Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li].[Cl:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[C:11]1=[O:22].[NH4+].[Cl-].[CH3:25][CH2:26][O:27][C:28]([CH3:30])=[O:29]>C1COCC1>[CH2:26]([O:27][C:28](=[O:29])[CH2:30][C:11]1([OH:22])[C:12]2[C:17](=[CH:16][C:15]([O:20][CH3:21])=[CH:14][CH:13]=2)[CH2:18][CH2:19][CH:10]1[Cl:9])[CH3:25]
Reactant: COc1ccc2c(c1)CCC(Cl)C2=O
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)c2ccc(OC)cc2CCC1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of EtOAc (7.2 ml, 73.96 mmol) in THF (20 ml) is slowly added under an atmosphere of argon at −78° C. to a solution of lithium diisopropylamine (prepared from 10.5 ml of diisopropylamine (73.96 mmol) and 46.2 ml of 1.6 M n-BuLi in hexane (73.96 mmol)) in THF (20 ml). After stirring at −78° C. for 30 minutes, a solution of 2-chloro-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (7.79 g, 36.98 mmol) in THF (20 ml) is slowly added during 30 minutes. The reaction mixture is stirred at −78° C. for 24 h. TLC analysis indicates complete conversion of starting material. The reaction mixture is diluted with EtOAc and poured into a sat aqueous solution of NH4Cl. The organic layer is separated and washed with brine. After drying over Na2SO4, the solvent is removed. Purification by FCC (hexane/EtOAc 920:80 to 880:120) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.22 (t, J=9 Hz, 3H), 2.33-2.41 (m, 2H), 2.80-3.12 (m, 4H); 3.12 (s, 1H), 3.78 (s, 3H), 4.12 (q, J=9 Hz, 2H), 5.01-5.04 (m, 1H), 6.60-6.62 (m, 1H), 6.78-6.82 (m, 1H), 7.52 (d. J=10 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([Cl:16])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:17]I.[H-].[Na+]>CN(C=O)C>[CH3:17][N:13]1[CH:12]=[N:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)=[N:15][CH:14]1[Cl:16]
Reactant: CI
Reactant: Fc1ccc(Nc2ncnc(Cl)n2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C=NC(Nc2ccc(F)c(Cl)c2)=NC1Cl
Reaction time: 3 h

Procedure:
To a mixture of (3-chloro-4-fluoro-phenyl)-(4-chloro-[1,3,5]triazin-2-yl)-amine (1.7 g, 6.56 mmol) and MeI (1.5 mL) in DMF (20 mL) under a nitrogen atmosphere was added NaH (60% dispersion, 0.53 mg, 13.3 mmol). The mixture was stirred for 3 h. The reaction was quenched by the addition of water and the organic extracts are taken up in EtOAc, dried over anh. MgSO4 and concentrated under reduced pressure. The crude product was purified via medium pressure liquid chromatography using CH2Cl2 as the solvent system to give N-methyl-2-chloro-4-(3-chloro-4-fluoroanilino)-1,3,5-triazine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:8][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)(=[O:19])=[O:18]
Reactant: Cn1ccnc1CO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1ccnc1COS(C)(=O)=O

