Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:4][N:3]=1
Reactant: C1CCNC1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCCC3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and pyrrolidine by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[NH2:5].F[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([NH:5][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1)[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: CC(C)C[C@H](N)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Reactant: COC(=O)c1ccc(F)nc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(N[C@@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cn3)cc2)nc1
Temperature: 107.5 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
A mixture of crude (S)-3-methyl-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}butan-1-amine (66.34 g, 192.4 mmol), methyl 6-fluoronicotinate (32.8 g, 212 mmol), and freshly pulverized and dried (150 C, vacuum oven, 12 h) tripotassium phosphate (75.6 g, 356 mmol) was purged with dry nitrogen then diluted with N,N-dimethylacetamide (320 ml). The mixture was heated to 110° C. (107-108° C. internal temperature) for 24 hours. The reaction was diluted with water (˜1.5 L) and the resulting mixture was stirred vigorously for 15 minutes. The aqueous portion was decanted, leaving behind a thick amorphous solid. This material was washed with water (2×1 L). The resulting solid was dissolved in ethyl acetate and the remaining water was removed via azeotropic distillation (rotary evaporator, approximately 2×1 L ethyl acetate). The combined aqueous layers were stirred vigorously for 12 hours resulting in the precipitation of an additional aliquot (approximately 500 mg) of the crude product that was combined with the originally recovered material. The crude material was purified via ISCO MPLC (SiO2, 0-75% ethyl acetate in heptane) to yield the product (53.0 g, 62%) as a white foam. 1H NMR (400 MHz, CDCl3, δ): 8.93 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.97 (dd, J=8.5, 2.1 Hz, 1H), 7.92 (dd, J=8.9, 2.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 6.25 (d, J=8.8 Hz, 1H), 5.79 (d, J=6.5 Hz, 1H), 4.73-4.85 (m, 1H), 3.84 (s, 3H), 1.77-1.86 (m, 1H), 1.65-1.77 (m, 2H), 1.01 (d, J=6.1 Hz, 3H), 0.97 (d, J=6.1 Hz, 3H). MS (M+1): 444.5.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1.[Br:33][CH2:34][CH2:35]Br>>[Br:33][CH2:34][CH2:35][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:31])([CH3:32])[C:21]=2[CH:20]=1
Reactant: BrCCBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Product: CCOC(=O)c1ccc(-c2ccc(OCCBr)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 28.3 %

Procedure:
In a manner similar to that of Example 1a, by reaction of 6 g (14 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 4 ml (46.2 mmol) of 1,2-dibromoethane. 2.12 g of ethyl 4′-(2-bromoethoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (yield=28%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([C:15](=O)[N:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[Cl:29][C:30]1[C:31]([C:40]([F:43])([F:42])[F:41])=[N:32][N:33]([CH2:36]C(O)=O)[C:34]=1[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1.CCOC(C)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:13][CH2:12][C:11]3([CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:36][N:33]4[C:34]([CH3:35])=[C:30]([Cl:29])[C:31]([C:40]([F:42])([F:43])[F:41])=[N:32]4)[CH2:27][CH2:26]3)[CH2:15]2)=[CH:18][C:19]=1[O:24][CH3:25]
Reactant: COc1cc(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)ccc1Cl
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC3(CCN(C(=O)Cn4nc(C(F)(F)F)c(Cl)c4C)CC3)C2)ccc1Cl
Temperature: 0 °C

Procedure:
2-(4-Chloro-3-methoxy-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (90 mg, 1 equiv) was treated with 4 mL of 4N HCl in dioxane at rt for 1 h. The volatile was removed and to the residue were added 3 mL of THF and 3 mL of dichloromethane. After cooling to 0° C., the solution was treated with 2 mL of 1M LiAlH4 in THF over night (allowed to warm to room temperature). 10 drops of water, 10 drops of 1N NaOH, and then 10 drops of water were added. The organic layer was collected and dried under vacuum. The residue was taken up in 1 mL of DMF, and to the solution were added (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (55 mg, 1 equiv), HATU (95 mg, 1.1 equiv), TEA (150 μL, 3 equiv). After stirring at rt over night, the mixture was taken up in EtOAc, washed with saturated sodium NaHCO3. Purification by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) gave 1-[2-(4-Chloro-3-methoxy-phenyl)-2,8-diaza-spiro[4.5]dec-8-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone. LCMS observed for (M+H)+: 505. Retention time: 5.28 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a 4.5 minutes gradient of 20% to 95% B with a 1.1 minutes wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/99.9% acetonitrile).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=O)=[N:10]2)=[CH:5][CH:4]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:38]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[S:38])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(=O)N3CCN(C)CC3)cc2-c2ccccc2)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc(C(=S)N3CCN(C)CC3)cc2-c2ccccc2)cn1

