Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@H:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:48]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41]1)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(C[C@H]1CCCNC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H]1CCCN(C(=O)c2ccccc2)C1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 71 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide bis(trifluoroacetate) and benzoyl chloride as the starting materials in 71% yield. LCMS for C32H32ClN6O2 (M+H)+: m/z=567.0.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C:16]=2[CH:30]=1.CC(C1C=C(C(C)C)C(S([N:46]=[N+:47]=[N-:48])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C>>[N:46]([CH:19]1[N:18]=[C:17]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:16]2[CH:30]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[N:21]([CH3:22])[C:20]1=[O:23])=[N+:47]=[N-:48]
Reactant: CN1C(=O)CN=C(c2cccnc2)c2cc(Cl)ccc21
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Product: CN1C(=O)C(N=[N+]=[N-])N=C(c2cccnc2)c2cc(Cl)ccc21
Yield: 90.2 %

Procedure:
As illustrated in the scheme above and following General Procedure 6, KHMDS (10.5 mL of 0.5 M in toluene, 5.25 mmol), 7-chloro-1,3-dihydro-1-methyl-5-(3-pyridinyl)-2H-1,4-benzodiazepin-2-one (1.43 g, 4.99 mmol), trisyl azide (3.86 g, 12.5 mmol) and acetic acid (1.26 mL, 22.0 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (1:1 CH2Cl2:EtOAc) provided the title compound as a yellow foam (1.47 g, 90%). 1H-NMR (CDCl3): δ 8.80 (s, 1H), 8.76 (d, J=3.6 Hz, 1H), 8.14 (dt, J=1.6 Hz, J=8.0 Hz, 1H), 7.61 (dd, J=2.0 Hz, J=8.4 Hz, 1H), 7.44 (ddd, J=0.8 Hz, J=4.8 Hz, J=8.0 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 4.56 (s, 1H), 3.48 (s, 3H). MS (ESI) (M+H)+=327.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[N:13]1([CH2:19][CH2:20][OH:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(O)CCCCC1>[Cl:1][C:2]1[C:8]([N:16]2[CH2:17][CH2:18][N:13]([CH2:19][CH2:20][OH:21])[CH2:14][CH2:15]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OC1CCCCC1
Product: Nc1cc(N2CCN(CCO)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 14 h
Yield: 88.3 %

Procedure:
To a solution of 4.14 g of 4,5-dichloro-2-nitroaniline and 2.73 g of 1-piperazine ethanol in 20 ml of cyclohexanol, 2.65 g of sodium carbonate was added, and stirred for 14 hours at 150° C. After cooling the reaction liquid to room temperature, water was added thereto, followed by extraction with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (chloroform/methanol=10/1) to provide 5.31 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6]([NH2:14])=[N:5]2.Cl.N[OH:17]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[N:14][OH:17])[NH:5]2
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]c1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]c1=NO
Temperature: 25 °C
Yield: 77.6 %

Procedure:
An adaptation of the method of Harsanyi et al., Liebigs Ann. Chem. 190 (1973), was used. A mixture of 6,7-dichloro-3-aminoquinoxalin-2(1H)-one (50 mg, 0.22 mmol) and hydroxylamine hydrochloride (33 mg, 0.47 mmol; Aldrich Co.) in 2 mL of ethanol was heated to reflux. The resulting brown suspension was stirred under reflux for 12 h. The resulting brown suspension was allowed to cool to 25° C. A brown precipitate appeared. The mixture was vacuum filtered and the brown solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 42 mg (79%) of 6,7-dichloro-3-(hydroxyimino)-1,4-dihydroquinoxalin-2-one: mp dec.>270° C. 1H NMR (300 MHz, DMSO-d6) δ 11.306 (br s, 1H, NH), 11.049 (br s, 1H, NH), 10.148 (br s, 1H, NOH), 7.403 (s, 1H, H-5), 7.018 (s, 1H, H-8). Mass: calcd. for C8H5Cl2N3O2 (M+) M/Z 244.9759, found 244.9769.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][CH2:21][C:22](=[O:24])[CH3:23].C(Cl)(Cl)Cl>CCOCC>[Cl-:20].[CH2:21]([P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:22]([CH3:23])=[O:24]
Reactant: CC(=O)CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 20 °C

