Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[N:37]1([CH2:43]CO)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:43][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: OCCN1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCN4CCCCC4)cc3C)c2cc1OC
Yield: 56.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-piperidino-1-ethanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (42 mg, yield 51%).
Reaction SMILES: [C:1]([O:4][CH:5]1[O:10][CH:9]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:14])[CH:7]=[CH:6]1)(=O)[CH3:2].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CC>C(OCC)C>[CH2:1]([O:4][CH:5]1[O:10][CH:9]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:14])[CH:7]=[CH:6]1)[CH2:2][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: CC(=O)OC1C=CC(=O)C(C(C)C)O1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOC1C=CC(=O)C(C(C)C)O1
Yield: 92.1 %

Procedure:
In 50 ml of ethyl ether were dissolved 3.96 g of 6-acetoxy-2-isopropyl-2H-pyran-3(6H)-one and 4.84 g of cetyl alcohol with stirring. Into the solution was gradually added 0.1 ml of anhydrous stannic chloride at a temperature of 5 ° to 10° C. The reaction mixture was stirred at room temperature for 7 hours, washed twice with aqueous sodium hydrogencarbonate solution and once with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. By the distillation of solvent was obtained 7.0 g of 6-cetyloxy-2-isopropyl-2H-pyran-3(6H)-one [compound 1] in a yellow viscous oily form.
Reaction SMILES: [NH2:1][C@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH2:7][CH3:8])=[O:4].[P:15](Cl)(Cl)(=[O:27])[O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(Cl)[Cl:31]>>[Cl:31][C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[O:16][P:15](=[N:1][C@H:2]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][CH3:8])=[O:4])=[O:27]
Reactant: ClCCl
Reactant: CCCOC(=O)[C@H](N)c1ccccc1
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Product: CCCOC(=O)[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)c1ccccc1
Yield: 59 %

Procedure:
Using the general procedure for synthesizing naphthyl (amino acid ester) phosphorochloridates the hydrochloride salt of (R)-propyl 2-amino-2-phenylacetate (2.00 g, 8.71 mmol), naphthalen-1-yl phosphorodichloridate (2.27, 8.71 mmol) and TEA (2.42 mL, 17.41 mmol) were combined in 20 mL of dry DCM, to give (2R)-propyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate in 59% yield (2.15 g), as a clear, yellow, thick oil.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:18]1([C:24]([CH:26]=O)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH3-]C#N.[Na+]>CO>[C:18]1([CH:24]([OH:25])[CH2:26][NH:15][C:14]2[CH:16]=[CH:17][C:11]([CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[CH:12][CH:13]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: O=CC(=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(NCC(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
4-(N-Boc-2-aminoethyl)aniline 28 (1.25 g, 5.29 mmole) was dissolved in methanol (30 mL), followed by addition of phenyl glyoxal 24 (0.708 g, 5.28 mmole). The reaction mixture was stirred for 1 h at rt, prior to addition of NaCNBH3 (0.665 g, 10.6 mmole). The final mixture was stirred for 12 h at rt, concentrated, and purified by flash silica column chromatography (2 to 5% MeOH/CH2Cl2) to give N-(2-phenyl-2-hydroxyethyl)-4-(N-Boc-2-aminoethyl)-aniline as a pale yellow oil (1.71 g, 91%): Rf=0.18 in 5% MeOH/CH2Cl2. 1H-NMR (CD3OD, 299.96 MHz): δ (ppm) 7.4–7.25 (m, 5H), 7.0–6.95 (d, 2H), 6.63–6.60 (d, 2H), 4.85–4.79 (dd, 1H), 3.3–3.21 (t, 2H), 3.2–3.15 (m, 2H), 2.64–2.5 (t, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22](C=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH2:36]([NH:38][CH2:39][CH2:40][OH:41])[CH3:37].[C:42](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:42][N:38]([CH2:39][CH2:40][OH:41])[CH2:36][CH3:37])=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Reactant: CC(=O)O
Reactant: CCNCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCO)Cc1ccc2c(c1)cc(-c1cc(OC)c(OS(C)(=O)=O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 59.5 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with 2-(ethylamino)ethanol (0.195 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (212 mg, 1.00 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-{1-(tert-butoxycarbonyl)-5-[N-(2-hydroxyethyl)-N-ethylaminomethyl]indol-2-yl}isoindolinone (68.3 mg, yield 60%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-amino-5-bromo-phenyl)-phenyl-methanone and 102 mg of 4-Ethyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.13 (t, 3H, J=7.6 Hz), 2.54 (q, 2H, 14.8 Hz, 7.6 Hz), 7.08 (d, 2H, J=8.8 Hz), 7.35–7.43 (m, 4H), 7.46 (d, 1H, J=2.4 Hz), 7.55–7.63 (m, 4H), 7.69 (d, 1H, J=8.8 Hz), 9.78 (s, 1H). m/z 445.3 (M++1).
Reaction SMILES: [CH3:1][C:2]([C:6]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH3:15])[CH3:14])[CH2:8][N:7]=1)([S:4][CH3:5])[CH3:3].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[CH3:3][C:2]([C:6]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH3:15])[CH3:14])[CH2:8][N:7]=1)([S:4]([CH3:5])=[O:24])[CH3:1]
Reactant: CSC(C)(C)C1=NCN(C(C)C)C(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CN=C(C(C)(C)S(C)=O)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.5 g of 6-(1-methyl-1-methylmercaptoethyl)-3-isopropyl-3,4-dihydro-2H-1,3,5-oxadiazin-2-one (Example 1) are dissolved in 100 ml of chloroform. The resultant solution is cooled to -10° C., and a solution of 9.5 g of m-chloroperbenzoic acid in 120 ml of chloroform is then added dropwise. The reaction mixture is subsequently stirred for 1 hour at room temperature and then concentrated. The residual crude product is recrystallised from a 1:1 mixture of ethyl acetate and hexane, affording the title compound of the formula ##STR7## with a melting point of 120-°121° C. (compound 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][CH:56]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)[OH:57])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][N:54]([CH2:55][CH:56]([C:58]2[CH:59]=[CH:60][C:61]([Cl:64])=[CH:62][CH:63]=2)[OH:57])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccc(Cl)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.6 %

