Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([O:31]CC)=[O:30].[OH-].[K+]>C1COCC1.O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([OH:31])=[O:30]
Reactant: CCCCC(=O)c1c(-c2ccc3c(C)c(OC(Cc4ccccc4)C(=O)OCC)ccc3c2)oc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(C)c(OC(Cc4ccccc4)C(=O)O)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 4 of Example 6, ethyl 2-{[1-methyl-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate (0.495 g, 0.926 mmol) was hydrolyzed with potassium hydroxide (0.153 g, 2.73 mmol) in THF (7.5 mL) and water (7.5 mL) to afford 2-{[1-methyl-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid. Conversion to the sodium salt by treating with 1N sodium hydroxide (0.72 mL, 0.72 mmol) in methanol (12 mL) furnished the title compound as a cream-colored solid (0.228 g), mp 221-222° C. Mass spectrum (+ESI, [M+H]+) m/z 507. 1HNMR (500 MHz, DMSO-d6): δ8.25 (d, 1H, J=1.7 Hz), 8.0-8.05 (m, 2H), 7.75-7.8 (m, 2H), 7.7 (dd, 1H, J=7.3 Hz and 0.8 Hz), 7.35-7.45 (m, 4H), 7.15 (t, 1H, J=7.3 Hz), 4.45 (dd, 1H, J=9.8 Hz and 3.1 Hz), 3.25 (dd, 1H, J=13.9 Hz and 2.7 Hz), 3.05 (q, 1H, J=7.9 Hz), 2.7 (t, 2H, J=7.3 Hz), 2.4 (s, 3H), 1.5-1.55 (m, 2H), 1.1-1.15 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C33H30O5Na: Calculated: C, 74.99; H, 5.53; N, 0.00. Found: C, 74.63; H, 5.38; N, 0.08.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=O)=[CH:4][CH:3]=1.[NH3:13]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:13])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: N
Product: NC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 4-Hydroxyphenylacetate (4) (0.83 g) was dissolved in saturated methanolic ammonia (30 ml) and placed in a thick walled tube with Teflon screw cap. The solution was stirred in this sealed tube at room temperature for 72 hours. Reaction mixture was concentrated and redissolved in methanol-chloroform (2:8 volume by volume, 75 ml). No crystallization occurred so the solution was concentrated to half its volume and hexane was added with heating. Cooling to 0° C. gave crystals of 4-Hydroxyphenylacetamide (13) (0.524 g). This was confirmed by spectroscopy--1H NMR (d6DMSO+CF3CO2D) δ 3.23 (s, 2 H), 6.63 (d, 2 H), 7.00 (d, 2 H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:19][C@@H:20]([C@H:23]1[CH2:27][O:26][C:25]2([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[O:24]1)[CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C(OCC)C>[CH2:12]([O:19][C@@H:20]([C@H:23]1[CH2:27][O:26][C:25]2([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[O:24]1)[CH:21]=[O:22])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.9 %

Procedure:
15.0 g of pyridinium chlorochromate and 10.0 g of crushed 3A molecular sieves were added to a solution of 5.50 g (0.019 mol) of β(R)-benzyloxy-1,4-dioxaspiro[4,5]-decane-2(R)-ethanol in 200 ml of dichloromethane. The mixture was stirred at room temperature for 20 hours, then diluted with 200 ml of diethyl ether and filtered. The filtrate was evaporated to give 4.30 g of α(S)-benzyloxy-1,4-dioxaspiro[4,5]decane-2(R)-acetaldehyde which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.C([Li])CCC.Cl>C1COCC1>[Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5]([B:18]([OH:19])[OH:17])=[CH:4][N:3]=1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(B(O)O)cnc(Cl)c2n1
Temperature: -75 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
8-Chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I) (2.5 g, 8.2 mmol) and triisopropylborate (1.9 ml, 8.2 mmol) were dissolved in 80 ml THF and cooled to −75° C. n-Butyllithium (1.6M in hexane) (5.1 ml, 8.2 mmol) was added drop wise at −70° C. The reaction mixture was stirred for 1 hour at −75° C. and for 1 hour without ice-bath. 10 ml 2N HCl-solution were added and extracted three times with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was crystallized in acetonitrile to get the desired compound as a red solid (1.05 g, 58%), MS: m/e=221.3 (M−H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].C(N(CC)CC)C.Cl[CH2:20][C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:21]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[S:11][CH:20]=1)[CH3:27]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1=CSc2cc([N+](=O)[O-])ccc2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.6 %

