Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1Cl)[CH3:2].[CH3:14][S:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1[O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([S:15][CH3:14])[CH:17]=1)[CH3:2]
Reactant: CSc1cccc(O)c1
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(F)cnc1Oc1cccc(SC)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution of ethyl-2-chloro-5-fluoro-nicotinoate (50.4 g, 0.247 mol) (prepared according to the method of J. Med. Chem., 1993, 36(18), 2676–88, page 2684, column 2, 3rd example, ethyl-2-chloro-5-fluoropyridine-3-carboxylate) (29 g, 0.143 mol) and 3-methylsulphanyl-phenol (20 g, 0.143 mol) (prepared according to the method of WO 98/45268, page 68, preparation 61) in dioxane (300 mL) was treated with caesium carbonate (46.5 g, 0.143 mol) at room temperature. The reaction mixture was heated to 100° C. and stirred for 48 hours. The reaction mixture was concentrated in vacuo and the residue taken up in water (600 mL) and extracted with ethyl acetate (3×250 mL). The organics were combined, washed with brine (200 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:toluene (99.75:0.25 to 99.5:0.5) to yield the title product as a yellow oil, 27.1 g (62%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:11][C:12]1[CH:13]=[C:14]([C@@H:18]([NH:20][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=2)[CH3:19])[CH:15]=[CH:16][CH:17]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C@@H:18]([NH:20][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=2)[CH3:19])[CH:13]=1)=[O:9]
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(N)c1
Reactant: Nc1cncc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](Nc1cncc(Cl)n1)c1cccc(NC(=O)c2cncc(N)c2)c1
Yield: 38 %

Procedure:
To a mixture of 5-aminonicotinic acid (35 mg, 0.25 mmol), N-[(1S)-1-(3-aminophenyl)ethyl]-6-chloropyrazin-2-amine (125 mg, 0.5 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (95 mg, 0.5 mmol) in N,N-dimethylformamide (2 mL) was added 1-hydroy-7-azabenzotriazole (1 mL, 0.5-0.7M in N,N-dimethylformamide, 0.5 mmol) then N-methylmorpholine (0.055 mL, 0.5 mmol) and the mixture was stirred at room temperature for 16 hours. After this time the mixture was diluted with ethyl acetate (40 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated under reduced pressure to give a yellow oil which was purified by flash chromatography (silica, ethyl acetate/methanol) to give 5-amino-N-(3-{(1S)-1-[(6-chloropyrazin-2-yl)amino]ethyl}phenyl)nicotinamide (35 mg, 38%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][C:4]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=1[NH2:6].[N:14]([O-])=O.[Na+].O>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[C:4]2[C:5](=[CH:7][CH:8]=[C:9]([Br:11])[CH:10]=2)[NH:6][N:14]=1
Reactant: Nc1ccc(Br)cc1CC(F)(F)F
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1n[nH]c2ccc(Br)cc12
Temperature: 15 °C

Procedure:
18 parts of 2-(2,2,2-trifluoro-ethyl)-4-bromo-aniline are dissolved in 490 parts by volume of glacial acetic acid. To this solution, well stirred at 15° C., is added all at once a solution of 4.9 parts of sodium nitrite in 11.9 parts of water. At the end of 3 days, the acetic acid is evaporated and the residue is taken up in 40 parts of water, the solid filtered off, washed and dried. 18 parts of 3-trifluoromethyl-5-bromo-indazole are thus obtained.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[C:7]([C:9]([C:17]#[N:18])=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:8].[CH2:19]1COCC1>>[C:7]([CH:9]([C:17]#[N:18])[C:10]([CH3:16])([C:2]1[CH:3]=[N:4][N:5]([CH3:19])[CH:6]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:8]
Reactant: CCOC(=O)C(C)=C(C#N)C#N
Reactant: C1CCOC1
Reactant: Ic1cn[nH]c1
Product: CCOC(=O)C(C)(c1cnn(C)c1)C(C#N)C#N
Temperature: -30 °C
Reaction time: 2 h

