Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:31](ON1C(=O)CCC1=O)=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OC(C)(C)C)=O.[NH2:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51].[CH3:57][N:58]1[C@@H:75]2[CH2:76][C:63]3[CH:64]=[CH:65][C:66]([O:77][CH3:78])=[C:67]4[O:68][C@H:69]5[C:70]([CH2:72][CH2:73][C@@H:74]2[C@:61]5([C:62]=34)[CH2:60][CH2:59]1)=[O:71]>>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:31]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH3:57][N:58]1[C@@H:75]2[CH2:76][C:63]3[CH:64]=[CH:65][C:66]([O:77][CH3:78])=[C:67]4[O:68][C@H:69]5[C:70]([CH2:72][CH2:73][C@@H:74]2[C@:61]5([C:62]=34)[CH2:60][CH2:59]1)=[O:71]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN)C(=O)O

Procedure:
Lys-Lys-Ile-Hydrocodone was prepared by a similar method except the amino acid starting material was Boc-Lys(Boc)-Lys(Boc)-OSu and the conjugate starting material was Ile-Hydrocodone.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([S:16]([Cl:19])(=[O:18])=[O:17])[C:7]=1[OH:20])(=O)C.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[ClH:19].[NH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH:9]=[C:8]([S:16]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[Cl:21])(=[O:17])=[O:18])[C:7]=1[OH:20]
Reactant: NCc1ccccc1Cl
Reactant: CC(=O)NCc1cc(C(C)(C)C)cc(S(=O)(=O)Cl)c1O
Product: CC(C)(C)c1cc(CN)c(O)c(S(=O)(=O)NCc2ccccc2Cl)c1
Product: Cl

Procedure:
This compound is prepared analogously to Examples 11c and 11d from 2-acetamidomethyl-6-chlorosulfonyl-4-(1,1-dimethylethyl)-phenol and o-chlorobenzylamine.
Reaction SMILES: C(Cl)Cl.[Br:4][C:5]1[C:6]([Cl:26])=[CH:7][C:8](F)=[C:9]([S:11]([N:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]2=3)(=[O:13])=[O:12])[CH:10]=1.[CH3:27][O-:28].[Na+].Cl>CO.O>[Br:4][C:5]1[C:6]([Cl:26])=[CH:7][C:8]([O:28][CH3:27])=[C:9]([S:11]([N:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]2=3)(=[O:13])=[O:12])[CH:10]=1
Reactant: C[O-]
Reactant: O=S(=O)(c1cc(Br)c(Cl)cc1F)N1CCCCc2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Cl)c(Br)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of DCM (8 mL) containing 1-(5-bromo-4-chloro-2-fluoro-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine (2.35 g, 5.6 mmol) was added 25% sodium methoxide in methanol (7.5 mL). The resulting suspension was stirred at rt for 3 hrs, followed by repartitioning with DCM (45 mL) and water (50 mL). A 6 N HCl solution was added dropwise until the aqueous layer pH was 7. The organic layer was separated, washed with water (2×30 mL), dried over MgSO4, and evaporated to afford 1-(5-bromo-4-chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine as the pale yellow foam (2.38 g). MS: 430.0 (M+H)+; tR=6.21 min (method 4). NMR (CDCl3), δ, 8.070 (1H, s), 7.130-7.219 (3H, m), 7.025-7.082 (1H, m), 6.761 (1H, d, J=7.5 Hz), 3.868 (3H, s), 3.733 (2H, m), 2.808-2.845 (2H, m), 1.902-1.940 (2H, m), 1.568-1.667 (2H, m).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[C:14]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([CH:33]4[CH2:36][O:35][CH2:34]4)[CH2:29][CH2:28]3)=[CH:25][CH:26]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=O)C.[OH-].[Li+].O>C1COCC1.C(O)(C)C>[OH:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[C:14]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([CH:33]4[CH2:36][O:35][CH2:34]4)[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1
Reactant: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(N4CCN(C5COC5)CC4)nc3)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)nc(Nc2ccc(N3CCN(C4COC4)CC3)nc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
A mixture of 197f (200 mg, 0.30 mmol) and lithium hydroxide (70 mg, 3.0 mmol) in THF (9 mL), i-propanol (6 mL), and water (1 mL) was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and diluted with water (4 mL). It was then extracted with dichloromethane (2×10 mL) and the combined dichloromethane extract was concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 197 (59 mg, 30%) as yellow solid. MS-ESI: [M+H]+ 638. 1H NMR (500 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.70 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.14-8.11 (m, 1H), 7.59 (s, 1H), 7.55 (d, J=5.0 Hz, 1H), 6.82 (d, J=9.5 Hz, 1H), 6.58 (s, 1H), 4.93 (t, J=5.5 Hz, 1H), 4.60-4.54 (m, 3H), 4.48-4.42 (m, 3H), 4.26-4.08 (m, 3H), 3.86 (d, J=12.0 Hz, 1H), 3.54 (s, 3H), 3.44-3.40 (m, overlap, 5H), 2.66-2.53 (m, 2H), 2.46-2.47 (m, 2H), 2.35-2.33 (m, 4H), 1.80-1.68 (m, 4H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C@H:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH2:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)=O)=[CH:9][CH:8]=2)[CH2:4]1.Cl.[NH2:32][OH:33].C([O-])(O)=O.[Na+]>>[CH3:1][O:2][CH:3]1[CH2:4][N:5]([C:7]2[CH:8]=[CH:9][C:10]([C@H:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH2:14]/[C:15](/[C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)=[N:32]\[OH:33])=[CH:11][CH:12]=2)[CH2:6]1
Reactant: NO
Reactant: COC1CN(c2ccc([C@@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC1CN(c2ccc([C@@H](C/C(=N\O)c3ccnc(C)c3)c3ccccc3C)cc2)C1

