Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:23].[C:24]1([CH3:55])[CH:29]=[CH:28][C:27]([S:30]([N:33]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([Sn](CCCC)(CCCC)CCCC)[CH:39]=3)[CH2:34]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1>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>[CH:14]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:23])=[C:2]([C:37]4[CH:36]=[C:35]5[C:40](=[CH:39][CH:38]=4)[CH2:41][N:33]([S:30]([C:27]4[CH:28]=[CH:29][C:24]([CH3:55])=[CH:25][CH:26]=4)(=[O:32])=[O:31])[CH2:34]5)[C:11]=3[O:12][CH3:13])[C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)[CH2:16][CH2:15]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CN(S(=O)(=O)c1ccc(C)cc1)C2
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(Br)c(F)cc2c1=O
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(OC)c(-c3ccc4c(c3)CN(S(=O)(=O)c3ccc(C)cc3)C4)c(F)cc2c1=O

Procedure:
In 5 ml of toluene was suspended 0.25 g of ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate, and to this suspension were added 0.55 g of 2-(p-toluenesulfonyl)-5-tributylstannylisoindoline and 0.09 g of bis(triphenylphosphine)palladium (II) chloride, after which the resulting mixture was heated under reflux for eight hours under an argon stream. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by a column chromatography (eluent: chloroform), after which diethyl ether was added thereto. The crystals formed were collected by filtration to obtain 0.19 g of colorless, crystalline ethyl 1-cyclopropyl-6-fluoro-8-methoxy-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([O:12][CH3:13])=[O:11].CCN(CC)CC>CC#N>[CH3:13][O:12][C:10](=[O:11])[CH2:9][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccn1
Reactant: COC(=O)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CSc1ccccn1
Yield: 94.3 %

Procedure:
A solution of 2-mercaptopyridine (484 mg, 4.35 mmol), methyl bromoacetate (0.45 ml, 4.8 mmol), and Et3N (0.79 ml, 5.7 mmol) in CH3CN (22 ml) was stirred at room temperature for 20 h to give (pyridin-2-ylsulfanyl)-acetic acid methyl ester as a colorless oil (752 mg, 94%) after aqueous work-up and purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:23][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([C:15]4[O:14][CH:18]=[CH:17][CH:16]=4)[CH:20]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1cccc(-c2ccco2)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(-c4ccco4)c3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 3-furan-2-yl-benzylamine (112 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(3-furan-2-yl-benzylamino)-2H-phthalazin-1-one: 59 mg (26.0%): m/z (M+H)=352. 1H-NMR (DMSO-d6) δ: 12.34 (s, 1H), 7.93 (d, 1H), 7.72 (m, 3H), 7.59 (d, 1H), 7.40 (m, 1H), 7.30 (m, 1H), 7.18 (dd, 1H), 6.92 (d, 1H), 6.86 (s, 1H), 6.58 (m, 1H), 4.47 (d, 2H).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:36]1[C:40]2=[N:41][CH:42]=[CH:43][CH:44]=[C:39]2[NH:38][CH:37]=1.[CH3:45][O:46][CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52](B2OC(C)(C)C(C)(C)O2)=[CH:51][CH:50]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:45][O:46][CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([C:36]2[C:40]3=[N:41][CH:42]=[CH:43][CH:44]=[C:39]3[NH:38][CH:37]=2)=[CH:51][CH:50]=1
Reactant: Brc1c[nH]c2cccnc12
Reactant: COCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: COCCOC
Product: COCOc1ccc(-c2c[nH]c3cccnc23)cc1
Yield: 14 %

Procedure:
To a suspension of Xphos (0.695 g), 3-bromo-1H-pyrrolo[3,2-b]pyridine (3.59 g), 2-[4-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.81 g) and Cs2CO3 (11.86 g) in DME (50 mL) and water (10 mL) was added Pd2(dba)3 (0.334 g). The mixture was refluxed overnight under Ar atmosphere. The mixture was added to water and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column Chromatography (AcOEt/hexane) to give the title compound (0.650 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26]CC3C=CC=CC=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCN(c1ccc(O)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 15 h
Yield: 82 %