Procedure:
Isopropylmagnesium chloride LiCl complex (1627 μl, 2.115 mmol, 1.3 M in THF) was added to a THF solution of 4-iodo pyrazole (400 mg, 1.923 mmol) cooled to −30° C. The reaction was stirred for hours with the temperature maintained between −20 and −30° C. After two hours, ethyl 3,3-dicyano-2-methylprop-2-enoate (1442 μl, 1.442 mmol, 1 M solution in benzene) was quickly added and the reaction was warmed to room temperature and stirred for five minutes. The reaction was then quenched with saturated aqueous NH4Cl and extracted between EtOAc. The organic layer was dried (sodium sulfate) and concentrated in vacuo. Purification by silica gel column chromatography using a hexanes/EtOAc gradient afforded the title product as a clear oil, 1H NMR (500 MHz, CHCl3-d): δ 7.44 (s, 1H); 7.42 (s, 1H); 4.44 (s, 1H); 4.28-4.19 (m, 2H); 3.86 (s, 3H); 1.84 (s, 3H); 1.25 (t, J=7.12 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH:20]=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N+:23]([C:26]1[CH:45]=[CH:44][C:29]([CH2:30][O:31][C:32]([N:34]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][CH:36]=[CH2:37])=[O:33])=[CH:28][CH:27]=1)([O-:25])=[O:24].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][N:41]2[CH2:42][CH2:43][CH:38]([N:34]([C:32]([O:31][CH2:30][C:29]3[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:45][CH:44]=3)=[O:33])[CH2:35][CH:36]=[CH2:37])[CH2:39][CH2:40]2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC(C=O)C(c2ccccc2)C1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(CC2CC(NC(=O)OC(C)(C)C)CC2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.2 %

Procedure:
To a solution of 1-((SR)-((t-butoxycarbonyl)amino)-3-(SR)-(formyl)-4-(SR)-phenylcyclopentane (from Step G, derived from Higher Rf isomer in Step E) (30 mg, 0.11 mmol) in 1,2-dichloroethane (3 mL) was added 4-(N-(4-nitrobenzyloxycarbonyl)(N-allyl)amino)piperidine hydrochloride (45 mg, 0.126 mmol) and DIPEA (0.022 mL, 0.126 mmol). After 15 min, sodium triacetoxyborohydride (45 mg, 0.22 mmol) was added and the reaction was stirred at RT for 6 h. The reaction was diluted with methylene chloride, quenched with aq. sodium carbonate and extracted 3 times with methylene chloride. The organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by Prep TLC eluting with 5% methanol in methylene chloride to give the title product (66 mg) as the free amine.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=[C:17]([Cl:26])[CH:16]=1>>[Cl:26][C:17]1[CH:16]=[C:15]([O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: Oc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnc(Cl)cc1Oc1cccc2ccccc12
Yield: 62.4 %

