Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[CH:4]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2cccc(Cl)c2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A 0.5 M solution of 1-bromomethyl-3-chloro-benzene (102.7 mg, 0.5 mmol) in acetone was added to a suspension of 4-hydroxy-benzaldehyde (67.2 mg, 0.55 mmol), K2CO3 (207.3 mg, 1.5 mmol) and KI (10.8 mg, 0.065 mmol) in acetone (7 ml). The reaction mixture was stirred for 2 hours at 70° C.
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:14](I)([CH3:16])[CH3:15].O.[OH-].[Na+]>C(O)C>[F:1][C:2]1[C:10]([O:11][CH:14]([CH3:16])[CH3:15])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)I
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1c(F)c(F)cc(C(=O)O)c1F

Procedure:
2,4,5-Trifluoro-3-hydroxybenzoic acid (4.0 g) was added together with isopropyl iodide (4.7 g) to a mixed liquid of distilled water (10 ml) and ethanol (20 ml), in which sodium hydroxide (1.83 g) had been dissolved. The mixture was stirred and heated under reflux for 23 hours. The reaction mixture was concentrated under reduced pressure. The resultant residue was acidified with concentrated hydrochloric acid, and water (25 ml) was added to conduct extraction twice with chloroform (25 ml). A collected chloroform layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to column chromatography (silica gel: 75 g, eluent; chloroform: methanol:acetic acid=500:20:1) to obtain 2,4,5-trifluoro-3-isopropyloxybenzoic acid as a solid residue.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[O:15].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1>>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:14](=[O:15])/[CH:13]=[CH:12]/[C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1Br)Nc1ccc2[nH]ccc2c1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1-c1cccnc1)Nc1ccc2[nH]ccc2c1

Procedure:
Analogous to the procedure used to prepare Example 100, (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (120 mg, 0.29 mmol) and pyridine-3-boronic acid (58 mg, 0.47 mmol, Frontier Scientific) provided, after purification by silica gel chromatography (gradient: 0-20%EtOAc in hexane), the title product as a yellow solid. MP 196-197° C. MS (ESI, pos. ion) m/z: 408 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8].[C:16]([C:18]1[S:19][C:20]([CH3:24])=[CH:21][C:22]=1[OH:23])#[N:17]>CC(C)=O>[C:16]([C:18]1[S:19][C:20]([CH3:24])=[CH:21][C:22]=1[O:23][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8])#[N:17]
Reactant: CCOP(=S)(Cl)OCC
Reactant: Cc1cc(O)c(C#N)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1cc(C)sc1C#N
Temperature: 20 °C
Reaction time: 15 h
Yield: 76.4 %

Procedure:
7 g of potassium carbonate and 9.5 g of O,O-diethyl chlorothiophosphate were added to a solution of 7 g of 2-cyano-3-hydroxy-5-methyl-thiophene in 100 ml of acetone and the mixture was stirred for 15 hours at 20° C. and was then filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 11.2 g of 2-cyano-3-(diethoxythiophosphoryloxy)-5-methyl-thiophene with a refractive index of nD20 =1.534.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(O[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:34]([N:28]1[CH2:29][CH:10]2[CH:9]([C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12][C:11]2=[O:14])[CH2:27]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(c2cccc(Cl)c2)(c2cccc(Cl)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCC(c2cccc(Cl)c2)(c2cccc(Cl)c2)C2CN(Cc3ccccc3)CC12
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (15 drops) is added to a solution of 4,4-bis-(3-chlorophenyl)-cyclohexenone (26.8 g) and N-butoxymethyl-N-trimethylsilylmethylbenzylamine (33 cc) in dry dichloromethane (200 cc). The reaction mixture is brought to reflux and then stirred for 16 hours after having allowed the temperature to return to 25° C. and for a further 15 minutes after addition of potassium carbonate (16 g). After filtering and concentrating the filtrate to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 7 cm, height 40 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (75/25 by volume) and collecting 500 cc fractions. Fractions 12 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-benzyl-7,7-bis-(3-chlorophenyl)-4-perhydroisoindolone (16.2 g) in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]1)=[O:7].[F:27][C:28]1[CH:29]=[C:30]([C:34](=[N:36]O)[NH2:35])[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([C:34]2[N:36]=[C:24]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=4)[CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])[CH2:9]3)[O:26][N:35]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COCCNC(=O)N1CC(C(=O)O)CC(c2ccc(C(F)(F)F)cc2)C1
Reactant: NC(=NO)c1cccc(F)c1
Product: COCCNC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
100 mg (0.267 mmol) of the compound from Example 105A and 77 mg (0.497 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 64 mg (55% of theory)
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.[N+:13]([O-])([OH:15])=[O:14]>CCOCC>[CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[C:7]([N+:13]([O-:15])=[O:14])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Product: CC1(C)Cc2c([N+](=O)[O-])ccc(O)c2O1
Reaction time: 0.33 h

