Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH:10]([CH3:11])[CH2:9][CH:8]=[C:7]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH2:6]1)([OH:3])=[O:2].[CH:17](I)([CH3:19])[CH3:18]>>[CH:17]([N:14]1[N:15]=[N:16][C:12]([C:7]2[CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH:10]([CH3:11])[CH2:9][CH:8]=2)=[N:13]1)([CH3:19])[CH3:18]
Reactant: CC(C)I
Reactant: CC1CC=C(c2nnn[nH]2)CN1CC(=O)O
Product: CC1CC=C(c2nnn(C(C)C)n2)CN1CC(=O)O

Procedure:
The title compound was prepared from 28 (5 g, 0.022 mol) as described in Example 5, using isopropyl iodide instead of methyl iodide. Yield: 3.23 g (0.012 mol, 55%) as an oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([NH2:17])[C:10](=[CH:15][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12]>N1C=CC=CC=1>[CH3:1][S:2]([NH:17][C:9]1[C:10](=[CH:15][CH:16]=[C:7]([F:6])[CH:8]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(F)cc1N
Solvent: c1ccncc1
Product: COC(=O)c1ccc(F)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (0.68 g) was added dropwise to a stirred solution of methyl 4-fluoroanthranilate (1 g) in pyridine (dried over 4A sieves, 10 ml) at 0°-5°. After 18 hours at room temperature, the mixture was cooled to 0°-5° and further methanesulphonyl chloride (0.68 g) was added dropwise. The mixture was stirred for 24 hours at room temperature. Aqueous work up and recrystallisation from ethanol gave methyl N-(methylsulphonyl)-4-fluoroanthranilate, mp 115.5°-116.5°. (Compound 19).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OCC)(=[O:18])[CH3:17]>[I-].C([N+](CC)(CC)CC)C>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][CH2:16][OH:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(C)=O
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Product: OCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 140 °C
Reaction time: 26 h
Yield: 83 %

Procedure:
0.5 gram of dibenzylamine (2.5 mmol), 0.446 gram of ethylenecarbonate (5 mmol) and 0.215 gram of tetraethylammoniumiodide (083 mmol) were mixed together at room temperature. The solid mixture was then heated at 140° C. and the resulting suspension was stirred at this temperature for 26 hours. The reaction mixture was diluted with ethyl acetate and extracted with 10 mL of a 0.5M solution of sodium hydroxide. The aqueous phase was washed with ethyl acetate and the combined organic phases were washed twice with brine. The organic phase was dried on magnesium sulfate, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel (eluant: ethylacetate/hexane 1/2) to afford 0.5 gram of N,N-dibenzyl-2-aminoethanol (yield: 83%) as an oil.
Reaction SMILES: [CH2:1]([C@@:5]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:9][C@H:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C@H:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=2)[NH:6]1)[CH:2]([CH3:4])[CH3:3].[C:35]([C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([C:43]([N:6]2[C@@H:7]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:17]=3)[C@@H:8]([C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]=3)[CH2:9][C@@:5]2([CH2:1][CH:2]([CH3:4])[CH3:3])[C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[O:44])=[CH:46][CH:47]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)C[C@@]1(C(=O)OC(C)(C)C)C[C@H](c2cnccn2)[C@H](c2cccc(-c3ccccc3)c2)N1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CC(C)C[C@@]1(C(=O)OC(C)(C)C)C[C@H](c2cnccn2)[C@H](c2cccc(-c3ccccc3)c2)N1C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The ester from stage A was acylated with 4-tert-butylbenzoyl chloride in a similar manner to that described in Intermediate 3, to afford rel-(2S,4S,5R)-1-(4-tert-butylbenzoyl)-2-isobutyl-4-pyrazin-2-yl-5-(3-phenyl-phenyl)-pyrrolidine-2-carboxylic acid, tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:21])=[O:4].[Se](O)(O)=[O:23]>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH:21]=[O:23])=[O:4]
Reactant: CCOC(=O)Cc1c(Cl)ccc2c1cc(C)n2C(=O)OC
Reactant: O=[Se](O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1c(Cl)ccc2c1cc(C=O)n2C(=O)OC
Temperature: 100 °C

