Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7]Cl.[C:10]([NH:13][C:14]([NH2:16])=[S:15])(=[NH:12])[NH2:11]>CC(C)=O>[ClH:1].[NH:13]([C:14]1[S:15][CH:7]=[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[N:16]=1)[C:10]([NH2:12])=[NH:11]
Reactant: N=C(N)NC(N)=S
Reactant: O=C(CCl)CCCCCl
Solvent: CC(C)=O
Product: Cl
Product: N=C(N)Nc1nc(CCCCCl)cs1
Reaction time: 48 h

Procedure:
In 200 ml of acetone solution of 23.5 g of 1,6-dichloro-2-hexanone was added 16.4 g of guanylthiourea and the solution was stirred for two days. The solvent distilled away and the residue was purified by a silica gel column chromatography using a mixture of chloroform and methanol as the developing solvent to provide 2-guanidino-4-(4-chlorobutyl)thiazol hydrochloride (this product shows a melting point of 113° to 114° C. after the recrystallization from a mixture of ethanol and ether). This hydrochloride was dissolved in 300 ml of water, and to the solution was added 100 ml aqueous solution of 17.4 g of potassium carbonate. The obtained solution was extracted three times each time with 500 ml, 200 ml and 200 ml of chloroform. The extracted solution was combined and dried over anhydrous potassium carbonate and the solvent was distilled away. The obtained crystals were recrystallized from a mixture of ether and n-hexane to provide 20 g of 2-guanidino-4-(4-chlorobutyl)thiazole having a melting point of 83° to 84° C. ##STR52##
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[C:6]1([CH3:13])[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CCCC)CCCC)CCC.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C.O>[CH3:13][C:6]1[C:11]2[O:12][C:2](=[O:3])[S:4][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccccc1O
Reactant: O=C(Cl)SCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cccc2sc(=O)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
Chlorocarbonylsulfenyl chloride (30.5 mmol, 2.58 ml) was added to a solution of o-cresol (Compound 101) (27.7 mmol, 3.00 g) and tributylamine (30.5 mmol, 7.35 ml) in dichloroethane (48 mL) at 0° C., and the mixture was stirred at room temperature for 2 hours. Aluminum chloride (66.6 mmol, 8.88 g) was then added to the reaction mixture at 0° C., and the mixture was stirred at room temperature overnight. Water (10 ml) was then added to the reaction mixture at 0° C., after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over sodium sulfate. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution=100/0→30/70) to afford 7-methylbenzo[d][1,3]oxathiol-2-one (Compound 102) (2.46 g, 53%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[N:30]1([CH:35]2[CH2:38][NH:37][CH2:36]2)[CH2:33][CH:32]([OH:34])[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:38][CH:35]([N:30]5[CH2:33][CH:32]([OH:34])[CH2:31]5)[CH2:36]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: OC1CN(C2CNC2)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CC(O)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.15 g, 0.38 mmol), [1,3′]biazetidinyl-3-ol (0.098 g, 0.77 mmol) and 4 Å molecular sieves (0.8 g) in DCE (8 mL) was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (0.162 g, 0.77 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 20:80) to give 494 as an off-white solid (0.101 g, 53%). LCMS (Method I): RT=2.31 min, [M+H]+ 504.2. 1H NMR (400 MHz, DMSO-d): δ 8.03-7.98 (m, 1 H); 7.65-7.60 (m, 1 H); 7.28-7.22 (m, 2 H); 5.26 (d, J=6.8 Hz, 1 H); 4.28-4.21 (m, 4 H); 4.19-4.15 (m, 3 H); 3.83 (s, 2 H); 3.79-3.75 (m, 7 H); 3.47-3.35 (m, 2 H); 3.20 (q, J=7.4 Hz, 2 H); 3.02 (t, J=6.8 Hz, 2 H); 2.82 (t, J=6.8 Hz, 3 H); 1.36-1.29 (q, J=7.4 Hz, 3 H)
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][C:19](=CC#N)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1.[H][H].[CH3:27][OH:28]>[Pd].C>[CH3:27][O:28][C@H:19]1[CH2:18][CH2:17][C@H:16]([C:13]2[CH:14]=[CH:15][C:10]([N:6]3[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[O:8][C:7]3=[O:9])=[CH:11][CH:12]=2)[CH2:21][CH2:20]1
Reactant: COC[C@H]1CN(c2ccc(C3CCC(=CC#N)CC3)cc2)C(=O)O1
Reactant: [H][H]
Reactant: CO
Agent: [Pd]
Product: COC[C@H]1CN(c2ccc([C@H]3CC[C@H](OC)CC3)cc2)C(=O)O1