Procedure:
4-[(4-Benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (9.59 g, 21.2 mmol) was dissolved in 1:1 THF/MeOH (100 mL), treated with 20% Pd/C (1.0 g), and shaken under an atmosphere of H2 (47 psi) for 15 hours. The reaction was filtered and the solution was concentrated. The crude material was chromatographed on silica gel eluting with 4:1 hexane/EtOAc to give 6.3 g (82%) of the desired product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][Cl:21])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(OCCCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
3.0 g of 4-(3-phenylpropyloxy)benzyl alcohol were dissolved in 30 ml of chloroform, and 1.77 g of thionyl chloride were further fed dropwise to the resultant solution. The solution was then stirred for 1 hour at room temperature. After completed the reaction, the solution reacted was poured into ice-water and extracted with chloroform. The organic layer resulted was dried with anhydrous magnesium sulfate, and the solvent used was distillated under reduced pressure, thereby affording 3.2 g of 4-(3-phenylpropyloxy)benzylchloride.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH:9]1[C:14]2[C:15]3[C:28](=O)[C:20]4S[C:22]5C=CC=[CH:24][C:23]=5[C:19]=4[C:18](=O)[C:16]=3SC=2C=CC=1.O>C1COCC1>[C:23]([C:19]1[CH:18]=[CH:16][C:15]([C:14]#[CH:9])=[CH:28][CH:20]=1)([CH3:22])([CH3:24])[CH3:2]
Reactant: O=C1c2sc3ccccc3c2C(=O)c2sc3ccccc3c21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(C(C)(C)C)cc1
Temperature: 24.5 °C
Reaction time: 0.17 h

Procedure:
In another flame dried flask, a solution of 1-tert-butyl-4-ethynyl-benzene (3.56 g, 22.5 mmol) in THF (20 ml) is prepared, and the freshly prepared LDA is added to this solution within 10 minutes. The temperature is maintained in the range between 23-26° C. by cooling, and the solution is stirred for another 10 minutes at ambient temperature. Then dibenzo[d,d′]benzo[1,2-b;4,5-b′]dithiophene-6,12-dione (educt 1) (2.40 g, 7.5 mmol) is added as a solid, and the mixture heated to 50° C. and stirred for 52 hours at this temperature. The clear red solution is poured carefully into water (100 ml), and the product extracted with chloroform (80 ml). The aqueous layer is extracted again with chloroform (80 ml), and the combined organic layers are washed with brine and dried (sodium sulphate). Removal of the solvent leaves the crude product as light brown crystals. The crystals are refluxed in methanol (50 ml) (incompletely dissolved) and the mixture allowed to crystallise over night. The solid is then filtered off and washed with methanol thrice (7 ml each time) and dried in vacuo to give the product as beige crystals. 1H-NMR (CDCl3, 300 MHz) δ 1.29 (s, 9H, C(CH3)3); 3.09 (s, 1H, OH); 7.27, 7.36 (AA′BB′, 4H, Ph H); 7.43, 7.48 (2 “tr”, 1H each), 7.89 pp (d, J=6.5 Hz, 1H), 8.54 (d, J=8.2 Hz, 1H) benzothiophene H. 13C-NMR (CDCl3, 75 MHz) δ 31.47 (C(CH3)3); 35.17 (q, C(CH3)3); 64.79 (q, COH); 87.80, 88.69 (2 q, C≡C); 118.96 (q), 123.03, 124.84, 125.13, 125.77 (benzothiophene CH); 125.46, 131.76 (Ph CH); 130.90 (q), 136.15 (q), 140.37 (q), 144.11 (q), 152.48 (q).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([N:30]([CH2:32][CH3:33])[CH3:31])[CH:27]=2)[C:22]1=[O:34])(=O)C.Cl[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:54]=[C:48]3[CH2:49][N:50]([CH3:53])[CH2:51][CH2:52][N:47]3[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+].O.[OH-].[Li+]>C(OCC)(=O)C.O.O1CCOCC1.CN(C=O)C>[CH2:32]([N:30]([CH3:31])[C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:34])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:36]3[CH:37]=[C:38]([NH:44][C:45]4[CH:54]=[C:48]5[CH2:49][N:50]([CH3:53])[CH2:51][CH2:52][N:47]5[N:46]=4)[C:39](=[O:43])[N:40]([CH3:42])[N:41]=3)[C:6]=1[CH2:5][OH:4])[CH2:29]2)[CH3:33]
Reactant: CCN(C)c1ccc2c(c1)CN(c1cccc(B3OC(C)(C)C(C)(C)O3)c1COC(C)=O)C2=O
Reactant: CN1CCn2nc(Nc3cc(Cl)nn(C)c3=O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C)c1ccc2c(c1)CN(c1cccc(-c3cc(Nc4cc5n(n4)CCN(C)C5)c(=O)n(C)n3)c1CO)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 106e (366 mg, 0.788 mmol), 106f (194 mg, 0.656 mmol), sodium carbonate (348 mg, 3.28 mmol), DMF (2 mL), water (2 mL) and 1,4-dioxane (10 mL). After bubbling nitrogen through the resulting suspension for 30 min, tetrakis(tri-phenylphosphine)palladium(0) (152 mg, 0.131 mmol) was added. A reflux condenser was attached to the flask, and the reaction mixture was heated at reflux for 16 h. After this time, the mixture was diluted with ethyl acetate (150 mL) and water (100 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layers were washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in THF (2 mL), water (2 mL) and methanol (2 mL). Lithium hydroxide monohydrate (138 mg, 3.28 mmol) was added, and the mixture was stirred at room temperature for 16 h. After this time, the mixture was diluted with ethyl acetate (150 mL) and water (100 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layers were washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 90:10 methylene chloride/methanol) to afford 106 in 14% yield (51 mg) as an amorphous off-white solid: mp 145-147° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.89 (s, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.49-7.47 (m, 2H), 7.41 (dd, J=7.0, 2.0 Hz, 1H), 6.87-6.84 (m, 2H), 5.99 (s, 1H), 4.82 (s, 2H), 4.62 (t, J=5.5 Hz, 1H), 4.40 (d, J=5.5 Hz, 2H), 3.96 (t, J=5.5 Hz, 2H), 3.75 (s, 3H), 3.52-3.50 (m, 4H), 2.98 (s, 3H), 2.79 (t, J=5.5 Hz, 2H), 2.35 (s, 3H), 1.09 (t, J=7.0 Hz, 3H); MS (ESI+) m/z 555.3 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH2:10][CH2:9]2)(=[O:3])[CH3:2]>[O-2].[O-2].[Mn+4].C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc2c1NCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1cccc2cc[nH]c12
Reaction time: 5 h
Yield: 76 %