Procedure:
In analogy to example 1, step 2, from (R)-3-[4-(3-methoxy-azetidin-1-yl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (ESI+): m/z=416.3 ([M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[CH:7]=1.[CH3:22][C:23]([O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32])([CH3:26])[C:24]#[CH:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>N1C=CC=CC=1>[C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([O:27][C:23]([CH3:22])([CH3:26])[C:24]#[CH:25])[CH:29]=4)[CH:21]=[CH:20][CH:19]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: C#CC(C)(C)Oc1cccc(C(=O)O)c1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: C#CC(C)(C)Oc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(C)=O)sc4c3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x), 3-[(1,1-dimethylprop-2-yn-1-yl)oxy]benzoic acid (215 mg, 1.07 mmol) in pyridine (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (407 mg, 1.07 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→0/100), and crystallized from ethyl acetate to give the title compound (181 mg, 70%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[O:12])=[CH:5]2
Reactant: OCc1cc2cc(F)ccc2[nH]1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=Cc1cc2cc(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.9 %

Procedure:
To a stirred solution of crude (5-fluoro-1H-indol-2-yl)methanol 46 (1.55 g, 9.39 mmol) in anhydrous CH2Cl2 (50 mL) at cold-bath temperature (0° C.) was added portionwise pyridinium chlorochromate (PCC) (2.22 g, 10.29 mmol). Reaction was stirred at ambient temperature for 4 hours. Reaction was diluted with CH2Cl2 and filtered through a pad of celite and washed with CH2Cl2. After evaporation of solvent, crude product was silica-column chromatographed (Biotage) using Acetone:Hexane as an eluent to yield 5-fluoro-1H-indole-2-carbaldehyde 47 (0.627 g, 41% yield).
Reaction SMILES: N[C@@H:2]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C@@H:3](O)[CH2:4][CH2:5][CH:6]1[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][CH2:8][S:7]1(=[O:15])=[O:14].N[C@@H:25](CC1CCCCC1)[C@@H](O)CCCC1S(=O)(=O)CCCS1(=O)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[C:62]([N:69]1[C@@](C)(C2CCCCC2)[C@H](CCOS(C)(=O)=O)[O:71][C:70]1([CH3:89])[CH3:88])([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63].S1(=O)(=O)CCCS(=O)(=O)C1>>[C:62]([N:69]1[C@@H:17]([CH2:18][CH:23]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:25]2)[C@H:2]([CH2:3][CH2:4][CH2:5][CH:6]2[S:7](=[O:14])(=[O:15])[CH2:8][CH2:9][CH2:10][S:11]2(=[O:12])=[O:13])[O:71][C:70]1([CH3:88])[CH3:89])([O:64][C:65]([CH3:66])([CH3:67])[CH3:68])=[O:63]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)O[C@@H](CCOS(C)(=O)=O)[C@]1(C)C1CCCCC1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)CCCC1S(=O)(=O)CCCS1(=O)=O
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)CCC1S(=O)(=O)CCCS1(=O)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=S1(=O)CCCS(=O)(=O)C1
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](CCCC2S(=O)(=O)CCCS2(=O)=O)OC1(C)C

