Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@H:16]([CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:71])[C:67]([F:70])([F:69])[F:68])[C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:60])([OH:59])=[O:58])([OH:40])=[O:39])=[O:18])=O)(C)(C)C>ClCCl>[NH2:15][C@H:16]([CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:71])[C:67]([F:68])([F:70])[F:69])[C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:59])([OH:60])=[O:58])([OH:40])=[O:39])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)C(F)(F)F)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3OC(=O)[C@H](N)CCCCNC(=O)C(F)(F)F)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 88.4 %

Procedure:
A 10% solution of trifluoroacetic acid in dichloromethane (0.21 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-6-(2,2,2-trifluoroacetamido)hexanoate (Compound tk54) (5.3 mg, 5.52 μmol) in dichloromethane (0.1 mL), and the mixture was stirred at room temperature for 55 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-6-(2,2,2-trifluoroacetamido)hexanoate (Lys(Tfa)-pdCpA) (Compound tk55) (4.2 mg, 88%).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]CC)=O)(=O)[CH:2]([CH3:4])[CH3:3].[CH3:12][NH:13][NH2:14]>C(O)C>[OH:9][C:7]1[N:13]([CH3:12])[N:14]=[C:1]([CH:2]([CH3:4])[CH3:3])[CH:6]=1
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: CNN
Solvent: CCO
Product: CC(C)c1cc(O)n(C)n1
Yield: 88 %

Procedure:
To a solution of 30.0 grams of ethyl isobutyrylacetate in 130 ml of ethanol (anhydrous,5% methanol) at 10 C. was added dropwise over 30 minutes a solution of 8.7 grams of methyl hydrazine in 30 mls of ethanol. The reaction temperature did not exceed 20 C. After twenty minutes of additional stirring the cooling bath was removed and 2 ml of glacial acetic acid was added. After one hour of stirring at room temperature the reaction was then refluxed for four hours. After stirring overnight at room temperature the reaction was concentrated to yield a yellowish solid. This solid was stirred with 100 ml of hexanes for 30 minutes and the off-white solid was collected and rinsed with 75 ml of hexanes. The solid was dried in a vacuum oven at 45 C. overnight to yield 23.3 g of the desired product, mp 120-122 C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.CS(C)=[O:19].C([O-])([O-])=O.[K+].[K+]>O>[CH3:15][C:6]([CH3:16])([CH2:5][CH2:4][CH:3]([OH:19])[CH3:2])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CS(C)=O
Reactant: CC(C)(CCCCBr)COC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(O)CCC(C)(C)COC1CCCCO1
Temperature: 25 °C
Yield: 85 %

Procedure:
In a 250 ml flask equipped with a magnetical stirrer and reflux condenser were placed 6-bromo-1(tetrahydropyranyloxy)-2,2-dimethylhexane (10 g, 0.034 mol) and DMSO (50 ml), then the mixture was treated with K2CO3 (10 g 0.068 mol) in water (100 ml). The reaction mixture was heated under reflux for two days, then was allowed to cool to room temperature and quenched with water (150 ml). The solution was adjusted to pH 7 with 1M HCl and extracted with ether (3×100 ml). The organic layers combined were then washed with saturated NH4Cl (150 ml) and brine (150 ml), dried (MgSO4), and the solvent was removed under reduced pressure, to provide 6.63 g of the above-titled compound as a colorless liquid (85% yield). 1H NMR CDCl3, δ (ppm): 4.40-4.50 (m, 1H), 3.90-3.75 (m, 1H), 3.38 (t, J=6.8 Hz, 1H), 2.97 (d, J=9.3 Hz, 1H), 2.50 (brs, 1H, OH), 1.90-1.20 (m, 12H), 0.84 (s, 3H), 0.86 (s, 3H); 13C NMR CDCl3, δ (ppm): 99.0, 76.2, 62.3, 61.8, 38.8, 34.0, 33.4, 30.5, 25.4, 24.4, 24.3, 19.9, 19.3.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9](Cl)[C:5]=1[C:6]([OH:8])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([SH:25])[CH:22]=[CH:23][CH:24]=1.Cl>O1CCCC1.CCCCC>[Cl:3][C:4]1[C:5]2[C:6](=[O:8])[C:22]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)[S:25][C:9]=2[C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1
Reactant: COc1cccc(S)c1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(=O)c3c(Cl)ccc([N+](=O)[O-])c3sc2c1
Reaction time: 20 h

