Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22]C)[CH:19]=[C:18]([O:24]C)[CH:17]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([OH:24])[CH:19]=[C:20]([OH:22])[CH:21]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)NCc2cc(OC)cc(OC)c2)cc1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCc2cc(O)cc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A solution of 2-chloro-4-[[(3,5-dimethoxybenzyl)amino]carbonyl]benzoic acid, methyl ester (0.50 g, 1.4 mmol) in dry dichloromethane (20 mL) was cooled to −78° C. A solution of boron tribromide (1 M in dichloromethane; 10 mL, 10 mmol) was added and the solution was allowed to warm to room temperature and stir overnight. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4), filtered, and evaporated to give 2-chloro-4-[[[(3,5-dihydroxyphenyl)methyl]amino]carbonyl]benzoic acid, methyl ester (400 mg, 90%) as a white solid, mp 152–155° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH:16]([F:18])[F:17])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH:20]([CH3:24])[C:21]([OH:23])=[O:22]>>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH:16]([F:18])[F:17])=[CH:4][C:5](=[O:8])[N:6]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:7]=1
Reactant: O=c1cc(-c2cc(Cl)ccc2C(F)F)c(Cl)c[nH]1
Reactant: CC(Br)C(=O)O
Product: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C(F)F)cc1=O

Procedure:
118 mg (0.41 mmol) of 5-chloro-4-[5-chloro-2-(difluoromethyl)phenyl]pyridin-2(1H)-one and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 35° C. Yield: 112 mg (76% of theory)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH:27]([C:28]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OC(C)C
Product: CC(C)OC(Cc1cccc(CCOC(=O)Nc2ccccc2)c1)C(=O)O

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(O)[CH2:17][CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH2:17][CH2:18][OH:19])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1ccc(CC(=O)OC)cc1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCNc1ccc(CC(=O)OCCCO)cc1

Procedure:
A mixture of 2.25 g. of methyl 4-(allylamino)phenylacetate, 280 mg. of 1,3-propanediol and 1.37 g. p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 3-hydroxypropyl 4-(allylamino)phenylacetate.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])C=O.C[O:22][C:23]1C=C([CH:28]=[CH:29][C:30]=1OC)C=O.[CH3:33][NH:34][NH2:35].O.NN>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([C:29]2[CH:28]=[N:35][N:34]([CH3:33])[C:23](=[O:22])[CH:30]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1ccc(C=O)cc1OC1Cc2ccccc2C1
Reactant: CNN
Agent: NN
Solvent: O
Product: COc1ccc(-c2cnn(C)c(=O)c2)cc1OC1Cc2ccccc2C1

Procedure:
Using a method similar to Working Example 1 (1)-(4), 3-(2-indanyloxy)-4-methoxybenzaldehyde was substituted for 3,4-dimethoxybenzaldehyde and methylhydrazine for hydrazine hydrate to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](I)[CH3:17].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:16][CH3:17]
Reactant: Oc1ccc(F)cc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.7 %

Procedure:
To a solution of 2-bromo-4-fluorophenol (25.8 g) in DMF (100 ml) was added K2CO3 (20.5 g) and ethyl iodide (23.2 g). The mixture was stirred for 24 h at room temperature. Water (400 ml) was added and the mixture was extracted with hexane. The organic phase was washed with water, dried, filtered over a plug of silica gel and evaporated to yield 30.1 g of 2-bromo-1-ethoxy-4-fluoro-benzene as a colorless oil. MS: 220 ([M+H]+).
Reaction SMILES: [N:1]1([OH:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[I-]>>[N:1]1([O:14][N:1]2[C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N:6]=[CH:5][C:4]=3[N:3]=[CH:2]2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: On1cnc2cnc3ccccc3c21
Agent: [I-]
Product: c1ccc2c(c1)ncc1ncn(On3cnc4cnc5ccccc5c43)c12