Procedure:
To a solution of 50 mg (0.26 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 80 mg of TBTU (0.26 mmol) in 4 ml DMF, were added 0.22 ml (1.28 mmol) of N,N-diisopropyl-ethyl amine. After stirring for 5 min at rt, 81 mg (0.26 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 30 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 2:1) to give 60 mg (42%) of a light yellow solid. MS (ISP): 495.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([OH:13])=O)[CH:6]=1)=[O:4].[Cl-].[Mg+2].[Cl-].Cl.[CH2:18]([NH2:20])[CH3:19].C(N(CC)CC)C>ClCCl>[CH2:18]([NH:20][C:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][N:8]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:13])[CH3:19]
Reactant: CCN
Reactant: COC(=O)c1ccnc(C(=O)O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cc(C(=O)OC)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
A mixture of 4-(methoxycarbonyl)picolinic acid (1.00 g, 5.12 mmol) and magnesium chloride (312 mg, 3.28 mmol) in dichloromethane (10 mL) is stirred at room temperature for 0.5 hour. Then, ethylamine hydrochloride (627 mg, 7.69 mmol) and triethylamine (1.07 mL, 7.69 mmol) are added. After stirring at room temperature for 20 hours, the mixture is poured onto water (50 mL). The aqueous phase is extracted with EtOAc (50 mL×2). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (3:11:1) to give 525 mg (49% yield) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:13](O)(=[O:16])[CH2:14][CH3:15]>>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: CCC(=O)O
Reactant: N[C@@H]1CCCc2c(Br)cncc21
Product: CCC(=O)N[C@@H]1CCCc2c(Br)cncc21
Yield: 97 %

Procedure:
In analogy to the procedure described for the preparation of intermediate A-4 [D], (+)-(R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate A-11) and propionic acid gave the title compound as white solid in 97% yield. MS: 283.5 (M+H+, 1 Br).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: OCCNCCO
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N(CCO)CCO)c2c1

Procedure:
The title compound was prepared in analogy to Example 11-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2′-iminodiethanol. MS obsd. (ESI+) [(M+H)+] 442, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J=7.83, 1.26 Hz, 1 H), 7.81 (s, 1 H), 7.83 (s, 1 H), 7.63 (td, J=7.58, 1.26 Hz, 1 H), 7.56-7.39 (m, 2 H), 7.30 (dd, J=8.46, 1.89 Hz, 1 H), 6.78 (s, 1 H), 5.18 (s, 2 H), 4.57 (brs, 2 H), 3.73-3.56 (m, 6 H), 3.56-3.43 (m, 4 H), 2.42 (s, 3 H).
Reaction SMILES: [NH:1]1[C:6](=O)[CH:5]=[CH:4][C:3]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]1=2.O(Cl)[Cl:15].[P+3]>>[Cl:15][C:6]1[N:1]=[C:2]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3]2=[CH:4][CH:5]=1
Reactant: ClOCl
Reactant: O=c1ccc2c([nH]1)CCCCCC2
Agent: [P+3]
Product: Clc1ccc2c(n1)CCCCCC2