Procedure:
The requisite 1-chloro-6-methoxy-4-nitrothioxanthone was prepared as follows: To a prewashed (pentane) suspension of NaH in 500 ml of tetrahydrofuran cooled to 0° was added dropwise over about 25 minutes a solution of 35.4 g of 2,6dichloro-5-nitrobenzoic acid in 200 ml of tetrahydrofuran. After about five minutes a solution of 20 g of m-methoxybenzenethiol in 50 ml of tetrahydrofuran was added, and the mixture was stirred for 20 hours as it gradually came to ambient temperature. The mixture was treated with a 10% aqueous hydrochloric acid solution, extracted into ethyl acetate, dried, and the solvent was removed in vacuo. The orange gum was purified by flash chromatography on SiO2 with a 90:5:0.5 mixture of methylene chloride:methanol:acetic acid. The resulting oil was sufficiently pure for use in the next step. A solution of this material (24.8 g) in 120 ml of trifluoroacetic acid was treated with 60 ml of trifluoroacetic anhydride and allowed to stir at room temperature for 30 minutes. The solution was diluted with acetonitrile, and the precipitate was collected and triturated with boiling acetonitrile to give 15.8 g of the product, mp 254°-258°.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH:32]=O)[CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:23]=1[CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:18][CH2:19][CH3:20].O>CN(C)C=O>[CH2:17]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](/[CH:32]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][C:36]([CH3:37])([CH3:38])[CH3:39])[C:23]=1[CH2:40][NH:41][C:42]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:48])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(C=O)cc12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(=O)OCC)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (1.1 mL, 5.5 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (0.22 g, 5.5 mmol) (60% in oil), and the mixture was stirred at room temperature for 10 min. To the obtained mixture was added a solution of tert-butyl (4-butoxy-6-formyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (2.45 g, 5.5 mmol) in N,N-dimethylformamide (10 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl (E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate (2.03 g, 71.7%), as an amorphous.
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:1])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: O=C1NC(=O)c2c(CCCCCCCCN3CCOCC3)cccc21
Reactant: NN
Solvent: CO
Product: NCCCCCCCCN1CCOCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 8-morpholinyloctylphthalimide (275 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.C(N(CC)CC)C.[F:35][C:36]([F:41])([F:40])[C:37](O)=O>ClCCl>[CH3:25][S:24][C:21]1[N:22]=[CH:23][C:12]2[C:11](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]4[N:27]=[C:37]([C:36]([F:41])([F:40])[F:35])[O:1][N:2]=4)[CH:5]=3)[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]=2[N:20]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(C(F)(F)F)n3)c1)C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
(S)—N′-Hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (190 mg, 0.49 mmol) obtained in Step 1 of Example 75 was dissolved in dichloromethane (1.5 mL), and the mixture was cooled to 0° C. after adding triethylamine (0.14 mL, 0.99 mmol). Thereafter, anhydrous trifluoroacetic acid (0.14 mL, 0.99 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-9-methylthio-5-[3-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (186 mg, 81%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15].O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28].Cl.C(N=C=NCCCN(C)C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16][N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28])=[O:15]
Reactant: COCCOCCOCCOCCC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-{2-[2-(2-Methoxyethoxy)ethoxy]ethoxy}propionate (131 mg, 0.45 mmol) was dissolved in trifluoroacetic acid and left at room temperature for 1 hour. The solvent was removed in vacuo and residual trifluoroacetic acid was removed by evaporation from dioxane. The deprotected intermediate was dissolved in dichloromethane and treated with N-hydroxysuccinimide (57 mg, 0.49 mmol) and ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed twice with water. The organic phase was dried over MgSO4 and concentrated in vacuo to provide 122 mg (82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1.Cl.[C:14](=O)([O-])[O-].[K+].[K+]>CO>[OH:12][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:7]=1[C:8]([O:10][CH3:14])=[O:9]
Reactant: COc1ccc(O)c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(OC)ccc1O

Procedure:
A mixture of 73 g of 5-methoxysalicylic acid, and 95 ml of concentrated hydrochloric acid in 700 ml of methanol was heated under reflux for 48 hours. Potassium carbonate (10 g) was added, and the mixture concentrated to an oily residue which was dissolved in 250 ml of ethyl acetate. This solution was washed with two 100 ml portions of 10% sodium bicarbonate solution, then dried over anhydrous sodium sulfate. Evaporation of solvent afforded the title compound as an amber oil.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([OH:13])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[C:19]([O:18][C:16]([NH:15][CH2:14][C:10]1([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCC1(O)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1(O)CCNC1

Procedure:
18.7 g (61 mmol) of 1-benzyl-3-tert.-butoxycarbonylaminomethyl-3-hydroxypyrrolidine are dissolved in 120 ml of methanol and hydrogenated on 3 g of 5% strength Pd/active carbon at 90° C. and 100 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is recrystallized from ethyl acetate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][NH2:16])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25]([C:27](=O)[CH2:28][CH3:29])[CH:26]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25](/[C:27](=[N:16]/[NH:15][C:13](=[O:14])[C:12]2[CH:17]=[CH:18][CH:19]=[C:10]([S:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)(=[O:9])=[O:8])[CH:11]=2)/[CH2:28][CH3:29])[CH:26]=1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CCC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: CC/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 31.6 %

