Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]([O:38][C:39](=[O:48])[NH:40][CH2:41][CH:42]=[CH:43][Si](C)(C)C)([CH3:37])([CH3:36])[CH3:35].I[C:50]1[CH:68]=[CH:67][C:53]([O:54][CH2:55][C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[N:59]=[C:58]([CH3:66])[CH:57]=2)=[CH:52][CH:51]=1>C1C=CC=CC=1.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:34]([O:38][C:39](=[O:48])[NH:40][CH2:41][C:42]([C:50]1[CH:68]=[CH:67][C:53]([O:54][CH2:55][C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[N:59]=[C:58]([CH3:66])[CH:57]=2)=[CH:52][CH:51]=1)=[CH2:43])([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1cc(COc2ccc(I)cc2)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)NCC=C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: C=C(CNC(=O)OC(C)(C)C)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 50 °C
Yield: 14.7 %

Procedure:
THF (1.5 mL), Pd(OAc)2 (20 mg, 0.089 mmol, 8% eq) and 1,2-bis(diphenylphosphino)ethane (35.5 mg, 16% eq) were mixed under N2, degassed and stirred to give orange yellow mixture. A premixed solution of (3-trimethylsilanylallyl)-carbamic acid tert-butyl ester (250 mg, 1.09 mmol) from (7b) and 4-(4-iodo-phenoxymethyl)-2-methyl-quinoline (410 mg, 1.0 eq) from (7c) in benzene (3 ml) was added. The resulting mixture was heated at 50° C. over the weekend, then cooled to rt, diluted with ether, washed with water, dried and concentrated. {2-[4-(2-Methyl-quinolin-4-ylmethoxy)-phenyl]-allyl}-carbamic acid tert-butyl ester (65 mg, 14.8%) was obtained after the crude was purified by flash column chromatography (20%–40% ethyl acetate-hexanes). MS Found: (M+H)+=405.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[Br:17]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([Br:17])=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(F)cc1C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Br)cc(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.5 %

Procedure:
To a mixture of 0.78 g of 2-amino-5-fluorobenzoic acid and 100 ml of N,N-dimethylformamide was added 1.1 g of N-bromosuccinimide at room temperature, and the mixture was stirred at room temperature for 5 hours. After water was added to the reaction mixture, a deposited precipitate was collected by filtration, and then washed with acetone to obtain 0.43 g of 2-amino-3-bromo-5-fluorobenzoic acid of the formula:
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH:22]([CH3:24])[CH3:23])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)C.[Cl-].[Ca+2].[Cl-]>O.[Fe]>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[NH2:19])[CH:22]([CH3:24])[CH3:23])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1)C2(c1cccc([N+](=O)[O-])c1)C(C)C
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCCCCCN1CC2C(C1)C2(c1cccc(N)c1)C(C)C
Yield: 104.8 %

Procedure:
To a stirred suspension of 3-hexyl-6-isopropyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane (Preparation 60, 0.18 g, 0.54 mmol), ethanol (15 ml) and iron powder (0.27 g, 4.88 mmol) was added calcium chloride (0.06 gmu 0.54 inmol) in water (3 ml). The reaction mixture was heated under reflux for 3 h and then filtered through a pad of Celite®, the mother liquors were concentrated in vacuo. The residue was dissolved in dichloromethane and filtered again through a Sep-Pak® Plus cartridge containing silica (1.5 g), (Water Division Millipore), to remove any residual iron salts and then concentrated to give the crude title compound as a yellow solid (0.17 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)[C:5]#[N:6].O.O.Cl[Sn]Cl>C1COCC1.CCO>[NH2:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cc(N)cc(Br)c1
Temperature: 25 °C
Reaction time: 12.5 h
Yield: 62.9 %