Procedure:
To 30 g. (0.186 mole) of 7-acetylindoline in 415 ml. of methylene chloride was added 48.5 g (0.56 mole) of manganese dioxide and the mixture refluxed through a soxhlet filled with 4A molecular sieves for 22 hours. The mixture was cooled and an additional 48.5 g. of manganese dioxide was added. Fresh molecular sieves were added and the refluxing continued for 5 hours. The same amount of manganese dioxide and molecular sieves were added again and the refluxing was continued for one hour. The mixture was filtered and the filtrate concentrated to dryness. The residue was triturated with hexane and filtered, 22.57 g. (76% yield), m.p. 65°-66° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(Cl)(Cl)C(O)=O.COC(OC)OC.[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N([O-])=O.[Na+].Cl>O>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: c1ccccc1
Agent: Cl
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: O=N[O-]
Solvent: O
Solvent: COC(OC)OC
Product: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 22 h
Yield: 106.7 %

Procedure:
A mixture of 4-nitro-aniline (3.77 g; 0.0273 mole), trichloroacetic acid (6 g; 0.0367 mole), cuprous chloride (0.14 g; 0.0014 mole) and trimethylorthoformate (5.8 g; 0.0548 mole) in benzene (140.6 g; 1.8 mole) was heated to 60° C. Aliquots of sodium nitrite (2.3 g; 0.0333 mole) were added to the thus obtained mixture. The mixture was maintained under stirring for 22 hours at 60° C. and then hydrolyzed with water and diluted hydrochloric acid. The organic layer was separated, washed with water and concentrated. Crystallization of the residue from methanol afforded 5.8 g of 4-nitro-biphenyl, melting at 114°-116° C. Yield, 80%.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:15][CH2:14][CH2:13][C:12]3[S:11][C:10]([C:16]([NH2:18])=[O:17])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:20]([C:22]1([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23]1)#[CH:21]>>[F:19][C:3]1[C:2]([C:21]#[C:20][C:22]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:7][C:6]2[C:8]3[N:9]=[C:10]([C:16]([NH2:18])=[O:17])[S:11][C:12]=3[CH2:13][CH2:14][O:15][C:5]=2[CH:4]=1
Reactant: C#CC1(O)CCCC1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2c(s1)CCOc1cc(F)c(C#CC3(O)CCCC3)cc1-2