Procedure:
To a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (16.4 g, 0.1 mol) in 150 ml of ether, 70% nitric acid (9.0 g, 0.1 mol) was slowly dropwise added at room temperature. The reaction solution was stirred for further 20 minutes, then washed with water, dried over anhydrous sodium sulfate and concentrated. The solid substance thereby obtained, was repeatedly recrystallized from hexane-ethyl acetate, whereby 6.2 g of 2,3-dihydro-2,2-dimethyl-4-nitro-7-benzofuranol and 6.0 g of 2,3-dihydro-2,2-dimethyl-6-nitro-7-benzofuranol as its 6-nitro isomer, were obtained. The melting points of these products were 164°-165° C. and 125°-126° C., respectively. Further, the structures of these intermediate phenols were confirmed by 1H-NMR spectra. 2,3-Dihydro-2,2-dimethyl-4-nitro-7-benzofuranol thus obtained, was reacted with O-ethyl-S-n-propylthiophosphoryl chloride in the same manner as in Example 1, whereby the compound (No. 6) identified in Table 1 was obtained.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.[N:11]1([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[N:11]1([CH2:17][CH2:18][C:19]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[NH:1][CH:2]=[CH:3][C:4]2=3)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: c1cc2c([nH]1)CCCCN2
Reactant: O=C(Cl)CCN1CCCCC1
Solvent: ClCCl
Product: O=C(CCN1CCCCC1)N1CCCCc2[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-piperidin-1-yl-propionic acid (472 mg, 3 mmol) in DCM (15 mL) at 0° C. was added oxalyl chloride (4.5 mmol) followed by one drop of DMF. After stirring for 2 hours at rt, the solvent was removed to give 3-piperidin-1-yl-propionyl chloride as a white solid. To a solution of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (347 mg, 2.55 mmol) in DCM (10 mL) was added TEA (1 eq.) and 1-piperidinepropionic acid chloride. The mixture was stirred at rt for overnight. The reaction was diluted with DCM, washed with NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 230 mg of 3-piperidin-1-yl-1-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepin-4-yl)-propan-1-one as a light brown gel.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[OH:32])[CH2:27][CH2:26]1>CN(C)C=O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[OH:32])[CH2:27][CH2:26]2)=[CH:7][CH:6]=1)[CH3:13]
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(CCCCl)CC1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4.18 g (0.02 mole) of ethyl p-nitrophenylacetate in 200 mL of ethanol is subjected to catalytic hydrogenation. The mixture is filtered to remove the catalyst and the filtrate is concentrated to obtain quantitative yield of ethyl 4-aminophenylacetate. To an agitated solution of the ethyl 4-aminophenylacetate and 2.02 g (0.02 mole) of triethylamine in 50 ml of dimethylformamide is added dropwise a solution of 7.58 g (0.020 mole) of 1-(3-chloropropyl)-α,α-bis(4-fluorophenyl)-4-piperidinemethanol in 20 ml of dimethylformamide. After stirring at ambient temperature for 4 hr the reaction mixture is heated at 70° C. for 4 hr. The reaction mixture is concentrated and the crude product partitioned between methylene chloride and water. The methylene chloride solution is washed with water, dried over anhydrous magnesium sulfate, and concentrated to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH2:16]>>[F:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(N)cc1F
Reactant: O=C(O)Cc1ccccc1Br
Product: COc1ccc(Nc2ccccc2CC(=O)O)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-fluoro-4-methoxyaniline to yield 2-[(3-fluoro-4-methoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][N:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][CH:12]=[N:13][C:6]=2[O:5][CH:4]([CH2:14][CH2:15][C:16]#[N:17])[CH2:3]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:8](=[S:27])[C:7]2[CH:10]=[CH:11][CH:12]=[N:13][C:6]=2[O:5][CH:4]([CH2:14][CH2:15][C:16]#[N:17])[CH2:3]1
Reactant: CN1CC(CCC#N)Oc2ncccc2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CN1CC(CCC#N)Oc2ncccc2C1=S
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To a solution of 11.0 g (0.04 mole) of 2,3,4,5-tetrahydro-4-methyl-5-oxopyrido[3,2-f][1,4]-oxazepine-2-propanenitrile in 175 ml toluene was added 10.5 g (0.026 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide. The reaction mixture was heated to reflux for 2 hr with vigorous mechanical stirring. Another 3.0 g (0.007 mole) of 2,4bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane2,4-disulfide was added and heating continued for 1 hr additional. The reaction mixture was allowed to cool and stand overnight at room temperature. Toluene was removed by rotary evaporation (90° C., water aspirator) and the residue taken up in 200 ml chloroform. This was washed with 2×50 ml 2M aqueous potassium hydroxide and concentrated by rotary evaporator (90° C., water aspirator). Crystallization ensued upon cooling. Recrystallization from isopropyl alcohol afforded 1.60 g (13.8%) product, m.p. 155°-56° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32]OS(C)(=O)=O)[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:19][CH:18]=2)[C:13]1=[O:31])[CH3:11].[NH:39]1[CH:43]=[N:42][CH:41]=[N:40]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:38])([CH2:32][N:39]1[CH:43]=[N:42][CH:41]=[N:40]1)[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])=[CH:21][CH:22]=2)[C:13]1=[O:31])[CH3:11]
Reactant: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 90 °C
Yield: 47.7 %