Procedure:
3-(Morpholinosulfonyl)benzohydrazide (40 mg, 0.140 mmol) and 1-(5-chloro-2-hydroxyphenyl)propan-1-one (25.9 mg, 0.140 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (20 mg). 1H NMR (400 MHz, acetone-d6): δ 8.26 (m, 2H), 8.00 (d, 1H, J=7.6 Hz), 7.84 (t, 1H, J=8.0 Hz), 7.64 (d, 1H, J=2.4 Hz), 7.33 (m, 1H), 6.98 (d, 1H, J=9.2 Hz), 3.69 (m, 4H), 3.10 (q, 2H, J=7.6 Hz), 2.99 (m, 4H), 1.26 (t, 3H, J=7.6 Hz). ESI-MS: 452.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([CH3:30])([O:25][Si](C)(C)C)[CH2:9][CH2:10]S(C2N(C3C=CC=CC=3)N=NN=2)(=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:34][C@H:35]1[CH2:39][CH2:38][C@H:37]([CH:40]=O)[C@H:36]1[CH2:42][CH2:43][S:44][C:45]1[S:46][CH:47]=[C:48]([C:50]([O:52]CC)=[O:51])[N:49]=1)(=O)C>>[CH:1]1([CH2:7][C:8]([OH:25])([CH3:30])[CH2:9]/[CH:10]=[CH:40]/[C@H:37]2[CH2:38][CH2:39][C@H:35]([OH:34])[C@@H:36]2[CH2:42][CH2:43][S:44][C:45]2[S:46][CH:47]=[C:48]([C:50]([OH:52])=[O:51])[N:49]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1csc(SCC[C@H]2[C@@H](OC(C)=O)CC[C@@H]2C=O)n1
Reactant: CC(CCS(=O)(=O)c1nnnn1-c1ccccc1)(CC1CCCCC1)O[Si](C)(C)C
Product: CC(O)(C/C=C/[C@H]1CC[C@H](O)[C@@H]1CCSc1nc(C(=O)O)cs1)CC1CCCCC1

Procedure:
By the same procedure as a series of reactions of Example 43→Example 44→Example 45 using 5-({4-cyclohexyl-3-methyl-3-[(trimethylsilyl)oxy]butyl}sulfonyl)-1-phenyl-1 H-tetrazole instead of the compound 41 and using the compound 49 instead of the compound 42, the title compound having the following physical data was obtained.
Reaction SMILES: C(O[CH2:5][CH:6]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]([C:34](=[O:36])[CH3:35])[C:31](=[O:33])[CH3:32])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:7]([O:9][CH3:10])=[O:8])(=O)C.C(N(CC)CC)C>C(Cl)Cl>[C:31]([N:30]([C:34](=[O:36])[CH3:35])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:6](=[CH2:5])[C:7]([O:9][CH3:10])=[O:8])(=[O:33])[CH3:32]
Reactant: COC(=O)C(COC(C)=O)N(Cc1ccccc1N(C(C)=O)C(C)=O)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)OC)N(Cc1ccccc1N(C(C)=O)C(C)=O)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 g (1.97 mmol) of methyl 3-acetoxy-2-[(2-diacetylaminobenzyl)-(4-methoxybenzenesulfonyl)amino]propionate and 0.826 ml (5.92 mmol) of triethylamine in 5 ml of CH2Cl2 was stirred at room temperature overnight. The solution was diluted with 30 ml of CH2Cl2 and washed with 20 ml each of H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give a brown oil. Anal. for C22H24N2O7S: Calc'd: C,57.4; H,5.3; N,6.1; S,7.0; Found: C,56.2; H,5.5; N,5.6; S,7.2.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:12]=[C:11]([CH3:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:7]=1N.[BrH:17]>O.[Cu]Br>[Br:17][C:7]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]([CH3:13])=[CH:12][C:6]=1[F:5]
Reactant: Cc1cc(F)c(N)cc1[N+](=O)[O-]
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A solution of sodium nitrite (7.6 g, 110 mmol) in water (30 mL) was added dropwise over 15 min to a stirred suspension of 2-fluoro-4-methyl-5-nitroaniline (17 g, 100 mmol) in hydrobromic acid, (48%, 150 mL) and water (30 mL) at 0° C. The mixture was stirred at 0° C. for 15 min then added portionwise over 10 min to a stirred suspension of copper(I)bromide (16.5 g, 112 mmol) in hydrobromic acid (48%, 50 mL) and water (90 mL) at 0° C. The mixture was stirred at 0° C. for 30 min then warmed to room temperature and stirred for 3 h. The mixture was poured onto ice-water (500 mL) and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; heptane-ethyl acetate (19:1)] to give the product (11.8 g, 50%) as an off-white solid: IR νmax (nujol)/cm−1 2925, 2855, 1571, 1523, 1478, 1349, 1264, 1103, 895, 671 and 589; NMR δH (400 MHz, CDCl3) 8.27 (1H, d, J 6.5), 7.10 (1H, d, J 9.1), 2.60 (3H, s).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][N:12]([CH3:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)(C)(C)C>C1COCC1.CCO>[ClH:1].[ClH:1].[NH2:9][CH2:10][CH2:11][N:12]([CH3:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CN(C)CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CN(C)CCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (10 ml) was added to a solution of ethyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)(methyl)amino)acetate (intermediate 83, 3.05 g, 11.13 mmol) in THF (20 ml) and EtOH (100 ml) at room temperature. After stirring 1 h at room temperature the reaction mixture was evaporated, ethanol (20 ml) added, evaporated, further ethanol (50 ml) added and then stirred at 60° C. for 70 min. The cooled reaction mixture was then evaporated to give the title compound as a pale-yellow glass. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, br, 3H), 4.19 (q, 2H), 4.26-4.15 (m, 2H), 3.44 (s, br, 2H), 3.21 (s, br, 2H), 2.88 (s, 3H), 1.21 (t, 3H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]=[CH:18][C:19]1[CH:47]=[CH:46][C:22]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH2:32][CH2:33][CH2:34][S:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:29]=[CH:28][C:27]=2[OH:45])=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]=[CH:18][C:19]1[CH:47]=[CH:46][C:22]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH2:32][CH2:33][CH2:34][S:35]([C:38]3[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=3)(=[O:37])=[O:36])[CH:29]=[CH:28][C:27]=2[O:45][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(Nc1cc(CCCS(=O)(=O)c2ccc(Cl)cc2)ccc1O)c1ccc(C=Cc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1ccc(C=Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.5 %

