Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:32])[C:29]([OH:31])=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.OC1C=CC=C[N+]=1[O-].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:32][C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:31]
Reactant: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: [O-][n+]1ccccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
A mixture of (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (250 mg, 0.56 mmol), 2-hydroxypyridine-N-oxide (124 mg, 1.1 mmol), morpholine (0.098 ml, 1.1 mmol), diisopropylethylamine (0.195 ml, 1.1 mmol) and EDCI (214 mg, 1.1 mmol) in DMF (2 ml) was stirred at room temperature for 18 hours. Additional coupling agents were added (1 equivalent) and the mixture was stirred for 2 hours more. The reaction mixture was directly injected on an HPLC column (C18, 5 microns, 20 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient) to give the title compound as a white solid (180 mg, 62%); NMR Spectrum 1.58 (d, 3H), 3.70-3.40 (m, 8H), 5.79 (s, 2H), 5.88 (q, 1H), 7.29 (d, 1H), 7.35 (s, 1H), 7.51 (s, 1H), 7.75 (m, 2H), 7.84 (m, 1H), 8.10 (s, 1H), 8.51 (s, 2H), 9.04 (s, 1H), 11.12 (br s, 1H); Mass spectrum: MH+ 516.
Reaction SMILES: O[CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:12]([NH:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:11]1=[O:46])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].N1C=CC=CC=1.S(Cl)([Cl:55])=O>C1COCC1.O1CCOCC1.O1CCOCC1>[Cl:55][CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:12]([NH:26][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:11]1=[O:46])[C:3]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4]
Reactant: CC(C)(C)OC(=O)C(O)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCOC1CCCCO1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCOC1CCCCO1
Yield: 97.8 %

Procedure:
1-(1-Hydroxy-1 -t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(4-tetrahydropyranyloxybut-2-ynylthio)azetidin- 2-one (646mg) was dissolved in dry THF/dioxan (1:1, 12ml) and the solution, under nitrogen, was cooled to -15°. Dry pyridine (227mg) in dioxan (1ml) was then added followed by the dropwise addition of thionyl chloride (357mg) in 1:1 tetrahydrofuran/dioxan (5ml) over 1-2 minutes. After a further 15 minutes the precipitated solid was filtered off and the filtrate evaporated to dryness. Dry toluene was added and the solution decanted from any solid, and evaporated to give 1-(1-chloro-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(4-tetrahydropyranyloxybut-2-ynylthio)azetidine-2-one as an amorphous solid (650mg) after drying overnight in vacuo.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH2:40])[CH:34]=1>>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH:40][CH2:39][C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Yield: 49.7 %

Procedure:
Method E. Reaction of oxalyl chloride (61 λL, 0.70 mmol) and benzoic acid 29 (204 mg, 0.47 mmol) with subsequent couping to 3-pyridinylmethylamine (53 λL, 0.52 mmol) gave benzamide 30 (123 mg, 50%) as a white powder: mp (EtOAc) 224-227° C.; 1H NMR δ 9.20 (t, J=5.9Hz, 1 H, CONH), 8.57 (d, J=1.7Hz, 1 H, H-2′), 8.47 (dd, J=4.7, 1.6Hz, 1 H, H-6′), 8.00 (d, J=8.6Hz, 2 H, H-2, H-6), 7.88 (d, J=8.6Hz, 2H, H-3, H-5), 7.85 (ddd, J=8.6, 2.3, 1.9Hz, 2 H, H-2″, H-6″), 7.70-7.76 (m, 3H, H-4′, H-3″, H-5″), 7.36 (ddd, J=7.8, 4.7, 0.6Hz, 1 H, H-5′), 4.73 (s, 2 H, CH2SO2), 4.51 (d, J=5.9Hz, 2 H, CH2N), 2.22 (s, 3 H, CH3); 13C NMR δ 165.5, 158.1, 150.0, 148.9, 148.1, 137.8, 135.5, 135.2, 134.9, 132.3 (2), 130.4 (2), 128.8, 128.2, 128.1 (2), 125.7, 125.4 (2), 123.5, 52.8, 40.5, 9.7; MS m/z 526.1 (MH+, 100%), 528.1 (MH+, 100%). Anal. calcd for C24H20BrN3O4S.½H2O: C, 52.95; H, 4.07; N, 7.72. Found: C, 52.74; H, 3.67; N, 7.60%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[N:3][CH:2]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccncn1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccncn1)N1CCN(c2nc(-c3ccccc3)ns2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl pyrimidin-4-ylcarbamate (200 mg, 0.739 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (182 mg, 0.739 mmol), diisopropylethylamine (0.258 ml, 1.48 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (110 mg, 40.7%) as a solid.
Reaction SMILES: Cl[CH2:2][CH:3](Cl)[CH3:4].[CH3:6][NH2:7].[C:8](=[O:10])=[O:9]>>[CH3:6][N:7]1[CH:3]([CH3:4])[CH2:2][O:9][C:8]1=[O:10].[CH3:6][N:7]1[CH2:2][CH:3]([CH3:4])[O:9][C:8]1=[O:10]
Reactant: CC(Cl)CCl
Reactant: CN
Reactant: O=C=O
Product: CC1CN(C)C(=O)O1
Product: CC1COC(=O)N1C
Temperature: 160 °C

