Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]([C:19]1[C:20]([OH:26])=[N:21][C:22]([OH:25])=[CH:23][CH:24]=1)#[N:18]>CN(C)C(=O)C>[C:8]([O:25][C:22]1[N:21]=[C:20]([OH:26])[C:19]([C:17]#[N:18])=[CH:24][CH:23]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(O)nc1O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(OC(=O)c2ccccc2)nc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
A 0.51 ml quantity of triethylamine and 0.43 ml of benzoyl chloride were added to a solution of 1.00 g of 3-cyano-2,6-dihydroxypyridine in 40 ml of N,N-dimethylacetamide. The mixture was stirred at room temperature for 15 minutes. To the reaction mixture were added 0.51 ml of triethylamine and 0.43 ml of benzoyl chloride, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered and the filtrate was concentrated under a reduced pressure. The concentrate was washed with chloroform and with water, giving 1.06 g of the title compound in a yield of 60%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[O:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O1CCOCC1>[CH2:13]([NH:12][C:8]1[C:6]2[N:7]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4ccco4)ncnc23)CC1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4ccco4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-furfurylamino-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 203°-205° C.) and piperazine in dioxane at 80° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:43]2[C:44]([F:48])=[CH:45][CH:46]=[CH:47][C:42]=2[Cl:41])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: OB(O)c1c(F)cccc1Cl
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4c(F)cccc4Cl)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-6-fluorophenyl)boronic acid gave 280. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.89 (s, 1H), 7.61-7.46 (m, 4H), 7.40 (ddd, J=9.6, 8.2, 1.4 Hz, 1H), 5.06 (t, J=5.2 Hz, 1H), 3.68 (d, J=2.8 Hz, 5H), 3.33-3.17 (m, 2H), 2.82 (s, 3H), 1.66-1.49 (m, 4H). LCMS (ES+) m/z 495 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[N:9]2)[CH2:4][O:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](Cn2ccc([N+](=O)[O-])n2)O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reaction time: 16 h
Yield: 98.5 %

Procedure:
1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-3-nitro-1H-pyrazole (14.5 g) was diluted in 60 mL of ethanol and 10% palladium on carbon (1.4 g) was added. The mixture was hydrogenated on a Parr apparatus at 50 psi for 16 hr. The mixture was filtered and the solvent was removed to afford the product 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (12.4 g, 98%) as a pale yellow oil. LR-ES-MS m/z calculated for C9H15N3O2 [M]+197, observed [M+H] 198; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 (s, 3H), 1.30 (s, 3H), 3.70 (dd, J=8.5, 6.0 Hz, 1H), 3.85-4.02 (m, 3H), 4.28 (quin, J=6.0 Hz, 1H), 4.56 (s, 2H), 5.36 (d, J=2.1 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][S:6][CH:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Li+].[OH-]>C1COCC1.CO>[C:11]1([CH2:10][CH2:9][CH2:8][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:39])[C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[S:6][CH2:5][CH2:4][C:3]([OH:40])=[O:2])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CCSC(CCCc1ccccc1)c1ccc(OCCCOc2ccc(C(=O)C(F)(F)F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCSC(CCCc1ccccc1)c1ccc(OCCCOc2ccc(C(=O)C(F)(F)F)cc2)cc1
Reaction time: 12 h
Yield: 82 %

Procedure:
A mixture of 300 mg of the product from Step 5 and 1.5 mL of 1M LiOH in 12 mL of 5:1 THF/MeOH was stirred for 12 hrs. at r.t. The reaction mixture was then treated with 10 mL of PH-7 buffer and extracted with EtOAc (50 mL). The extract was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluted with 2:1 Hexane/EtOAc containing 1% AcOH to give 240 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[C:20]([O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:19]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][C:20]=3[O:33][CH2:34][CH2:35][O:36][CH3:37])[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COCCOc1cc(OC)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c[nH]c2c(-c3ccc(OC)cc3OCCOC)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A43) the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:60]=[CH:59][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][O:27]C5CCCCO5)[CH:19]=4)[CH2:16][N:15]([CH2:34][CH2:35][S:36]([N:39](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)(=[O:38])=[O:37])[C:14]3=[O:58])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][OH:27])[CH:19]=4)[CH2:16][N:15]([CH2:34][CH2:35][S:36]([NH2:39])(=[O:37])=[O:38])[C:14]3=[O:58])=[CH:9][CH:8]=2)=[CH:59][CH:60]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)CCN2C[C@H](c3cccc(OCCOC4CCCCO4)c3)N(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)CCN1C[C@H](c2cccc(OCCO)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.7 %