Procedure:
5,6,7,8,9,10-Hexahydrocycloocta[b]pyridin-2(1H)-one was heated with excess phosphorus (III) oxychloride at 100° C. for 8 h. The solvent was removed under vacuum. The residue was treated with ice and 1M aqueous potassium carbonate solution, and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. Flash chromatography on silica gel, eluting with a mixture of 96% dichloromethane and 4% methanol gave 2-chloro-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine as a brown oil; 1H NMR (CDCl3, 300 MHz) 7.32 (d, 1H), 7.06 (d, 1H), 2.92 (m, 2H), 2.74 (m, 2H), 1.79 (m, 2H), 1.69 (m, 2H), 1.38 (m, 4H) ppm; 13C NMR (CDCl3, 75 MHz) 161.86, 147.73, 140.19, 135.65, 122.26, 34.33, 32.30, 31.52, 30.83, 26.26, 26.14; MS (ES) 196/198 (M+H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@H:12]1[C:15](=[O:16])[NH:14][C@H:13]1[C:17]([O:19]C)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CO.O>[O:1]([CH2:8][C:9]([NH:11][C@H:12]1[C:15](=[O:16])[NH:14][C@H:13]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1NC(=O)[C@@H]1NC(=O)COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1C(=O)O

Procedure:
Methyl cis-3-phenoxyacetamido-4-oxoazetidine-2-carboxylate is treated with K2CO3 in methanol-water as above to give cis-3-phenoxyacetamido-4-oxoazetidine-2-carboxylic acid, mp 150°-51° from ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[F:9][C:10]1[CH:33]=[CH:32][C:13]([O:14][C:15]2[C:16](=[O:31])[NH:17][N:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:12][CH:11]=1.N>>[Cl:8][C:4]1[CH:3]=[C:2]([N:17]2[C:16](=[O:31])[C:15]([O:14][C:13]3[CH:32]=[CH:33][C:10]([F:9])=[CH:11][CH:12]=3)=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH:19]=[N:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1
Reactant: Clc1cccc(Br)c1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, substituting 1-bromo-3-chlorobenzene in place of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 25 mg, 5.3%). mp 211-213° C. 1H NMR (300 MHz, DMSO-d6) δ 3.30 (s, 3H), 7.15 (d, J=9 Hz, 4H), 7.51-7.64 (m, 3H), 7.71-7.75 (m, 1H), 7.91 (d, J=9 Hz, 2H), 8.06 (d, J=9 Hz, 2H), 8.41 (s, 1H). MS (DCI/NH3) m/z 471 (M+H)+,488 (M+NH4)+. Anal. calc. for C23H16ClFN2O4S.0.5H2O: C, 57.62; H, 3.44; N, 5.85. Found: C, 57.62; H, 3.52; N, 5.48.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([OH:21])([C:15]([NH:17]CC=C)=[O:16])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C[N+]1([O-])CC[O:35]CC1.[CH3:39][C:40]([CH3:42])=[O:41].O>[Os](=O)(=O)(=O)=O>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([OH:21])([C:15]([NH:17][CH2:39][CH:40]([OH:41])[CH2:42][OH:35])=[O:16])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCNC(=O)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C(=O)NCC(O)CO)C1
Reaction time: 15 h
Yield: 72 %