Procedure:
1-[(1R, 2S)-2-(2,4-Difluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H, 3H)-imidazolone(0.55 g) was dissolved in 15 ml of dimethylformamide, to which 0.329 g of 1H-1,2,4-triazole and 1.34 g of potassium carbonate were added. The mixture was heated at 90° C. for 5 hours. After cooling, the reaction solution was diluted with 60 ml of ethyl acetate, and washed with 30 ml of water, 1N-hydrochloric acid (30 ml×2) and 30 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=2:1). The desired fraction was concentrated and the residue was recrystallized from a mixture of 2 ml of ethyl acetate and 10 ml of diisopropyl ether to give 0.25 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (yield: 47%) as colorless powdery crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>O.[OH-].[Na+]>[C:15]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6](=[O:14])[NH:5]2)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)c(=O)[nH]c2cc(N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)[nH]c(=O)c(=O)n2C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 0.3 g (1.3 mmol) 6-amino-1-methylquinoxaline-2,3(1H,4H)-dione in a mixture of 15 ml water and 0.6 ml 4N sodium hydroxide was added 5 ml acetic acid anhydride. Stirring was continued at 25° C. for 2 h. The precipitate was filtered off and washed with water to give 0.21 g (68%) of 6-acetamido-1-methylquinoxaline-2,3(1H,4H)-dione. M.p. 390° C. NMR (DMSO-d6): 10.1 (1H, broad s), 9.7 (1H, broad s), 7.5-7.0 (3H), 3.43 (3H, s), 2.0 (3H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[CH3:27])[NH2:23].C([O-])(O)=O.[Na+]>C(O)C>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH3:16])[N:5]=[CH:4][C:3]([C:17]#[N:18])=[C:2]2[NH:23][C:22]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:20]([OH:19])[CH:21]=1)[CH3:14]
Reactant: Cc1ccc(N)cc1O
Reactant: CCOc1cc2c(Cl)c(C#N)cnc2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2cc1OC
Yield: 47.4 %

Procedure:
A mixture of 1.00 g (3.82 mmol) of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile and 0.563 g (4.58 mmol) of 3-hydroxy-4-methylaniline in 20 mL of ethanol was refluxed under N2 for 8 h. Saturated NaHCO3 was added, volatile material was removed and the residue was azeotroped with ethanol. The crude product was slurried with hexane, filtered, washed with water and cold ethanol and dried. Recrystallization from ethanol gave 0.632 g of 6-ethoxy-4-(3-hydroxy-4-methylphenylamino)-7-methoxyquinoline-3-carbonitrile as light yellow crystals: mass spectrum (electrospray, m/e): M+H 349.9.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]1([C:16]2C=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8](C(O)=O)=[CH:9][CH:10]=[CH:11][CH:12]=1>ClCCl.CN(C)C=O>[C:16]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1-c1ccccc1