Procedure:
To a stirring solution of 845 mg (3.72 mmol) of 3-bromo-5-nitrobenzonitrile in 5 mL of THF and 5 mL of EtOH was added 4.2 g (18.6 mmol) of SnCl2.2H2O in several portions. The reaction became slightly exothermic and was stirred at r.t. for about 12.5 h. The mixture was concentrated and 30 mL of 2 N NaOH was added. After the mixture was stirred for 2 h, H2O and EtOAc were added, and the organic layer was washed with 50 mL of H2O and 40 mL of brine. The aqueous layer was extracted with EtOAc and washed with brine. The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (35% EtOAc/hexanes) provided 461 mg of 3-amino-5-bromobenzonitrile as a yellow solid in 63% yield.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH2:16]1[O:24][C:23]2[CH:22]=[CH:21][C:20]([CH2:25][CH2:26][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:28])=[CH:19][C:18]=2[O:17]1>CCCCCC.O1CCCC1>[O:24]1[C:23]2[CH:22]=[CH:21][C:20]([CH2:25][CH2:26][C:27]3([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:28][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]3)=[CH:19][C:18]=2[O:17][CH2:16]1
Reactant: O=C(CCc1ccc2c(c1)OCO2)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(CCc2ccc3c(c2)OCO3)(c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 0.22 mL of methyl acetoacetate, 90 mg of NaH 60% dispersion in oil, 1 mL of 2.1M n-butyl lithium in hexane, 500 mg of 3-(3,4-methylenedioxyphenyl)propiophenone and 15 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature and stirred for 2 hours. The crude product was triturated from diethyl ether to afford a solid (m.p. 112°-114° C. ). 1H NMR (CDCl3) δ 2.20-2.28 (m, 2 H), 2.37-2.44 (m, 1 H), 2.61-2.69 (m, 1 H), 2.95 (dd, 2 H), 3.32 (dd, 2 H), 5.90 (s, 2 H), 6.52-6.70 (m, 3 H), 7.33-7.44 (m, 5 H).
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.N([O-])=[O:14].[Na+].[OH-].[Na+]>OS(O)(=O)=O.O>[OH:14][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2
Reactant: O=N[O-]
Reactant: Cc1ccc2ncc(N)cc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2ncc(O)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
A solution of 3-Amino-6-methylquinoline [(1.21 g, 7.65 mmol), prepared according to J. Chem. Soc. 2024-2027 (1948) Morley, J. S.; Simpson, J. C. E.] in 6N H2SO4 (25 ml) was cooled in an ice bath. To the solution NaNO2 (560 mg, 8.10 mmol) in water (2 ml) was added and stirred for 30 min at 0 degrees. Separately 5% H2SO4 was refluxed and above Diazo reaction mixture was added to this refluxing solution. After 30 min the reaction mixture was cooled to room temperature, and was neutralized by 6N NaOH. The resulting insoluble material was collected by filtration. This solid was recrystallized by CHCl3/AcOEt to afford compound (308) (348 mg, 29%).
Reaction SMILES: [Br:1]Br.C(O)(=O)C.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([CH3:23])[CH:10]=1>O>[Br:1][C:14]1[CH:13]=[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:11]([CH3:23])=[CH:10][C:9]=1[O:8][CH3:7]
Reactant: BrBr
Reactant: COc1ccc(Cc2ccc(C)cc2)c(C)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C)c(Cc2ccc(C)cc2)cc1Br
Temperature: 110 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Br2 was added dropwise to an acetic acid (35 mL) solution of 4-methoxy-2-methyl-1-(4-methylbenzyl)benzene while cooled on ice. The reaction mixture was stirred at 110° C. for two hours. After the reaction mixture was added with water while cooled on ice and extracted with ethyl acetate, the organic phase was washed with a saturated sodium bicarbonate aqueous solution and brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to obtain a yellow oily title compound (4.21 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=O)=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.CSC.CO>C1COCC1>[CH3:10][N:8]([CH2:6][C:5]1[CH:11]=[CH:12][C:2]([NH2:1])=[CH:3][C:4]=1[C:13]([F:14])([F:16])[F:15])[CH3:9]
Reactant: CN(C)C(=O)c1ccc(N)cc1C(F)(F)F
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)Cc1ccc(N)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of 4-amino-N,N-dimethyl-2-(trifluoromethyl)benzamide (8.3 g, 23.59 mmol) in THF (100 mL) stirred under a N2 atmosphere at 20° C. was added BH3.DMS (11.20 mL, 118 mmol) dropwise. The reaction mixture was stirred at 80° C. for 2 h. To the solution was added MeOH, then concentrated in vacuo to give the crude product. The crude material was purified by silica column chromatography (DCM/MeOH=30:1). All fractions found to contain product by TLC (DCM/MeOH=10:1, Rf=0.4) were combined and concentrated to yield light yellow oil of 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline (4 g, 18.33 mmol, 78.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.99 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.67 (d, 8.0 Hz, 1H), 4.57 (s, 2H), 2.96 (s, 6H); ES-LCMS m/z 219.2 (M+H).
Reaction SMILES: [O-]S(C(F)(F)[F:6])(=O)=O.F[N+]1C(Cl)=CC=CC=1Cl.[F:18][C:19]1[C:36]([NH:37][S:38]([CH2:41][CH2:42][CH3:43])(=[O:40])=[O:39])=[CH:35][CH:34]=[C:33]([F:44])[C:20]=1[C:21]([NH:23][C:24]1[CH:25]=[C:26]2[CH:32]=[CH:31][NH:30][C:27]2=[N:28][CH:29]=1)=[O:22]>CC#N.CCOC(C)=O>[F:18][C:19]1[C:36]([NH:37][S:38]([CH2:41][CH2:42][CH3:43])(=[O:40])=[O:39])=[CH:35][CH:34]=[C:33]([F:44])[C:20]=1[C:21]([NH:23][C:24]1[CH:25]=[C:26]2[C:32]([F:6])=[CH:31][NH:30][C:27]2=[N:28][CH:29]=1)=[O:22]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(F)c3c2)c1F
Temperature: 60 °C
Yield: 25.9 %

