Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:20][CH2:19]2)=[O:17])=[C:9]([CH3:30])[CH:8]=1>C1COCC1.O>[CH3:27][C:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:31])=[O:5])=[CH:8][C:9]=2[CH3:30])[CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(CCCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
Lithium hydroxide monohydrate (108 mg, 2.6 mmol) was added to a solution of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid methyl ester from Example E43.1 (500 mg, 1.3 mmol) in THF (12 ml) and water (6 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% acetic acid:4% methanol:94% dichloromethane) then recrystallised from chloroform and pet. ether to yield the title compound (439 mg, 91%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]([OH:13])=O)=[CH:5][N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][CH:28]1[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1>>[N:30]12[CH2:35][CH2:34][CH:33]([CH2:32][CH2:31]1)[CH:28]([NH:27][C:11]([C:6]1[C:7]([O:9][CH3:10])=[N:8][C:3]([N:2]([CH3:1])[CH3:14])=[N:4][CH:5]=1)=[O:13])[CH2:29]2
Reactant: COc1nc(N(C)C)ncc1C(=O)O
Reactant: NC1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1nc(N(C)C)ncc1C(=O)NC1CN2CCC1CC2

Procedure:
Following the procedure of Example 22, 2-(dimethyl-amino)-4-methoxy-5-pyrimidinecarboxylic acid, 1,1'-carbonyl-diimidazole and 3-aminoquinuclidine are reacted to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[Na].Br[C:7]1[N:14]=[C:13]([NH2:15])[CH:12]=[C:11]([NH2:16])[C:8]=1[C:9]#[N:10]>O>[NH2:16][C:11]1[C:8]([C:9]#[N:10])=[C:7]([O:4][CH:2]([CH3:3])[CH3:1])[N:14]=[C:13]([NH2:15])[CH:12]=1
Reactant: CC(C)O
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [Na]
Solvent: O
Product: CC(C)Oc1nc(N)cc(N)c1C#N
Temperature: 150 °C
Yield: 53 %

Procedure:
A heavy walled, sealable tube suitable for microwave heating was charged with 6 mL of 2-propanol and 150 mg (6.5 mmol) of sodium. The mixture was stirred at 95° C. until all of the sodium had reacted (15 minutes), then 650 mg (3.05 mmol) of 2-bromo-4,6-diaminonicotinonitrile was added. The tube was sealed, and the mixture was heated with a microwave apparatus at 150° C. for 10 minutes then cooled and diluted with 30 mL of water. The precipitate was collected, washed with water until pH=7, then dried under reduced pressure at 95° C. to provide 312 mg (53%) of pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:22][O:21][C:19](=[O:20])[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4′-hydroxy-4-nitro-biphenyl (2.00 g, 7.51 mmol), prepared in the previous step, methyl bromoacetate (853 mL, 9.02 mmol) and potassium iodide (86 mg, 0.75 mmol) in 50 mL of acetone was stirred at room temperature until the mixture became cloudy. Potassium carbonate (2.26 g, 16.4 mmol) was added and the reaction refluxed overnight. The reaction was concentrated under reduced pressure and the residue partitioned between methylene chloride and water. The organic layer was separated, washed with water, dried (Na2SO4) and the solvent removed under reduced pressure to give (4′-nitro-biphenyl-4-yloxy)-acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH2:11][O:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[BrH:22]>C(O)(=O)C>[Br:22][CH2:11][CH2:12][CH2:13][C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:9]([OH:10])=[O:14]
Reactant: O=C1OCCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Br
Solvent: CC(=O)O
Product: O=C(O)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 5.8 parts of 3,3-bis(4-fluorophenyl)tetrahydro-2H-pyran-2-one and 30 parts of a solution of hydrobromic acid in glacial acetic acid was stirred over week-end at room temperature. The reaction mixture was poured onto water. The precipitated product was filtered off and dissolved in 2,2'-oxybispropane. The organic phase was washed with water, dried, filtered and evaporated. The residue was boiled in a mixture of 42 parts of 2,2'-oxybispropane and 42 parts of petroleumether. The product was filtered off and crystallized from 2,2'-oxybispropane, yielding 1.27 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetic acid; mp. 161° C. (intermediate 16).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1>[Pd].C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccc(O)cc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCc1ccc(O)cc1)c1ccccc1