Procedure:
Using the method of Example 3, Step A, naphthalen-1-ol (2.62 g, 18.2 mmol), 60% sodium hydride in mineral oil (727 mg, 18.2 mmol), and ethyl 4,6-dichloronicotinate (4.00 g, 18.2 mmol) afforded ethyl 6-chloro-4-(naphthalen-1-yloxy)nicotinate (3.72 g, 62% yield) as an oil. 1H NMR (CDCl3) δ 8.86 (s, 1H), 7.94 (d, 2H), 7.82 (d, 1H), 7.49-7.61 (m, 3H), 7.22 (d, 1H), 6.54 (s, 1H), 4.43 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: NC([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=1)=[CH:9][CH:8]=2)CC.[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH2:26]([O:33][C:34]([NH:6][CH2:5][CH2:13][CH2:12][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH:11]=2)[NH:6][CH:5]=1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCC(N)c1cc2cc(OCc3ccc4ccccc4n3)ccc2[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NCCCc1c[nH]c2ccc(OCc3ccc4ccccc4n3)cc12)OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1-aminopropyl-5-(2-quinolylmethoxy)-indole (1.0 g) and benzyloxycarbonyl chloride (1.0 ml) in toluene was heated at 100° C. for 15 minutes. The cooled solution was concentrated in vacuo and the resultant product purified by chromatographed on silica gel using 30%-ethyl acetate in n-hexanes as eluent to yield 1-(3-(benzyloxycarbonylamino-n-propyl)-5-(2-quinolylmethoxy)-indole (0.27 g), m.p. 109°-111° C.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=O.[C:16](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[CH:16]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
To solution of Example 1C (2 g, 9.38 mmol) in methanol (20 mL) was added potassium carbonate (3.89 g, 28.1 mmol) and the mixture was stirred for 30 minutes. Dimethyl 1-diazo-2-oxopropylphosphonate (3.60 g, 18.76 mmol) was added and the mixture was stirred for 12 hours. The mixture was filtered through diatomaceous earth and concentrated to afford crude material which was purified by column chromatography (silica gel, 15% ethyl acetate in hexane) to afford the title compound. 1H NMR (300 MHz, CDCl3): δ 1.41 (s, 9H), 1.55-1.59 (m, 1H), 1.67-1.69 (m, 2H), 1.96-1.99 (m, 1H), 2.06-2.07 (m, 1H), 2.43-2.44 (m, 1H), 2.93-3.02 (m, 2H), 3.69-3.75 (m, 1H), 3.9-4.0 (m, 1H).
Reaction SMILES: I(O)(=O)(=O)=[O:2].[F:6][C:7]([F:36])([F:35])[CH2:8][CH2:9][C@H:10]([NH:13][C@@H:14]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[C:15]([F:18])([F:17])[F:16])[CH2:11][OH:12]>C(#N)C.[O-2].[O-2].[O-2].[Cr+6]>[F:36][C:7]([F:6])([F:35])[CH2:8][CH2:9][C@H:10]([NH:13][C@@H:14]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[C:15]([F:16])([F:17])[F:18])[C:11]([OH:2])=[O:12]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CS(=O)(=O)c1ccc(-c2ccc([C@H](N[C@H](CO)CCC(F)(F)F)C(F)(F)F)cc2)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2ccc([C@H](N[C@@H](CCC(F)(F)F)C(=O)O)C(F)(F)F)cc2)cc1
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
A stock oxidant suspension was prepared by stirring periodic acid (2.28 g) and chromium trioxide (4.6 mg) in wet acetonitrile (0.75% water) to create a suspension of total volume of 22.8 mL. The oxidant suspension (4.22 mL) was then added to a stirred solution of (2S)-5,5,5-trifluoro-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}amino)pentan-1-ol (0.35 g, 0.74 mmol) in wet acetonitrile (3.7 mL) dropwise while maintaining the temperature at 0-5° C. The reaction mixture was allowed to warm to ambient temperature after one hour and then stirred for an additional 4 hours. The reaction was quenched with aqueous sodium hydrogen phosphate (6 g/100 mL) and toluene was added and the mixture shaken vigorously. The organic phase was washed with 1:1 brine:water, then with aqueous sodium bisulfite (2.2 g/50 mL), then brine. The organic layer was then dried with sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by silica gel chromatography using 5-10% methanol in methylene chloride as eluant to yield (2S)-5,5,5-trifluoro-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}amino)pentanoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH3:15])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Oc1cnc(Cl)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
A mixture of 0.17 g of 2-chloro-5-hydroxypyrimidine, 0.22 g of methyl 2-bromopropionate, 0.20 g of anhydrous potassium carbonate and 2.6 ml of N,N-dimethylformamide was stirred at 60° C. for 1 hour. The reaction solution was cooled to room temperature, then, poured into water, and extracted with t-butyl methyl ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.17 g of 2-chloro-5-[1-(methoxycarbonyl)ethoxy]pyrimidine.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]1=[O:13])=[O:5])[CH3:2].[Br:16]Br>C(OCC)C>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8]([Br:16])[C:7]=1[OH:13])=[O:5])[CH3:15]
Reactant: BrBr
Reactant: CCN(CC)C(=O)C1CC(C)CCC1=O
Solvent: CCOCC
Product: CCN(CC)C(=O)C1=C(O)C(Br)CC(C)C1
Temperature: 0 °C
Yield: 100.1 %