Procedure:
1.1 g of (R)-[4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl]-phenyl]-cyclohexylidene]-acetonitrile were dissolved in 50 ml of methanol, treated with 0.2 g of 10% Pd-charcoal and hydrogenated at room temperature at normal pressure until the theoretical hydrogen uptake had taken place. The catalyst was filtered off under suction and the filtrate was evaporated in a vacuum. The oily residue was chromatographed over 15 g of silica gel. Elution was carried out with dichloromethane/ethyl acetate 9:1. The fractions which were pure according to thin-layer chromatography were pooled and crystallized from ethyl acetate/hexane. 0.64 g of (R)-[trans-[4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-cyclohexyl]-acetonitrile was obtained as white crystals of m.p. 90°-91°. ##EQU1##
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[O:6][CH2:5][C@H:4]([N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]4[CH3:23])=[N:12][C:11]([C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=4)=[N:10][C:9]=3[CH2:8]2)[CH2:3]1.O1CCC(C=O)C1>>[CH3:36][C:2]1([CH3:1])[O:6][CH2:5][C@@H:4]([N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]4[CH3:23])=[N:12][C:11]([C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=4)=[N:10][C:9]=3[CH2:8]2)[CH2:3]1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN([C@H]2COC(C)(C)C2)C3)cc1
Agent: O=CC1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN([C@@H]2COC(C)(C)C2)C3)cc1

Procedure:
and 1-(4-(7-((R)-5,5-dimethyltetrahydrofuran-3-yl)-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (no2): Compounds no1 and no2 were prepared by the general procedure of Example 267, by substituting 5,5-dimethyldihydrofuran-3(2H)-one for tetrahydrofuran-3-carbaldehyde, then followed by chiral separation to afford products no1 and no2. LC-MS: m/z=+495 (M+H)+.
Reaction SMILES: CO.C([NH2:7])CCC.[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2C(=O)C3C(=CC=CC=3)[C:19]2=[O:28])[S:9]1>C1(C)C=CC=CC=1>[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:7])=[O:28])[S:9]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Reactant: CCCCN
Solvent: Cc1ccccc1
Solvent: CO
Product: NC(=O)NCCCCCC1CCSS1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 ml of methanol and 2 ml of butylamine were added to a solution of 1:6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for 5 hours and 30 minutes. The reaction mixture was then allowed to stand overnight at room temperature. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 5 ml of tetrahydrofuran were added to the residue. 0.32 ml of trimethylsilyl isocyanate was then added dropwise to the resulting mixture, whilst ice-cooling, and then the mixture was stirred at room temperature for 3 hours and 30 minutes. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to silica gel column chromatography, using 1:0 and 5:1 by volume mixtures of ethyl acetate and methanol as eluent. The solvent was removed from the eluate by distillation under reduced pressure. The residue was recrystallized from ethyl acetate, to give 80 mg of the title compound as yellow crystals, melting at 74 to 78° C.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH2:11])[CH3:10])=[CH:5][CH:4]=1.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1.O1CCC[CH2:20]1>>[CH3:20][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:11][CH2:13][CH2:12][CH2:18][S:15]([OH:14])(=[O:17])=[O:16])[CH3:10])=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: O=S1(=O)CCCO1
Reactant: COc1ccc([C@@H](C)N)cc1
Product: Cc1ccc([C@@H](C)NCCCS(=O)(=O)O)cc1
Temperature: 25 °C