Procedure:
The title compound was prepared as described in General Method 3 from 3-(4-hydroxy-phenyl)-1-phenyl-prop-2-en-1-one (25.5 g, 113.6 mmol), 5% Pd on BaSO4 (1.0 g), and THF (400 mL). The catalyst was filtered, and the filtrate was concentrated . The residue was recrystallized from 50% EtOH, to give the title compound, m.p. 118°-119° C.
Reaction SMILES: C([O:4][C:5]1[C:6](Br)=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[CH:8]2)(=O)C.[CH2:24]([O:26]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:25]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[OH:4][C:5]1[C:6]([C:24](=[O:26])[CH3:25])=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:15])=[O:16])[CH:9]=[CH:8]2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)Oc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1c(O)ccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
4-Bromo-1-(phenylsulfonyl)-1H-indol-5-yl acetate (Intermediate 22, 0.57 g, 1.5 mmol) was dissolved in toluene (10 mL) under an atmosphere of N2 gas and 1-ethoxyvinyl-tributylstannane (0.78 g, 2.2 mmol) and bis-(triphenylphosphin)-palladium(II)-chloride (50.8 mg, 0.072 mmol) were added and the mixture was heated at 110° C. After 30 minutes additional catalyst (25 mg, 0.036 mmol) was added and the mixture was heated at 110° C. for an additional 3 hours, cooled and filtered through a plug of silica gel using EtOAc as the eluent. The filtrate was washed with 1 M HCl and saturated aqueous brine, dried over (MgSO4) and evaporated. The crude product was dissolved in THF/1 M HCl 2:1 (40 mL) and stirred for 30 minutes at room temperature. The mixture was evaporated and partitioned between water and DCM. The organic phase was dried (MgSO4) and evaporated. The crude material was purified by flash chromatography on silica gel using 10% petroleum ether in DCM as the eluent to give the title compound (100 mg) as a light yellow solid. MS m/z 316 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][CH2:14][C:15]3=[O:18])=[CH:11][CH:10]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24]>CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:24][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:17]=[C:16]4[C:12]([CH2:13][CH2:14][C:15]4=[O:18])=[CH:11][CH:10]=3)[N:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: O=C1CCc2ccc(Oc3cncc(Cl)n3)cc21
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3ccc4c(c3)C(=O)CC4)n2)cc(OC)c1OC
Yield: 10 %

Procedure:
Using Method EE with 2-chloro-6-(indanone-6-oxy)-pyrazine (200 mg, 0.77 mmol) and 3,4,5-trimethoxyaniline (169 mg, 0.92 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (30 mg). Yield: 10%. 1H NMR (250 MHz, DMSO-d6) δ 2.73 (t, 2H, H3, J=5.4 Hz), 3.13 (t, 2H, H2, J=5.8 Hz), 3.37 (s, 6H, [CH3O]3+5), 3.54 (s, 3H, [CH3O]4), 6.72 (s, 2H, Harom2′+6′), 7.37 (d, 1H, Harom 7, J=2.2 Hz), 7.52 (dd, 1H, Harom 5, Jm=2.3 Hz, Jo=7.2 Hz), 7.64 (d, 1H, Harom 4, J=8.3 Hz), 7.81 (s, 1H, HPz 5), 7.98 (s, 1H, HPz 3), 9.57 (s, 1H, NH). m/z: 408.1 [(M+H)+, calcd for C22H21N3O5 407.1].
Reaction SMILES: [NH2:1][CH:2]([CH3:27])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])=[C:8]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]=1)=[O:4].[CH3:28][C:29](=O)[CH3:30].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:18][C:13]1[C:12]([C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH:2]([NH:1][CH:29]([CH3:30])[CH3:28])[CH3:27])=[N:7][C:8]=2[C:19]#[C:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: CC(C)=O
Reactant: Cc1noc(C)c1-c1ccc(NC(=O)C(C)N)nc1C#Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1noc(C)c1-c1ccc(NC(=O)C(C)NC(C)C)nc1C#Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-amino-N-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-6-(2-phenylethynyl)pyridin-2-yl]propanamide (example 165, 20 mg, 0.06 mmol), propan-2-one (16.2 ml, 0.28 mmol), acetic acid (4 μl, 0.07 mmol), MeOH (0.5 ml) and sodium cyanoborohydride (5.5 mg, 0.08 mmol) is stirred at 50° C. for 30 minutes. The reaction mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 11 mg (48%). HPLC-MS: M+H=403; tR=1.52 min (*Method—1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:15])[CH2:10][CH2:11][N:12]([CH2:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: FC1(c2ccc(Cl)cc2)CCNCC1
Reactant: C=CC(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCN1CCC(F)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94 %

Procedure:
To a solution of 3-[4-(4-chlorophenyl)-4-fluoropiperidine hydrochloride (280 mg, 1.12 mmol) in methanol (5 mL) was added sodium bicarbonate (500 mg, 5.94 mmol) followed by methyl acrylate (1 mL). The resulting mixture was stirred at room temperature for 14 hours then filtered and concentrated under reduced pressure. The residue was treated with ethyl acetate (10 mL) and the resulting suspension re-filtered and concentrated under reduced pressure. This afforded methyl 3-[4-(4-chlorophenyl)-4-fluoropiperidin-1-yl]propionate as a viscous yellow oil in 94% yield, which was used without further purification.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:9][C:10]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2ccc(C(F)(F)F)cc2)Oc2ccccc2O1