Procedure:
In analogy to Example 3, there are obtained from2-[(2S,3S)-3-amino-4-cyclohexyl-2-hydroxy-butyl]-1,3-dithiane 1, 1,3,3-tetroxide or from 2-[(3S, 4S)-4-amino-5-cyclohexyl-3-hydroxypentyl]-1,3-dithiane 1,1,3,3-tetroxide or from 2-[(4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-hexyl ]-1,3-dithiane 1,1,3,3-tetroxide [dihydrochloride, m.p. 209°-210° , FAB 382, obtainable from (4S,5S)-3-BOC-4-cyclohexyl-methyl-5-(2-methansulfonyloxy-ethyl)-2,2-di-methyl-oxazolidine via the corresponding 5-(2-cyanoethyl)-, 5-(2-carboxyethyl)-(m.p. 190° (decomposition)), 5-(2-methoxy-carbonyl-ethyl)-(oil; FAB 384), 5-(3-hydroxy-propyl)-(m.p. 60°-61°; FAB 356) and 5-(3-methanesulfonyloxy-propyl)-compounds (m.p. 63°-64°, FAB 434), react ion of the last mentioned compound with 1,3-dithiane 1,1,3,3-tetroxide to yield 2-[3-((4S,5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl- 5-oxazolidinyl)-propyl]-1,3-dithiane 1,1,3,3-tetroxide (FAB 522) and cleavage with methanolic hydrochloric acid at 25° the following 1,3-dithiane 1,1,3,3-tetroxides:
Reaction SMILES: [C:1]([NH:9][C:10]1[C:53]([Se:54][CH3:55])=[CH:52][N:13]([C@@H:14]2[O:44][C@H:18]([CH2:19][O:20][C:21]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22]3[CH:27]=[CH:26][C:25]([O:30][CH3:31])([O:28][CH3:29])[CH2:24][CH:23]=3)[C@@:16]([Si](C(C)(C)C)(C)C)([OH:17])[CH2:15]2)[C:12](=[O:56])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.CO>ClCCl>[C:1]([NH:9][C:10]1[C:53]([Se:54][CH3:55])=[CH:52][N:13]([C@@H:14]2[O:44][C@H:18]([CH2:19][O:20][C:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])([O:30][CH3:31])[CH2:26][CH:27]=3)[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:56])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1(OC)C=CC(C(OC[C@H]2O[C@@H](n3cc([Se]C)c(NC(=O)c4ccccc4)nc3=O)C[C@@]2(O)[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccccc2)=CC1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COC1(OC)C=CC(C(OC[C@H]2O[C@@H](n3cc([Se]C)c(NC(=O)c4ccccc4)nc3=O)C[C@@H]2O)(c2ccccc2)c2ccccc2)=CC1
Reaction time: 8 h
Yield: 91 %