Procedure:
To a solution of (R)-(+)-1-(4-methoxyphenyl)ethylamine (5.83 g, 38,6 mmol) in tetrahydrofuran (25 mL) was slowly added 1,3-propanesultone (4.56 g, 36.8 mmol). The solution was stirred at reflux for 4 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with THF (25 mL) and acetone (25 mL). The solid was suspended in EtOH (200 mL). The suspension was stirred at reflux for 15 min. The solid was collected by filtration, washed with cold EtOH (50 mL), and dried in a vacuum oven (50° C.), to afford compound FN (5.6 g, 56%). 1H NMR (D2O, 500 MHz) δ ppm 7.26 (d, 2H, J=8.3 Hz), 6.90 (d, 2H, J=8.3 Hz), 4.22 (m, 1H), 3.68 (s, 3H), 2.92 (m, 1H), 2.76 (m, 3H), 1.90 (m, 2H), 1.49 (d, 3H, J=6.8 Hz). 13C NMR (D2O, 125 MHz) δ ppm 159.87, 129.34, 128.18, 114.85, 57.99, 55.58, 48.05, 44.21, 21.45, 18.21. ES-MS 272 (M−1).
Reaction SMILES: I[CH3:2].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+]>C1COCC1>[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccccc2n1C
Yield: 49.7 %

Procedure:
Iodomethane (4.98 mL, 80 mmol) was added dropwise to a mixture containing ethyl indole-2-carboxylate (1.89 g, 10 mmol) and sodium hydride (1.2 g, 60% dispersion, prewashed by hexane) in anhydrous THF (60 mL) in a flame dried flask under argon at 0° C. After 4 h at RT the reaction was concentrated on the rotavap. The residue was taken into EtOAc and washed sequentially with H2O and saturated NaCl. Drying (MgSO4) and concentration gave the title compound (1.01 g, 50%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[CH:17]=2)[C:12]1=[O:24])(=[O:3])[CH3:2].[CH2:25]([Br:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Br-:32].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[CH:17]=2)[C:12]1=[O:24])(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1C(C)=O)C2
Reactant: BrCc1ccccc1
Product: COc1cc2c(cc1OC)C(=O)C(Cc1cc[n+](Cc3ccccc3)cc1C(C)=O)C2
Product: [Br-]

Procedure:
The title compound 33 is prepared according to the procedure reported in Example 38.1 with compound 32 (46 mg, 0.14 mmol) and benzyl bromide (34 μL, 0.28 mmol) as reactants. White solid. (Yield 62.3 mg, 91%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][OH:14])[CH:2]=1.[C:15]([O:22]C(OC(C)(C)C)=O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[OH-].[Na+]>O.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][OH:14])[CH:2]=1.[C:18]([O:17][C:15](=[O:16])[O-:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: OCC#Cc1cnc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)[O-]
Reaction time: 4 h

Procedure:
To a dry 1-L three-necked round-bottom flask equipped with a nitrogen inlet and overhead stirrer was charged 3-(3-quinolyl)-2-propyn-1-ol (15.81 g, 86.39 mmol), di-tert-butyl dicarbonate (22.48 g, 103 mmol, 1.19 equiv), n-tetrabutyl ammonium hydrogen sulfate (0.86 g, 2.54 mmol, 0.029 equiv) and methylene chloride (300 mL). The resulting suspension was mechanically stirred while a 25% w/w aqueous NaOH solution (38 g) was added in over a period of 5 minutes. The biphasic mixture which resulted was stirred for 4 hours after which time the reaction was found to be complete by HPLC and TLC. The mixture was diluted with water (200 mL) and methylene chloride (100 mL). After stirring for 10 minutes and settling for 15 minutes the layers were separated. The organic layer was washed with water (1×200 mL) and 20% aq., NaCl (1×200 mL). The organic was then stirred with 15 g of sodium sulfate, filtered and then stripped to an oil under reduced pressure. The residual oil was taken up in isopropyl acetate/hexane (1:1, 100 mL) and passed through a small pad of silica gel (8 g). The pad was rinsed with the same eluent (100 mL). The combined filtrates were concentrated under reduced pressure and rigorously dried in a vacuum oven to yield the 3-(3-quinolyl)-2-propyn-1 ol t-butyl carbonate as a light orange-yellow colored oil: 24.50 g, 100%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].C(O[CH2:19][CH3:20])(=O)C>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:19]([CH3:20])[CH3:9])=[N:6][CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
5-Bromopyridin-2(1H)-one (5 g, 28.7 mmol) and potassium carbonate (9.93 g, 71.8 mmol) were mixed in dimethyl sulfoxide, and at room temperature, 2-iodoisopropyl (3.73 ml, 37.3 mmol) was added thereto, and stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, and washed with water and saturated saline in that order. The organic layer was dried with sodium sulfate, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (eluate: ethyl acetate/hexane=20/80 to 50/50) to obtain the entitled compound (4.72 g, 76%) as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:11][C:12]([F:16])([CH3:15])[CH2:13][OH:14]>>[F:11][C:12]([F:16])([CH3:15])[CH2:13][O:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(F)(F)CO
Product: CC(F)(F)COc1ccc(C(=O)O)cn1
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (1.79 g, orange oil) from 6-chloronicotinic acid (1.3 g, 8.25 mmol) and 2,2-difluoropropan-1-ol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]1([O:15][CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[Br:8][C:12]1[CH:13]=[CH:14][C:9]([O:15][CH3:16])=[CH:10][CH:11]=1
Reactant: COc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Zr+4]
Agent: [Cl-]
Product: COc1ccc(Br)cc1
Yield: 98 %