Procedure:
1-Fluoro-2,6-dichloropyridinium triflate (31 mg, 0.1 mmol) was added to 2,6-difluoro-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (39 mg, 0.1 mmol) in MeCN (4 mL). The mixture was heated at 60° C. for 18 hours and then cooled to room temperature. The mixture was then diluted with EtOAc, washed with brine, dried over MgSO4 and concentrated. The crude product was purified using silica gel chromatography (ISCO) using 5% MeOH in CH2Cl2 as eluent, and subsequently reverse phase HPLC to give 2,6-difluoro-N-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (10.7 mg, 26%). 1H NMR (400 MHz, d6-DMSO) δ 11.51 (s, 3H), 10.97 (s, 3H), 9.77 (s, 3H), 8.41 (s, 6H), 7.70-7.38 (m, 6H), 7.26 (t, J=8.5, 3H), 3.45-2.96 (m, 32H), 2.50 (s, 57H), 2.36-2.09 (m, 1H), 1.77 (dd, J=7.5, 15.1, 6H), 1.00 (t, J=7.4, 9H); m/z (LC-MS) M+1=413.4.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc(O)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(C=O)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-3-hydroxybenzaldehyde (4.55 g, 29 mmol) in DMF (30 mL) was added K2CO3 (4.8 g, 34.9 mmol) followed by MeI (2.7 mL, 43.6 mmol), and the mixture was stirred at room temperature for 16 hours. Following concentration in vacuo, the residual was taken up in ethyl acetate, washed with H2O, brine, dried over Na2SO4, and concentrated. Purification by column chromatography on silica gel with ethyl acetate/hexanes 1/5 afforded 2-chloro-3-methoxybenzaldehyde 7a (4.68 g, 94%) as a colorless oil, which solidified upon standing. GCMS (EI) m/z 170, 172 (M+).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:14]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:13][NH:12][C:9]3=[CH:10][N:11]=2)[CH:5]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O[N:34]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C>[NH3:1].[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([NH:34][C:17](=[O:19])[CH2:16][CH2:15][C:14]2[C:8]3[C:9](=[CH:10][N:11]=[C:6]([N:4]4[CH:5]=[N:1][N:2]=[CH:3]4)[CH:7]=3)[NH:12][CH:13]=2)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CCc1c[nH]c2cnc(-n3cnnc3)cc12
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N
Product: O=C(CCc1c[nH]c2cnc(-n3cnnc3)cc12)NN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.6 %