Procedure:
1.10 g of 1,2-dichloropropane and 7.18 g of a 40% methylamine aqueous solution were charged in a 20 ml pressure vessel made of SUS316 and 2.11 g of a carbon dioxide gas was absorbed under a pressure of about 0.5 MPa, followed by heating at 160° C. for 4 hours. As a result, 3,4-dimethyl-1,3-oxazolidin-2-one and 3,5-dimethyl-1,3-oxazolidin-2-one were obtained in a total yield of 64% and 1,3,4-trimethylimidazolidin-2-one was obtained in a 23% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].[CH3:44][C:45]1([CH3:55])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:48][NH:47][CH2:46]1>>[CH2:39]([N:34]([CH2:35][CH2:36][CH2:37][CH3:38])[C:33]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])=[CH:13][C:9]=2[C:10]([N:47]2[CH2:46][C:45]([CH3:55])([CH3:44])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:48]2)=[O:11])[N:4]=1)=[O:43])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Reactant: CC1(C)CNCc2ccccc21
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C(C)(C)C2)c(C)c1Cl
Yield: 35.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 93B, 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 32 mg, 0.051 mmol) and 4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline (Milestone Pharmtech, 9 mg, 0.056 mmol) were converted to the title compound (14 mg, 34%) following purification by preparative HPLC. 1H NMR (DMSO-d6, 1:1 mixture of amide rotamers) δ 8.64 (s, 1H), 8.20 (d, J=7.7 Hz, 1H), 8.14-7.90 (m, 5H), 7.78-7.59 (m, 3H), 7.36 (t, J=7.7 Hz, 1H), 7.26-7.13 (m, 2H), 7.11-7.02 (m, 0.5H), 6.99-6.89 (m, 0.5H), 4.85-4.20 (m, 2H), 3.58 (br s, 0.5H), 3.51-2.98 (m, 5H), 2.57-2.52 (m, 0.5H), 2.24 (s, 1.5H), 2.18 (s, 1.5H), 1.43-0.94 (m, 14H), 0.82 (t, J=7.3 Hz, 1H), 0.74 (t, J=7.3 Hz, 2H), 0.69 (t, J=7.4 Hz, 1.5H), 0.64 (t, J=7.4 Hz, 1.5H); MS(ESI+) m/z 768.3 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[N:23]([N:37]=[CH:38][N:39]=4)[C:24]([C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[C:32](=[O:36])[NH:31][CH2:30]5)=[CH:25][N:26]=3)=[CH:16][CH:15]=2)[C:10](=[O:40])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[O:40]=[C:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]2[C:22]3[N:23]([N:37]=[CH:38][N:39]=3)[C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[C:32](=[O:36])[NH:31][CH2:30]4)=[CH:25][N:26]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(-c4ccc5c(c4)CNC5=O)n4ncnc34)cc2)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2cc(-c3cnc(Nc4ccc(N5CCNCC5=O)cc4)c4ncnn34)ccc21
Yield: 86.3 %