Procedure:
To a solution of 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazine (173 mg) obtained in Example 62 in toluene (10 mL), 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawson reagent, 222 mg) was added. The mixture was refluxed for 14 hours under heat. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, water, and saturated brine, followed by drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel thin-layer chromatography (chloroform-methanol), to thereby give the title compound as an amorphous product (61 mg, 33%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].Cl[CH2:13][CH:14]1[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH:14]1([CH2:13][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:16][CH2:15]1
Reactant: ClCC1CC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C=O)cc1OCC1CC1
Temperature: 80 °C
Yield: 78.5 %

Procedure:
A vigorously stirred mixture of 3-hydroxy-4-methoxybenzaldehyde (20 g, 131 mmol), chloromethylcyclopropane (18.2 mL, 197 mmol) and powdered potassium carbonate (27.3 g, 197 mol) in dimethylflormamide (400 mL) was heated under an argon atmosphere at 80° C. for 9 h. The mixture was allowed to cool and was filtered through Celite. The filtrate was concentrated under reduced pressure, the residue was extracted twice with ethyl acetate, the organic extract was washed five times with saturated aqueous sodium carbonate and was dried (sodium sulfate). The solvent was removed in vacuo to provide an off-white solid (21.2 g, 78%): m.p. 67°-69° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[CH2:34][NH2:35]>>[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[CH2:34][NH:35][C:15]([C:14]1[CH:18]=[CH:19][N:20]=[CH:21][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:28]=[N:27][CH:26]=[N:25][CH:24]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=1)=[O:11])=[O:17]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Reactant: NCC1CCCO1
Product: O=C(NCC1CCCO1)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Yield: 77 %

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with (tetrahydrofuran-2-yl)methanamine, providing the title compound as yellow solid (77%).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:13][CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCN(c2nc(-c3ccccc3)ns2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 89.1 %

Procedure:
A solution of ethyl 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperidine-4-carboxylate (1.12 g, 3.53 mmol), an aqueous 2 N sodium hydroxide solution (4 ml), tetrahydrofuran (20 ml) and ethanol (12 ml) was stirred at 80° C. for 1 hour. Thereto 2 N hydrochloric acid (4 ml) was added and the solvent was distilled off under reduced pressure. The residue was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to yield 910 mg (89.2%) of the desired product.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]2[CH2:19][CH2:20][N:21]=[C:3]12.[C:22]([NH:29][C@H:30]([C:38](O)=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(N(CC)CC)C>[C:25]([O:24][C:22]([NH:29][C@@H:30]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:38]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]2[CH2:19][CH2:20][N:21]=[C:3]12)=[O:39])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NC1N=C(c2ccccc2)c2ccccc2N2CCN=C12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N2CCN=C12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude 4(R,S)-amino-2,4-dihydro-6-phenyl-1H-imidazo-[1,2-a]-[1,4]-benzodiazepine (1.37 g), Boc-L-phenyl-alanine (1.37 g, 5.17 mmole), 1-hydroxybenzotriazole (0.07 g, 5.17 mmole), and 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride (0.99 g, 5.17 mmole) are combined in DMF (30 mL) and stirred at room temperature. The pH of the reaction mixture is adjusted to 8.5 with triethylamine, and after 1/2 hour, the DMF is removed in vacuo, and the residue partitioned between ethyl acetate and 10% citric acid solution (10 mL). The layers are separated and the organic phase is washed with sodium bicarbonate solution (NaHCO3, saturated). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and evaporated to dryness in vacuo to give the title compound as a mixture of diastereomers.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([N:22]([C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([N:22]([C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)(=[NH:42])[NH2:2]
Reactant: CCOC(=O)CN(C(=O)c1ccccc1)c1ccc2c(C)cc(COc3ccc(C#N)cc3)nc2c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccccc1)c1ccc2c(C)cc(COc3ccc(C(=N)N)cc3)nc2c1

Procedure:
Prepared analogously to Example 1e from 2-[(4-cyanophenyl)-oxymethyl]-4-methyl-7-[N-(ethoxycarbonylmethyl)-benzoylamino]-quinoline and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:40])[CH:17]([C:18]([O:20]CC2C=CC([N+]([O-])=O)=CC=2)=[O:19])[N:16]2[C:31](=[O:39])[CH:32]([NH:33][C:34]3[NH:35][CH:36]=[CH:37][N:38]=3)[C@H:15]2[S:14]1>C(O)C.C(Cl)Cl.[Pd]>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH3:12][C:13]1([CH3:40])[CH:17]([C:18]([OH:20])=[O:19])[N:16]2[C:31](=[O:39])[CH:32]([NH:33][C:34]3[NH:38][CH:37]=[CH:36][N:35]=3)[C@H:15]2[S:14]1
Reactant: CC1(C)S[C@@H]2C(Nc3ncc[nH]3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCO
Product: CC1(C)S[C@@H]2C(Nc3ncc[nH]3)C(=O)N2C1C(=O)O