Procedure:
A solution of 2-amino-5-nitro-benzenethiol (Example 8a, 4.1 g, 23.9 mmol) in tetrahydrofuran (60 mL) was treated with triethylamine (4.8 g, 47.8 mmol) and ethyl chloroacetoacetate (4.3 g, 26.3 mmol). The reaction mixture was stirred at 25° C. for 12 h, concentrated in vacuo, taken up in ethyl acetate, and heated at 80° C. for 3 h. The reaction mixture was allowed to cool to 25° C., washed with brine solution, dried over sodium sulfate, and concentrated in vacuo. The resulting brown solid was triturated with diethyl ether to afford the desired product, (7-nitro-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (5.8 g, 20.7 mmol, 87% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.32 (t, 3H, J=7.1 Hz), 3.49 (s, 2H), 4.21 (q, 2H, J=7.0 Hz), 4.89 (s, 1H), 6.91 (d, 1H, J=8.7 Hz), 8.00 (dd, 1H, J1=9.5 Hz, J2=2.3 Hz), 8.12 (d, 1H, J=3.1 Hz), 10.95 (bs, 1H). LC-MS (ESI) calcd for C12H12N2O4S [M+H+] 281.05. found 281.23 [M+H+].
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH:26]=[O:27])[CH3:25])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].Cl>CN(C)C=O>[CH:26]([N:24]([CH2:23][C:20]1[CH:19]=[C:15]2[C:16]([O:18][C:1](=[O:2])[NH:13][C:14]2=[CH:22][CH:21]=1)=[O:17])[CH3:25])=[O:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C=O)Cc1ccc(N)c(C(=O)O)c1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C=O)Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reaction time: 1 h

Procedure:
There was suspended, in 15.2 mL of N,N-dimethylformamide, 3.82 g of 1,1′-carbonyl-diimidazole (CDI) and the resulting suspension was cooled to 5° C. To this slurry, there was added 4.0 g of 2-amino-5-(N-formyl-N-methylamino-methyl)benzoic acid in two portions, followed by the stirring of the same for one hour. After the confirmation of the disappearance of the starting material by HPLC, seed crystals were added to the slurry while dropwise adding 40.3 mL of a 1M hydrochloric acid aqueous solution to separate out solid and the resulting solid was isolated through filtration under reduced pressure. After washing the solid with 120 mL of water, it was dried at 70° C. for 13 hours under reduced pressure to thus give 3.20 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:20])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:29]([Cl:30])=[CH:28][C:25]([CH:26]=O)=[C:24]([OH:31])[CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[NH2:20][C:9]1[N:10]=[CH:11][N:12]=[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH2:26][C:25]3[CH:28]=[C:29]([Cl:30])[C:22]([Cl:21])=[CH:23][C:24]=3[OH:31])[CH2:16][CH2:15]2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Nc1ncnc(N2CCNCC2)c1-c1ccc(F)cc1
Reactant: O=Cc1cc(Cl)c(Cl)cc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: Nc1ncnc(N2CCN(Cc3cc(Cl)c(Cl)cc3O)CC2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A reaction mixture of 5-(4-fluoro-phenyl)-6-piperazin-1-yl-pyrimidin-4-ylamine (400.0 mg; 1.46 mmol; 1.00 eq.), 4,5-dichloro-2-hydroxy-benzaldehyde (279.5 mg; 1.46 mmol; 1.00 eq.), Acetic acid (87.8 mg; 1.46 mmol; 1.00 eq.) and sodium triacetoxy borohydride (926.1 mg; 4.39 mmol; 3.00 eq.) in DCE (10 ml) was stirred overnight at RT. The reaction solution was diluted with DCM and washed with brine. The organic layer was dried and concentrated, which was added 10 ml of ether and stirred for 5 mins. The precipitate was filtered to afford the title as white off solid (528 mg, yield 80.5%). LC-MS: (M+1=448, obsd.=448/450).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:12]3[C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=[CH:19][N:20]=3)[CH:10]=2)[CH:6]=[N:7]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C(O)c1cccnc1Cl
Product: O=C(O)c1cccnc1Nc1ccc2cn[nH]c2c1
Temperature: 150 °C