Procedure:
To a suspension of 3-(5-(1,2,4-triazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propionic acid (0.23 g) in dry DMF (3 mL) was added 1-benzylpiperazine (0.1 mL, 0.58 mmol), 1-hydroxybenzotriazole (66 mg, 0.49 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (93 mg, 0.49 mmol) and triethylamine (68 μL, 0.4 mmol) and this mixture was stirred at ambient temperature under nitrogen for 24 hours. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (25 mL) and water (20 mL). The two phases were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organics were dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica eluting with 90:10:1, DCM:MeOH:NH3 to give the title compound (30 mg, 19%) as a colourless solid. mp 185° C. (dec.). 1H NMR (360 MHz, CDCl3 :d4 -MeOH 9:1) δ 2.29-2.34 (2H, m), 2.35-2.42 (2H, m), 2.70 (2H, t, J=7.4Hz), 3.12 (2H, t, J=7.4Hz), 3.36-3.43 (2H, m), 3.48 (2H, s), 3.58-3.64 (2H, m), 7.24-7.35 (5H, m), 7.37 (1H, s), 7.67 (1H, s), 8.60 (1H, s) and 8.93 (2H, s).
Reaction SMILES: CN1CCCCC1.[CH3:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1.[NH2:19][CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][C:31]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)=[O:32])[CH:28]=2)[O:23][C:22]([CH3:43])([CH3:42])[CH:21]1[OH:44]>ClCCl>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][NH:33][C:31](=[O:32])[CH2:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[O:23][C:22]([CH3:43])([CH3:42])[CH:21]([OH:44])[CH:20]3[NH:19][S:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[CH:10]=2)(=[O:17])=[O:16])=[CH:36][CH:37]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC1(C)Oc2ccc(CC(=O)NCc3ccc(Cl)cc3)cc2C(N)C1O
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: Cc1cccc(S(=O)(=O)NC2c3cc(CC(=O)NCc4ccc(Cl)cc4)ccc3OC(C)(C)C2O)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
15 mg PS-methylpiperidine and a solution of 6.0 mg 3-methylbenzenesulfonyl chloride in 0.5 ml dichloromethane were added in succession in a sample well of a sample plate for automatic parallel synthesis to a solution of 9 mg of the 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-4-chlorobenzyl acetamide obtained above in 0.5 ml dichloromethane. The sample plate was shaken for 40 hours at room temperature, and then 20 mg AMPS was added to the well. The plate was shaken for a further 16 hours at room temperature before the liquid reaction phase was separated from the resin, and the resin was washed twice with 1 ml portions of dichloromethane. The solvent of the combined organic phases was evaporated at reduced pressure, and the title compound was obtained in a purity of 95% (determination by HPLC-MS), [M+H]+ 529.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]2[C:19]=1[C:20](=[O:29])[C:21](=[O:28])[NH:22]2.Cl>C1COCC1.CCCCCC>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]2[C:19]=1[C:20]([OH:29])([C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=1)[C:21](=[O:28])[NH:22]2
Reactant: Brc1ccc2ccccc2c1
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1Nc2cc(Cl)cc(Cl)c2C1(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
To a solution of 2-bromonaphthalene (2.952 g) in anhydrous THF (25 mL) was added portion wise a solution of n-butyl lithium in n-hexane (1.55 N, 10.12 mL) at −78° C. The reaction solution was stirred for 30 minutes. To the mixture was then added portion wise a solution of 4,6-dichloroisatin (1.54 g) in anhydrous THF (25 ml) for 50 minutes. The reaction mixture was stirred for 2 hours. Then the mixture was allowed to warm to room temperature. To the mixture was added 1N HCl and extracted by ethyl acetate. The organic phase was separated, washed with 1N HCl and brine and dried over MgSO4 and concentrated . Purification was carried out by silica gel chromatography (hexane:ethyl acetate, 2:1 to 1:1 gradient) to give the title compound (0.652 g, yield: 27%).
Reaction SMILES: [P:1]([O-:26])([O:22][CH2:23][CH2:24]Br)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>C1(C)C=CC=CC=1>[P:1]([O-:26])([O:22][CH2:23][CH2:24][N+:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2]
Reactant: CCCCCCCCCCCCOCCOCCOP(=O)([O-])OCCBr
Reactant: c1ccnnc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOCCOCCOP(=O)([O-])OCC[n+]1ccccn1
Temperature: 60 °C
Yield: 40 %

Procedure:
3,6-Dioxaoctadecyl 2-bromoethyl phosphate (3.0 g) and pyridazine (5 g) are dissolved in toluene (60 ml) and warmed at 60° C. The solvent is distilled off, silver carbonate and methanol are added, and the mixture is refluxed. The insolubles are filtered off, the filtrate is concentrated to dryness, and the residue is purified by silica gel chromatography (developing solvent: chloroform-methanol-water) to give 1.2 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([O:13][CH:14]([CH3:16])[CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:18][S:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]CS([O-])(=O)=O)=[CH:25][CH:24]=1)(=[O:21])=[O:20]>>[CH3:1][O:2][C:3](=[O:17])[CH:4]([O:13][CH:14]([CH3:15])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:30][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([O:22][S:19]([CH3:18])(=[O:20])=[O:21])=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)OC(C)C
Reactant: CS(=O)(=O)Oc1ccc(CCCS(=O)(=O)[O-])cc1
Product: COC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OC(C)C