Procedure:
A solution of p-nitrobenzyl 2,2-dimethyl-6-(imidazol-2-yl)aminopenam-3-carboxylate toluene-p-sulphonate (360 mg.) in a mixture of ethanol (18 ml.) and CH2Cl2 (5 ml.) was hydrogenated at atmospheric pressure for 3 hours in the presence of 10% w/w palladium-on-carbon (180 mg.). The mixture was filtered, the filtrate evaporated and the residual yellow gum triturated with ether to give 2,2-dimethyl-6-(imidazol-2-yl)aminopenam-3-carboxylic acid toluene-p-sulphonate as a yellow solid (258 mg.) having the following n.m.r. in d6DMSO: 1.5 (s, 3H); 1.6 (s, 3H); 2.30 (s, 3H); 4.35 (s, 1H); 5.46 (d, 1H); 5.66 (d, 1H); 6.97 (s, 2H); 7.10 (d, 2H); 7.50 (d, 2H); 8.7-9.0 (br, 1H). By integration the product was 50% pure and contained 2 moles of toluene-p-sulphonic acid per mole of β-lactam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][CH:3]=1.[Br:15]Br.C(O)(=O)C>O>[Br:15][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([C:2]=1[Cl:1])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)cccc1OC
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(OC)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 6-chloro-2-methoxybenzoate (1.8 g, 8.4 mmol), bromine (1.41 g, 8.8 mmol) and acetic acid (5 ml) is stirred at room temperature for 24 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is separated and concentrated and the residue is purified by column chromatography (petrol ether: ethyl acetate, 95:5 v/v) yielding the pure product as a yellow oil, 1.7 g, (69.%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:11][C:10]2[C:12]([CH3:26])=[C:13]([O:18]CC3C=CC=CC=3)[C:14](C)=[C:15]([CH3:16])[C:9]=2[O:8]1)(=[O:3])[CH3:2].[CH2:27](O)C>[Pd]>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:11][C:10]2[CH:12]([CH3:26])[C:13]([OH:18])([CH3:27])[CH:14]=[C:15]([CH3:16])[C:9]=2[O:8]1)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)OCCC1Cc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Agent: [Pd]
Product: CC(=O)OCCC1CC2=C(O1)C(C)=CC(C)(O)C2C

Procedure:
150 mg palladium on 5% carbon is added to a solution of 1.8 g of 2-(RS)-(2-acetoxyethyl)-2,3-dihydro-5-benzyloxy-4,6,7-trimethylbenzofurane in 25 ml of absolute ethanol. The solution is kept under a hydrogen pressure of 50 psi for one hour at room temperature. After filtration of the catalyzer, on Celite, the solvent is evaporated, leaving 1.3 g of a white solid. m.p. 90°-92° C.; (IR)(KBr) 3389 (νOH), 1738 cm-1 (νCOCH3); 1H-NMR (CDCl3); δ5.1-4.6 (1H,m), 4.2 (2H,t), 3.3-2.7 (2H,m) 2.2 (3H,s), 2.05 (6H,s), 2.0 (3H,s), 2.0-1.8 (2H,m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][S:9][C:10](SC)=[N:11][C:12]#[N:13]>C(#N)C>[C:12]([N:11]=[C:10]([S:9][CH3:8])[NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)#[N:13]
Reactant: CSC(=NC#N)SC
Reactant: Nc1cccnc1
Solvent: CC#N
Product: CSC(=NC#N)Nc1cccnc1
Yield: 73.9 %

Procedure:
A suspension of 3-aminopyridine (5.16 g, 54.8 mmol) and dimethyl N-cyanodithioiminocarbonate (8.02 g, 54.8 mmol) in acetonitrile (200 mL) was heated at reflux for 6 days. The solution was cooled and concentrated to a volume of 75 mL where upon a white solid precipitated from solution. The solid was collected by filtration and washed with 50% ether/hexanes (500 mL) to provide 7.79 g of the desired product as a pale yellow solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:37])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:20]2[CH:21]=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8]([F:36])[CH:7]=1.O1CCCC1>CO>[F:36][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][CH:13]([C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=2)=[CH:24][CH:25]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]([OH:37])=[O:4]
Reactant: CCCCCCC(Oc1ccc(C(=O)OC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCC(Oc1ccc(C(=O)O)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Yield: 86.6 %

