Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][N:17]=1
Reactant: Clc1ccc(Br)cn1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc(Cl)nc2)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 87.5 %

Procedure:
A flask was charged with 4-methoxyphenylboronic acid (1.0 g, 6.8 mmol), 5-bromo-2-chloropyridine (1.0 g, 5.2 mmol), Pd(PPh3)4 (50 mg, 0.043 mmol), potassium carbonate (1.08 g, 7.8 mmol), 1,4-dioxane (40 mL) and water (4 mL). The mixture was stirred at 100° C. under Argon for 20 h, and evaporated to afford a crude product. The crude product was purified by chromatography on silica gel (petroleum ether:ethyl acetate=40:1) to give the title compound (1.0 g, 88% yield) as white solids. MS: m/z 220.0 [M+H+].
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4]O.Br[CH2:8][C:9]1[C:10]([I:16])=[CH:11][C:12]([F:15])=[N:13][CH:14]=1.[OH2:17]>>[F:15][C:12]1[N:13]=[CH:14][C:9]([CH2:8][O:17][CH:3]([OH:6])[CH3:4])=[C:10]([I:16])[CH:11]=1
Reactant: OCCO
Reactant: Fc1cc(I)c(CBr)cn1
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CC(O)OCc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
Add sodium hydride (54 mg, 2.25 mmol) to 2.5 mL ethylene glycol at 0° C. and stir for 30 min at RT. Add 5-bromomethyl-2-fluoro-4-iodo-pyridine (0.69 g, 2.14 mmol) and heat it to 120° C. for 30 min. Cool to RT, dilute with 70 mL of water, and extract with ether (3×50 mL). Combine organic layers, wash with saturated aqueous sodium chloride, thy over MgSO4, and remove the solvent. Purify by chromatography with diethylether to obtain the title compound (240 mg, 38%). MS (ES) m/z 296 [M+1]+.
Reaction SMILES: Br.Br.[N:3]1([CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[N:3]1([CH2:8][C:9]2([C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=3)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: Oc1ccc2c(c1)C(CN1CCCC1)NCC2
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CCCC2)NCCc2ccc(O)cc21

Procedure:
Prepared as Ex. No. 5, from 3 g (7.61 mmoles) of 1-(pyrrolidin-1-yl)methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 1.9 g (9.31 mmoles) of 3,4-dichlorophenylacetic acid, 2.3 ml (16.36 mmoles) of triethylamine and 3.2 g (15.61 mmoles) of dicyclohexylcarbodiimide in 110 ml of dry chloroform.
Reaction SMILES: O1CCCC1.C[O:7][C:8]([C:10]1[CH:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:11]=1)=[O:9].[OH-].[Li+].Cl>O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:12]2[N:11]=[C:10]([C:8]([OH:9])=[O:7])[CH:15]=[N:14][C:13]=2[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a tetrahydrofuran (5 ml) solution of 6-(4-fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid methyl ester (0.48 g, 1.52 mmol, 1.0 eq) was added a solution of lithium hydroxide (1M, 1.52 ml, 1.52 mmol, 1.0 eq) in water. The mixture was stirred overnight at room temperature after which time the resulting solution was acidified with hydrochloric acid (pH˜5) and aqueous phase extracted with ethyl acetate (2×10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to afford 6-(4-fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid as white crystals. Yield=0.42 g (91%). 1H NMR (400 MHz, DMSO): δ 1.46-1.53 (6H, m), 3.22-3.25 (4H, m), 7.32 (2H, t, J=8.87 Hz), 7.82-7.86 (2H, m), 8.62 (1H, s).
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.[CH:9]1([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[CH:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][N:33]=5)[S:31][C:24]=34)=[C:18]([F:40])[CH:17]=2)=[O:14])[CH2:11][CH2:10]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.ClCCl.CN(C=O)C>[CH:9]1([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[CH:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([CH2:38][N:5]6[CH2:6][CH2:7][C:3]([F:8])([F:2])[CH2:4]6)=[CH:34][N:33]=5)[S:31][C:24]=34)=[C:18]([F:40])[CH:17]=2)=[O:14])[CH2:11][CH2:10]1
Reactant: FC1(F)CCNC1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCC(F)(F)C5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.7 %