Procedure:
9-Bromo-8-fluoro-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide (0.25 g) was reacted with 1-ethynylcyclopentanol similar to as described in Procedure E to afford 157 mg of 8-fluoro-9-[2-(1-hydroxycyclopentyl)ethynyl]-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide following reverse phase hplc purification. MS (Q1) 338 (M)+. 1H NMR (400 MHz, DMSO) δ 8.65 (d, J=8.6 Hz, 1H), 8.45 (s, 1H), 7.84 (s, 1H), 7.03 (t, J=25.1 Hz, 1H), 5.29 (d, J=38.1 Hz, 1H), 4.38 (t, J=4.8 Hz, 2H), 3.40 (t, J=4.8 Hz, 2H), 2.02-1.86 (m, 4H), 1.85-1.57 (m, 5H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:34]=[O:35])C>>[CH2:1]([S:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([CH:34]=[O:35])=[C:13]2[N:12]=[C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1cccc(Nc2cc(SCc3ccccc3)n3nccc3n2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c(SCc3ccccc3)cc(Nc3cccc(Cl)c3)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To 7-(benzylthio)-N-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine (4.1 g, 11.3 mmol) in DMF (42 mL), POCl3 (6.3 mL, 67.6 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was stirred for 3 hours at room temperature. Then, the reaction was quenched by slow addition to ice cold 6N NaOH. The mixture was diluted with water and the solid was collected by filtration. The solid was washed several more times with water then dried under vacuum overnight. The product, 7-(benzylthio)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde, was collected as a solid in 83% yield. LCMS (M+1=395)
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([N:9]([CH2:15][C:16]2[CH:35]=[CH:34][C:19]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[S:7][CH:8]=1)([CH3:3])[CH3:2].O.Cl>CO.O1CCCC1.[OH-].[Na+]>[CH:1]([C:4]1[N:5]=[C:6]([N:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=3)=[CH:34][CH:35]=2)[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(OCc2ccc(CN(CCC(C)C)c3nc(C(C)C)cs3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCN(Cc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1nc(C(C)C)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Methyl 3-{4-[(4-{[(4-isopropyl-1,3-thiazol-2-yl)(3-methylbutyl)amino]methyl}benzyl)oxy]phenyl}propanoate (140 mg) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), and 2N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, acidified with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was dried using Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated to give the title compound (120 mg, yield 88%) as a pale-yellow oil.
Reaction SMILES: [C:1]([NH2:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:52][O:53][CH2:54][CH2:55]Br)[C:47]([O:49]CC)=[O:48])[N:45]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1C=CC=C[CH:23]=1.CS(C)=O>O>[C:21]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:52][O:53][CH2:54][CH2:55][NH:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:47]([OH:49])=[O:48])[N:45]=1)([C:22]1[CH:23]=[CH:3][CH:2]=[CH:1][CH:8]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)C(=NOCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 60 °C
Reaction time: 82 h

Procedure:
A mixture of 75 g of tritylamine, 50 g of syn isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(2-bromoethoxyimino)-acetate and 100 ml of dimethylsulfoxide was stirred under argon at 60° C. for 82 hours and after the temperature returned to room temperature, 10 volumes of water were added thereto. The mixture was vacuum filtered and the recovered product was washed with water and dissolved in a liter of chloroform. The solution was washed with water, with an aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure at less than 40° C. The residue was added to a mixture of 320 ml of dioxane, 2 liters of absolute ethanol and 200 ml of sodium hydroxide solution and the mixture was stirred at room temperature for 24 hours and was evaporated to dryness under reduced pressure at not more than 40° C. The residue was empasted 5 times with 60 ml of a 1-7 dioxane-ethanol mixture and was then added to a liter of water and a liter of chloroform. The pH of the mixture was adjusted to 2 by stirring with sufficient N hydrochloric acid and the decanted organic phase was washed with water and with aqueous saturated sodium chloride solution, was dried and evaporated to dryness under reduced pressure at less than 40° C. The residue was suspended in 300 ml of dichloroethane and the mixture was heated at 50° C. for 15 minutes and was then vacuum filtered at room temperature. The product was successively rinsed with dichloroethane, isopropyl ether and ether and dried to a constant weight to obtain 40 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(2-tritylaminoethoxyimino)acetic acid in the form of a powder melting at 176° C.
Reaction SMILES: [H-].[Na+].[CH2:3]1COCC1.[CH2:8]([O:10][CH2:11][CH2:12][CH2:13][NH:14][CH:15]=[O:16])[CH3:9].CI>CCCCCC>[CH2:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:3])[CH:15]=[O:16])[CH3:9]
Reactant: CCOCCCNC=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CI
Product: CCOCCCN(C)C=O
Reaction time: 0.5 h

Procedure:
NaH (washed with n-hexane in advance, 2.01 g, 76.24×1.1 mmol) was added to a dry THF (100 mL) solution of N-(3-ethoxypropyl)formamide (10.00 g, 76.24 mmol) under an argon atmosphere with ice-bath cooling, and stirred for 30 minutes. A dry THF (10 mL) solution of methyl iodide (5.7 mL, 76.24×1.2 mmol) was added dropwise to the reaction mixture under an argon atmosphere with ice-bath cooling, it was then stirred for 30 minutes, and further stirred at room temperature for 90 minutes. NaH (washed with n-hexane in advance, 0.20 g, 76.24×0.1 mmol) was again added and it was stirred at room temperature for 1 hour. After cooling with ice-bath, n-hexane (100 mL) was added to the reaction mixture and it was stirred for 1 hour, and insoluble materials were then removed by filtration with a pad of Celite. A residue obtained by concentrating the filtrate to dryness was purified by vacuum distillation (fraction at 0.6 kpa, 91° C. collected), and FEP (4.17 g, 28.68 mmol, 38%) was obtained as a pale yellow clear liquid.