Procedure:
1.54 ml (0.018 mol) of oxalyl chloride are added dropwise to a suspension of 3 g (0.015 mol)) of biphenyl-2-carboxylic acid in 100 ml of dichloromethane and 0.3 ml dimethylformamide at 0° C. After the reaction has ended the reaction mixture is concentrated by distillation and the biphenyl-2-carboxylic acid chloride is further reacted as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:25][CH2:24]2)=[O:19])[CH:6]=[CH:7][C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([O:29][CH:30]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:28]2)=[O:19])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COCCOCOc1ccc(C=CC(=O)NCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C=CC(=O)NCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)ccc1O
Yield: 66.3 %

Procedure:
To a solution of 292 mg (0.508 mmol) of the amide compound in methanol (8 ml) was added 112 mg (0.589 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 20 minites. Water was added to the reaction mixture, which was adjusted to a pH value of 11 by the addition of an aqueous solution of sodium carbonate and then extracted with ethyl acetate. The organic layer was washed with water and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (50:1), to give 164 mg (0.337 mmol) of 1-[2-[3-(3-methoxy-4-hydroxyphenyl)-2-propenoyl]aminoethyl]-4-benzhydroxypiperidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:9][CH2:10][NH2:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCc1ncc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ncc(Cl)cc1Cl
Reaction time: 2 h
Yield: 100 %

Procedure:
Tert-butyl 2-(3,5-dichloropyridin-2-yl)ethylcarbamate (50 mg, 0.17 mmol) was diluted with DCM (500 uL) followed by the addition of TFA (500 μl). After stirring for 2 hours, the reaction was concentrated and placed under vacuum to yield the desired compound (32 mg, 0.17 mmol, 98% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[Cl:32][CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37].C(N(CC)CC)C>C(Cl)Cl>[Cl:32][CH2:33][CH2:34][CH2:35][C:36]([NH:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])=[O:37]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)CCCCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a magnetically stirred solution of 0.300 g (0.63 mmol) of the product of Example 17 in 6 mL of CH2Cl2 at 0° C. was added 70 μL (0.63 mmol) of 4-chlorobutyryl chloride and 96 mg (0.95 mmol) of triethylamine. The reaction was stirred for 1.5 h and allowed to warm to room temperature. The reaction mixture was then partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was separated, washed with aq. NaHCO3, brine, then dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–20% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 577.0 (M+1), 578.9 (M+3); Rt=5.05 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:22]3)=[O:20])=[CH:13][C:12]=2[N+:30]([O-:32])=[O:31])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].CCN(CC)CC.ClC(OCC)=O>C1COCC1>[OH:2][CH2:1][C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]3[CH2:22][CH2:23][N:24]([C:27](=[O:29])[CH3:28])[CH2:25][CH2:26]3)=[O:20])=[CH:13][C:12]=2[N+:30]([O-:32])=[O:31])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3cccc(C(=O)O)c3)c([N+](=O)[O-])c2)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3cccc(CO)c3)c([N+](=O)[O-])c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a stirred solution of benzoic acid from Example 92A (255 mg, 0.56 mmol) in 5 mL of anhydrous THF at 0° C. was added in turn Et3N (102 mL, 0.73 mmol) and ethyl chloroformate (70 mL, 0.73 mmol). After 60 minutes, the reaction mixture was filtered through celite plug into a stirred solution of NaBH4 in water at 0° C. The resulting reaction mixture stirred at 0° C. for 2 hours before it was extracted with EtOAc (2×20 mL). The combined organic layers were washed with 3N HCl, brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The crude product was purified using Gilson Preparative HPLC as described in Example 38B to give the title compound (80 mg, 32% yield) as a light-yellow solid. 1H NMR (d6-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.40-3.79 (m, 8H), 4.56 (s, 2H), 5.38 (br s, 1H), 6.85 (d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.52 (br s, 3H), 7.57 (br s, 2H), 7.91 (dd, J=2.1, 8.7 Hz, 1H), 8.66 (d, J=2.1 Hz, 1H). MS (APCI+) (M+NH4)+ at m/z 459.