Procedure:
3,3-Difluoropyrollidine hydrochloride (0.200 g, 1.39 mmol) was suspended in DCM and washed with 3M NaOH. The organic phase was separated, dried over anhydrous MgSO4 and filtered into a solution of aldehyde 47 (0.090 g, 0.20 mmol) and acetic acid (0.03 mL, 0.5 mmol) in a 10:1 dichloromethane/DMF mixture (45 mL), which was stirred for 20 min at RT. Then sodium triacetoxyborohydride (0.128 g, 0.60 mmol) was added and the reaction mixture was stirred at RT for 18 h and partitioned between dichloromethane and water. The organic phase was washed with saturated aqueous NaHCO3, then dried (anhydrous MgSO4) and concentrated. Silica gel chromatography (10% methanol/ethyl acetate), of the residue followed by a second column (10% methanol/chloroform) afforded title compound 315 (0.045 g, 42% yield) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.74 (s, 1H); 8.57 (d, J=2.7, 1H); 8.52 (d, J=5.3, 1H); 8.34 (s, 1H); 8.26 (d, J=8.0, 1H); 7.88 (dd, J=8.2, 2.1, 1H); 7.73 (dd, J=13.7, 2.5, 1H); 7.38 (t, J=9.0, 1H); 7.22-7.19 (m, 1H); 6.65 (d, J=5.3, 1H); 6.60 (d, J=2.7, 1H); 3.71 (s, 2H); 2.92 (t, J=13.3, 2H); 2.73 (t, J=7.0, 2H); 2.57-2.52 (m, 1H); 2.27 (septet, J=7.0, 2H); 0.67-0.63 (m, 2H); 0.45-0.41 (m, 2H). MS (m/z): 540.6 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:12][CH2:13][CH2:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:11])[CH:5]=[CH:6][C:7]=1[OH:8].CS(C)=O.[OH-].[Na+].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1>O>[ClH:34].[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:12][CH2:13][CH2:14][CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=1
Reactant: Cc1cc(CC(C)NCCC(c2ccccc2)c2ccccc2)ccc1O
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(CC(C)NCCC(c2ccccc2)c2ccccc2)ccc1OCc1ccc(Cl)cc1
Product: Cl
Reaction time: 1 h

Procedure:
The mixture of 7.18 g of 1-(3-methyl-4-hydroxyphenyl)-2-(3,3-diphenylpropylamino)-propane, 50 ml of dimethylsulfoxide and 2 ml of 10 N-aqueous sodium hydroxide is stirred for 1 hour at 60°. After cooling to room temperature 3.32 g of 4-chlorobenzyl chloride are added and the mixture stirred overnight at said temperature. It is poured into water, extracted with ethyl acetate, the extract dried and evaporated. The residue is taken up in isopropanol, the solution acidified with isopropanolic hydrogen chloride, the precipitate collected and washed with diethyl ether, to yield the 1-[3-methyl-4-(4-chlorobenzyloxy)-phenyl]-2-(3,3-diphenylpropylamino)-propane hydrochloride melting at 166°-168°.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]3[N:18]([CH3:19])C4C=CC=CC=4N=3)=[CH:9][C:7]=2[N:8]=1)[CH2:2][CH3:3].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:38][OH:39])=[CH:28][CH:27]=1.[CH3:40][N:41](C)[C:42](=O)C>>[CH2:1]([C:4]1[N:8]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH2:38][OH:39])=[CH:28][CH:27]=2)[C:7]2[CH:9]=[C:10]([C:14]3[N:18]=[CH:19][N:41]([CH3:42])[CH:40]=3)[CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: OCc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc2cc(-c3nc4ccccc4n3C)cc(C)c2[nH]1
Reactant: CC(=O)N(C)C
Product: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.098 g (3.6 mmol) of 2-n-propyl-4-methyl-6-(1′-methylbenzimidazol-2-yl)benzimidazole, 0.41 g of potassium terc-butylate (3.65 mmol) and 15 ml of N,N-dimethylacetamide, a solution of 1 g (3.6 mmol) of 4′-bromomethyl-2-hydroxymethylbiphenyl (II) in 10 ml of N,N-dimethylacetamide is added dropwise at room temperature in 30 minutes. Reaction mixture is stirred at room temperature overnight and subsequently evaporated under reduced pressure to produce 2.69 g of oily residue. Raw product is purified on chromatographic column (silica gel, dichloromethane-methanol 9:1) to yield 1.51 g of pure product in a form of brown oil.
Reaction SMILES: C(S[C:9]1[S:10][C:11]([CH2:14][N:15]2[C:20](=[N:21][N+:22]([O-:24])=[O:23])[N:19]([CH3:25])[CH2:18][O:17][CH2:16]2)=[CH:12][N:13]=1)C1C=CC=CC=1.[ClH:26].ClCl>ClC1C=CC=CC=1>[Cl:26][C:9]1[S:10][C:11]([CH2:14][N:15]2[C:20](=[N:21][N+:22]([O-:24])=[O:23])[N:19]([CH3:25])[CH2:18][O:17][CH2:16]2)=[CH:12][N:13]=1
Reactant: CN1COCN(Cc2cnc(SCc3ccccc3)s2)C1=N[N+](=O)[O-]
Reactant: Cl
Agent: ClCl
Solvent: Clc1ccccc1
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Reaction time: 2 h