Procedure:
A solution of 55 g of triphenylphosphine, 15.5 ml of chloroacetone and 165 ml of chloroform was refluxed for 45 minutes and after cooling to 20° C., the mixture was poured into 1.65 liters of ether. The mixture was vacuum filtered and the recovered product was washed with ether and dried under reduced pressure to obtain 26.9 g of acetonyltriphenylphosphonium chloride. The said product was added to 270 ml of aqueous 10% sodium carbonate solution and the mixture was stirred for 16 hours and was vacuum filtered. The product was washed with water and dried under reduced pressure to obtain 20.3 g of raw product which was crystallized from 50% aqueous methanol to obtain 16 g of acetonylidene triphenylphosphorane melting at 207°-208° C.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.[CH2:12]([C@H:14]1[CH2:19][C@H:18]2[C@H:20]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C@H:15]1[O:33][C:34](=[O:37])[CH2:35]Br)[C@@H:28]1[C:23](=[CH:24][C:25](=[O:32])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)[CH3:13]>CC(C)=O>[CH2:12]([C@H:14]1[CH2:19][C@H:18]2[C@H:20]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C@H:15]1[O:33][C:34](=[O:37])[CH2:35][O:7][C:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8])[C@@H:28]1[C:23](=[CH:24][C:25](=[O:32])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)[CH3:13]
Reactant: O=C(O)C1CCCC1
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)C1CCCC1
Yield: 106.6 %

Procedure:
In 40 ml of acetone is dissolved 0.6 g of cyclopentanecarboxylic acid, and 6.0 ml of 1N-NaOH and 16 ml of water are added, followed by addition of 1.2 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 6 hours. The solvent is distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. After serial passage of diisopropyl ether-n-hexane mixtures (1:9, 200 ml; 2:8, 200 ml; and 3:7, 200 ml), elution is carried out with 800 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.38 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:2].[Al+3].[Cl-:22].[Cl-].[Cl-].[Cl:25][CH2:26][CH2:27][C:28](Cl)=[O:29].Cl>ClCCl>[ClH:25].[Cl:25][CH2:26][CH2:27][C:28]([C:15]1[CH:16]=[CH:17][C:18]2[N:6]([CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([C:28](=[O:29])[CH2:27][CH2:26][Cl:22])=[CH:9][CH:8]=3)=[O:29]
Reactant: CCN(CC)CCn1c2ccccc2c2ccccc21
Reactant: [Cl-]
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Product: CCN(CC)CCn1c2ccc(C(=O)CCCl)cc2c2cc(C(=O)CCCl)ccc21
Yield: 73.7 %