Procedure:
A solution of catechol (5.5 g) and 4-(trifluoromethyl)acetophenone (10.3 g) in toluene (150 ml) containing a catalytic amount (0.2 g) of p-toluenesulphonic acid monohydrate was heated under reflux for 3 days. Water produced in the condensation was separated by means of a Dean-Stark trap. After removal of the solvent under reduced pressure, the residue was purified by chromatography on silica gel using methylene chloride as eluant. Pure 2-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-benzodioxole was obtained as a colourless oil (10.8 g, 77%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[N:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][CH:6]=1.S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH2:3][C:2]([F:14])([F:13])[F:1])[N:10]=1
Reactant: OCc1cccc(OCC(F)(F)F)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)COc1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol (0.32 g, 1.55 mmol, Step-3), thionyl chloride (0.23 mL, 3.10 mmol) in dichloromethane (16 mL) is stirred at room temperature for 1 hour. The organic solvent is concentrated under reduced pressure and dried to give 0.35 g (>99% yield) of the title compound as yellow oil. This material is used for the next reaction (Step-5) without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4](F)[CH:3]=1.[F:17][CH:18]([F:21])[CH2:19][OH:20].[H-].[Na+].C1COCC1>CN(C=O)C>[NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:20][CH2:19][CH:18]([F:21])[F:17])[CH:3]=1
Reactant: OCC(F)F
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OCC(F)F

Procedure:
The sub-title compound was prepared in accordance with Example 59 (f) using ethyl 4-amino-2-fluoro-5-nitrobenzoate (4.80 g; 21.0 mmol), 2,2-difluoroethanol (1.73 g; 21.0 mmol), sodium hydride (0.841 g; 60%; 21.0 mmol), THF (100 mL) and DMF (50 mL).
Reaction SMILES: [CH:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]1[N:23]=[C:22]([CH2:24][O:25][C:26]2[CH:43]=[CH:42][C:29]([CH2:30][N:31]3[C:39](=[O:40])[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:41])=[CH:28][CH:27]=2)[O:21][N:20]=1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:7][S:8]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:19]2[N:23]=[C:22]([CH2:24][O:25][C:26]3[CH:43]=[CH:42][C:29]([CH2:30][N:31]4[C:32](=[O:41])[C:33]5[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:39]4=[O:40])=[CH:28][CH:27]=3)[O:21][N:20]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2nc([C@@H]3CCCCN3)no2)cc1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2nc([C@@H]3CCCCN3S(=O)(=O)CC3CCCCC3)no2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.1 %

Procedure:
Cyclohexylmethanesulfonyl chloride (359 mg) [King. J. F. et al., J. Am. Chem. Soc., 1992, 114(5), 1743-9] was added to a solution of 2-[4-(3-[(2S)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-1,3-isoindolinedione hydrochloride (627 mg) [see Preparation 153 and triethylamine (0.4 ml) in dichloromethane (2 ml). The reaction mixture was stirred at room temperature for 18 hours after which time it was heated to 30° C. and stirred for a further 56 hours. The mixture was diluted with dichloromethane and washed with dilute aqueous hydrochloric acid solution, the organic layer dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 75:25, by volume, hexane:ethyl acetate to afford 2-[4-(3-[(2S)-1-cyclohexylmethylsulfonyl-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-1,3-isoindolinedione (192 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([CH3:23])[C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.[H][H]>CO.[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([CH3:23])[C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1cnc2c(N(C)c3ccc([N+](=O)[O-])cc3)ccnc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cnc2c(N(C)c3ccc(N)cc3)ccnc2c1
Reaction time: 4 h

Procedure:
To a mixture of 7-methoxy-N-methyl-N-(4-nitrophenyl)-1,5-naphthyridin-4-amine (0.233 g, 0.751 mmol) in MeOH (10 mL) at RT was added a suspension of 10% palladium on carbon (0.0799 g, 0.751 mmol) in EtOAc (10 mL). The mixture was exposed to an atmosphere of hydrogen (balloon). After 4 h, the mixture was filtered over celite and concentrated in vacuo. The crude yellow foam, N1-(7-methoxy-1,5-naphthyridin-4-yl)-N1-methylbenzene-1,4-diamine, was advanced without further purification. MH+=281.2@1.21 min.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[O:15]1[CH:13]([CH2:11][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:1][CH:2]=[CH2:3])[CH2:14]1
Reactant: ClCC1CO1
Reactant: C=CCc1ccccc1O
Product: C=CCc1ccccc1OCC1CO1

