Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:19]2[N:23]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]([CH3:31])=[C:21]([S:32]([NH:35][CH2:36][C:37]([CH3:43])([CH3:42])[C:38]([O:40]C)=[O:39])(=[O:34])=[O:33])[CH:20]=2)[CH:8]=[CH:9][C:10]=1[S:11](=[O:18])(=[O:17])[NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]([C:19]2[N:23]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]([CH3:31])=[C:21]([S:32]([NH:35][CH2:36][C:37]([CH3:43])([CH3:42])[C:38]([OH:40])=[O:39])(=[O:34])=[O:33])[CH:20]=2)[CH:8]=[CH:9][C:10]=1[S:11](=[O:18])(=[O:17])[NH:12][C:13]([CH3:15])([CH3:16])[CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)(C)CNS(=O)(=O)c1cc(-c2ccc(S(=O)(=O)NC(C)(C)C)c(C(C)(C)C)c2)n(CC2CCCCC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(S(=O)(=O)NCC(C)(C)C(=O)O)cc(-c2ccc(S(=O)(=O)NC(C)(C)C)c(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of ester 10 (60 mg, 0.09 mmol) in MeOH (5 mL) was added 6N NaOH (1 mL). The mixture was stirred at rt overnight, the solvent was removed and the residue was adjusted ph<2 with 4N HCl, then extracted with EA (3×) and the combined organic layers were washed with brine and dried over Na2SO4, evaporated and purified by prep-HPLC to give acid 11 (38 mg, 65%) as white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 12.29 (s, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.81 (s, 1H), 7.53 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.14 (t, J=6.8 Hz, 1H), 6.47 (s, 1H), 3.87 (d, J=6.8 Hz, 2H), 2.83 (d, J=7.2 Hz, 2H), 2.45 (s, 3H), 1.55 (s, 9H), 1.44 (d, 3H), 1.19-1.16 (m, 12H), 1.05 (s, 6H), 0.89-0.84 (m, 3H), 0.66-0.57 (m, 2H). MS Calcd.: 623.3; MS Found: 624.2 (M+1).
Reaction SMILES: C[Mg]Br.[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].Br[CH2:14][C:15]#[C:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Cl-].[NH4+]>CCOCC.O1CCCC1>[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:14][C:15]#[C:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(C)=CCC#CCBr
Reactant: C#CCCCCCCCl
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(C)=CCC#CCC#CCCCCCCCl
Temperature: 25 °C

Procedure:
To 21 ml. of 3M ethereal methyl magnesium bromide in 47.5 ml. of dry tetrahydrofuran under nitrogen was added 9.2 g. of 1-chloro-7-octyne in 15 ml. of tetrahydrofuran. The mixture was heated under reflux for 30 min., then was allowed to cool to room temperature during another 30 minutes after which 365 mg. of cuprous chloride was added. The mixture was heated under reflux for 20 min., then a solution of 14 g. of 1-bromo-6-methyl-undec-2-yn-5-ene in 12.9 ml. of tetrahydrofuran was added. The mixture was heated under reflux for 10 hrs. then cooled in an ice bath and 250 ml. saturated aqueous ammonium chloride was added. Ether was added and the mixture was filtered through Celite (diatomaceous earth filter ald) and separated. The thus obtained ether layer was washed with saturated aqueous sodium chloride, dried with magnesium sulfate, and evaporated. The thus obtained residue was distilled through a rocking short-path distillation apparatus, collecting 11.5 g. of a mixture comprising 1-chloro-14-methylnonadeca-7,10-dlyn-13-ene at a bath temperature of 180°-190°/0.005 mm.
Reaction SMILES: N1C=CC=CC=1.Br[CH:8](Br)[C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:24])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[N:13][CH:14]=1.[CH2:26]([OH:29])[CH2:27][OH:28].[BH4-].[Na+]>CCOCC.C(O)C.O>[F:23][C:17]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=1[CH:15]([OH:24])[C:12]1[CH:11]=[CH:10][C:9]([CH:8]2[O:29][CH2:26][CH2:27][O:28]2)=[CH:14][N:13]=1
Reactant: OCCO
Reactant: O=C(c1ccc(C(Br)Br)cn1)c1cc(F)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: OC(c1ccc(C2OCCO2)cn1)c1cc(F)ccc1F
Temperature: 90 °C
Reaction time: 17 h
Yield: 51.8 %