Procedure:
Under ice-cooling, ethyl bromoacetate (87 mg, 0.52 mmol) was added dropwise to a mixture of 4-[2-(2-benzothiazolyl)vinyl]-5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-hydroxybenzanilide (307 mg, 0.52 mmol), potassium carbonate (145 mg, 1.05 mmol) and dimethylformamide (10 ml), and the resulting reaction solution was stirred at room temperature for 12 hours. Water was added to the reaction solution and the product formed was extracted with ethyl acetate. The resulting extract was washed with water and brine in that order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (eluent=hexane:ethyl acetate=4:1) to give ethyl 2-[4-[2-(2-benzothiazolyl)vinyl]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (219 mg, 0.32 mmol, 62%) as colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:18]=[CH:17]3)[C@@H:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].[CH3:30][C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[C@@H:10]([NH:12][C:32](=[O:33])[C:31]([CH3:36])([CH3:35])[CH3:30])[CH3:11])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Reactant: CC(C)(C)C(=O)Cl
Product: CCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(C)(C)C)cc1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-(4-ethylphenyl)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}propan-2-amine (7a, 20 mg, 50 μmol) and 2,2-dimethylpropanoyl chloride (18 mg, 150 μmol). Yield 17 mg (71%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[CH:10][NH:11][C:4]=12.[Cl:12][CH2:13][CH2:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)O>C(Cl)(Cl)Cl>[Cl:12][CH2:13][CH2:14][C@H:15]([N:11]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:9]=[CH:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccnc2cc[nH]c12
Reactant: O[C@H](CCCl)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccnc2ccn([C@@H](CCCl)c3ccccc3)c12
Yield: 33 %

Procedure:
1-(3-Chloro-1-(S)-phenyl-propyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine 79 was prepared from 7-methoxy-1H-pyrrolo[3,2-b]pyridine and 3-chloro-1-(R)-phenyl-propan-1-ol following the procedure of steps 1 and 2 of Example 11 (33% yield, 170 mg, [αD=−149° (CHCl3, c=1)])
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:16]([O:18]CC)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O>CO>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:16]([OH:18])=[O:17])=[C:10]([C:12]([F:14])([F:13])[F:15])[N:11]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1sc(N2CCOCC2)nc1C(F)(F)F
Yield: 98.9 %

Procedure:
Add ethyl 2-morpholino-4-(trifluoromethyl)thiazole-5-carboxylate (4.58 g, 14.8 mmol) to a mixture of 1 N NaOH (20 mL) in MeOH (20 mL), and heat the reaction to 50° C. for 1 h. Concentrate the reaction under reduced pressure, and add H2O to the residue. Acidify the mixture to pH 4, and filter the solid. Wash the solid with H2O, and dry to obtain the title compound (4.13 g, 99%). ES/MS m/z 283.0 (M+1).