Procedure:
1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide (88 mg, 0.166 mmol) and 4-methylmorpholine N-oxide (58 mg, 0.496 mmol) were dissolved in acetone/water (4:1; 10 mL) and osmium tetroxide (2.5 wt. % in water; 0.1 mL) was added. The solution was stirred at ambient for 15 h, then was quenched with saturated sodium bisulfite (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase HPLC gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2,3-dihydroxypropyl)-3-hydroxyazetidine-3-carboxamide (68 mg, 0.120 mmol, 72% yield): 1H NMR (400 MHz, d6-DMSO): 8.65 (br s, 1H), 7.72 (t, 1H), 7.58 (dd, 1H), 7.41-7.36 (m, 1H), 7.34-7.28 (m, 1H), 7.21-7.12 (m, 1H), 6.92 (br s, 1H), 6.72 (ddd, 1H), 5.00-4.10 (br, 2H), 5.10-4.99 (m, 2H), 4.39 (d, 1H), 4.20 (d, 1H), 4.02 (d, 1H), 3.54-3.45 (m, 1H), 3.34-3.21 (m, 2H), 3.06-2.96 (m, 1H); MS (EI) for C20H19F3IN3O5: 566 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)[CH:15]=1)(=[O:13])=[O:12].[OH:33][CH:34]([CH:45]([OH:56])[C:46]([O:48]N1C(=O)CCC1=O)=O)[C:35]([O:37]N1C(=O)CCC1=O)=O.[CH2:57]([N:59]([CH2:62][CH3:63])[CH2:60][CH3:61])C>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[C:25]([Cl:31])[CH:26]=1)[CH2:23][N:22]([CH3:32])[CH2:21][CH:20]2[C:16]1[CH:15]=[C:14]([S:11]([NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:35](=[O:37])[CH:34]([OH:33])[CH:45]([OH:56])[C:46]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:61]3[C:29]4[C:63](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH2:62][N:59]([CH3:57])[CH2:60]3)[CH:15]=2)(=[O:13])=[O:12])=[O:48])(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CCN(CC)CC
Reactant: O=C(ON1C(=O)CCC1=O)C(O)C(O)C(=O)ON1C(=O)CCC1=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCN)c2)C1
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCNC(=O)C(O)C(O)C(=O)NCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask was placed a solution of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (300 mg, 0.60 mmol, 1.00 equiv) in DMF (5 mL), bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxysuccinate (92.5 mg, 0.27 mmol, 0.45 equiv) and triethylamine (TEA; 1.0 g, 9.88 mmol, 16.55 equiv). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, Water with 0.05% TFA and CH3CN (20% CH3CN up to 40% in 5 min, up to 100% in 2 min); Detector, uv 220&254 nm. This resulted in 192.4 mg (28%) of a TFA salt of the title compound as a white solid. 1H-NMR (300 MHz, DMSO, ppm) δ 7.92 (d, J=7.8 Hz, 2H, 7.82 (m, 2H), 7.67 (t, J=7.8 Hz, 2H), 7.57 (m, 2H), 7.55 (d, J=6.9 Hz, 2H), 6.86 (m, 2H), 4.84 (s, 2H), 4.79 (s, 2H), 4.54 (d, 2H), 4.48 (s, 2H), 3.92 (m, 2H), 3.53 (m, 22H), 3.18 (s, 6H), 3.07 (t, J=5.4 Hz, 4H). MS (m/z): 1119 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:5].[CH2:32]([N:36]=[C:37]=[O:38])[CH2:33][CH2:34][CH3:35]>>[CH2:32]([NH:36][C:37](=[O:38])[NH:1][C:2]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:13]1)=[O:5])[CH2:33][CH2:34][CH3:35]
Reactant: Nc1cc(Cl)ccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)Nc1cc(Cl)ccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
{2-amino-4-chloro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide and n-butylisocyanate}: mp 195°-197° C.; 1H NMR (CDCl3)ppm: 0.93 (3H, t), 1.30-1.90 (11H, m), 2.91 (2H, m), 3.24 (2H, td), 3.31 (2H, dd), 4.25 (1H, s), 4.67 (1H, bs), 6.36 (1H, bs), 6.87 (1H, dd), 7.14-7.41 (11H, m), 8.51 (1H, d), 10.38 (1H, s).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.N1C(C)=CC=CC=1C.Cl[Sn](Cl)(Cl)Cl.[CH2:25]=[O:26].Cl.[OH2:28]>C1(C)C=CC=CC=1>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[C:7]([OH:28])[C:6](=[CH:5][CH:4]=1)[CH:25]=[O:26]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: C=O
Reactant: O
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: O=Cc1ccc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of p-trifluoromethylphenol (7.1 g, 44 mmol) and 2,6-lutidine (1.9 g, 17.6 mmol) in toluene (80 mL) was slowly added SnCl4 (1.2 g, 4.4 mmol). The solution was stirred at room temperature for 20 minutes. Paraformaldehyde was added (3.2 g, 106 mmol) and the reaction was stirred at 110° C. for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (250 mL), and adjusted to pH 1 with concentrated HCl. The mixture was extracted with diethyl ether (500 mL), and the organic layer was washed twice with saturated brine and dried over Na2SO4. The solvent was removed by rotary evaporation to leave a yellow oil. The oil was loaded onto a silica gel column and eluted with 6:1 hexane:ethyl acetate. The yield of product was 1.0 g (12%). 1H NMR(CDCl3): δ7.21-7.91 (m, 12H), 9.91 (s, 1H), 11.32 (s, 1H).