Procedure:
To a pyridine solution (60 ml) of the 5-dibromomethyl-2-(2,5-difluorobenzoyl)pyridine (Compound A) (3.91 g, 10 mmol) obtained in Referential Example 20 was added ethylene glycol (6.2 g, 100 mmol). While heating at 90° C., the resulting mixture was stirred for 17 hours. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was dissolved in ether (200 ml). The resulting solution was washed with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was dissolved in ethanol (60 ml). To the resulting solution was added sodium borohydride (190 mg, 5 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 1 hour. After the addition of water, the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=5:1 to 1:1) to give the title compound (1.52 g, 52%) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[C:23]([NH2:41])=[CH:24][C:25]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:28][CH2:27][C:26]=2[CH:40]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:41][C:23]2[C:22]([O:21][CH3:20])=[CH:40][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CCN1CCOCC1)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CCN2CCOCC2)CC3)ncc1Cl
Yield: 9 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 8-Methoxy-3-(2-morpholin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine. Product isolated as and off-white foam (10 mg, 9%). MS (ESI+): 566 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 11.02 (s, 1H), 8.69 (d, J=8 Hz, 1H), 8.12 (s, 1H), 8.10 (s, 1H), 7.52-7.43 (m, 3H), 7.09 (t, 8 Hz, 1H), 6.66 (s, 1H), 6.25 (d, J=4 Hz, 1H), 3.88 (s, 3H), 3.74 (t, J=4.5, 4H), 3.05 (d, J=5 Hz, 3H), 2.88 (br s, 2H), 2.79 (br s, 2H), 2.71 (br s, 6H), 2.56 (m, 2H), 2.52 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:12][C:13]([OH:15])=[O:14])#[N:2]
Reactant: O=C(O)CC(=O)O
Reactant: N#Cc1cccc(C=O)c1
Product: N#Cc1cccc(C=CC(=O)O)c1

Procedure:
3-Cyanobenzaldehyde was reacted with malonic acid by the method described in Example 2(a) to give the title product, m.p. ca 240° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[CH:12]=[C:13]([CH3:15])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([C:6]1[N:11]2[C:12]([N+:16]([O-:18])=[O:17])=[C:13]([CH3:15])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(C)cn12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cccc2nc(C)c([N+](=O)[O-])n12
Temperature: 0 °C

Procedure:
To a solution of 1.02 g (5.0 mmol) of 5-ethoxycarbonyl-2-methyl-imidazo[1,2-a]pyridine in 2.5 ml of conc. sulfuric acid was added dropwise, while stirring under ice-cooling, 2.0 ml of conc. nitric acid. The mixture was stirred for 10 minutes at the same temperature. The reaction mixture was poured into ice-water, whose pH was adjusted to 3-4 with a 10% aqueous solution of NaOH. The resulting crystalline precipitates were collected by filtration, washed with water and dried, followed by further purification by column chromatography (eluent: ethyl acetate) to afford 752 mg of the desired compound (60.4%, a yellow solid).
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:30][C:31]1[C:35]([C:36]([OH:38])=O)=[CH:34][O:33][N:32]=1.[CH3:39][O:40][C:41]1[CH:61]=[CH:60][C:44]([O:45][C:46]2[CH:59]=[CH:58][C:49]([CH2:50][NH:51][C:52]([C:54]3([NH2:57])[CH2:56][CH2:55]3)=[O:53])=[CH:48][CH:47]=2)=[C:43]([C:62]([F:65])([F:64])[F:63])[CH:42]=1>CN(C=O)C>[CH3:39][O:40][C:41]1[CH:61]=[CH:60][C:44]([O:45][C:46]2[CH:59]=[CH:58][C:49]([CH2:50][NH:51][C:52]([C:54]3([NH:57][C:36]([C:35]4[C:31]([CH3:30])=[N:32][O:33][CH:34]=4)=[O:38])[CH2:55][CH2:56]3)=[O:53])=[CH:48][CH:47]=2)=[C:43]([C:62]([F:63])([F:64])[F:65])[CH:42]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Reactant: Cc1nocc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4conc4C)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
37 μL (0.26 mmol) of triethylamine and 84.4 mg (0.26 mmol) of TBTU were added to a solution of 33.4 mg (0.26 mmol) of 3-methylisoxazole-4-carboxylic acid in 5 mL DMF and the mixture was stirred for 10 min at RT. Then 100 mg (0.26 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide (from 85a) was added and the mixture was stirred for 4 h at ambient temperature and overnight at 40° C. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]1([C:25]2=[CH:26][C:27]3[C:28]([CH:33]([O:36][Si](C(C)C)(C(C)C)C(C)C)[CH2:34][CH2:35]2)=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:19]1([C:25]2=[CH:26][C:27]3[C:28]([CH:33]([OH:36])[CH2:34][CH2:35]2)=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)[Si](OC1CCC(c2ccccc2)=Cc2cccnc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC1CCC(c2ccccc2)=Cc2cccnc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
TBAF (1.041 mL, 1.041 mmol) was added to the THF (5 mL) solution of (E)-6-phenyl-9-(triisopropylsilyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridine (0.2049 g, 0.521 mmol) at rt. The reaction was stirred at room temperature for 6 hours. The solvent was removed via vacuum to give the crude product. MS(ESI)[M+H+]=238.25.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH2:26](C([Sn])=C(CCCC)CCCC)[CH2:27]CC>O1CCOCC1>[C:20]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:11][C:2]([CH:26]=[CH2:27])=[N:3]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Solvent: C1COCCO1
Product: C=Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 90 °C
Yield: 78 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (0.5 g, 1.44 mmol) in 1,4-dioxane (10 mL) was added Pd(TPP)2Cl2 (0.101 g, 0.144 mmol) and tributylvinyltin (2.285 g, 7.20 mmol) under a nitrogen stream. Upon completion of addition, the reaction mixture was heated to reflux at 90° C. for 16 h. After this time, the reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (20% ethyl acetate, hexane) to yield 5-phenyl-N-(pyridin-2-ylmethyl)-2-vinylquinazolin-4-amine (0.38 g, 78% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.22 (dd, 1H, J=4.8 Hz), 7.76 (d, 1H, J=1.6 Hz), 7.75 (s, 1H), 7.70 (dt, 1H, J=2 Hz, 8 Hz), 7.45-7.56 (m, 5H), 7.20-7.28 (m, 3H), 6.72 (dd, 1H, J=10.4 Hz, 17.2 Hz), 6.64 (t, 1H, J=3.6 Hz), 6.56 (dd, 1H, J=1.6 Hz, 17.2 Hz), 5.67 (d, 1H, J=10.4 Hz), 4.62 (d, 2H, J=4.0 Hz). LCMS Method T: retention time 1.500 min; [M+1]=339.2; HPLC Method A2: purity 98.1%, retention time=8.74 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:41])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 44 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 44% of theory, Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1) C26H26N6O4 (486.5) ##EQU25##
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:20][CH2:19]C3(OCCO3)[CH2:13][CH2:12]2)[CH:3]=1.OC1N2N=CC=C2N=C(C2CC[N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])CC2)C=1.O1C2(CCC(C3C=C(O)N4N=CC=C4N=3)CC2)OCC1>>[Cl:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:12][CH2:13][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:19][CH2:20]2)[CH:3]=1
Reactant: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(O)n3nccc3n2)CC1
Agent: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)n3nccc3n2)CC1