Procedure:
A solution of (1-methyl-1H-imidazol-2-yl)-methanol (Bionet Research, 66 mg, 0.59 mmol), triethylamine (0.25 mL, 0.89 mmol), and methanesulfonyl chloride (69 μL, 0.89 mmol) in 5 mL THF were processed as described in Example 1C to give the crude material which was used directly in the next reaction.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:11]([NH:13][C@H:14]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([NH:46][C@H:47]([C:54]([NH:56][C@H:57]([C:67]([O:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:68])[CH2:58][CH2:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:55])[CH2:48][O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:45])[CH2:38][O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:35])[C@@H:27]([CH3:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:24])[CH2:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3].[NH:76]([C:111]([O:113][C:114]([CH3:117])([CH3:116])[CH3:115])=[O:112])[C@H:77]([C:84]([NH:86][C@H:87]([C:96]([NH:98][C@H:99]([C:101](ON1C(=O)CCC1=O)=[O:102])[CH3:100])=[O:97])[CH2:88][C:89](=[O:95])[O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:85])[CH2:78][O:79][C:80]([CH3:83])([CH3:82])[CH3:81].CCN(CC)CC.O>CN(C=O)C>[NH:76]([C:111]([O:113][C:114]([CH3:115])([CH3:117])[CH3:116])=[O:112])[C@H:77]([C:84]([NH:86][C@H:87]([C:96]([NH:98][C@H:99]([C:101]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:11]([NH:13][C@H:14]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([NH:46][C@H:47]([C:54]([NH:56][C@H:57]([C:67]([O:69][C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=1)=[O:68])[CH2:58][CH2:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:55])[CH2:48][O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:45])[CH2:38][O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:35])[C@@H:27]([CH3:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:24])[CH2:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:12])[CH:8]([CH3:9])[CH3:10])=[O:5])[CH3:3])=[O:102])[CH3:100])=[O:97])[CH2:88][C:89](=[O:95])[O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:85])[CH2:78][O:79][C:80]([CH3:81])([CH3:82])[CH3:83]
Reactant: C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C
Reaction time: 17 h

Procedure:
A solution of H-Ala-Val-Asp(OtBu)-Thr(tBu)-Ser(tBu)-Ser(tBu)-Glu(OtBu)-OC6H5 0.708 mmol) in DMF (34 mL) was cooled to 0° and Boc-Ser(tBu)-Asp(OtBu)-Ala-OSu 510 mg, 0.85 mmol, 1.2 eq) added. Stirring proceeded at 0° for 30 min and 25° for 17 h while the pH was maintained at ~8 by addition of Et3N. Water (150 mL) was added with stirring and the product was collected by filtration and dried in vacuo. The solid was washed with CH3OH (2×20 mL) and dried in vacuo. Yield: 586 mg (53.3%); mp >250°; [α]D25 -23.06° (c 1, TFE); Rf 0.51 (CHCl3 :MeOH:AcOH; 80-2-0.4); Rf 0.72 (CHCl3 :MeOH:AcOH; 80-5-2). Anal. calc. for C76H131N10O23 (1552.93): C, 58.78; H, 8.50; N, 9.01. Found: C, 58.65; H, 8.32; N, 8.93.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][C:27]([C:29]5[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=5)=[CH:28][N:23]4[N:22]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.O[N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[N:40]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[N:39]1([O:34][C:33](=[O:35])[C:32]2[CH:31]=[CH:30][C:29]([C:27]3[N:26]=[C:24]4[N:23]([CH:28]=3)[N:22]=[C:21]([C:18]3[CH:17]=[CH:16][C:15]([N:12]5[CH2:11][CH2:10][CH:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:14][CH2:13]5)=[CH:20][CH:19]=3)[S:25]4)=[CH:37][CH:36]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[N:40]1
Reactant: On1nnc2ccccc21
Reactant: COCCCCCOC1CCN(c2ccc(-c3nn4cc(-c5ccc(C(=O)O)cc5)nc4s3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COCCCCCOC1CCN(c2ccc(-c3nn4cc(-c5ccc(C(=O)On6nnc7ccccc76)cc5)nc4s3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of 4-[2-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (1.28 g) and 1-hydroxybenzotriazole (465 mg) in dichloromethane (50 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (943 mg), and the mixture was stirred overnight at ambient temperature. The reaction mixture was evaporated in vacuo. To the resulting precipitate was added water (50 ml), and the solid was washed with water and IPE (50 ml) and dried under reduced pressure for 3 hours to give 4-[2-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]imdazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid benzotriazol-1-yl ester (1.26 g).
Reaction SMILES: [CH:1]([N:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[C:27]([CH2:38][O:39][CH3:40])[CH:26]=3)[O:22][N:21]=2)[CH:15]=1)[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7])([CH3:3])[CH3:2].O1CCOCC1.[ClH:47]>>[ClH:47].[CH:1]([N:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[C:27]([CH2:38][O:39][CH3:40])[CH:26]=3)[O:22][N:21]=2)[CH:15]=1)[CH2:5][C:6]([OH:8])=[O:7])([CH3:3])[CH3:2]
Reactant: COCc1cc(-c2nc(-c3cccc(CN(CC(=O)OC(C)(C)C)C(C)C)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Solvent: C1COCCO1
Product: COCc1cc(-c2nc(-c3cccc(CN(CC(=O)O)C(C)C)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Tert-butyl N-isopropyl-N-(3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycinate (58 mg, 0.11 mmol) was dissolved in a 4N solution of HCl in dioxane (1.34 ml, 5.35 mmol). The reaction mixture was stirred at RT for 36 hours, and then concentrated under vacuum. The crude product was suspended in ACN and the precipitate was filtered off to give the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 9.60 (br s, 1H), 8.45 (m, 1H), 8.34 (m, 1H), 8.23-8.15 (m, 2H), 7.92-7.85 (m, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.40-7.26 (m, 3H), 7.18-7.12 (m, 1H), 4.46 (s, 2H); 4.23 (d, J=12.8 Hz, 1H), 4.17 (d, J=12.8 Hz, 1H), 4.18-3.85 (m, 2H), 3.81-3.58 (m, 1H), 3.26 (s, 3H), 2.04 (s, 3H), 1.34 (d, J=6.4 Hz, 6H). LC/MS (Method B): 484.3 (M−H)−, 486.3 (M+H)+. HPLC (Method A) Rt 4.67 min (Purity: 100%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:26]2[C:25](=[O:31])[CH2:24][C@@:23]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:22])[C:13](=[CH2:21])[CH2:14]N2CCOCC2)[CH2:3]1>[Pd].C(OCC)(=O)C>[CH3:14][CH:13]([CH3:21])[C:12](=[O:22])[C@@H:11]1[C@:23]2([CH3:32])[C@H:8]([C@H:7]3[C@H:26]([C:25](=[O:31])[CH2:24]2)[C@:27]2([CH3:30])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:29][CH2:28]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: C=C(CN1CCOCC1)C(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 44.3 %