Procedure:
A solution of 3-oxo-4-{4-[5-(1-oxo-2,3-dihydro-1H-isoindol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (59 mg, 0.1 mmol) in 3:1 DCM:TFA (1.2 mL) is stirred at room temperature for 1 hour. The reaction mixture is diluted with DCM and basified with sat. NaHCO3. The aqueous layer is extracted with DCM (3×) and the organic layers are combined, dried over MgSO4, filtered and concentrated under vacuum to afford the title compound as a yellow solid (38 mg, 86%). 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 3.07 (2H, m), 3.44 (2H, s), 3.64 (2H, m), 4.50 (2H, s), 7.32 (2H, d), 7.83 (1H, d), 8.04-8.10 (4H, m), 8.22 (1H, s), 8.70 (1H, br s), 8.74 (1H, s), 10.25 (1H, s). LCMS: Rt 7.17 min (93.7%), m/z (APCI) 441 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.[CH2:33]([N:35]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.CN>O.C(N(CC)CC)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH:35][CH3:33])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (800 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (500 mg), 1-hydroxybenzotriazole (350 mg) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 30 min. Then triethylamine (440 mg) and methylamine hydrochloride (230 mg) were added to the mixture. The whole was stirred at room temperature for 20-h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were washed with ethyl acetate-hexane to give the title compound (540 mg, 67%) as pale yellow crystals. The crystals were recrystallized from acetone-hexane to give colorless prisms. MS 475 (MH+). mp 201-202° C.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][C:6]#[N:7])C.[NH2:11][C:12]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:20][C:18]1[CH:19]=[C:12]2[C:13]([CH:14]=[C:5]([C:6]#[N:7])[CH:4]=[N:11]2)=[CH:16][CH:17]=1
Reactant: Nc1cc(Br)ccc1C=O
Reactant: CCOC(CC#N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cnc2cc(Br)ccc2c1
Yield: 75.1 %

Procedure:
A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by flash chromatography (0-3% methanol in dichloromethane) followed by trituration in diethyl ether provided the title compound (1.75 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (dd, J=8.72, 1.89 Hz, 1 H) 8.08 (d, J=8.84 Hz, 1 H) 8.38 (d, J=2.02 Hz, 1 H) 9.13 (d, J=1.52 Hz, 1 H) 9.21 (d, 1 H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16](=[O:21])[C:17]([O:19]C)=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[Li+].[OH-]>O.CO.O1CCCC1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([C:16](=[O:21])[C:17]([OH:19])=[O:18])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: COC(=O)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(C(=O)C(=O)O)cc(C(C)(C)C)c1O

Procedure:
3,5-Bis(1,1-dimethylethyl)-4-hydroxy-α-oxo-benzeneacetic acid, methyl ester (20.0 g, 68.4 mmol) and LiOH (3.2 g, 439.1 mmol) are combined in 125 mL of a water-methanol-tetrahydrofuran mixture (1:1:1). The reaction warms to ca 50° C. and is maintained at this temperature using a heating bath for 5 hours under nitrogen atmosphere. The reaction is poured onto ice water and extracted with diethyl ether (3×). The cold aqueous layer is acidified with aqueous 12N HCl and extracted with diethyl ether (3×). The combined ethereal layers from the second extraction are washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo to give an oil. Crystallizing from diethyl ether/pentane gives 14.0 g of a first crop (mp 125°-126° C.) and 2.7 g as a second crop (mp 124°-125.5° C.). The total yield is 16.7 g (19.0 g theor., 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[C:5]([OH:10])=[C:4]([CH2:11]O)[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>Cl.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][C:18]2[CH:19]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=2[OH:20])[C:5]([OH:10])=[C:6]([CH2:8][C:18]2[CH:19]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=2[OH:20])[CH:7]=1
Reactant: OCc1cc(Cl)cc(CO)c1O
Reactant: Oc1ccc(F)cc1
Agent: Cl
Solvent: c1ccccc1
Product: Oc1ccc(F)cc1Cc1cc(Cl)cc(Cc2cc(F)ccc2O)c1O

Procedure:
A mixture of 4-chloro-2,6-bis(hydroxymethyl)phenol (4.8 g), 4-fluorophenol (16.0 g), benzene (25 ml) and hydrochloric acid (5 drops) was heated on a boiling water bath until all the benzene had evaporated. On cooling the mixture deposited colourless crystals of 4-chloro-2,6-bis(5-fluoro-2-hydroxybenzyl)phenol (11.9 g), mp 228° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:27][CH3:28])=[C:4]([CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([CH2:12][CH2:13][CH:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]4)=[C:3]([O:27][CH3:28])[C:2]([F:1])=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1c(F)cc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1c(F)cc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of tert-butyl 4-[2-(5-fluoro-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperidine-1-carboxylate (0.0245 g, 0.0623 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0100 g, 0.0685 mmol) and piperidine (0.100 mL, 1.01 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(2{-2-[(1H-indazol-3-yl)methylene]-5-fluoro-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperidine-1-carboxylate (0.0231 g, 71%).
Reaction SMILES: [K].[CH3:2][CH2:3][O:4][C:5]([CH:7]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8]1)=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].[C:23]1(C)C=CC=C[CH:24]=1>>[C:5]([C:7]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:8][CH2:9][CH2:10][C:11]1=[O:12])([O:4][CH2:3][CH3:2])=[O:6]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: Cc1ccccc1
Reactant: O=C(O)CCCCCCBr
Agent: [K]
Product: CCOC(=O)CCCCCCC1(C(=O)OCC)CCCC1=O