Procedure:
A mixture of 6-aminoindazole (6.7 g) and 2-chloronicotinic acid (8 g) was heated neat at 150° C. for 2 h. The reaction was cooled and washed with acetone to give 2-(1H-indazol-6-ylamino)pyridine-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:12][CH3:13])[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]1[Cl:11].[C:14]1(=[O:19])[O:18][CH:17]=[CH:16][O:15]1>>[Cl:11][C:4]12[C:3]([O:2][CH3:1])([O:12][CH3:13])[C:7]([Cl:8])([C:6]([Cl:9])=[C:5]1[Cl:10])[CH:17]1[CH:16]2[O:15][C:14](=[O:19])[O:18]1
Reactant: O=c1occo1
Reactant: COC1(OC)C(Cl)=C(Cl)C(Cl)=C1Cl
Product: COC1(OC)C2(Cl)C(Cl)=C(Cl)C1(Cl)C1OC(=O)OC12
Temperature: 90 °C
Reaction time: 63 h
Yield: 94.5 %

Procedure:
In a 500 mL 3N RB flask equipped with a water condenser, N2 flow adapter and thermometer, was placed 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopentadiene (20.7 g, 0.078 mol) and vinylene carbonate (6.7 g, 0.078 mol). The mixture was heated to 90° C. for 4 h, then at 60° C. for 63 h. The reaction was judged complete by TLC and upon cooling, the product solidified, was recrystallized from THF and filtered to provide a white solid (25.80 g, 94%). (TLC 20% EtOAc/hexanes Rf 0.29); 1H NMR (400 MHz, CDCl3) δ 5.13 (s, 2H), 3.59 (s, 3H), 3.56 (s, 3H); GCMS m/z 348 (M)+; mp 160–162° C.; Anal. Calcd. for C10H8Cl4O5: C, 34.32; H, 2.30. Found C, 34.32; H, 2.27.
Reaction SMILES: C[C@@H]1[C@@H](C2C=CC=CC=2)OC(=O)N1[C:14](=[O:25])[C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH3:16].[OH-].[Li+].OO.S([O-])([O-])=[O:31].[Na+].[Na+]>O1CCCC1.O>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C@@H:15]([CH3:16])[C:14]([OH:25])=[O:31]
Reactant: COc1ccccc1[C@@H](C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@H]1C
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1[C@@H](C)C(=O)O
Reaction time: 3 h

Procedure:
To a solution, cooled to +5° C., of 10.88 g of (4R, 5R)-4-methyl-5-phenyl-3-[(R)-2-(2-methoxyphenyl)propionyl]-2-oxazolidinone in 300 cm3 of tetrahydrofuran and 100 cm3 of water are added 2.71 g of lithium hydroxide and 13 cm3 of aqueous 30% hydrogen peroxide solution. The reaction mixture is stirred for 3 hours at this temperature, followed, after returning to room temperature, by addition of aqueous sodium sulphite solution and then dichloromethane, and the phases are separated after settling. The aqueous phase is acidified with 4N aqueous hydrochloric acid solution and extracted with dichloromethane, and the organic phase is then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized in hexane, filtered off and dried. 5.24 g of (R)-2-(2-methoxyphenyl)propionic acid are obtained, in the form of white crystals melting at 102° C.; [α]D20 =-76° (c=1; methanol).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+].O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[O:20])=[CH:15][C:14]=1[N+:29]([O-])=O>O1CCCC1>[NH2:29][C:14]1[CH:15]=[C:16]([C:19]([C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22])=[O:20])[CH:17]=[CH:18][C:13]=1[NH2:12]
Reactant: Nc1ccc(C(=O)C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)C(=O)c2ccccc2)cc1N
Reaction time: 0.33 h