Procedure:
9-(2-Diethylaminoethyl)carbazole (68) (17.9 g, 67.3 mmol, 1 eq) was dissolved in dry dichloromethane (150 mL). Anhydrous AlCl3 (45 g, 337 mmol, 5 eq) was added portion-wise with stirring and cooling in an ice bath. 3-chloro-propionyl chloride (32.4 mL, 337 mmol, 5 eq) was added dropwise, while maintaining the internal temperature below 5° C. The reaction mixture was stirred at this temperature for 15 h, poured into cold 3% HCl (violent foaming should be avoided) and extracted with CHCl3 (5×500 mL). The extracts were evaporated and the resulted green oil triturated with diethyl ether (5×50 mL) to give 24 g (74%) of 3,6-di(3-chloropropionyl)-9-(2-diethylaminoethyl)-carbazole hydrochloride (69) as dark grey solid.
Reaction SMILES: Cl[C:2]1[CH:24]=C(Cl)[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=N[NH:28]1.C(Cl)(=O)C(Cl)=O.NCC1C=CN=CC=1>C(N(CC)CC)C.CN(C)C=O.ClCCl>[O:20]=[C:9]1[C:8]([C:6]([NH:5][CH2:4][C:3]2[CH:2]=[CH:24][N:28]=[CH:22][CH:21]=2)=[O:7])=[CH:13][C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[N:11][NH:10]1
Reactant: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Agent: NCc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccncc1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.15 cm3 of 4-(aminomethyl)pyridine and 0.19 cm3 of triethylamine, 0.14 g of 3-oxo-6-pyridin-4-yl-N-(pyridin-4-ylmethyl)-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at 254° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CO[C:7](=[O:24])[C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[C:10]([O:22][CH3:23])[CH:9]=1.[Cl-].[NH4+].O1CC[CH2:29][CH2:28]1>>[C:18]([Si:15]([CH3:16])([CH3:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([OH:24])([CH2:1][CH3:2])[CH2:28][CH3:29])=[CH:9][C:10]=1[O:22][CH3:23])([CH3:19])([CH3:20])[CH3:21]
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Reactant: COC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(O)(CC)c1ccc(O[Si](C)(C)C(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
Ethylmagnesium bromide (solution in diethyl ether, 25.5 mL, 77.4 mmol) was added to a solution of 4-(t-butyl-dimethyl-silanyloxy)-3-methoxy-benzoic acid methyl ester (Example 176-(1); 7.9 g, 25.5 mmol) in tetrahydrofuran (50 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=10:1) to give the title compound (8.05 g, 98%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:11](=[O:40])[NH:12][C@@H:13]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:14](=[O:33])[N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)[CH3:10])C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:34]1([C@H:13]([NH:12][C:11](=[O:40])[C@@H:9]([NH:7][CH3:6])[CH3:10])[C:14](=[O:33])[N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1CCC[C@H]1c1cccc(Oc2ccccc2)c1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1CCC[C@H]1c1cccc(Oc2ccccc2)c1)C1CCCCC1
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To a solution of ((S) 1-{(S)-1-cyclohexyl-2-oxo-2-[(S)-2-(3-phenoxy-phenyl)-pyrrolodin-1-yl]-ethylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester (450 mgs, 0.79 mmol) in CH2Cl2 (20 mL) is added TFA (10 mL) and stirred for 30 minutes. The mixture is concentrated under reduced pressures and purified by reverse phase column chromatography to give the product as a TFA salt (370 mgs, 82%). LCMS m/z 464.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:12][CH2:11][C:10](=[O:27])[N:9]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([NH2:16])[CH2:12][CH2:11][C:10](=[O:27])[N:9]1[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CCC(=O)N1Cc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)C(N)CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A solution of (2-benzyl-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3,7-dioxo-[1,2]diazepan-1-yl]-acetic acid tert-butyl ester (5a) (150 mg, 0.31 mmol) and hydrazine monohydrate (17.3 mg, 35 mmol) in ethanol (1.5 mL) was stirred at room temperature for 6 hours. Solvent was removed in vacuo. The residue was taken up into acetic acid (1.5 mL) and stirred at room temperature for 30 min. The mixture was evaporated in vacuo and the resulting residue was dissolved in ethyl acetate (20 mL), washed with 5% Na2CO3 then water. The aqueous solution was extracted with ethyl acetate (20 mL×2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was evaporated to dryness in vacuo to afford 107 mg (98% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 1.45 (s, 9H), 1.70-1.78 (m, 1H), 2.30-2.48 (m, 2H), 3.10-3.15 (m 1H), 3.30-3.38 (m, 1H), 3.95-4.00 (d, 1H), 4.36-4.40 (d, 1H), 4.45-4.49 (d, 1H), 5.07-5.12 (d, 1H), 7.28-7.38 (m, 5H). Analytical HPLC: 8.03 min. LC-MS (ES+): m/e=348 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.F[B-](F)(F)F.[O:17]=[N+:18]=[O:19].O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:18]([O-:19])=[O:17])[C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]=O
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1O
Reaction time: 2 h