Procedure:
tert-Butyl 4-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate was synthesized in a manner similar to the synthesis of 7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine, but with tert-butyl 4-(7-hydroxypyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate substituted for 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-ol.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].C(N(C(C)C)CC)(C)C.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O.C(OCC)(=O)C.C(Cl)CCl>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:8])=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(C(=O)O)ccc1O
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-hydroxy-3-[(methyloxy)carbonyl]benzoic acid (may be prepared as described in Description 107, 1.31 g, 6.68 mmol) in N,N-dimethylformamide (10 ml) was added diisopropylethylamine (2.33 ml, 13.36 mmol), morpholine (1.75 ml, 20.03 mmol), HOBT (1.33 g, 8.68 mmol) and EDC (2.56 g, 13.36 mmol). The solution was stirred at room temperature for 18 hours then another equivalent of EDC was added (1.28 g, 13.38 mmol). The solution was stirred for another 6 hours then ethyl acetate (20 ml) and water were added. The organic layer was separated, washed with water (3×10 ml), dried (MgSO4) and the solvent removed in vacuo to give a gum. Purification by MDAP yielded the title compound as a gum. 560 mg.
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]([NH:11][C@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)=[O:10])[CH:5]=1>O.CO.C1COCC1>[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]([NH:11][C@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)=[O:10])[CH:5]=1
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cc(C)on1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)N[C@@H]2CCc3ccc(C(=O)O)cc32)no1
Reaction time: 5 h
Yield: 59 %

Procedure:
LiOH (3.0 g, 42.66 mmol, 8 eq) in water (30 ml) was added dropwise to a cooled (0° C.) solution of (R)-methyl 3-(5-methylisoxazole-3-carboxamido)-2,3-dihydro-1H-indene-5-carboxylate (B-25) (1.6 g, 5.3 mmol, 1 eq) in MeOH:THF (1:1, 60 ml), and stirring was carried out for 5 h at RT. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure and the residue was taken up in water (50 ml), adjusted to pH 2 with KHSO4 and extracted with DCM (2×100 ml). The combined organic phases were washed with sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. Yield: 59% (900 mg, 3.14 mmol).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([F:28])[CH:20]=1>>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([C:10]2[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:20][C:21]=1[F:28])(=[O:27])[CH3:26]
Reactant: CC(=O)c1ccc(Br)cc1F
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Product: CC(=O)c1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F