Procedure:
In step (3) of Reaction Scheme II a 1H-imidazo[4,5-c]quinolin-1-yl alcohol of Formula X is alkylated with an iodide of Formula XVII to provide a 1H-imidazo[4,5-c]quinolin-1-yl ether of Formula XVIII. The alcohol of Formula X is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form an alkoxide. The iodide is added to the alkoxide solution at ambient temperature. After the addition is complete the reaction is stirred at an elevated temperature (˜100° C.).
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.Br[C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:23][C:22]1[C:17]([N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: Clc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ncccc1Cl)C2
Temperature: 120 °C
Reaction time: 48 h

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (435 mg, 2.26 mmol), 2-bromo-3-chloropyridine (400 mg, 1.88 mmol), and potassium carbonate (390 mg, 2.83 mmol) were combined in dry dimethylformamide (10 mL) and stirred at 120° C. for 48 hours. The mixture was allowed to cool room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (85:15 hexanes:ethyl acetate) to provide the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH3:43])=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[ClH:25].[ClH:25].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([C:32]([CH3:43])=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1nc2ccc(Cl)nn2c1C
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1C
Product: Cl

Procedure:
2.38 g of 4 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.03 g of ethyl 2-(6-chloro-3-methylimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 160° C. for 7.5 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated under reduced pressure and dissolved in 5 ml of ethyl acetate; 0.96 ml of a 4 N solution of hydrogen chloride in ethyl acetate was added, followed by concentration again. The residue was powdered by the addition of ethyl ether, collected by filtration and dried to yield 666 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH:20]=[CH:21][CH:22]=1.[Br:32]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:32])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][P:24](=[O:31])([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])[CH:20]=[CH:21][CH:22]=1
Reactant: CCCCOc1nc(N)c2ncn(Cc3cccc(CP(=O)(OCC)OCC)c3)c2n1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCOc1nc(N)c2nc(Br)n(Cc3cccc(CP(=O)(OCC)OCC)c3)c2n1
Yield: 49 %

Procedure:
To a solution of 61 (134.9 mg, 0.30 mmol) in CHCl3 (5 mL) was added a 10% (v) solution of Br2 in chloroform. The reaction was stopped when starting material was consumed, monitored by HPLC. Bromine was quenched with a saturated Na2SO3 solution and product extracted with DCM (2×10 mL). Organics were washed with water (2×10 mL) and brine (1×10 mL) and dried over Na2SO4. Purified by flash column eluting 100% ethyl acetate. Evaporation of solvent gave 76.0 mg (49%) of 62 as a yellow solid. LCMS: m/z for C21H29BrN5O4P++H observed 526.1 and 528.1 at 2.37 minutes of a 3.5 minute run, eluting 5-95% CH3CN in H2O.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4([NH:44]C(=O)OC(C)(C)C)[CH2:43][CH2:42][CH2:41]4)=[CH:36][CH:35]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][CH:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:24][CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CO.[ClH:54]>C(OCC)(=O)C>[ClH:54].[NH2:44][C:40]1([C:37]2[CH:36]=[CH:35][C:34]([N:33]3[C:11]4=[N:12][C:13]([C:16]5[CH:17]=[C:18]([N:22]6[CH2:27][CH2:26][CH:25]([C:28]([N:29]([CH3:31])[CH3:30])=[O:32])[CH2:24][CH2:23]6)[CH:19]=[CH:20][CH:21]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:39][CH:38]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: CN(C)C(=O)C1CCN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)c4n3)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C(=O)C1CCN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(N)CCC6)cc5)c4n3)c2)CC1
Yield: 100 %