Procedure:
5-Chloro-4-ethoxycarbonylmethyl-2-methyl-indole-1-carboxylic acid methyl ester (398 mg, 1.28 mmol) is dissolved under an atmosphere of argon in dioxane (18 ml). Selenious acid (331 mg, 2.56 mmol) is added, and the reaction mixture is heated to 100° C. for 18 hours. TLC analysis indicates complete conversion of the starting material. The reaction mixture is diluted with EtOAc and poured on water. The organic layer is washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated. The solid residue is purified by FCC (hexane/EtOAc 2:1) to afford the title compound. 1H NMR (DMSO, 400 MHz) δ 1.20 (t, J=6.6 Hz, 3H), 4.09 (s, 3H), 4.12 (q, J=6.6 Hz, 2H), 4.19 (s, 2H), 7.64 (d, J=10.8, 1H), 8.09 (d, J=10.8, 1H), 10.32 (s, 1H); ES-MS: 346.1.1 [M+Na]+.
Reaction SMILES: [OH-].[Na+].N1CCC[C@H]1C(O)=O.[CH3:11][O:12][N:13]=[C:14]1[CH2:18][N:17]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:23][CH:22]=2)=[O:20])[C@H:16]([C:34]([O:36]C)=[O:35])[CH2:15]1.O1CCOCC1>O>[CH3:11][O:12][N:13]=[C:14]1[CH2:18][N:17]([C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:25][CH:26]=2)=[O:20])[C@H:16]([C:34]([OH:36])=[O:35])[CH2:15]1
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CON=C1C[C@@H](C(=O)O)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1
Yield: 91 %

Procedure:
A solution of sodium hydroxide (73 mg, 1.81 mmol) in water (1.2 ml) was added to a proline oximether methyl ester derivative, e.g. methyl (2S,4 EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate (391 mg, 1.1 mmol) in 3:1 dioxane:water (12 ml) and the reaction stirred for 3 h. The reaction mixture was then washed with diethyl ether (2×10 ml), and the aqueous phase acidified to pH 2 (0.1N HCl) and extracted into ethyl acetate. The ethyl acetate layer was then dried over magnesium sulfate, filtered and the solvent was then removed in vacuo to give the desired product, e.g. (2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylic acid in 91% yield as an oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>CCCCCC.CCOC(C)=O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:6]2[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(N)cc(C(F)(F)F)c2)cc1

Procedure:
The title compound is prepared as described in Example 13 but using 3-amino-5-bromobenzotrifluoride (RYAN SCIENTIFIC) and 4-methoxyphenylboronic acid (Aldrich). Title compound: ES-MS: 266.0 [M-H]−; single peak at tR=4.61 min (System 1); Rf=0.20 (Hexane/EtOAc, 3:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([NH:15][CH3:16])=[C:11]([CH:17]=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:21]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:22][C:23]([O:25]CC)=O.N1CCCCC1>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[N:15]([CH3:16])[C:23](=[O:25])[C:22]([C:21]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][C:11]=3[CH:10]=[N:9]2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CNc1c(C=O)cnn(Cc2ccc(OC)cc2)c1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cnn(Cc3ccc(OC)cc3)c(=O)c2n(C)c1=O
Reaction time: 18 h

Procedure:
A mixture of 1-(4-methoxybenzyl)-5-(methylamino)-6-oxo-1,6-dihydropyridazine-4-carbaldehyde (4) (3.78 g, 13.8 mmol), diethyl malonate (4.20 mL, 27.7 mmol), piperidine (1.44 mL, 14.5 mmol), and EtOH (100 mL) was stirred at reflux in an oil bath for 5 h. The reaction mixture was allowed to stand at RT for 18 h to afford a suspension. The solid was collected by suction filtration, washed with EtOH (10 mL), and dried in vacuo to afford ethyl 7-(4-methoxybenzyl)-1-methyl-2,8-dioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyridazine-3-carboxylate as a tan solid. MS (ESI, pos. ion) m/z: 370 (M+1).
Reaction SMILES: C([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:15])[NH:8][C:7](=[O:16])[CH2:6]1)(C)(C)C.[BH4-].[Na+].O>S(=O)(=O)(O)O>[Cl:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[NH:5][CH2:6][C:7](=[O:16])[NH:8]2
Reactant: CC(C)(C)N1CC(=O)Nc2cccc(Cl)c21
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=C1CNc2c(Cl)cccc2N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-tert-Butyl-5-chloro-3,4-dihydro-1H-quinoxalin-2-one from Example 12C (1.5 g, 6.1 mmol) was suspended in 2N sulphuric acid (45 ml) and stirred for 18 h. The mixture was filtered and the filtrate was neutralised with sodium hydrogen carbonate, extracted with EtOAc, dried and evaporated. The residue was taken up in ethanol (30 ml) and cooled in an ice/water bath. Sodium borohydride (460 mg, 12 mmol) was added and the mixture was allowed to warm to room temperature over 2 h. Water (1 ml) was added and the mixture was evaporated. The residue was triturated with ice-cold water, filtered, washed with ice-cold water and dried in vacuo over phosphorous pentoxide to give an orange solid; yield 550 mg, 49%.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([Cl:3])=[O:15])=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1ccc(Br)cc1
Yield: 102.5 %