Procedure:
Preparation and polymerization of 3,4-diaminobenzil-A reduction solution made from sodium dithionite (0.6 grams), sodium hydroxide (0.3 grams) and water (10 ml) was stirred under nitrogen. 4-amino-3-nitrobenzil (270 mg) dissolved in tetrahydrofuran (4 ml) was added to the reduction solution. The color changed from pale yellow to dark brown indicating the progress of the reduction. Reaction was completed in 20 minutes and extraction by dichloromethane removed the organic layer. Drying with magnesium sulfate and solvent removal yielded the brown 3,4-diaminobenzil. Upon dissolving the 3,4-diaminobenzil in m-cresol and heating to 180° C. for 3 hours, complete polymerization took place. The polymerization is indicated by bleaching of the reddish brown monomer to a yellowish brown polymer, the polymer may be isolated by precipitation with methanol as yellowish brown powder from the cresol solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:38])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=4[Cl:37])=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:39]([OH:41])=[O:40].C[O-].[Na+:44]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:38])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][C:28]=4[Cl:37])=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:39]([O-:41])=[O:40].[Na+:44]
Reactant: O=C(Nc1ccc(-c2ccc(C(F)(F)F)cc2Cl)nn1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccc(-c2ccc(C(F)(F)F)cc2Cl)nn1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 6-chloro-7-(4-(6-(2-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.030 g, 0.050 mmol) in MeOH (2 ml) was added a 0.5M solution of sodium methoxide in methanol (0.099 ml, 0.050 mmol), and the reaction was stirred for 2 hours. The reaction was concentrated to yield the desired compound (0.030 g, 0.048 mmol, 96% yield). MS (apci) m/z=603.9 (M-Na+2H).
Reaction SMILES: C(N(CC)CC)C.N1C=CC=CC=1.[CH3:14][CH:15]([CH3:20])[CH2:16][C:17](Cl)=[O:18].[Cl:21][C:22]1[N:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([N:32]3[CH:40]([OH:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]3=[O:42])=[N:29]2)=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:14][CH:15]([CH3:20])[CH2:16][C:17]([O:41][CH:40]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:42])[N:32]1[C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[N:31][C:22]([Cl:21])=[CH:23][CH:24]=2)[N:29]=1)=[O:18]
Reactant: CC(C)CC(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
Triethylamine (12.2 g), pyridine (90 cc) and then 3-methylbutyryl chloride (9.7 g) is added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (12.5 g) in methylene chloride (600 cc), while the temperature is maintained in the region of 25° C. After 4 hours' stirring at a temperature in the region of 25° C., 3-methylbutyryl chloride (0.7 g) is added again and the mixture is stirred for a further 16 hours at this temperature. The reaction mixture is then concentrated to dryness under reduced pressure (3 kPa) and the residue is taken up with water (500 cc). The insoluble product formed is separated by filtration, washed, dried and then recrystallized in a mixture of isopropyl ether and ethyl acetate (50:50 by volume). 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 3-methylbutyrate (7.9 g), m.p. 154° C., is thereby obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:10]>C1(C)C=CC=CC=1>[CH3:10][C:9]([C:2]1[CH:3]=[C:4]([C:9]([CH3:10])([CH3:8])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:1]=1[OH:7])([CH3:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: C=C(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(c1ccccc1)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Temperature: 140 °C

Procedure:
This intermediate is made by reacting a mixture of 705.8 grams (7.5 moles) of phenol with 1772.7 grams (15 moles) of alpha-methylstyrene in the presence of 25.7 grams (0.135 moles) of P-toluenesulfonic acid monohydrate catalyst. This mixture is heated under nitrogen at 140° C. for 2.5 hours. The reaction mixture is cooled at 110° C. and 1125 ml of toluene is added. After washing the resulting solution at 80° C. with 750 ml of an aqueous solution of 37.5 grams of sodium carbonate and 75 grams of sodium chloride, the organic phase is washed thrice with 1000 ml of aqueous sodium chloride solution; then dried over anhydrous sodium sulfate; filtered and vacuum distilled. The above-named product is obtained as the main fraction boiling at 172°-175° C./0.15-0.18 mm Hg in a yield of 1229.8 grams (49.6% of theory). The product melts at 63°-65° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:34]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=4)=[O:35])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(C)cc4)cc3)cc2C1=O