Procedure:
Bromination using NBS has been found to be applicable for use with a wide range of aromatic starting materials or substrates, as is summarized in Table 1. For example, anisole can be brominated by use of 1 equivalent of NBS in the presence of 5 mol % of ZrCl4 at −78° C. to afford p-bromoanisole in 98% yield as sole product (Table 1, Entry 1). However, in the absence of ZrCl4 the halogenation does not proceed, even at room temperature (Table 1, Entry 1).
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:16]([CH:21]=2)[C:17]([O:19]C)=[O:18])(=O)=O)=CC=1.[OH-].[K+]>C(O)C.O>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([CH:21]=1)[C:17]([OH:19])=[O:18]
Reactant: COC(=O)c1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(O)ccc1OCc1ccccc1

Procedure:
Methyl 5-{[(4-methylphenyl)sulfonyl]oxy}-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 75; 22.0 g, 53.3 mmol) was boiled with potassium hydroxide (20.95 g, 373 mmol) in a mixture of ethanol (320 ml) and water (80 ml) overnight. After the ethanol had been evaporated, the aqueous solution was washed with ethyl acetate (500 ml), and then acidified with concentrated HCl. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and evaporated in vacuo to yield the title compound as a yellow oil. 14 g.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:18][C:17]2[CH:16]=[CH:15][C:14]3[N:13]=[C:12]([OH:19])[C:11]([OH:20])=[N:10][C:9]=3[C:8]=2[CH:7]=1)=[O:5])C>[OH-].[Na+]>[C:4]([C:6]1[S:18][C:17]2[CH:16]=[CH:15][C:14]3[N:13]=[C:12]([OH:19])[C:11]([OH:20])=[N:10][C:9]=3[C:8]=2[CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2c(ccc3nc(O)c(O)nc32)s1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2c(ccc3nc(O)c(O)nc32)s1
Yield: 51.9 %

Procedure:
8-Ethoxycarbonyl-2,3-dihydroxythieno[3,2-f]quinoxaline (2.0 g, 6.9 mmol) was stirred in 30 ml of 2N sodium hydroxide at room temperature for 2 h. The solution was filtered, and after acidification of the filtrate with 4M hydrochloric acid, the resulting precipitate was collected by filtration and washed with water. The crude product was dissolved in 2N sodium hydroxide and reprecipitated with 4M hydrochloric acid to give 0.94 g (52%) of the carboxylic acid, m.p. >350° C. dec.; IR (KBr): 3300-2200, 1690 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH:9]([CH3:12])[C:8](=O)[NH:7][C:6]=2[CH:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH:9]([CH3:12])[C:8](=[S:24])[NH:7][C:6]=2[CH:14]=1
Reactant: CC1CNc2ccc(F)cc2NC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC1CNc2ccc(F)cc2NC1=S