Procedure:
5-methyl-2-oxo-cyclohexanecarboxylic acid diethylamide (46) (4.4 g, 21 mmol) was dissolved in diethyl ether (5 mL) and cooled to 0° C. under N2. Bromine (3.32 g, 21 mmol, 1.1 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to room temperature over 90 min. The mixture was slowly poured into ice-cold saturated aqueous sodium carbonate solution (40 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were dried and concentrated in vacuo to afford 6.1 g (quantitative) of 3-bromo-2-hydroxy-5-methyl-cyclohex-1-enecarboxylic acid diethylamide (47) as an off-white solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 0.8-1.20 (9H, m, CH3 and N(CH2CH3)2), 1.80-2.40 (5H, m, CH2CH(CH3)CH2), 3.15-3.55 (4H, m, N(CH2CH3)2), 4.65-4.74 (1H, m, CHBr), and 12.04 (1H, s, OH).
Reaction SMILES: OO.[F:3][C:4]1[CH:9]=[C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:17][C:18](=[O:26])[C@:19]([OH:25])([CH3:24])[C:20]([F:23])([F:22])[F:21].C(OCC)(=[O:29])C.[OH2:33]>C(O)(=O)C>[F:3][C:4]1[CH:9]=[C:8]([S:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:29])=[O:33])[CH:7]=[CH:6][C:5]=1[NH:17][C:18](=[O:26])[C@:19]([OH:25])([CH3:24])[C:20]([F:23])([F:21])[F:22]
Reactant: C[C@@](O)(C(=O)Nc1ccc(Sc2ccccc2)cc1F)C(F)(F)F
Reactant: O
Reactant: CCOC(C)=O
Agent: OO
Solvent: CC(=O)O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1F)C(F)(F)F
Temperature: 100 °C

Procedure:
Hydrogen peroxide (0.2 ml of a 30 wt. % solution in water) was added to a solution of (R)-N-[2-fluoro-4-(phenylthio)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 7) (0.212 g) in glacial acetic acid (0.5 ml) and the mixture was stirred and heated at 100° C. for 75 minutes then allowed to cool. Ethyl acetate (20 ml) was added and the solution was washed with water (20 ml), saturated sodium hydrogen carbonate solution (10 ml) and brine and then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 20-30% ethyl acetate/hexane to give the title compound (0.155 g) as a solid. M.p. 121-122° C.; NMR: 1.58 (s, 3H), 7.58-7.7 (m, 4H), 7.8 (d, 1H), 7.9-8.05 (m, 4H), 9.8 (brs, 1H); MS: 390 (M−H)−; EA: C16H13F4NO4S 0.5H2O requires C, 48.0; H, 3.5; N, 3.5%; found: C, 47.8; H, 3.5; N, 3.4%.
Reaction SMILES: [N:1]([C@@H:4]([CH3:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][CH:16]([O:19]C(OCC)C)[CH2:15][C:13]3=2)[CH:8]=[N:7]1)=[N+:2]=[N-:3].C(OC1C=C2C(C=NN2C[C@@H](O)C)=CC=1)C1C=CC=CC=1>>[N:1]([C@@H:4]([CH3:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][CH:16]([OH:19])[CH2:15][C:13]3=2)[CH:8]=[N:7]1)=[N+:2]=[N-:3]
Reactant: CCOC(C)OC1COc2ccc3cnn(C[C@H](C)N=[N+]=[N-])c3c2C1
Agent: C[C@H](O)Cn1ncc2ccc(OCc3ccccc3)cc21
Product: C[C@@H](Cn1ncc2ccc3c(c21)CC(O)CO3)N=[N+]=[N-]

Procedure:
This compound was synthesized by following the procedure described in Example 2, Step I but using 1-((S)-2-azidopropyl)-8-(1-ethoxyethoxy)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazole, which was prepared from (S)-1-(6-benzyloxyindazol-1-yl)-propan-2-ol instead of (R)-1-(6-benzyloxyindazol-1-yl)-propan-2-ol as described: oil (0.45 g, 79%); LC/MS (+APCI) m/z 274 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C(Cl)Cl.[C:15](Cl)(=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:24])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1Cl
Yield: 26.1 %