Procedure:
4-N-benzoyl-5-methylseleno-3′-t-butyldimethylsilyl-5′-O-(4,4-dimethoxytrityl)-2′-deoxycytidine (compound 3) 280 mg (MW 8553, 0.33 mmol) was placed in a flask and dried under high vacuum before it was dissolved in anhydrous THF. The solution was placed in an ice-water bath under dry argon tetra-Butylammonium fluoride 0.44 ml (1M solution in THY, 1.2 eq.) and acetic acid 0.03 ml (1.2 eq.) were injected dropwise simultaneously to make solution pH keep about 7. The reaction mixture was stirred for overnight before it was completed (monitored on TLC, 3% methanol in dichloromethane, Rf=0.35). The crude product was extracted by EtOAc and NaCl solution (sat.) three times, and the combined organic layer was dried over anhydrous MgSO4, followed by filtration and solvent evaporation. The residue was purified on a silica gel column (equilibrated with CH2Cl2) and eluted with a methanol/dichloromethane gradient (0.5-5%) to afford the desired product compound 4225 mg. (yield=91%). 1H-NMR (400 MHz, DMSO) δ: 2.04 (s, 3H, SeCH3), 2.21-2.26 and 2.69-2.76 (2×m, 2H, H-2′), 3.34-3.47 (2×m, 2H, H-5′), 3.79 (s, 6H, 2×OMe), 4.15-4.17 (m, 1H, H-3′), 4.46-4.48 (m, 1H, H-4′), 6.14-6.17 (t, J=6.4 Hz, 1H, H-1′), 6.84-7.79 (m, 18H, arom-H), 8.48 (s, 1H, H-6). 13C NMR (100 MHz, DMSO) δ: 11.02 (SeCH3), 41.99 (C-2′), 55.27 (OMe), 63.11 (C-5′), 72.41 (C-3′), 86.67 (C-4′), 86.94 (arom-C), 87.87 (C-1′), 102.39 (C-5), 113.31 (arom-C), 127.07 (arom-C), 128.04 (arom-C), 128.07 (arom-C), 128.29 (arom-C), 129.68 (arom-C), 129.45 (arom-C), 130.00 (arom-C), 130.92 (arom-C), 132.70 (arom-C), 134.22 (arom-C), 135.47 (NHCO), 144.41 (arom-C), 144.32 (C-2), 150.83 (C-6), 158.69 (C-4), 172.28 (arom-C).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([CH2:24][NH:25][C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=3)[N:29]=[C:28]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[N:27]=2)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[NH2:45][C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1.CCN(CC)CC>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([CH2:24][NH:25][C:26]2[N:27]=[C:28]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[N:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:5]([NH:45][C:46]4[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=4)=[O:11])=[CH:34][CH:33]=3)[N:31]=2)[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CC(CNc2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(CNc2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CCOCC3)n2)C1
Reaction time: 0.25 h
Yield: 29.7 %

Procedure:
To a stirred solution of triphosgene (269 mg, 0.90 mmol) in CH2Cl2 (5 mL) was added 3-{[4-(4-Amino-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester (500 mg, 1.13 mmol) at 25° C. The reaction mixture was stirred for 15 min and 4-aminopyridine (319 mg, 3.39 mmol) and NEt3 (1.56 mL, 11.3 mmol) were added and the reaction mixture was stirred for additional 1 hr. The solvents were removed on a rotary evaporator and the crude mixture was purified by semi-prep-HPLC (TFA-method) to give 3-({4-Morpholin-4-yl-6-[4-(3-pyridin-4-yl-ureido)-phenyl]-[1,3,5]triazin-2-ylamino}-methyl)-azetidine-1-carboxylic acid tert-butyl ester (150 mg, 16% yield); MS (ESI) m/z 562.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:50]=[CH:49][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:45]([O:47]C)=[O:46])[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CCN(CC)CC>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:45]([OH:47])=[O:46])[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:35])=[O:31])=[CH:49][CH:50]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methyl N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-L-phenylalaninate (20 mg, 0.029 mmol) was dissolved in 1.6 ml MeOH and 0.2 ml H2O. Et3N (0.2 ml, 1.44 mmol) was added and the mixture was stirred overnight. The mixture was heated to 80° C. for 7 h. The mixture was purified by preparative HPLC using a C8 column (25×300 mm). A gradient from 20% to 40% MeCN in 0.1 M ammonium acetate was used as mobile phase. The product fraction was concentrated and lyophilized to yield 7 mg (36%). M/z: 688.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([Mg]Br)[CH3:16].[Cl-].[NH4+]>O1CCCC1>[CH2:15]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (10.1 g, 50.7 mmol) in tetrahydrofuran (40 mL) was added dropwise over 30 minutes to a stirred, cooled (0° C.) solution of ethyl magnesium bromide (1.0M in tetrahydrofuran, 50.7 mL, 50.7 mmol) in tetrahydrofuran (30 mL). The mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was poured into saturated aqueous ammonium chloride (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 3:1 isohexane:ethyl acetate, to give the title compound (8.5 g, 73%). m/z (ES+) 230 (M+1).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)[CH2:14][CH2:13]1.[NH3:23].O>C1(C)C=CC=CC=1>[NH2:23][C:15]([CH:12]1[CH2:14][CH2:13]1)=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: N
Reactant: CCOC(=O)CC(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(N)C1CC1
Reaction time: 8 h