Procedure:
190 g of 3-(2-benzylthio-thiazol-5-yl-methyl)-5-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine are introduced over a period of 5 minutes, with stirring, into a mixture of 300 g of hydrochloric acid (32%) and 150 g of chlorobenzene. 124 g of chlorine are introduced at 20° C. over a period of 4 hours. After 2 hours, excess chlorine is removed by the introduction of nitrogen, and the phases are then separated. The aqueous phase is adjusted to pH 5 with sodium hydroxide solution (30%) and then filtered, and the filtration residue is washed with water and dried in vacuo at 50° C. The title product is obtained in a purity of 97%.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1c[nH]c2ccccc2c1=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (3.17 g, 14.6 mmol) and 4-methoxybenzylchloride (2.18 mL, 16.0 mmol, 1.1 equiv) were combined in N,N-dimethylformamide (50 mL) and stirred at ambient temperature for 72 hours. The mixture was poured into water (500 mL) and extracted with dichloromethane (2×250 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was treated with water (500 mL), hexanes (500 mL) and ethyl acetate (500 mL) and aged for 30 minutes. The mixture was filtered and the solid was dissolved in dichloromethane (500 mL) and combined with the filtrate. The filtrate was partitioned and the aqueous layer was discarded. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: C1S[CH:5]([C:6]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]=2[NH:16][S:17]([CH3:20])(=[O:19])=[O:18])SCC1.CC[O:24]C(C)=O.CCCCCC.C1C([N+]([O-])=O)=CC([N+]([O-])=O)=C(O)C=1>CN(C)C=O.CC(C)=O.[Cu]=O.[Cu](Cl)Cl>[CH3:20][S:17]([NH:16][C:7]1[CH:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:6]=1[CH:5]=[O:24])(=[O:19])=[O:18]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)c(C2SCCCS2)c1
Agent: Cl[Cu]Cl
Agent: O=[Cu]
Agent: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(NS(C)(=O)=O)c(C=O)c1
Yield: 79 %