Procedure:
2-Isopropoxy-3-[4-(2-{4-methylsulfonyloxyphenyl}ethoxy)phenyl]propanoic acid methyl ester was synthesized from 3-(4-hydroxyphenyl)-2-isopropoxypropanoic acid methyl ester and 2-(4-methanesulfonyloxyphenyl)ethylmethanesulfonate (described in Example 1b) using the same method as in Example 58e.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][SH:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S-:17].[Na+].II.Cl>O.C1COCC1.CCO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][S:17][CH3:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCS)C(=O)O
Agent: Cl
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CSSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 159.3 %

Procedure:
(S)-2-((tert-butoxycarbonyl)amino)-4-mercaptobutanoic acid (Boc-L-Hcs-OH) (188 mg, 0.4 mmol) was dissolved in H2O/THF (50% v/v, 16 mL). To the solution was added sodium thiomethoxide (560 mg, 8.0 mmol) at 0° C. Then, a solution of iodine in 95% EtOH was added dropwise until the color of the reaction system changed from colorless to brown. The mixture was stirred for 1.5 h with warming to room temperature. After removing THF under reduced pressure, reaction mixture was neutralized by 1 N HCl aq. until pH 2-3. The solution was extracted with EtOAc. The extract was washed with saturated NaS2O4 aq. and brine, and dried over MgSO4. Concentration under reduced pressure followed by flash chromatography over silica gel with EtOAc/Hexanes/AcOH (75:25:1) gave Boc-L-Hcm-OH (179.3 mg, 80% yield): 1H NMR (360 MHz, CDCl3) δ 5.06 (s, 1H), 4.44 (s, 1H), 2.78 (t, J=7.7 Hz, 2H), 2.42 (s, 3H), 2.35 (m, 1H), 2.09 (m, 1H), 1.45 (s, 9H); LRMS (ESI) m/z calcd for C10H20NO4S2 (M+H)+ 282.1. found 282.1.
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:11][C:12]([NH2:14])=[S:13]>C(O)C>[NH2:14][C:12]1[S:13][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH3:10])[N:11]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A mixture of ethyl 2-chloroacetoacetate (50 g, 0.30 mol, Aldrich) and thiourea (45.6 g, 0.60 mol) in 400 mL of absolute ethanol was heated to reflux. After refluxing overnight the reaction mixture was allowed to cool to room temperature and then concentrated to half the original volume in vacuo. The remaining ethanol solution was poured into H2O (1 L) and made basic (pH 10) with 2N NaOH. An off-white solid precipitated immediately. The mixture was stirred for 10 minutes and then the solid was removed by vacuum filtration and dried to give 54.75 g (98% yield) of the desired product as a white solid: 1H NMR (CDCl3) δ5.5 (bs, 2H), 4.25 (q, 2H), 2.5 (s, 3H), 1.35 (t, 3H).
Reaction SMILES: [C:1]([N:11]1[CH2:19][C@H:17]([OH:18])[CH2:16][C@H:12]1[C:13](O)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]>C1COCC1>[CH2:4]([O:3][C:1]([N:11]1[CH2:19][C@H:17]([OH:18])[CH2:16][C@H:12]1[CH2:13][OH:14])=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1CO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
To an ice cold solution of 4.76 g (18 mmoles) of CBZ hydroxyproline (Sigma Chemical Co.) in 20 mL of dry THF was added 45 mL of a 1M solution borane-THF complex in THF (Aldrich). After stirring under argon for 15 min at 0°-5° C., and 4.5 h at room temperature, the mixture was quenched with 50 mL of methanol. After 30 min, the solution was concentrated. The residual colorless syrup was purified by flash chromatography (3.5×23 cm silica) using a gradient of methanol in methylene chloride. The product eluted with 10% methanol. The fractions containing pure product were stripped of solvent to give 2.18 g (46% yield) of 1 as a colorless syrup.