Procedure:
1.1 g of p-toluenesulphonic acid are added to 49.9 g (0.32 mol) of ethyl cyclopropylcarbonylacetate in 200 ml of dry toluene and the mixture is saturated with ammonia gas at room temperature with stirring. After allowing to stand overnight, the mixture is boiled under reflux for 8 hours in a water separator, ammonia gas being continuously introduced. The mixture is allowed to cool overnight and is filtered, and the toluene solution is concentrated in vacuo and removed by distillation in a high vacuum up to 65° C. from unreacted starting material. The substance is subsequently found in the residue. Yield: 11.9 g (24% of theory).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](=[O:35])[CH:29]=[C:30]([CH3:34])[O:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](=[O:35])[CH:29]=[C:30]([CH3:34])[O:31]2)=[CH:26][CH:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1cc(=O)c2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(Oc3ccc4c(=O)cc(C)oc4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 100 °C
Yield: 92.1 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (130 mg, 0.4 mmol), (prepared as described for the starting material in Example 10), 7-hydroxy-2-methylchromone (88 mg, 0.5 mmol), (Bull Soc. Chim. Fr. 1995, 132, 233), and potassium carbonate (83 mg, 0.6 mmol) was heated at 100° C. for 1.5 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4), and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (170 mg, 92%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH:8]=O.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH:8]=[C:21]1[S:17][C:18](=[O:23])[NH:19][C:20]1=[O:22]
Reactant: O=C1CSC(=O)N1
Reactant: COCOc1ccc(C=O)cc1OCOC
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COCOc1ccc(C=C2SC(=O)NC2=O)cc1OCOC
Reaction time: 0.03 h

Procedure:
A mixture of 3,4-Bis-methoxymethoxy-benzaldehyde (5 mmol), thiazolidine-2,4-dione (5 mmol), benzoic acid (0.5 mmol), and piperidine (0.5 mmol) in toluene (150 mL) was heated to reflux for 15 h. Upon cooling, to the reaction mixture was added hexane (50 mL). The resulting suspension was gently stirred for 2 min and then allowed to settle. It was then filtrated and the solid was washed with cold benzene. 5-(3,4-Bis-methoxymethoxy-benzylidene)-thiazolidine-2,4-dione was obtained as a yellow solid (yield 92%). 1H-NMR (300 MHz, CDCl3) δ (ppm) 7.81 (s, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.28-7.25(m, 1H), 7.18-7.15 (m, 1H), 5.32 (s, 2H), 5.63 (s, 2H), 3.57 (s, 3H), 3.54 (s, 3H). 13C-NMR (75 MHz) δ (ppm) 168.1, 167.6, 149.8, 147.9, 134.6, 127.7, 126.1, 121.0, 118.8, 116.8, 96.0, 95.5, 56.9, 56.8.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1>CN(C=O)C>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[O:19][CH2:18][CH2:17][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:12][CH:11]=1
Reactant: BrCCOC1CCCCO1
Reactant: Oc1ccc(N2CCOCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(N2CCOCC2)ccc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
4-morpholinophenol (0.358 g, 2 mmol) in DMF (5 mL) was cooled to 0° C. To this solution was added 60% NaH (0.192 g, 4.8 mmol). After the bubbling ceased, 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.501 g, 2.4 mmol) in DMF (2 mL) was added to the above solution. The solution was stirred at room temperature for 2 hours, and partitioned between EtOAc and water. The aqueous layer was extracted with additional EtOAc, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with 7:3 hexanes/EtOAc to give 0.48 g of the title compound (78%).