Procedure:
To a solution of 2.0 g (1.1×10-2 mol) of 3-chloro-4-hydroxy benzoic acid in 40 ml of dried methylene chloride containing 3.0 g (9.2×10-3 mol) of pyridine was added dropwise 3.0 g (9.2×10-3 mol) of nonanoic acid chloride, which were stirred under reflux for 7 hours. After the completion of the reaction, the solution was washed with an aqueous solution of 1 normal hydrochloric acid and further with water and dried on anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the resulting product was purified through a silica gel column chromatography using methylene chloride and ethanol at 9:1 (v/v) as a developing solution and then recrystallized with 5 ml of ethanol to obtain 750 mg (yield: 25%) of a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]O)=[CH:39][CH:38]=1.N(C([O-])=O)=NC([O-])=O>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[S:12](=[O:14])(=[O:13])[N:11]([CH2:41][C:40]3[CH:43]=[CH:44][C:37]([O:36][CH3:35])=[CH:38][CH:39]=3)[C:10](=[O:15])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=C1CN(c2ccc(I)cc2)S(=O)(=O)N1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(c3ccc(I)cc3)S2(=O)=O)cc1

Procedure:
The title compound of Example 45, 5-(4-iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (355.9 mg, 1.05 mmol) is dissolved in THF (20 mL) in a 40 mL capacity septum capped vial, and stirred under argon balloon. Triphenylphosphine (552 mg, 2.11 mmol) is added as a solid and stirred until dissolved, then 4-methyoxybenzyl alcohol (0.156 mL, 1.26 mmol) is added by syringe. The stirred reaction is cooled in an ice bath, and disopropyl azodicarboxylate (0.415 mL, 2.11 mmol) is added slow dropwise by syringe. After two h, the reaction is concentrated in vacuo and the residue is taken up in CH2Cl2. Chromatography on a 35 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 10:90 (EtOAc:hexane) to 30:70 over 15 min gives 5-(4-iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid. 1H-NMR (300 MHz, CDCl3) 3.80 (s, 3H), 4.37 (s, 2H), 4.79 (s, 2H), 6.89 (d, J=7.5, 2H, aryl), 7.03 (d, J=7.5, 2H), 7.41 (d, J=7.5, 2H), 7.73 (d, J=7.5, 2H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.N#C[Br:27]>O1CCCC1>[CH2:1]([S:8][C:9]1[N:13]=[C:12]([Br:27])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CSc2ncn(-c3ccccc3)n2)cc1
Reactant: N#CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1nc(SCc2ccccc2)nn1-c1ccccc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
3-Benzylthio-1-phenyl-1,2,4-triazole (5 g) in dry tetrahydrofuran (50 ml) at -70° C. was treated dropwise with n-butyllithium (1.05 equivs). The solution was stirred at -70° C. for 10 minutes and cyanogen bromide (1.98 g) was added rapidly. The mixture was allowed to warm to room temperature and was then quenched with ethanol. The volatile materials were removed in vacuo, and the crude product was chromatographed on silica using dichloromethane to give 4.3 g of the desired product as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[C:10]([Cl:16])[CH:9]=2)=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[C:10]([Cl:16])[CH:9]=2)=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2cc(F)c(Cl)cc2[nH]1
Product: CCOC(=O)c1cc2cc(F)c(Cl)cc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=399.4 (M+H+), was prepared in accordance with the general method of example 12b) from 6-chloro-5-fluoro-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:16](=[O:34])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>O.C(O)C>[C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:16](=[O:34])[C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:33])[C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[CH:21][CH:22]=2)[CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(C(=O)N2CC(C(=O)O)Cc3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To 3-ethoxycarbonyl-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.6 g) are added an aqueous solution of sodium hydroxide (0.1 g) in water (1 ml) and ethanol (5 ml). The mixture is stirred at room temperature for 15 minutes, and acidified with diluted hydrochloric acid, extracted with dichloromethane. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane→dichloromethane:methanol=50:1), and recrystallized from ethanol to give 3-carboxy-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.4 g) as white powder, m.p. 221°-223° C.