Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7].[H][H].O(C(C)C)[K].CCCCCC>C1C=CC=CC=1>[CH3:1][CH:2]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7]
Reactant: CC(C)=CCCC(C)=Nc1ccccc1
Reactant: [H][H]
Agent: CC(C)O[K]
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CC(C)=CCCC(C)Nc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of N-(1,5-dimethyl-4-hexenylidene)aniline (2.0 g) in benzene (2 ml) was added under a flow of hydrogen gas to a mixture of RuHCl(R,R—BINAP)(R,R—CYDN) (5 mg) and KOiPr (5 mg) in a Schlenk flask. The flask was then cooled to liquid nitrogen temperature, filled with H2 gas, closed and allowed to gradually warm to room temperature. The mixture was vigorously stirred for 24 hours. A 1H NMR spectrum of the reaction mixture indicated complete conversion of the imine to the amine. Hexane (10 ml) was added to the mixture, which was then eluted (hexane) through a short column of silica gel in order to remove the spent catalyst and KOiPr. Evaporation of the hexane under reduced pressure resulted in spectroscopically pure N-(1,5-dimethyl-4-hexenyl)aniline, as verified by 1H and 13C NMR.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])([CH3:36])[CH3:35])[C:31]([CH2:42][O:43][CH2:44][CH3:45])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:47].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl.O>[NH2:47][C:26]1[C:25]2[N:30]=[C:31]([CH2:42][O:43][CH2:44][CH3:45])[N:32]([CH2:33][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])([CH3:36])[CH3:35])[C:24]=2[C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:29][C:28]=2[N:27]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reaction time: 8 h

Procedure:
mCPBA (11.2 g, 39.2 mmol) was added to a solution of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (prepared as described in Parts A-D of Example 52, 17.2 g, 35.6 mmol) in dichloromethane (350 mL). The solution was stirred overnight and additional mCPBA (approximately 1-2 g) was added. After 20 minutes, concentrated ammonium hydroxide (150 mL) was added. The mixture was stirred for 10 minutes and p-toluenesulfonyl chloride (8.20 g, 42.8 mmol) was added in portions. The mixture was stirred at ambient temperature for 2 days, then was filtered. A white solid was obtained, which was slurried in water, filtered, and dried to yield 11.7 g of N-{2-[4-amino-7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide. A small sample, 500 mg, was purified to yield 300 mg of analytically pure N-{2-[4-amino-7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide as a white solid, mp 264-266° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([OH:15])=O)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ClCCl.C[N:29]1[CH2:34][CH2:33]OCC1>C(OCC)(=O)C.CCCCCC>[CH2:16]([NH:24][C:13](=[O:15])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]([NH:29][CH2:34][CH2:33][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:12])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(=O)O
Reactant: NCCc1ccccc1
Reactant: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine t-butoxycarbonylaminomalonic acid (0.465 g, 2.12 mmol), phenethylamine (0.715 mL, 5.70 mmol), and dichloromethane (25 mL). Add N-methylmorpholine (0.752 mL, 6.85 mmol). Cool in an ice bath. Add benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate complex (3.15 g, 6.85 mmol). Remove the ice bath and allow to warm to ambient temperature. After 18 hours, dilute the reaction mixture with ethyl acetate, extract with an aqueous 5% sulfuric acid solution, a saturated sodium bicarbonate solution, and then brine. Dry the organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 2/1 ethyl acetate/hexane to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)Cc3ccccc3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)Cc2ccccc2)c1
Yield: 52.2 %

Procedure:
To a mixture of methyl 3,3-dimethyl-2-(3-(2-phenylacetamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (139 mg, 0.32 mmol) in methanol (5 mL) and water (2.5 mL) was added a solution of sodium hydroxide (220 mg, 5.50 mmol) in water (2.5 mL). The resultant mixture was heated for reflux for 1.5 hours. The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=5. The precipitates were collected by filtration, purified by preparative thin layer chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to afford 3,3-dimethyl-2-(3-(2-phenylacetamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a solid. (70 mg, yield: 52.2%). MS (ESI+APCI) M+1-OH=397.2.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][C:18]=23)[CH:14]=[N:13]1)([CH3:11])[CH2:8][CH2:9][OH:10].C(Cl)Cl>>[CH3:1][S:2]([O:10][CH2:9][CH2:8][C:7]([CH3:6])([N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[CH:24]=[CH:25][C:18]=23)[CH:14]=[N:13]1)[CH3:11])(=[O:4])=[O:3]
Reactant: CC(C)(CCO)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(CCOS(C)(=O)=O)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
TEA (38.0 μL, 0.000273 mol) and methanesulfonyl chloride (21.1 μL, 0.000273 mol) were added sequentially to a solution of 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol (prepared as in Example 58) (81 mg, 0.00020 mol) in DCM (4 mL, 0.05 mol) at 0° C. The reaction mixture was held at this temperature for 1.5 hours, then was quenched by the addition of water. The reaction mixture was extracted with DCM four times. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford crude 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butyl methanesulfonate (87 mg). MS(ES): 479 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[O:26][CH3:27].N1CCCCC1>C(O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:14](=[O:15])/[C:13](=[CH:22]/[C:21]2[CH:24]=[CH:25][C:18]([OH:17])=[C:19]([O:26][CH3:27])[CH:20]=2)/[C:12]([CH3:16])=[N:11]1
Reactant: CC1=NN(c2nc3ccccc3s2)C(=O)C1
Reactant: COc1cc(C=O)ccc1O
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(/C=C2/C(=O)N(c3nc4ccccc4s3)N=C2C)ccc1O