Procedure:
tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[4-(dimethylcarbamoyl)piperidin-1-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (3.4 g, 4.9 mmol) was deprotected with methanol (15 mL) and 4M HCl in ethyl acetate (15 mL) for 18 h at rt. The mixture was solidified with ethyl acetate and collected with filtration to give the titled compound (2.9 g, 100%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:12](=O)[C:11]2[C:6](=[CH:7][C:8]([NH:16][C:17](=[O:19])[CH3:18])=[C:9]([O:14][CH3:15])[CH:10]=2)[NH:5][CH:4]=1)#[N:2].P(Cl)(Cl)([Cl:22])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:22][C:12]1[C:11]2[C:6](=[CH:7][C:8]([NH:16][C:17](=[O:19])[CH3:18])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COc1cc2c(=O)c(C#N)c[nH]c2cc1NC(C)=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2c(Cl)c(C#N)cnc2cc1NC(C)=O
Temperature: 100 °C
Yield: 91.1 %

Procedure:
An amount of 10 g (0.039 mol) of N-(3-cyano-6-methoxy-4-oxo-1,4-dihydro-7-quinolinyl)acetamide was subsequently stirred in 29 mL (0.31 mol) of phosphorus oxychloride, heated at 100° C. for 0.5 hours, and cooled to 0° C. To this was slowly added a saturated solution of sodium bicarbonate and ethyl acetate. After separation of the layers, the organic layer was washed with saturated brine, dried over sodium sulfate, and evaporated to give a brown solid (9.8 g, 73% yield), mp 230-235° C.; 1H NMR (DMSO-d6) δ 9.77 (s, 11-1), 8.98 (s, 1H), 8.94 (s, 1H), 7.50 (s, 1H), 4.11 (s, 3H), 2.25 (s, 3H); HRMS (EI) m/z 275.0466 (M+1). Analysis for C13H10ClN3O2.0.75H2O: Found: C, 53.99; H, 3.83; N, 14.53. Calcd: C, 53.62; H, 3.68; N, 14.98.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:14](=[O:34])[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][C:16]=1[N+:31]([O-:33])=[O:32])=O.CC(C[Al]CC(C)C)C>ClCCl.C1(C)C=CC=CC=1>[CH3:22][O:21][C:19]1[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][C:16]([N+:31]([O-:33])=[O:32])=[C:15]([CH:20]=1)[C:14]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C@H:5]1[CH:3]=[O:2])=[O:34]
Reactant: COC(=O)[C@@H]1Cc2ccccc2N1C(=O)c1cc(OC)c(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: CC(C)C[Al]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)N2c3ccccc3C[C@H]2C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a stirred solution of the methyl ester 5 (4.4 g, 9.5 mmol) in anhydrous dichloromethane (11 mL) and toluene (33 mL) was added dibal-H (19 mL, 1.0 M in toluene) dropwise via a syringe pump in 30 minutes at −78° C. The mixture continued to be stirred at −78° C. for 3 hours and TLC (hexanes/AcOEt, 1:1.5) showed that the starting material was almost consumed. The reaction was quenched with methanol (0.4 mL) and 5% HCl (30 mL) at −78° C. Ethyl acetate (100 mL) was added and the dry ice/acetone bath was removed. The mixture was stirred at room temperature for 30 minutes and then transferred to a separatory funnel. The aqueous layer was extracted with AcOEt twice and the combined organic layers were washed with brine, saturated sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. It was filtered through celite and the solvents were removed under reduced pressure (temperature<35° C.). The residue was purified by flash chromatography (Hexanes/AcOEt, 1.5:1, 1:1, 1:1.5) to give the aldehyde 6 as a yellow solid (2.85 g, y=69%). 