Procedure:
3α-Hydroxy-21-methylene-21-morpholinomethyl-5α-pregnane-11,20-dione (500 mg) was hydrogenated over 10% palladium on carbon (50 mg) in ethyl acetate. The catalyst was filtered off and the filtrate evaporated to a white foam. The foam was purified by preparative t.l.c. (ethyl acetate/petrol) to give title compound (180 mg) as a white foam [α]D + 133° (c, 1.02).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([O:18][CH3:19])=[C:11](Cl)[CH:12]=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.C([NH:30][CH2:31][CH2:32][CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)(OC(C)(C)C)=O>>[NH2:30][CH2:31][CH2:32][CH:33]1[CH2:37][CH2:36][N:35]([C:11]2[CH:12]=[CH:13][N:14]3[C:9]([C:10]=2[O:18][CH3:19])=[C:8]([CH:20]2[CH2:21][CH2:22]2)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]3=[O:16])[CH2:34]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(OC)c(Cl)ccn2c1=O
Reactant: CC(C)(C)OC(=O)NCCC1CCNC1
Product: COc1c(N2CCC(CCN)C2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12

Procedure:
A series of procedures similar to Example 1 above is carried out, using Ethyl-8-chloro-1-cyclopropyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate (Precursor B) and 3-(N-boc-aminoethyl)pyrrolidine (Precursor D) as the starting materials.
Reaction SMILES: [Cl:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([S:11][CH3:12])[CH3:10])=[CH:5][N:4]=1.[N:15]#[C:16][NH2:17].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[Cl:1][C:2]([F:13])([F:14])[C:3]1[N:4]=[CH:5][C:6]([CH:9]([S:11]([CH3:12])=[N:17][C:16]#[N:15])[CH3:10])=[CH:7][CH:8]=1
Reactant: N#CN
Reactant: CSC(C)c1ccc(C(F)(F)Cl)nc1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: C1CCOC1
Product: CC(c1ccc(C(F)(F)Cl)nc1)S(C)=NC#N
Reaction time: 1 h
Yield: 46.7 %