Procedure:
1 g (4.32 mmol) of 2-(1,3-benzothiazol-2-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one and 1.97 g (12.96 mmol) of 4-hydroxy-3-methoxybenzaldehyde are stirred under reflux with the addition of 3 ml of piperidine in absolute ethanol for 2 hours. The mixture is then diluted with water and the orange-yellow precipitate is filtered off, then washed with water and a small amount of cold methanol and dried under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[CH:6]=2.[C:13]([Cu])#[N:14].CN(C=O)C>C(Cl)Cl>[Cl:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:13]#[N:14])[CH:3]=[N:4]2)=[CH:9][CH:8]=1
Reactant: Clc1ccc2cc(Br)cnc2c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cnc2cc(Cl)ccc2c1
Temperature: 150 °C

Procedure:
To a flask containing a stir bar was added 3-bromo-7-chloroquinoline (1.0 g, 4.1 mmol), CuCN (0.55 g, 6.2 mmol) followed by addition of DMF (25 mL). The resulting mixture was then heated to 150° C. overnight. When the reaction was complete as evidenced by LC analyisis, the reaction flask was taken out of the oil bath and cooled to RT. To the reaction mixture was then poured DCM (20 mL) and a precipitate formed immediately, which was filtered. The filtrated was washed with aq. NH4Cl, dried over sodium sulfate, and purified by flash chromatography. LC-MS (IE, m/z): 189 [M+1]+.
Reaction SMILES: O=C1C2C(C=CC=C2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][C:25]([NH2:27])=[O:26])[CH2:18][CH2:17]1.O.NN.C(O)(=O)C>C(O)C>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][C:25]([NH2:27])=[O:26])[CH2:18][CH2:17]1
Reactant: NC(=O)CCCC1CCN(CCCCN2C(=O)C3C=CC=CC3C2=O)CC1
Agent: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: NCCCCN1CCC(CCCC(N)=O)CC1
Temperature: 25 °C
Yield: 130.8 %

Procedure:
Compound 4 (0.30 g, 0.76 mmol) was dissolved in ethanol (5 mL). To the solution was added hydrazine monohydrate (0.11 mL, 2.28 mmol) followed by a catalytic amount of acetic acid (0.1 mL). The mixture was heated to reflux for two hours, cooled to room temperature, and concentrated under vacuum. The resulting residue was subjected to column chromatography eluting with 0-20% (20:80 ammonium hydroxide/methanol) in dichloromethane to afford the desired product 5 (0.24 g, 80%) as a colorless, viscous oil: 1H NMR (500 MHz, CD3OD) δ 1.25 (m, 4H), 1.55 (m, 6H), 1.72 (m, 2H), 2.00 (m, 2H), 2.18 (m, 3H), 2.36 (t, 2H), 2.74 (t, 2H), 2.96 (d, 2H), 3.28 (br, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[NH:4][C:5]([CH3:9])([CH3:8])[C:6]#[CH:7].[F:11][C:12]1[C:13](I)=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])/[C:15]/2=[CH:22]\[C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:10])[NH:4][C:5]([CH3:9])([CH3:8])[C:6]#[C:7][C:13]1[C:12]([F:11])=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:22]/[C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])/[C:16](=[O:21])[NH:17]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC(C)(C)NC(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C)(C)C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, (1,1-dimethyl-2-propynyl)-carbamic acid methyl ester (47.7 mg, 0.34 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give (Z)-[3-[2,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4yl]-1,1-dimethyl-2-propynyl]carbamic acid methyl ester. (Yield 40 mg, 77%).
Reaction SMILES: BrC[CH2:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7].Cl.Cl.[N:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[CH3:23]N(C)C=O.C(=O)(O)[O-].[Na+]>C(O)C>[N:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH3:3])[CH2:19][CH2:18]1
Reactant: CN(C)C=O
Reactant: CCCC(=O)CCBr
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)CCCCN1CCN(c2ncccn2)CC1
Yield: 57.2 %