Procedure:
Thionyl chloride (2.5 ml, 34.8 mmol) is added at ambient temperature to a solution of 4-bromophenylacetic acid (Aldrich, 5 g, 23.2 mmol) in 10 ml of toluene. The reaction medium is brought to reflux for 2 hours. After returning to ambient temperature, the toluene is evaporated and 5.55 g of raw 4-bromophenylacetyl chloride is obtained (gross yield=100%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[N+:23]([O-:25])=[O:24].Cl>C(O)(=O)C>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: CCOC(=O)Cc1ccc(-c2ccc3oc([N+](=O)[O-])c(C)c3c2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c([N+](=O)[O-])oc2ccc(-c3ccc(CC(=O)O)cc3)cc12
Temperature: 0 °C

Procedure:
A solution of 1.5 g. of the product of step C in 25 ml. of acetic acid and 10 ml. of 6N hydrochloric acid is heated at its reflux temperature for 45 minutes then poured into ice water. The precipitate is collected and recrystallized from an ethanol-N,N-dimethylformamide mixture to provide 4-(3-methyl-2-nitrobenzofuran-5-yl)phenylacetic acid, m.p. 229°-230° C.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:39]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH:39]1([NH:44][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]3[C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=4[CH:23]=[CH:24][C:15]=3[O:14][C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)(=[O:28])=[O:29])=[CH:38][CH:37]=2)[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: NC1CCCC1
Product: O=C(NC1CCCC1)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 95.4 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30 mmol, 0.6M in DMF) were combined to give 57 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 598 [M+H]+.
Reaction SMILES: C[Si](C)(C)[NH:3][C:4]1[C:5](=[CH:10][CH:11]=[CH:12][C:13]=1[CH3:14])[C:6]([O:8][CH3:9])=[O:7].CC#N.Cl[S:21]([C:24]1[N:34]=[C:27]2[N:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[N:26]2[N:25]=1)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:4]=1[NH:3][S:21]([C:24]1[N:34]=[C:27]2[N:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[N:26]2[N:25]=1)(=[O:22])=[O:23])=[O:7]
Reactant: COC(=O)c1cccc(C)c1N[Si](C)(C)C
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1cccc(C)c1NS(=O)(=O)c1nc2nc(C)cc(C)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution consisting of 145.9 mg (0.615 mmole) of methyl N-trimethylsilyl-3-methylanthranilate, 1 ml of CH3CN, and 80.4 mg (0.326 mmole) of 2-chlorosulfonyl-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine was stirred at room temperature and the reaction monitored by reverse phase HPLC. The reaction was about 30 percent complete after 4 hours. Pyridine, 29.1 μl (0.360 mmole), was added and the solution stirred for 10 min and again analyzed. Complete reaction had occurred. The solution was allowed to stand overnight. The CH3CN was removed under a nitrogen atmosphere and the residue treated with 2 ml of 1.0N HCl and 2 ml of CH2Cl2. The CH2Cl2 phase was transferred to a column containing 50 g of silica gel and chromatographed to obtain 112.5 mg of N-(2-methoxycarbonyl-6-methylphenyl)-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide (0.300 mmole, 92.0 percent yield) as a white crystalline solid, m.p. 181°-182° C. The solid was dissolved in CHCl3 and the solvent again removed in vacuo affording the product as a light yellow powder, m.p. 192°-194° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[N:16]([CH3:17])[CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[N:11]=1)([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH3:4][C:3]1([CH3:5])[CH2:2][O:1][C:28](=[O:30])[N:6]1[C:7]1[S:8][CH:9]=[C:10]([C:12]2[N:16]([CH3:17])[CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[N:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cn1cc(C#N)cc1-c1csc(NC(C)(C)CO)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1cc(C#N)cc1-c1csc(N2C(=O)OCC2(C)C)n1
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a solution of 5-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}-1-methyl-1H-pyrrole-3-carbonitrile (1.10 g, 3.98 mmol), prepared in the previous step, in dry tetrahydrofuran (10 mL) under nitrogen was added triethylamine (0.56 mL, 4 mmol), followed by triphosgene (1.18 g, 4 mmol). After 2 h, the mixture was partitioned between water and ethyl acetate. The organic layers were washed with water, dried (anhydrous sodium sulfate) and evaporated. The residue was then purified by silica gel column chromatography (ethyl acetate:hexanes, gradient elution) to afford the title compound (0.80 g, 66%) as an off white powder. HRMS: calcd for C14H14N4O2S [M+H]+, 303.09102; found (ESI, [M+H]+), 303.093, ANLC 99.4% at 210-370 nm, 8.6 min; 99.7% at 246 nm, 8.6 min, the Xterra® RP18 column, 3.5%, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([CH:11]2[CH2:13][CH2:12]2)[CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([N:6]([S:22]([CH3:21])(=[O:24])=[O:23])[S:22]([CH3:21])(=[O:24])=[O:23])=[C:4]([CH:11]2[CH2:12][CH2:13]2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N)c(C2CC2)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(N(S(C)(=O)=O)S(C)(=O)=O)c(C2CC2)cc1Cl
Temperature: 5 °C
Yield: 80 %