Procedure:
To a stirred solution of 2-[chloro(difluoro)methyl]-5-[1-(methylthio)-ethyl]pyridine (E) (0.32 g, 1.35 mmol) and cyanamide (0.058 g, 1.35 mmol) in THF (7 mL) was added iodobenzene diacetate (0.44 g, 1.35 mmol) in one portion at 0° C. and the resulting mixture was stirred at this temperature for 1 hr and then at room temperature for 2 hr. The solvent was then removed under reduced pressure and the resulting mixture was dissolved in CH2Cl2, washed with half-saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified on silica gel using 50 percent acetone in hexane to give 0.175 g of (1-{6-[chloro-(difluoro)methyl]pyridin-3-yl}ethyl)(methyl)-λ4-sulfanylidenecyanamide (F) as light-yellow oil in 48 percent yield. 1H NMR (300 MHz, CDCl3) δ 8.71 (d, J=1.8 Hz, 1H), 7.91 (dd, J=8.4, 1.8 Hz, 1H) 7.78 (d, J=8.4 Hz, 1H), 4.42 (q, J=6.9 Hz, 1H), 2.64 (s, 3H), 1.92 (d, J=6.9 Hz, 3H); LC-MS: mass calcd for CHH10ClF2N3S [M+1]+ 278. Found 278.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=CC=3S[C:3]=12.[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH2:20].Cl.N1C=CC=CC=1>CO>[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:16][CH:15]=[CH:14][C:3]=12
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: N#Cc1cnc2ccccc2c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of 250 mg (1.02 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, 530 mg (3.27 mmol) of 2,4-dichloroaniline and 112 mg of pyridine hydrochloride is heated until no 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile remained as measured by thin layer chromatography. The reaction mire is cooled to room temperature and the solid is treated with methanol and then partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the solid is collected by filtration to give 225 mg (66%) of a yellow solid. An analytical sample is obtained by column chromatography, eluting with 6:1 hexane/ethyl acetate, to provide a fight yellow solid, mp 260–262° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([CH2:35][OH:36])=[CH:4]1)[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([CH:35]=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(CO)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c(F)c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCn1cc(C=O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c(F)c21
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 65.3 %

Procedure:
To a yellow solution of 1-ethyl-8-fluoro-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one (10 g, 20.26 mmol) in Dichloromethane (DCM) (100 mL) was added manganese dioxide (17.62 g, 203 mmol), and the mixture was stirred at 25° C. for 6.5 h. LCMS indicated completion of the reaction. The solid was filtered off through Celite and washed with DCM, the filtrate was concentrated to afford 1-ethyl-8-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (6.5 g, 13.22 mmol, 65.3% yield) as a yellow solid that was used in the next step without further purification. LCMS (M+H)+: 492.2.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:29])=[C:6]([Cl:28])[C:7]([Cl:27])=[C:8]([CH:26]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])[CH:12]=1)=[O:10])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)Cl>[Cl:27][C:7]1[C:8]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([S:18]([N:21]=[CH:22][N:23]([CH3:24])[CH3:25])(=[O:19])=[O:20])[CH:12]=2)=[CH:26][C:4]2[CH2:1][CH:2]([CH2:3][OH:38])[O:29][C:5]=2[C:6]=1[Cl:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cc(C(=O)c2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)c(Cl)c(Cl)c1O
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1cc(C(=O)c2cc3c(c(Cl)c2Cl)OC(CO)C3)ccc1Cl
Temperature: 35 °C
Reaction time: 1 h