Procedure:
A solution of 17.9 g of 6-bromo-4-hexanone and 23.7 g of 1-(2-pyrimidinyl)piperazine dihydrochloride in 500 ml of ethanol and 100 ml of dimethylformamide containing 42 g of sodium bicarbonate is refluxed for 12 hours. The mixture is filtered through Celite, evaporated in vacuo, and the residue chromatographed over silica gel to give 15 g of 6-[4-(2-pyrimidinyl)-1-piperazinyl]-2-hexanone; mp 44°-47° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH2:4][CH2:5][CH3:6].[F:14][C:15]1[C:16]([C:34](O)=[O:35])=[N:17][CH:18]=[CH:19][C:20]=1[S:21][C:22]1[S:26][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:24][CH:23]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[F:14][C:15]1[C:16]([C:34]([NH:1][CH2:2][C:3]([OH:7])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH3:6])=[O:35])=[N:17][CH:18]=[CH:19][C:20]=1[S:21][C:22]1[S:26][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:24][CH:23]=1
Reactant: O=C(O)c1nccc(Sc2cnc(Nc3ccccn3)s2)c1F
Reactant: CCCC(O)(CN)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCC(O)(CNC(=O)c1nccc(Sc2cnc(Nc3ccccn3)s2)c1F)c1ccccc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
1-Amino-2-phenylpentan-2-ol (0.099 g, 0.45 mmol, 1.5 eq) was dissolved in NMP (3 mL) and to this solution was added 3-fluoro-4-(2-(pyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (0.101 g, 0.30 mmol), EDAC (0.089 g, 0.45 mmol, 1.5 eq), HOBt (0.042 g, 0.30 mmol, 1 eq) and diisopropylethylamine (0.16 mL, 0903 mmol, 3 eq). The resulting mixture was stirred at 23° C. for 2 h. The mixture was then purified on preparative HPLC (ammonium acetate/water/acetonitrile) and freeze dried to give the title compound (0.0552 g, 36%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 0.76 (3H, t, J=7.33 Hz), 0.84-0.96 (1H, m), 1.19-1.30 (1H, m), 1.68-1.79 (2H, m), 3.63 (2H, d, J=5.81 Hz), 5.29 (1H, s), 7.01 (1H, dd, J=6.82 and 5.56 Hz), 7.05 (1H, t, J=5.18 Hz), 7.12 (1H, d, J=8.34 Hz), 7.20 (1H, t, J=7.33 Hz), 7.31 (2H, t, J=7.71 Hz), 7.42-7.46 (2H, m), 7.78 (1H, td, J=7.77 and 1.89 Hz), 7.82 (1H, s), 8.22-8.26 (2H, m), 8.31 (1H, dd, J=5.05 and 1.01 Hz), 11.88 (1H, s). LC/MS (M+H)+: 510. HPLC ret. time (Condition J): 6.095 min. HRMS calcd: 510.1434; found: 510.1412.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.[CH:28]12[N:34]([S:35]([CH2:38][C:39]3[C:44]([C:45]([O:47][CH3:48])=[O:46])=[C:43]([O:49][CH3:50])[C:42](Br)=[CH:41][CH:40]=3)(=[O:37])=[O:36])[CH:31]([CH2:32][CH2:33]1)[CH2:30][CH2:29]2>>[CH:28]12[N:34]([S:35]([CH2:38][C:39]3[C:44]([C:45]([O:47][CH3:48])=[O:46])=[C:43]([O:49][CH3:50])[C:42]([C:23]4[CH:27]=[CH:26][O:25][CH:24]=4)=[CH:41][CH:40]=3)(=[O:37])=[O:36])[CH:31]([CH2:32][CH2:33]1)[CH2:30][CH2:29]2
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)N2C3CCC2CC3)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)N2C3CCC2CC3)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 6-(7-azabicyclo[2.2.1]heptane-7-ylsulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 177) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:27])[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1)[CH3:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.ClCCl>CO>[Cl:10][C:9]1[CH:8]=[C:7]([Cl:11])[CH:6]=[C:5]2[C:4]=1[C:3](=[O:2])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1)([CH3:15])[C:13](=[O:27])[NH:12]2
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OC)c([N+](=O)[O-])c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C2(C)C(=O)Nc3cc(Cl)cc(Cl)c3C2=O)cc1[N+](=O)[O-]
Yield: 64.6 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 4,6-dichloro-2-[2-(4-methoxy-3-nitro-phenyl)-propionylamino]-benzoic acid methyl ester (0.20 g, 0.47 mmol) and LiHMDS (1.40 mmol, 1M THF solution). After normal workup, the objective compound (120 mg, 71%) was obtained as yellow solid by a flash column chromatography (dichloromethane:methanol=30:1): 1H NMR (200 MHz, DMSO-d6) δ 1.60 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 7.05 (d, J=2.0 Hz, 1H, ArH), 7.29-7.37 (m, 2H, ArH), 7.61 (d, J=2.0 Hz, 1H, ArH); m.p. 255-256° C.; MS(EI) m/e 394 [M+], 207, 132, 119; HRMS m/e cacld. for C17H12N2O5Cl2 394.0123, found 394.0114.
Reaction SMILES: [Na].CC(S)(C)C.C[S:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.Cl>CN(C)C=O>[SH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1
Reactant: CSc1ccc(C=O)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)(C)S
Solvent: CN(C)C=O
Product: O=Cc1ccc(S)cc1
Temperature: 25 °C
Yield: 38.4 %