Procedure:
The title compound was synthesized from 2-allylphenol and epichlorohydrin by the method of Brandstrom et al. (Chem. Abs. 72, 12342n).
Reaction SMILES: C([O:4][CH:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[S:10]([CH3:13])(=[O:12])=[O:11])(=O)C.[OH-].[Na+].O>C(O)C>[OH:4][CH:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: CCCCCC(CCCN(CCCCCCC(=O)OCC)S(C)(=O)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(O)CCCN(CCCCCCC(=O)O)S(C)(=O)=O
Reaction time: 20 h

Procedure:
A solution composed of ethyl 7-[N-(4-acetoxynonyl)methanesulfonamido]heptanoate (6.0 g., 0.0134 mole), sodium hydroxide (1.66 g., 0.0414 mole), water (9 ml.), and ethanol (81 ml.) is kept at room temperature for 20 hours. Most of the solvent is removed in vacuo, water (150 ml.) is added and the solution extracted with ethyl acetate (100 ml.). Then the aqueous layer is acidified (hydrochloric acid) and extracted again with ethyl acetate (2× 75 ml.). The organic layer is dried over sodium sulfate then concentrated in vacuo to yield 7-[N-(4-hydroxynonyl)methanesulfonamido]heptanoic acid. The yield is 4.3 g. (88%).
Reaction SMILES: O.CC(C)([O-])C.[K+].C[O:9][C:10]([CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[CH:19]=2)[CH2:14][N:13]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:11]>C(OCC)C>[CH3:32][C:29]([O:28][C:26]([N:13]1[CH:12]([C:10]([OH:11])=[O:9])[CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[CH:19]=2)[CH2:14]1)=[O:27])([CH3:30])[CH3:31]
Reactant: COC(=O)C1Cc2cc(OC)c(OC)cc2CN1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: COc1cc2c(cc1OC)CN(C(=O)OC(C)(C)C)C(C(=O)O)C2
Temperature: 8 °C
Reaction time: 0.08 h
Yield: 101.4 %

Procedure:
Water (64 mg, 0.07 mL. 3.56 mmol) was added to a slurry of potassium t-butoxide (1.44 g, 12.8 mmol) in diethyl ether (25 mL) at 0° C. with stirring. After 5 minutes, the title B compound, 3,4-dihydro-6,7-dimethoxy-2,3(1H)-isoquinolinedicarboxylic acid 2-(1,1-dimethylethyl) 3-methyl ester (570 mg, 1.62 mmol) was added as a solution in 8 mL of ether. Stirring was continued for 45 minutes with warming to 8° C. after which the cooling bath was removed and stirring was continued at room temperature for 45 minutes. The reaction was quenched with 10 mL of saturated aqueous ammonium chloride, diluted with water, and extracted with ether. The aqueous solution was then acidified to pH 5 with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried (sodium sulfate) and concentrated to give 554 mg of the title compound as a viscous yellow oil.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=3[N:16]=2)[SH:14])=[CH:9][CH:8]=1.Cl>O.C1COCC1>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:18]2[NH:19][C:15]([CH:13]([SH:14])[C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:26])=[O:5])=[CH:8][CH:9]=3)=[N:16][C:17]=2[CH:23]=1
Reactant: COC(=O)c1ccc(C(S)c2nc3cc(OC)ccc3[nH]2)cc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C(S)c3ccc(C(=O)O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of LiOH.H2O (1.02 g, 24.4 mmol) in water (15 ml) was added to a suspension of 376a (3.99 g, 9.75 mmol of in THF (10 ml). The reaction mixture was stirred 16 h at room temperature. The reaction mixture was acidified with a solution of HCl 1 M to pH 4. The desired product was triturated 20 min. at 0° C. and then filtered and dried. Compound 376b was obtained as a white powder (100% yield, 3.05 g). 1H NMR: (DMSO) δ (ppm): 12.85 (bs, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.76 (dd, J=8.8, 2.2 Hz, 1H), 4.60 (s, 2H), 3.82 (s, 3H), MS: (calc.) 314.1, (obt.), 315.1 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[O:25][CH2:26][C:27]#[N:28])[C:19]([Cl:33])=[CH:18][N:17]=1>>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[O:25][CH2:26][C:27]#[N:28])=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCCOc2c(N)cccc21
Product: CC1(C)CCCOc2c(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)cccc21

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and [2-(2,5-dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile in an analogous manner to Example 179 heating at 130° C. Product was isolated as a white solid (26 mg, 34%). LCMS (m/e) 450 (M+H); 1H NMR (400 MHz, CDCl3) δ 10.58 (broad s, 1H), 8.15 (s, 1H), 8.08 (d, 1H, J=8.1 Hz), 7.93 (s, 1H), 7.55 (d, 1H, J=7.6 Hz), 7.19 (m, 2H), 7.03 (d, 1H, J=8.34 Hz), 6.97 (m, 2H), 4.88 (s, 2H), 4.02 (m, 2H), 2.01 (m, 2H), 1.67 (m, 2H), 1.37 (s, 6H).