Procedure:
14.7 g (31 mmol) of 5-allyl-4-hydroxy-3'-dimethylaminomethyleneaminosulfonyl-2,3,4'-trichlorobenzophenone are suspended, with exclusion of moisture, in 60 ml of methylene chloride and, while cooling in an icebath, a solution of 7.4 g (43 mmol) of 90% pure metachloroperbenzoic acid in 60 ml of methylene chloride is added dropwise. The mixture is stirred for about one hour in the icebath and then briefly heated to 35° to 40° C., whereupon a clear solution is obtained. After allowing to stand at room temperature overnight, a further 0.7 g of metachloroperbenzoic acid is added, the mixture is stirred at room temperature for 4 hours and then again heated to 35° C. The precipitate is filtered off, washed twice with 10 ml of methylene chloride each time, and then washed several times with aqueous sodium bicarbonate solution until the reaction is alkaline. The organic phase is dried over sodium sulfate, the solvent is distilled off, and the amorphous product is purified by chromatography on silica gel using toluene/ethyl acetate (3:1 to 1:3). After distilling off the solvent and recrystallizing from a little methanol, colorless crystals of melting point 180°-182° C. are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([C:38](=[O:47])/[CH:39]=[CH:40]/[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:22][C:23]([N:25]2[CH2:29][CH2:28][C@H:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26]2)=[O:24])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[NH2:30][C@H:27]1[CH2:28][CH2:29][N:25]([C:23](=[O:24])[CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([O:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:20][CH:19]=2)[C:38](=[O:47])/[CH:39]=[CH:40]/[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Oc3ccccc3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of [(S)-1-(2-{(4-phenoxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamic acid, tert-butyl ester 6 (60 mg) in dichloromethane (6 mL). The reaction mixture was stirred at room temperature for 30 min, and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1M NaOH, (×2), brine, dried (Na2SO4) and evaporated to dryness. The resultant residue was purified by column chromatography on silica gel, eluting with ethyl acetate/methanol/ammonium hydroxide (90:5:5) to give the title compound (10 mg). 1HNMR (300 MHz) (CDCl3) δ 1.6-2.3 (2H, m), 3.15-3.75 (5H, m), 4.40 (2H, m), 6.43 (1H, d, J=16 Hz), 7.02 (2H, d), 7.06 (2H, d), 7.15 (1H, t), 7.25-7.45 (9H, m) and 7.69 (1H, d, J=16 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl[S:21]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)[S:21]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)(=[O:23])=[O:22])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-27 from bis(4-methoxybenzyl)amine and methyl 4-(chlorosulfonyl)-benzoate (Example 5-10c). MS (M−H, 440.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.68 (s, 6H), 4.20 (s, 4H), 6.77 (d, 4H, J=10 Hz), 6.98 (d, 4H, J=10 Hz), 7.92 (dd, 2H J=8 Hz), 8.06 (dd, 2H, J=8 Hz). Elemental analysis: (found): C, 62.45%; H, 5.19%; and N, 3.06%. (theoretical): C, 62.57%; H, 5.25%; and N, 3.17%.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])[CH2:3]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C1COCC1>[CH3:14][S:15]([O:1][CH:2]1[CH2:3][N:4]([C:6](=[O:7])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5]1)(=[O:17])=[O:16]
Reactant: O=C(c1ccccc1)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Yield: 65.8 %

Procedure:
A stirred solution of (3-hydroxyazetidin-1-yl)(phenyl)methanone (13.5 g, 76.2 mmol), methanesulfonyl chloride (12.6 g, 110 mmol) and triethylamine (12.3 g, 121 mmol) in THF (300 ml) was heated at 50° C. for 3 h. Then, the reaction mixture was cooled to room temperature and the resulting precipitate was collected by filtration. The filtrate was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and water and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50:50 to 80:20, ethyl acetate/heptane) provided 1-benzoylazetidin-3-yl methanesulfonate (12.8 g, 66%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17](OS(C(F)(F)F)(=O)=O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:34]([O:36]CCCC)=[CH2:35].Cl>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:34]([C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=1)(=[O:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2CC1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a stirred solution of 3-(tert-butyloxycarbonyl)-7-trifluoromethylsulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (10 g, 25.3 mmol) in anhydrous dimethylformamide (100 ml) under argon at room temperature, was added triethylamine (7.05 ml, 50.6 mmol), butyl vinyl ether (16.4 ml, 126.6 mmol), 1,3-bis(diphenylphosphino)propane (0.412 g, 1 mmol) and palladium acetate (0.202 g, 0.9 mmol) sequentially. The resultant mixture was heated at 85° C. for 1.5 h and cooled to room temperature. 4% Aqueous hydrochloric acid (150 ml) was added and stirring continued for 0.5 h. The reaction mixture was extracted with dichloromethane (3×300 ml) and the combined organics washed with water (4×500 ml), dried (Na2SO4) and evaporated in vacuo to afford a brown gum. Chromatography on silica gel with 0-30% ethyl acetate—hexane gradient elution gave the title compound (5.8 g, 79%) as a colourless solid.