Procedure:
A solution of 4-chloro-2-nitrophenol (4 g, 23 mmol) in acetonitrile (100 ml) was cooled to −25 C.°, and gradually added with nitronium tetrafluoroborate powder (4.9 g). The reaction mixture was stirred for 2 hours while the temperature was raised to −10 C.°, and the reaction was stopped by adding 10 ml of water. The acetonitrile was evaporated under reduced pressure, and the residue was diluted with diethyl ether. The ether layer was washed with water, then washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated by vacuum concentration to obtain the title compound as yellow plate crystals (5.1 g).
Reaction SMILES: C(C[O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[N:23]([CH3:24])[CH2:22][CH2:21][C@:17]45[C:18]=2[C:19]=1[O:20][C@H:16]4[C@@H:15]([OH:25])[CH:14]=[CH:13][C@@H:12]35)(O)=O.ClC(OCC(C)C)=O>CN(C)C=O.O>[CH:8]1[C:9]2[CH2:10][C@H:11]3[N:23]([CH2:22][CH2:21][C@@:17]45[C@H:12]3[CH:13]=[CH:14][C@H:15]([OH:25])[C@@H:16]4[O:20][C:19]([C:18]=25)=[C:6]([OH:5])[CH:7]=1)[CH3:24]
Reactant: CN1CC[C@]23c4c5ccc(OCC(=O)O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
Carboxymethyl morphine (240 mg) suspended in 8 ml dry dimethyl formamide (DMF) was cooled to -15° C. and treated with 84 μl isobutyl chloroformate. The solid dissolved while stirring for 30 minutes at -15° C. Bovine serum albumin (BSA) (400 mg) dissolved in 56 ml water containing 2.6 g sodium bicarbonate was added to this solution and the mixture was kept at 0° C. overnight. It was then dialyzed against distilled water with four changes of water (dialysis 1:80) and lyophilized to give 350 mg of conjugate.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[CH2:36](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)[C:37]1[CH:42]=CC=C[CH:38]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH:35][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][CH2:6][C:37]([CH3:42])([CH3:38])[CH3:36])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:25])=[O:26])=[CH:22][CH:23]=1
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(F)cc3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CC(C)C[C@H](NCC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-4-methyl-2-(neopentylamino)pentanoic acid from Step A of Example 244 for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4S,6aS)-2-(4-fluorophenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step A for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.21-8.23 (m, 1H), 7.99-8.02 (m, 2H), 7.32 (t, J=8.5 Hz, 2H), 4.23-4.29 (m, 1H), 3.78 (dd, J=9.9, 2.9 Hz, 1H), 3.26 (dd, J=8.5, 5.7 Hz, 1H), 3.12-3.18 (m, 2H), 2.96 (dd, J=9.6, 7.1 Hz, 1H), 2.51-2.60 (m, 2H), 2.44-2.47 (m, 1H), 2.29-2.32 (m, 1H), 1.93-2.01 (m, 1H), 1.81-1.93 (m, 2H), 1.67-1.79 (m, 1H), 1.70 (ddd, J=13.5, 7.8, 5.7 Hz, 1H), 1.53-1.60 (m, 2H), 1.23-1.36 (m, 1H), 0.93 (d, J=6.7 Hz, 3H), 0.93 (s, 9H), 0.87 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 468 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:37].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:19]([C:16]2[CH:17]=[CH:18][C:13]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][C:2]=3[Cl:1])[NH:8][CH:7]=[C:6]4[C:11]([OH:37])=[O:12])=[CH:14][CH:15]=2)[CH2:20]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cc4c(C=O)c[nH]c4cc3Cl)cc2)C1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
To a solution of tert-butyl 3-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate (43 mg, 0.1 mmol) in acetonitrile (1.2 mL) and tert-butanol (1.2 mL) was added 2-methyl-2-butene (1.2 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (100 mg, 1.1 mmol) and sodium phosphate monobasic dihydrate (234 mg, 1.5 mmol) in water (0.6 mL). After the resulting mixture was stirred for 2 h at room temperature, additional sodium chlorite (134 mg, 1.47 mmol) and sodium phosphate monobasic dihydrate (312 mg, 2.0 mmol) in H2O (0.6 mL) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the aqueous residue was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in DMSO and purified via pre-HPLC to give 5-{4-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]phenyl}-6-chloro-1H-indole-3-carboxylic acid (16 mg, 36%) as a white solid. MS (ES+) 463.1 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](I)[CH3:17].O>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH2:16][CH3:17])[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)oc(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of 1 g (5.06 mmol) of 6-chloro-1H-benzo[d][1,3]oxazine-2,4-dione in DMF (20 ml) were carefully added 265 mg of sodium hydride (55% in mineral oil) at 0° C. This mixture was stirred for 30 min at RT and then 1.18 ml (7.59 mmol) of ethyl iodide were added. Stirring was continued for 16 h at RT, then water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The remaining residue was purified by crystallization from heptane to obtain 682 mg (60%) of 6-chloro-1-ethyl-1H-benzo[d][1,3]oxazine-2,4-dione as an off-white solid. 1HNMR (DMSO-d6, 300 MHz): δ 1.21 (t, J=7.0 Hz, 3H), 4.05 (q, J=7.0 Hz, 2H), 7.54 (d, J=9.1 Hz, 1H), 7.88 (dd, J=9.1 and 2.5 Hz, 1H), 7.96 (d, J=2.5 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH2:3]1
Reactant: OC1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCCC(O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixed solution containing 33.5 g of 3-hydroxypiperidine and 62.7 ml of triethylamine dissolved in 250 ml of methylene chloride was added dropwise a solution of 55.7 ml of benzyloxycarbonyl chloride in 150 ml of methylene chloride, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous citric acid and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 75.5 g of benzyl 3-hydroxypiperidine-1-carboxylate.