1H NMR (400 Hz, CDCl3): the compound appears as three distinct rotomers. δ 10.02 (s, 0.3H), 9.85 (s, 0.5H), 9.45 (s, 0.2H), 8.32-8.31 (m, 0.2H), 7.93 (s, 0.3H), 7.83 (s, 0.5H), 7.79 (s, 0.2H), 7.53-7.34 (m, 5.2H), 7.26-7.14 (m, 1.3H), 7.08 (s, 0.5H), 7.01-6.94 (m, 1H), 6.91-6.82 (m, 1H), 5.78 (d, J=8.4 Hz, 0.3H), 5.71 (d, J=8.4 Hz, 0.5H), 5.52-5.48 (m, 0.5H), 5.35-5.21 (m, 2.3H), 4.53-4.50 (m, 0.2H), 4.06 (s, 1.5H), 3.98 (s, 0.6H), 3.94 (s, 0.9H), 3.63-3.17 (m, 2H); HRMS (ESI, m/z): calc. 433.1400 (M+H)+, found 433.1387.
Reaction SMILES: [F:1][C:2]1[O:6][C:5]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:4]=2[CH:3]=1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:5]3[O:6][C:2]([F:1])=[CH:3][C:4]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:23]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cc2oc(F)cc2cc1-c1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2oc(F)cc2cc1-c1ccc(NC(=O)c2c(F)cccc2F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To a solution of 5-(2-fluoro-6-methylbenzo[b]furan-5-yl)-2-pyridylamine (231) (23 mg, 0.095 mmol) in 3 ml DCM was added 2,6-difluorobenzoyl chloride (36 μl, 3 eq) followed by addition of DIEA (149 μl). The resulting solution was stirred overnight at r.t. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 3 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (200 μl) at r.t. for 2 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(2-fluoro-6-methylbenzo[b]furan-5-yl)(2-pyridyl)]carboxamide (223) (24.9 mg, yield: 68.6%, purity>95%) as white solid.
Reaction SMILES: [OH:1][C:2]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:5].[CH3:26]O>Cl>[OH:1][C:2]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:26])=[O:15])=[O:5]
Reactant: COc1cc(C)c(C(=O)CCCCCCCCC(=O)O)c(O)c1OC
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCCCCCC(=O)c1c(C)cc(OC)c(OC)c1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
9-(2'-Hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1 wherein R=H3CO, X=H, Y=OH, n=8, in the free form) (0.197 part) was dissolved in methanol saturated with hydrogen chloride gas (7 volume parts) and the solution was stirred at room temperature for 20 minutes. The methanol was distilled off under reduced pressure and the residue was recrystallized from hexane-diethyl ether. The procedure provided methyl 9-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoate (formula II-1 wherein R=H3CO, X=H, Y=OH, n=8, in the form of methyl ester) (0.195 part) as colorless needles melting at 49°-53° C.
Reaction SMILES: [CH2:1]([Cl:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[N:12][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1.C(O)(C)C>C(OCC)(=O)C>[Cl-:8].[CH2:1]([N+:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:9])=[C:11]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[N:12]=2)=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(-c2ccncc2)nc1-c1cccc2ccccc12
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1ccc(-c2cc[n+](Cc3ccccc3)cc2)nc1-c1cccc2ccccc12
Product: [Cl-]
Temperature: 10 °C
Yield: 96.3 %