Procedure:
Under agitation, 500 g. of potassium salt of the ethyl ester of 2-oxocyclopentanecarboxylic acid is added to a boiling solution of 550 g. of the ethyl ester of 7-bromoenanthic acid in 6 l. of toluene; the mixture is further refluxed and, after one hour, another 250 g. of the potassium salt of the ethyl ester of 2-oxocyclopentanecarboxylic acid is added thereto. The reaction mixture is refluxed for another 24 hours, filtered after cooling, the solvent is distilled off, the residue is diluted with 3 l. of ether, washed with water, dried over Na2SO4, and the solvent is distilled off. After fractionation of the residue, 2-carbethoxy-2-(6-carbethoxyhexyl)-cyclopentanone is obtained as a colorless oil, b.p. = 165° (0.3 mm. Hg).
Reaction SMILES: [SH:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]([CH3:16])([SH:15])[CH3:14].Br[CH2:20][CH2:21][CH2:22][CH3:23].[H-].[Na+].CCCCCC>O1CCCC1.C(OCC)(=O)C>[CH2:20]([S:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]([SH:15])([CH3:16])[CH3:14])[CH2:21][CH2:22][CH3:23]
Reactant: CC(C)(S)CNc1ccccc1NCC(C)(C)S
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
1,2-Bis (2-mercapto-2-methylpropylamino)benzene (0.17 g, 6.1 ×10 -4 mol, 120 M %) and 0.07 g (5.1×10-4 mol, 100 M %) 1 -bromobutane were dissolved in 25 ml tetrahydrofuran (freshly distilled over Na). Sodium hydride (0.03 g, 6.25×10-4 mol, 102 M %) was then added. The mixture was stirred at room temperature under nitrogen for 3 hours. The reaction mixture was worked up as in Example 40. The product was isolated by radial chromatography on 1 mm silica plate, using hexane:ethyl acetate as the eluting solvent, giving 40 mg (23% yield) 2-(2-butylthio-2-methylpropylamino]-1-(2-mercapto-2-methylpropylamino)benzene as a yellow oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=1.O>CN(C)C=O>[CH3:37][C:32]1[C:31]([CH2:30][O:3][C:4]2[CH:28]=[CH:27][C:7]([CH2:8][N:9]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]3)=[CH:6][CH:5]=2)=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: Cc1ncccc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3C)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 3-Chloromethyl-2-methylpyridine (212 mg) was added to the mixture, which was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(2-methyl-3-pyridylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (581 mg, yield: 85%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][C@H:7]2[CH2:9][C@@H:4]1[C:5](=[O:10])[O:6]2)[CH3:2].[NH:11]([C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]2=[N:17][CH:18]=1)[NH2:12].C[Al](C)C.Cl>O1CCOCC1>[CH2:1]([C@@H:3]1[CH2:8][C@H:7]([OH:6])[CH2:9][C@@H:4]1[C:5]([NH:12][NH:11][C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]2=[N:17][CH:18]=1)=[O:10])[CH3:2]
Reactant: CC[C@@H]1C[C@H]2C[C@@H]1C(=O)O2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](O)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one (0.835 g, 5.96 mmol) in 1,4-dioxane (12 mL) was added 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (step D, 1.810 g, 5.96 mmol). The reaction mixture was heated at about 80° C. for about 16 h then cooled to ambient temperature. 1,4-Dioxane (25 mL) and trimethylaluminum (2 N in toluene, 9 mL, 18 mmol) were added sequentially. The reaction mixture was stirred at ambient temperature for about 30 min then HCl (1 N aqueous, 50 mL) was added dropwise and the reaction mixture was stirred for about 30 min. The layers were separated and the aqueous portion was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (10 mL), saturated aqueous NaHCO3 (15 mL), brine (15 mL) and dried over anhydrous MgSO4, filtered, and coned under reduced pressure. The residue was purified using silica gel chromatography (40 g) eluting with 100% EtOAc to give (1S,2R,4S)-2-ethyl-4-hydroxy-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide (1.887 g, 71%): LC/MS (Table 1, Method b) Rt=2.05 min; MS m/z: 444 (M+H)+.