82, 64.22, 63.68, 48.43, 45.62, 43.64, 41.27, 34.13, 34.05, 32.61, 32.36, 31.96, 31.93, 31.51, 29.63, 29.47, 27.10, 27.03, 25.94, 25.78, 24.03, 23.77, 22.81, 21.63, 20.78, 19.47, 14.33, 14.28. HRMS calcd for C31H50NO2Si [M+1]+ 496.3611, found 496.3615.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[O:21]C)[CH:6]=[CH:5]2.FC1C2C(=CC=C(O)C=2)N=C(C2C=CC(C(O)=O)=CC=2OC)C=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:21][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:12]=1[C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[N:8]=1)[C:16]([OH:18])=[O:17]
Reactant: COc1cc(C(=O)O)ccc1-c1ccc2cc(O)ccc2n1
Agent: BrB(Br)Br
Agent: COc1cc(C(=O)O)ccc1-c1cc(F)c2cc(O)ccc2n1
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)c(O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.5 %

Procedure:
70 mg of 4-(6-hydroxyquinolin-2-yl)-3-methoxybenzoic acid (Compound 48) was suspended in 10 ml DCM and 0.25 ml BBr3 was added. The mixture was stirred at room temperature for 2 days. 20 ml water was added to quench the reaction. DCM was removed by evaporation and the precipitate was filtered and washed with water and dried to obtain 29 mg of 3-hydroxy-4-(6-hydroxyquinolin-2-yl)benzoic acid. 1H NMR (DMSO-d6 300 MHz TMS): δ 10.34 (s, 1H), 8.45 (d, 1H), 8.30 (d, 1H), 8.24 (d, 1H), 7.97 (d, 1H), 7.46 (m, 3H), 7.26 (d, 1H), MS (ESI): m/z=282.30 [M+1]+.
Reaction SMILES: [O:1]([C:8]1[C:9]2[N:16]([CH2:17][CH:18]([O:22]CC)[O:19]CC)[CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[O:1]([C:8]1[C:9]2[N:16]([CH2:17][CH:18]([OH:22])[OH:19])[CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(Cn1ccc2ncnc(Oc3ccccc3)c21)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC(O)Cn1ccc2ncnc(Oc3ccccc3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
4-Phenoxy-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (1.1 g) was dissolved in dichloromethane (4.53 mL)/trifluoroacetic acid (4.53 mL), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The mixture was washed with saturated aqueous sodium hydrogen carbonate (80 mL), and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (826 mg) as a white solid.