Procedure:
A solution of 2-((4S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)phenyl)imidazolidin-1-yl)-N,N-bis(4-methoxybenzyl)-ethane-sulfonamide (40 mg, 0.046 mmol) in TFA (1 mL) is stirred at room temperature for 2 h and is then concentrated. The residue is dissolved in MeOH (1 mL) and NaOH (0.09 mmol, 1M aqueous solution) is added. The mixture is stirred at room temperature for 14 h and is treated with water (3 mL) and extracted with EtOAc (3×3 ml). The combined organic layers are concentrated and purified by flash column chromatography (silica gel, 0-100% EtOAc/hexane) to provide the title compound as a white solid (20 mg, 81%). 1H NMR (CDCl3, 400 MHz) δ 7.21-7.28 (m, 5H), 6.81-6.97 (m, 7H), 5.67 (s, 2H), 5.16 (dd, J=9.2, 6.8 Hz, 1H), 3.98-4.08 (m, 2H), 3.92 (m, 3H), 3.75-3.80 (m, 2H), 3.26-3.41 (m, 3H), 2.37 (br s, 1H); HPLC-MS calculated for C25H26ClN3O6S (M+H+) 532.1, found 532.1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:7]([O:28][CH3:29])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)=[C:18]([C:25](=[O:27])[CH3:26])[CH:19]=1
Reactant: COc1ccc(Oc2ccnc3cc(OCCCCl)c(OC)cc23)c(C(C)=O)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccnc3cc(OCCCN4CCOCC4)c(OC)cc23)c(C(C)=O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
1-(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methoxyphenyl)-1-ethanone (compound 121) (100 mg), morpholine (63 mg), and potassium carbonate (166 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (55 mg, yield 49%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1.CC([O-])(C)C.[Na+].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C1COCC1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1n[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cc1nn(C(=O)c2ccc(Cl)cc2)c2ccccc12
Reaction time: 0.42 h

Procedure:
To a cooled solution (ice bath, 0-5° C.) of methyl 2-(1H-indazol-3-yl)acetate (80 mg, 0.42 mmol) in THF (2.5 mL) was added tBuONa (2 M in THF, 252.4 μL, 0.50 mmol), and the mixture was stirred for 25 min at the low temperature. 4-Chlorobenzoyl chloride (88.3 mg, 0.50 mmol) was added and the reaction was aged overnight at room temperature. The reaction was quenched with saturated aqueous NH4Cl (provided in a commercial phase separator syringe) and the organic compound was extracted with CH2Cl2, washed with brine and water, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was subjected to flash chromatography (SiO2, ethyl acetate/hexane gradient) to afford the title compound as yellow oil, which permanently crystallized upon drying at high vacuum and storage at −20° C. Yield: 51 mg (37%). C17H13ClN2O3, Mr=328.75; 1H NMR (400 MHz, DMSO-d6) d: 3.65 (s, 3H), 4.16 (s, 2H), 7.50 (td, J=0.8/7.6 Hz, 1H), 7.63-7.66 (m, 2H), 7.71 (td, J=1.0/7.6 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 8.00-8.03 (m, 2H), 8.41 (d, J=8.4 Hz, 1H); LCMS (ESI) tR: 2.80 min (>99%, ELSD), m/z: 329.0 [M+1]+.
Reaction SMILES: C[C:2]1[C:3](=[O:20])N[C:5]2[C:10]([N:11]=1)=[CH:9][C:8](OCCCCC(O)=O)=[CH:7][CH:6]=2.[CH2:21]([C:23]1[C:24](=[O:41])[NH:25][C:26]2[C:31]([N:32]=1)=[CH:30][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=O)=[CH:28][CH:27]=2)[CH3:22]>>[CH2:21]([C:23]1[C:24](=[O:41])[NH:25][C:26]2[C:31]([N:32]=1)=[CH:30][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:11]([CH:10]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[CH2:2][CH2:3][OH:20])=[O:40])=[CH:28][CH:27]=2)[CH3:22]
Reactant: CCc1nc2cc(OCCCCC(=O)O)ccc2[nH]c1=O
Reactant: Cc1nc2cc(OCCCCC(=O)O)ccc2[nH]c1=O
Product: CCc1nc2cc(OCCCCC(=O)N(CCO)C3CCCCC3)ccc2[nH]c1=O
Yield: 47.2 %

Procedure:
In Example 70 the compound 1037 was replaced by compound 1013 to obtain the compound 1015.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:16]12[N:19]([C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=3)[CH:12]([CH2:18][CH2:17]1)[CH2:13][CH2:14][CH2:15]2
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: C1CC2CCC(C1)N2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(N2C3CCCC2CC3)cc1Cl
Temperature: 120 °C