Procedure:
Combine 2-methyl-2-propanethiol sodium salt (2.9 g, 26.3 mmol) and 4-(methylthio)benzaldehyde (2.0 g, 13.2 mmol) with dimethylformamide (40 mL) in a dry flask then heat at 160° C. for 4 hours. Cooled to room temperature, poured into 3N aqueous hydrochloric acid (400 mL) then extracted with dichloromethane (3×75 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (3 g). The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to yield 4-mercapto-benzaldehyde (0.7 g): 1H NMR (DMSO-D6, 300.00 MHz): 9.9 (s, 1H), 7.7 (d, 2H), 7.5 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O.[Cu]I>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][NH:8]2)=[CH:3][C:2]=1[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(OC)c1nc2c(cc1-n1ccnc1)CCCN2
Temperature: 120 °C

Procedure:
A suspension of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 12, 200 mg, 0.696 mmol), imidazole (66 mg, 0.969 mmol), Cs2CO3 (454 mg, 1.393 mmol) and CuI (27 mg, 0.142 mmol) in DMF (1.4 ml) was heated to 120° C. for 19 h. The reaction mixture was diluted with ethyl acetate and water, layers were separated and the aqueous layer was extracted with ethyl acetate (7×). Organic layers were combined, washed with water and brine, dried using Na2SO4, filtered, evaporated and dried to yield the title compound as a yellow solid. (UPLC-MS 3) tR 0.45 min, ESI-MS 275.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2ccccc2)cc1OCc1ccccc1
Reaction time: 1 h

Procedure:
A 60% suspension of sodium hydride in mineral oil (490 mg, 12.2 mmol) is stirred in 15 mL of DMF. To this mixture is carefully added benzenethiol (1.25 mL, 1.34 g, 12.2 mmol) and the mixture stirred for 1 h. To this solution is added portionwise 2-benzyloxy-4-fluoronitrobenzene (3.00 g, 12.1 mmol), giving initially a dark solution that eventually changed to pale yellow. When LC shows disappearance of starting material, the mixture is poured into ethyl acetate and extracted with water, 1N sodium hydroxide, and four times with brine. This solution is dried, filtered, and solvent removed under reduced pressure to leave a heterogeneous mixture that is triturated with hexane, filtered, and the solids washed with hexane to afford 2-benzyloxy-1-nitro-4-phenylsulfanylbenzene, mp 77-79° C.: NMR (CDCl3) δ 7.79 (d, 1H, J=8.6 Hz), 7.46 (m, 5H), 7.33 (m, 5H), 6.77 (d, 1H, J=1.8 Hz), 6.72 (dd, 1H, J=8.6, 1.8 Hz), 5.08 (s, 2H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][C:32]=2[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.[CH3:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([N:57]4[CH2:58][CH2:59][N:54]([CH3:53])[CH2:55][CH2:56]4)=[O:46])([CH3:43])[CH3:44])=[CH:33][C:32]=3[CH3:49])=[C:28]([CH:50]([CH3:51])[CH3:52])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CN1CCNCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(N)C(N)=O
Product: Cc1cc(OCCC(=O)NC(C)(C)C(=O)N2CCN(C)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-methylpiperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:26])[N:6]2[CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.O1CCOCC1.C(Cl)CCl.O[N:38]1[C:42](=[O:43])[CH2:41][CH2:40][C:39]1=[O:44]>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:26])[N:6]2[CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:23][N:38]2[C:42](=[O:43])[CH2:41][CH2:40][C:39]2=[O:44])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C1CCC(=O)N1O
Reactant: COCCOc1nc(N)c2nc(O)n(Cc3ccc(C(=O)O)cc3)c2n1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCCOc1nc(N)c2nc(O)n(Cc3ccc(C(=O)ON4C(=O)CCC4=O)cc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
The product of example 10 (2 mmol) is dissolved in dichloromethane or dioxane (10 mL) and EDC (2 mmol) is added. To this solution is added N-hydroxysuccinimide (2 mmol) and resulting mixture is stirred at room temperature for 1 h. The mixture is taken to dryness in vacuo and the crude product is purified by silica gel chromatography to yield 2 mmol of product that is suitable for conjugation reactions involving primary amines.