Procedure:
Benzyl chloride (0.82 g, 6.5 mmole) was added dropwise to 1.6 g (5.4 mmole) of 3-methyl-2-(α-naphthyl)-6-(4-pyridyl)pyridine and 5 ml of isopropyl alcohol, followed by heating under reflux for 3 hours. After completion of the reaction, 12 ml of ethyl acetate was added. After cooling to 10° C., the mixture was filtered, whereby 2.2 g (yield: 96.5%) of the target product was obtained. By the 1H-NMR, MS, IR and elemental analysis, it was confirmed to be the target product.
Reaction SMILES: CS(C)=O.[OH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:28][C:29](=[NH:33])[CH:30]([CH3:32])[CH3:31]>CC(=O)OCC>[CH:30]([C:29]1[N:33]=[C:12]([C:9]2[N:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=2)[O:14][N:28]=1)([CH3:32])[CH3:31]
Reactant: O=C(O)c1ccc(O)cn1
Reactant: CC(C)C(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)c1noc(-c2ccc(O)cn2)n1
Temperature: 90 °C

Procedure:
To DMSO (25 mL) was added 5-hydroxy-pyridine-2-carboxylic acid (1.0 g) and CDI (1.3 g). After 15 minutes N-hydroxy-isobutyramidine (820 mg) was added. After 1 hour the mixture was heated to 90° C. for 1 hour. After the mixture reached room temperature, it was diluted with EA and washed three times with HCl (0.1 M). The organic phase was dried (Na2SO4) and concentrated to provide the title compound. MS ESI+: m/z=206 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]([N:9]=[C:10]=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N-]=C=[O:14].[N].NC1C=CC=CC=1.[ClH:23]>C1COCC1>[C:10](=[O:11])=[O:14].[ClH:23].[CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [N-]=C=O
Reactant: C[C@@H](N=C=O)c1ccccc1
Agent: Cl
Agent: [N]
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: C[C@@H](N)c1ccccc1
Product: O=C=O

Procedure:
The preparation of compound (II) can be accomplished by methods well known to the skilled artisan of organic synthesis, and by methods taught in commonly assigned U.S. patent application Ser. No. 09/056,820, and Tet. Lett. 1994, 35(37), 6811-6814, the disclosures of which are hereby incorporated by reference. Dissolution of compound (II) in THF containing 5% v/v 1N HCl followed by treatment with about 2 equivalents of (R)-(+)-a-methylbenzyl isocyanate between 0° C. and ambient temperature effects condensation of the isocyanate with the aniline nitrogen of (II). The second equivalent of isocyanate is decomposed under the reaction conditions to give CO2 and (R)-(+)-a-methyl-benzylamine hydrochloride salt. The urea condensation product reacts further to condense intramolecularly with the ketone to give the bicyclic urea hemiaminal (IV) as a mixture of diastereomers. The second condensation event takes place only slowly at ambient temperature. However, heating the reaction to reflux (65° C.) completes the conversion to (IV) within a couple of hours. The resulting mixture is washed with water to remove the benzylamine salt, and the THF is replaced with toluene via reduced pressure distillation (75 to 90° C. at 240 to 400 torr) crystallize the product. The mixture is cooled to 0° C., the product filtered, washed with toluene, and dried in an oven at 70° C. under 25 mm Hg vacuum for 15 to 20 hours until constant weight is achieved. Isolated yields are generally about 90%.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.C1COCC1>CO>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(F)cc1CO
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4,5-Difluoro-2-nitro-benzoic acid (3.05 g, 15 mmol) was combined with THF (20 mL), and then BH3 THF (35 mL) was added over 15 min. The resulting mixture was stirred overnight at 60° C. and then cooled to room temperature. Methanol was added, and the resulting mixture was stirred 15 min. The solvent was removed to yield an oil, which was purified by silica gel chromatography to yield a residue.
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH:28]=O.CC(O)=O.[BH3-]C#N.[Na+]>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH2:28][NH:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1
Reactant: NC1COc2ccc3c(c2C1)C(=O)NC3
Reactant: O=CCCc1c[nH]c2ccc(F)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCc2ccc3c(c21)CC(NCCCc1c[nH]c2ccc(F)cc12)CO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 8-amino-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one (1) (200 mg, 0.98 mmol) in anhydrous MeOH (20 ml) was added 3-(5-fluoro-1H-indol-3-yl) propanal (2) (191 mg, 1 mmol), AcOH (0.14 ml), and NaBH3CN (123 mg, 1.96 mmol). Resulting reaction mixture was stirred at room temperature for 2 hr. The solvent was removed in vacuo and the residue was re-dissolved in CH2Cl2 (150 ml). The solution was washed with 1 N NaOH (20 ml) and H2O, Sat. NaCl. The organic solution was separated, dried over Na2SO4, then concentrated in vacuo. The crude compound was purified on silica gel eluting with EtOAc/Hexane (4:1) to yield (3) (304 mg, 82%) as a white solid. MS (APPI) m/z 380.