Procedure:
2-Chloro-4-fluorobenzonitrile (0.97 g, 6.2 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (0.92 g, 6.2 mmol), and N,N-diisopropylethylamine (1.6 g, 12 mmol) were combined in DMSO (15 mL) and heated at 120° C. for 16 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The aqueous phase was separated and extracted with diethyl ether. The organic layers were combined, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:24]3)=[N:21][CH:22]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C(=O)OC(C)(C)C)C1CCCN(c2ccc(N)cn2)C1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Yield: 80.4 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1.0 mmol) was reacted with tert-butyl (1-(5-aminopyridin-2-yl)piperidin-3-yl)(methyl)carbamate (442 mg, 1.45 mmol) to afford the desired product (446 mg, 80%) as an orange-red solid. ESI MS m/z 554 [C27H32BrN5O3+H]+
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]2[C:9](=[O:18])[C:10]3[C:15]([C:16](=[O:17])[C:7]=2[CH:6]=[C:5]([C:19]([O:21]C)=[O:20])[S:4]1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[OH-].[Na+].O.Cl>C1COCC1>[CH3:1][O:2][CH:3]1[C:8]2[C:9](=[O:18])[C:10]3[C:15]([C:16](=[O:17])[C:7]=2[CH:6]=[C:5]([C:19]([OH:21])=[O:20])[S:4]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: COC(=O)C1=CC2=C(C(=O)c3ccccc3C2=O)C(OC)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC1SC(C(=O)O)=CC2=C1C(=O)c1ccccc1C2=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methyl 1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho [2,3-c] thiine-3-carboxylate (106 mg, 0.33 mmol) was dissolved in THF (2 ml). 1.75M solution of sodium hydroxide (0.32 mg, 0.55 mmol) was added dropwise at 0° C. followed by water (0.5 ml). The reaction mixture was stirred at 0° C. for 3 hours, then water (10 ml) was added, and the reaction mixture was acidified to pH=3 with 5% hydrochloric acid. After that, the reaction mixture was extracted with dichloromethane (5×5 ml). Organic fractions were evaporated to dryness. The residue 98 mg (crude) was used in the next step.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](C(F)(F)F)[CH:22]=3)[CH2:17][CH2:16]2)[C:11](=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[Cl:32]C1C=CC=CC=1N1CCNCC1>>[Cl:32][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:12]2[C:11](=[O:31])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]2[CH2:1][CH3:2])[CH2:16][CH2:17]1
Reactant: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: Clc1ccccc1N1CCNCC1
Product: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2ccccc2Cl)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 7d, using 1-(2-chlorophenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[C:14]([C:18]1[CH:30]=[CH:29][C:21]([O:22][C:23]2[C:27](Cl)=[N:26][S:25][N:24]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([O:13][C:27]2[C:23]([O:22][C:21]3[CH:29]=[CH:30][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=3)=[N:24][S:25][N:26]=2)=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(Oc2nsnc2Cl)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(Oc2nsnc2Oc2ccc(C(C)(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a suspension formed by suspending 0.16 g of sodium hydride (60%) in N,N-dimethylformamide was added 0.6 g of 4-t-butylphenol and after stirring the mixture for one hour at 60° C., 0.81 g of 3-(4-t-butylphenoxy)-4-chloro-1,2,5-thiadiazole was added to the mixture followed by stirring for 12 hours at 100° C. After allowing to cool, the reaction mixture was poured in water and extracted with ether. The ether layer collected was washed twice each time with a diluted aqueous sodium hydroxide solution, water, and then a saturated aqueous sodium chloride solution. The ether layer thus washed was dried with anhydrous magnesium sulfate, concentrated, and purified by silica column chromatography to provide 0.84 g of 3,4-bis(4-t-butylphenoxy)-1,2,5-thiadiazole.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:34])[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH:47]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:34])[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH2:47][C:43]3[NH:42][CH:46]=[CH:45][N:44]=3)[CH2:28][C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ncc[nH]1
Reactant: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 101.8 %

Procedure:
The compound (242 mg) obtained in Example 87-4 and 2-imidazole carboxaldehyde (63.4 mg) were dissolved in anhydrous methanol (7.2 ml). Then, the solution was added with sodium cyanoborohydride (96.9 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 2 days. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and extracted with chloroform. Subsequently, the extract was washed with saturated saline solution and the residue was then dried with anhydrous magnesium sulfate, followed by distilling the solvent off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (282 mg) as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][C:50]=1[C:59]1[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=1>CN(C=O)C>[CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][C:50]=1[C:59]1[CH:60]=[C:61]([NH:65][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:62]=[CH:63][CH:64]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccc3ccccc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3ccccc3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.1 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.068 mmol) and HATU (0.029 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-naphthalen-2-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.010 g of product in 36% yield: LCMS (ESI) m/z 408 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][O:7]1.[OH-].[Li+]>CO>[CH3:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][C@H:6]2[CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([OH:19])=[O:2])=[CH:16][CH:15]=1
Reactant: COC(=O)C(C[C@H]1CCCO1)c1ccc(SC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc(C(C[C@H]2CCCO2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
A solution of 2-(4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester (0.693 g, 2.47 mmol) in methanol (10 mL) was treated with a 0.8M aqueous lithium hydroxide solution (4.01 mL, 4.94 mmol). The reaction mixture was stirred at 25° C. for 16 h and then was concentrated in vacuo to remove methanol. The remaining aqueous layer was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 2-(4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid (0.653 g, 99%) as a light yellow oil that crystallized upon standing: mp 105-107° C.; [α]23589=−14.93° (c=0.75, chloroform); EI-HRMS m/e calcd for C14H18O3S (M+) 266.0976. found 266.0976.