Procedure:
A mixture of Example 18B (1.0 equivalent) and triethylamine (2.3 equivalents) in tetrahydrofuran (0.5 M final concentration based on product from Example 18B) was cooled to 5° C. and treated dropwise with methane sulfonyl chloride (2.3 equivalents) maintaining the temperature below 20° C. After the addition was completed, the reaction mixture was warmed up to ambient temperature for 20 minutes and partitioned with water and methylene chloride. The organic layer was washed with 5% aqueous NaCl solution, dried (Na2SO4), filtered and concentrated. The resulting solid was triturated with isopropyl acetate/heptane (2:1), and the solid was collected by filtration and dried to constant mass (80% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[CH2:21](Br)[C:22]#C>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:21]#[CH:22])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: C#CCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
5.85 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. dimethylformamide is treated under nitrogen with 1.14 g. sodium borohydride at not greater than 30° C. The mixture is stirred for one hour at 15°-20° C, then treated with 5 ml. of propargyl bromide at 20°-25° C. After a further 3 hours, water is added and the crude product extracted with chloroform. The dried chloroform solution is passed through a column of silica gel to remove a little polar material. Pure 1-amino-2-nitro-4-(prop-2-yn-1-ylthio)benzene is obtained from the eluate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH3:19])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 79.1 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) in N,N-dimethylformamide (1.3 mL) was added potassium carbonate (269 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. Iodoethane (305 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=80/20→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (187 mg) as a pale-yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C@@:15]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C@@H:19]([O:31]C(C2C=CC([N+]([O-])=O)=CC=2)=O)[C@@H:18]2[C@H:16]1[C@H:17]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:13])([CH3:10])([CH3:9])[CH3:8].CO>C(OCC)(=O)C>[C:7]([O:11][C:12]([NH:14][C@@:15]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C@@H:19]([OH:31])[C@@H:18]2[C@H:16]1[C@H:17]2[C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
Potassium carbonate (5.11 g, 36.60 mmol) is added to a solution of di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-{[(4-nitrophenyl)carbonyl]oxy}bicyclo[3.1.0]hexane-2,6-dicarboxylate (9.00 g, 12.20 mmol) and methanol (122.01 mL, 3.01 moles), and then stirred at room temperature. After 1 hour, dilute the reaction mixture with ethyl acetate, wash with water (75 mL), brine (75 mL), dry over sodium sulfate, and concentrate under reduced pressure to give a residue. The residue is purified by flash chromatography, eluting with 10-60% ethyl acetate:hexanes to give the title compound (5.3 g, 9.01 mmol, 74%). MS (m/z): 610/612 (M+1).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]1([CH2:18][O:19][C:20](=[O:60])[CH2:21][N:22]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:30][CH2:29][N:28]([CH2:45][C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:27][CH2:26][N:25]([CH2:56][C:57]([OH:59])=[O:58])[CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:62][C:63]([N:65]([CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH3:101])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])=[O:64]>C1(C)C=CC=CC=1>[C:12]1([CH2:18][O:19][C:20](=[O:60])[CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH2:56][C:57]([O:59][CH2:62][C:63]([N:65]([CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH3:101])=[O:64])=[O:58])[CH2:26][CH2:27][N:28]([CH2:45][C:46]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:47])[CH2:29][CH2:30][N:31]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[CH2:32][CH2:33]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)CN1CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CC1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CBr
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COC(=O)CN1CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CC1
Yield: 68 %

Procedure:
DBU (820 μL; 5.5 mmol) was added to a suspension of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tris(phenylmethyl)ester (prepared according to Step E3 of Example 17) (3.71 g; 5.5 mmol) in toluene (350 mL) obtaining a clear solution, then 2-bromo-N,N-dioctadecylacetamide (prepared according to Example 5, Step A) (3.9 g; 6.05 mmol) dissolved in toluene (50 mL) was added dropwise. After 2 h the reaction mixture was filtered and the solvent was evaporated. The crude was suspended in CH3CN (50 mL) and the insoluble was filtered off with a paper filter. The solution was evaporated obtaining the desired product (4.63 g; 3.74 mmol). Yield 68%. The 13C-NMR, MS and IR spectra were consistent with the structure.