Procedure:
Add sodium hydroxide (5.0N, 0.09 mL, 0.42 mmol) to 3-fluoro-4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoic acid methyl ester (0.04 g, 0.085 mmol) in methanol (2 mL). Add tetrahydro-furan (1 ml) and stir for four hours. Acidify with 1.0 N HCl and extract desired compound with ethyl acetate three times. Dry organic fractions with Na2SO4, filter and concentrate under reduced pressure to provide 0.035 g (90%) of title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH2:2]1.[CH3:17][S:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[CH3:17][S:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]3[C:8]4[CH:9]=[CH:10][N:11]=[CH:12][C:13]=4[CH:14]=[CH:15][CH:16]=3)[CH2:2]2)=[CH:21][CH:20]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: c1cc(N[C@@H]2CCNC2)c2ccncc2c1
Product: CSc1ccc(CN2CC[C@@H](Nc3cccc4cnccc34)C2)cc1

Procedure:
Reaction of (R)—N-(pyrrolidin-3-yl)isoquinolin-5-amine and 4-(methylthio)-benzaldehyde using the method of Example 8 afforded the title compound.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1)C.C([C:29]1[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:30]=1[C:36]([C:38]1C=CC(O)=CC=1CC1C=CC=CC=1)=[O:37])C1C=CC=CC=1>>[CH3:20][O:19][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][O:35][C:33]2[CH:34]=[CH:29][C:30]([C:36](=[O:37])[CH2:38][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:31][CH:32]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:21]
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCBr)cc1)OC
Reactant: O=C(c1ccc(O)cc1Cc1ccccc1)c1ccc(O)cc1Cc1ccccc1
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(C(=O)Cc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 24, Step A and benzyl-4-hydroxyphenylketone in a manner analogous to that described for Example 24, Step B. MS(ES) for C29H25O5[M−H]−:455.2.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH:9]([OH:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CO[C:21](OC)([CH3:23])[CH3:22].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO>C(Cl)Cl>[CH2:6]([O:5][C:3]([CH:2]1[CH2:8][CH:9]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[O:18][C:21]([CH3:23])([CH3:22])[O:1]1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(O)CC(O)CC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C1CC(CC(=O)OC(C)(C)C)OC(C)(C)O1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 1-ethyl 6-tert.-butyl 2,4-dihydroxyadipate (1.6 g, 6.1 mmol) in methylene chloride (60 ml), dimethoxypropane (1.672 ml, 78 mmol) and pyridinium p-toluenesulfonate (251 mg, 1 mmol) were added and stirred under reflux conditions for one hour, followed by further stirring at 50° C for one hour while azeotropically removing methanol with methylene chloride. To the mixture, methylene chloride (60 ml) was added and stirred at 50° C. for one hour to remove methylene chloride. After adding water, the mixture was extracted with methylene chloride. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=7:1) to give pure 2-ethoxycarbonyl-4-tert.-butoxycarbonylmethyl-6,6-dimethyl-1,5-dioxane (1.23 g, 4.06 mmol). Yield, 67%.
Reaction SMILES: [NH2:1][C:2]1([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:6][N:5]([C:7]2[N:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[C:9]([CH3:16])[N:8]=2)[CH2:4][CH:3]1[CH2:17][OH:18].[C:25]([N:33]=[C:34]=[S:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[F:15][C:10]1[C:11]([O:13][CH3:14])=[N:12][C:7]([N:5]2[CH2:4][CH:3]([CH2:17][OH:18])[C:2]([NH:1][C:34]([NH:33][C:25](=[O:32])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[S:35])([C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH2:6]2)=[N:8][C:9]=1[CH3:16]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1nc(N2CC(CO)C(N)(c3cnccn3)C2)nc(C)c1F
Solvent: C1CCOC1
Product: COc1nc(N2CC(CO)C(NC(=S)NC(=O)c3ccccc3)(c3cnccn3)C2)nc(C)c1F
Yield: 95.4 %

Procedure:
To a stirred solution of [4-amino-1-(5-fluoro-4-methoxy-6-methyl-pyrimidin-2-yl)-4-pyrazin-2-yl-pyrrolidin-3-yl]methanol (930 mg, 2.78 mmol) in tetrahydrofuran (29 mL) under a nitrogen atmosphere is added benzoyl isothiocyanate (613 μL, 4.45 mmol). After stirring the reaction at room temperature for 1 hour the solvent is removed under reduced pressure. The resulting residue is purified by silica gel column chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (1.32 g, 95%). ES/MS (m/e): 498 (M+1).