Procedure:
The compound of example 23 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 4-methyl phenyl isocyanate. The compound of example 23 was used directly without isolation for the preparation of compound of example 24.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.CN([CH:25]=[O:26])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][C:9]([CH:25]=[O:26])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2occc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine (40 mg, 1.0 eq) dissolved in THF (1.7 ml) at −78° C. was added 1.6M solution of n-butyllithium (0.14 ml, 1.3 eq, 1.6M in hexanes). Reaction mixture was stirred at −78° C. for 30 minutes. DMF (0.05 ml, 4.0 eq) was added and reaction mixture was allowed to slowly warm up to room temperature and stirred for 90 minutes. Reaction mixture was quenched with water, and extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The crude reaction mixture was purified by flash chromatography to yield 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carbaldehyde (22 mg, 50%): 1H NMR (CDCl3, 400 MHz) δ 9.92 (s, 1H), 7.48 (s, 1H), 4.12 (m, 4H), 3.86 (dd, 4H); MS (Q1) 268 (M)+.
Reaction SMILES: Cl.[C:2](=[NH:9])(OC)[CH2:3][CH2:4][CH2:5][CH3:6].CN(C)C=O.[NH2:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1>C(N(CC)CC)C>[NH:9]=[C:2]([NH:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:24][CH:25]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CCCCC(=N)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC(=N)NCc1ccc(C(=O)O)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A 22 L, three-necked round bottom flask equipped with an air-powered mechanical stirrer was placed under a nitrogen atmosphere. The vessel was charged with methyl valerimidate hydrochloride (2.5 kg, 16 mol) and dimethylformamide (9.2 L). A thermometer was attached and the suspension cooled to 0°-15° C. with a cooling bath. Triethylamine (2.3 L) was added to the reaction at such a rate so that the internal temperature did not exceed 25° C. The cooling was stopped and the reaction was allowed to stir 1 hour. The reaction mixture was vacuum filtered using a Buchner funnel and a carboy (20 L). The filter cake was washed with additional dimethylformamide (1.0 L) and force-air dried for 15 min. The combined filtrates were saved. Another clean 22 L, three-necked round bottom flask equipped as above was placed under nitrogen. The vessel was charged with the combined filtrates from above followed by triethylamine (1.6 L) and 4-(aminomethyl)benzoic acid (1.7 kg, 11.5 mol). The thermometer was attached and the suspension was heated to an internal temperature of 65° C. with a heating mantle and a temperature controller. The heating was continued for 20 hours. The reaction was cooled to ambient temperature and filtered to yield 2.5 kg of product; 92% uncorrected yield.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][N:22]=1>>[F:20][C:21]1[N:22]=[CH:23][C:24]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1ccc(F)nc1
Product: O=C(O)c1cccc(COc2ccc(-c3ccc(F)nc3)cc2)c1

Procedure:
3-[4-(6-Fluoro-pyridin-3-yl)-phenoxymethyl]-benzoic acid was prepared using the procedure described above for the synthesis of Example 4 from 3-(4-iodo phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 2-fluoropyridine-5-boronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=324.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:11]=[CH:10][C:9]([C:12]3[N:13]=[N:14][N:15]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=4[CH3:26])[C:20]([OH:22])=O)[CH:16]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:27]([C:31]1[CH:32]=[C:33]([NH2:38])[C:34]([CH3:37])=[N:35][CH:36]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:32]=[C:33]([NH:38][C:20](=[O:22])[C:19]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:17]([N:15]3[CH:16]=[C:12]([C:9]4[CH:10]=[N:11][C:6]([NH:5][CH2:4][CH:1]5[CH2:3][CH2:2]5)=[CH:7][CH:8]=4)[N:13]=[N:14]3)[CH:18]=2)[C:34]([CH3:37])=[N:35][CH:36]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1ncc(C(C)(C)C)cc1N
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(NCC3CC3)nc2)nn1
Product: Cc1ccc(C(=O)Nc2cc(C(C)(C)C)cnc2C)cc1-n1cc(-c2ccc(NCC3CC3)nc2)nn1

Procedure:
Example 2 was prepared by coupling 3-{4-[6-(cyclopropylmethyl-amino)-pyridin-3-yl]-1,2,3-triazol-1-yl}-4-methyl-benzoic acid with 5-tert-butyl-2-methyl-pyridin-3-ylamine (See U.S. provisional application 60/567,693) in the same manner as Example 1. ESI MS m/z 496 [C29H33N7O+H]+.