Procedure:
A solution of 8-fluoro-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (6.2 g, 32 mmol) and Lawesson's reagent (25.9 g, 64 mmol) in tetrahydrofuran (300 mL) was heated at 80° C. for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1-2:1) to afford 8-fluoro-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione as a pale green solid (10.0 g, crude).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].C[C@@H:9](NC(=O)O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[Br-].[CH3:22]CN(CC)CC>C1(C)C=CC=CC=1>[CH3:22][O:5][C:3]([C:2]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11]2)=[O:4]
Reactant: C[C@H](Cc1ccccn1)NC(=O)O
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(CC)CC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)CNC2

Procedure:
A toluene solution (20 mL) of 7-4 (181 mg, 0.48 mmol), 2-5 (171 mg, 0.60 mmol) and Et3N (266 μl, 1.9 mmol) was refluxed for 3 h and then concentrated to dryness. The residue was purified by flash chromatography (silica, 3:2 CH2Cl2 /acetone) to provide 7-5 as a colorless gum.
Reaction SMILES: Br.[NH:2]1[C@@H:11]2[C@@H:6]([CH2:7][C:8]3[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:9]=3[CH2:10]2)[CH2:5][CH2:4][CH2:3]1.O.O.O.[C:20]([O-:23])(=O)[CH3:21].[Na+].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:2]1[C@@H:11]2[C@@H:6]([CH2:7][C:8]3[CH:15]=[C:14]([O:16][C:20](=[O:23])[CH3:21])[CH:13]=[CH:12][C:9]=3[CH2:10]2)[CH2:5][CH2:4][CH2:3]1)(=[O:27])[CH3:26]
Reactant: Oc1ccc2c(c1)C[C@H]1CCCN[C@H]1C2
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: Br
Agent: [Na+]
Solvent: O
Product: CC(=O)Oc1ccc2c(c1)C[C@H]1CCCN(C(C)=O)[C@H]1C2

Procedure:
A mixture of 1.4 g. of cis-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol hydrobromide, 2.1 g. of sodium acetate trihydrate, and 14 ml. of acetic anhydride was stirred and heated on a steam bath for one hour. The solvent was evaporated from the mixture and the resulting residue was partitioned between water and diethyl ether. The ether layer was washed with saturated aqueous sodium bicarbonate solution, dried, and filtered, and the filtrate was evaporated. The residue thus obtained was crystallized from hexane to yield cis-1,2,3,4,4a,5,10,10a-octahydro-1-acetyl-7-acetoxybenzo[g]quinoline, m.p. 108°-113° C. The nmr spectrum (CDCl3) showed 3 aryl protons (400-430 Hz) and two methyl singlets (125, 133 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@H:5]([OH:22])[CH2:6][CH:7]([NH2:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].[NH:24]1[C:28]([C:29]([OH:31])=O)=[CH:27][C:26]([C:32]([OH:34])=O)=[N:25]1.[CH3:35][O:36][CH2:37][CH2:38][NH:39][CH3:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C@H:5]([OH:22])[CH2:6][CH:7]([NH:21][C:29]([C:28]1[NH:24][N:25]=[C:26]([C:32](=[O:34])[N:39]([CH2:38][CH2:37][O:36][CH3:35])[CH3:40])[CH:27]=1)=[O:31])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Reactant: CNCCOC
Reactant: CCOC(=O)[C@H](O)CC(N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(C(=O)N(C)CCOC)n[nH]1
Reaction time: 0.03 h
Yield: 1.6 %

Procedure:
(R)-4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (900 mg, 3.0 mmol, 1.0 eq.), 3,5-pyrazoledicarboxylic acid (448 mg, 2.9 mmol, 1.0 eq.), N-(2-methoxyethyl)methylamine (256 mg, 2.9 mmol, 1.0 eq.), and HATU (1090 mg, 2.9 mmol, 1.0 eq.) were combined in DMF (5 mL), and the resulting mixture was stirred for 2 minutes. DIPEA (1 mL) was added and the mixture was stirred for 1 hour. The mixture was dried under vacuum, and the product was purified using reverse phase chromatography (10-70% MeCN/H2O; 0.05% TFA over 70 minutes) to yield (R)-5-biphenyl-4-yl-2-hydroxy-4-({5-[(2-methoxyethyl)methylcarbamoyl]-2H-pyrazole-3-carbonyl}amino)-pentanoic acid ethyl ester (25 mg) as a TFA salt.