Procedure:
The title compound was prepared using conditions analogous to those described in Example 1 using (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid and 1-(4-bromo-2-fluorophenyl)ethanone. 1H NMR (500 MHz, CDCl3) δ 8.19 (dd, J=7.9, 1.3, 1H), 7.95 (m, 1H), 7.63-7.57 (m, 1H), 7.57-7.52 (m, 1H), 7.38-7.30 (m, 2H), 7.28 (dd, J=7.5, 1.3, 1H), 2.70 (d, J=4.9, 3H), 1.05 (m, 9H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33]CC)=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>ClCCl>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: -30 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a stirred solution of acetic acid (2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (4.0 g, 6.93 mmol) prepared using the procedures described in J. Med. Chem. 2008, 51(5), 1145-49, in dichloromethane (40 mL) was added 1 molar solution of BBr3 (34.6 mL, 34.6 mmol) at −78° C. under nitrogen atmosphere. Reaction was stirred at −78° C. for 1.5 h and −30° C. for 1 h. Reaction mixture was poured over ice and neutralized with sat. NaHCO3 (20 mL), extracted with dichloromethane, concentrated and purified by silica gel column chromatography to furnish acetic acid (2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (2.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](O)=[N:7][C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:5][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:7][C:8]=2[Cl:23])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc3nc(Cl)ccc3c(O)n2)cc1
Product: COc1ccc(-c2cc3nc(Cl)ccc3c(Cl)n2)cc1
Yield: 96.2 %

Procedure:
2-Chloro-7-(4-methoxyphenyl)-[1,6]naphthyridin-5-ol (135 mg, 0.47 mmol) was dissolved in phosphorus oxychloride (2 mL, 21.5 mmol) and refluxed for 3 hours. An orange solid precipitated. The reaction mixture was diluted with dichloromethane (25 mL) and concentrated to an orange solid. The solid was re-dissolved in EtOAc (300 mL) and washed with saturated sodium bicarbonate solution (100 mL), brine (100 mL) and dried over magnesium sulfate. Filtration and concentration yielded 2,5-dichloro-7-(4-methoxy-phenyl)-[1,6]naphthyridine (138 mg, 86%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([NH:26]C(OC)=O)([CH2:23][CH2:24][CH3:25])[C:18](OCC)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl.[OH-].[K+]>O1CCCC1.CO.O>[NH2:26][C:17]([CH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:23][CH2:24][CH3:25])[CH2:18][OH:19]
Reactant: CCCC(CCc1ccccc1OCc1ccccc1)(NC(=O)OC)C(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(N)(CO)CCc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of ethyl 2-(2-(2-benzyloxyphenyl)ethyl)-2-methoxycarbonylaminopentanoate (2.3 g) in tetrahydrofuran (50 ml), under a nitrogen atmosphere, lithium borohydride (0.24 g) was added and the mixture was refluxed under heating for 2.5 hours. Then, a 2N dilute hydrochloric acid (5.5 ml) was added thereto and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate and the solvent was distilled away under reduced pressure. The residue obtained was dissolved in methanol (30 ml), and tetrahydrofuran (1 ml) and a 5N aqueous potassium hydroxide solution (10 ml) were added thereto and the mixture was refluxed under heating for 4 days. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate and the solvent was distilled away under reduced pressure. The reaction mixture was concentrated under reduced pressure to give the subject compound (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CC(C)=[O:33].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]([OH:33])=[O:5]
Reactant: CC(C)=O
Reactant: CCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C=O)c(Cl)c3)cc2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)O)c(Cl)c3)cc2)cc1
Reaction time: 3 h

Procedure:
The crude 2-chloro-4-{[p-(p-hexylphenyl)benzoyl]oxy}benzaldehyde (67.1 g) obtained was dissolved in 2500 ml of acetone. 80 ml of Jones' reagent were added dropwise to this solution within 45 minutes, the mixture warming slightly. The mixture was stirred for a further 3 hours, then the precipitated inorganic material was filtered off under suction and the acetone was distilled off on a rotary evaporator. The residue was suspended in water and the suspension was suction filtered. The crude 2-chloro-4-{[p-(p-hexylphenyl)benzoyl]oxy}benzoic acid obtained was washed neutral on the suction filter with water and then, for purification, boiled up with methanol, cooled, filtered off and dried. Yield 58.5 g; m.p. 163.8°-165.5° C.