Procedure:
A sample of 2-(methanesulfonylamino)-5-(methoxycarbonyl)benzaldehyde trimethylene mercaptal (7.66 g, 0.022 mol) dissolved in N,N-dimethylformamide (4.35 mL) and acetone (39.13 mL) was added over a 5-min period through a dropping funnel to a solution of copper (II) oxide (2.09 g, 0.026 mol), copper (II) chloride (7.0 g, 0.055 mol) in acetone (174.0 mL), and heated at reflux. After 2 h at reflux, thin-layer chromatography analysis (SiO2, EtOAc:hexane 1:1) showed disappearance of the starting material and the appearance of a new slightly higher Rf spot which gave a positive result when sprayed with 2,4-DNP. Upon cooling, the reaction was filtered through Celite and the cake was washed with 10% ethanol in dichloromethane. Water (125 mL) and dichloromethane (150 mL) were added to the filtrate. The layers were partitioned and the water layer extracted 2×100 mL dichloromethane. The combined organic layers were washed twice with water (100 mL), dried (Na2SO4), and filtered. Concentration of the filtrate gave a beige solid which was dried in vacuo to give 4.48 g (79%) of 2-(methanesulfonylamino)-5-(methoxycarbonyl)benzaldehyde, mp 161°-163° C. (ethanol).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19].[C:20]([OH:24])(=[O:23])[C:21]#[CH:22]>O1CCCC1.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][O:23][C:20](=[O:24])[C:21]#[C:22][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19]
Reactant: C#CC(=O)O
Reactant: BrCCCCCBr
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C#CCCCCCBr
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of 1.5 ml of diisopropylamine in 75 ml of tetrahydrofuran were added dropwise 135 ml of 1.5 M solution of butyl lithium in hexane, 75 ml of hexamethylphosphoramide (HMPA) and 6.15 ml of propiolic acid, successively, at -50° C., the mixture was allowed to heat to -10° C. over a period of 2 hours. To it was added dropwise 27.2 ml of 1,5-dibromopentane at -25° to -30° C., the solution allowed to heat to room temperature over a period of 2 hours, and stirred for one hour. The reaction mixture was poured into 500 ml of ice-water, extracted with methylene chloride, the extract washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in diethyl ether, there was added diazomethane-etherate until the solution was coloured pale yellow. After concentration under reduced pressure, the residue was purified by column chromatography on silica gel using chloroform as eluent to give 4.05 g of the subtitle compound having the following physical characteristics:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH3:23])[C:13]([O:19]C(=O)C)=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CN=C1>CCO>[OH:19][C:13]1[C:12]([CH3:23])=[C:11]2[C:16]([C:17](=[O:18])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[CH2:9][O:10]2)=[CH:15][CH:14]=1
Reactant: CC(=O)Oc1ccc2c(c1C)OCC(c1ccc(O)cc1)C2=O
Agent: c1c[nH]cn1
Solvent: CCO
Product: Cc1c(O)ccc2c1OCC(c1ccc(O)cc1)C2=O
Reaction time: 8 h

Procedure:
Acetic acid 3-(4-hydroxy-phenyl)-8-methyl-4-oxo-chroman-7-yl ester (18.37 g), imidazole (21.18 g, 6 equivalents) and 100% EtOH (536 ml) were added to a round bottom flask (2 L). The reaction mixture was refluxed and monitored by HPLC. The reaction was completed at 8 hours. The reaction mixture was reduced (—130 ml) on a rotary evaporator and poured into stirred, chilled distilled water (1.9 L). The water crash out was left stirring in the cold room overnight. The pale pink solid was collected by suction filtration. 1H NMR of the solid indicated it was 7-Hydroxy-3-(4-hydroxy-phenyl)-8-methyl-chroman-4-one with >95% purity. The solid was dried on the freeze dryer for 3 hours (8.31 g, 59%).
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:12])[CH3:3].[CH2:13]([O:15][N:16]=[CH:17][CH3:18])[CH3:14].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH2:13]([O:15][N:16]1[CH:17]([CH3:18])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:12])[CH3:14]
Reactant: C=C(C)C1CCCCCCC1=O
Reactant: CC=NOCC
Agent: CCON1C(=O)CCCCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCON1C(=O)CCCCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 23, 2-(prop-1-en-2-yl)cyclooctanone (1.50 g, 9.02 mmol), acetaldehyde O-ethyl oxime (1.18 g, 13.53 mmol), and SnCl4 (2.35 g, 9.02 mmol) in 1,2-dichloroethane (90 ml) were reacted to give the title product as a colorless liquid (1.98 g, 87% yield). E isomer>96%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=1.[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]>>[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:17][CH2:16]/[CH:15]=[C:14](/[C:11]2[CH:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:13][CH:12]=2)\[CH3:18])=[CH:33][CH:34]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]
Reactant: C/C(=C\CO)c1ccc(-c2ccccc2C)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccccc3C)cc2)cc1)OCC
Yield: 78.7 %

Procedure:
The title compound (1.80 g, 78%) was prepared as a colourless oil from (E)-3-(2′-methyl-biphenyl-4-yl)-but-2-en-1-ol (1.19 g, 4.99 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (1.31 g, 6.48 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: Cl.COC(=O)[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].CN1CC[O:19][CH2:18]C1.[C:22]([NH:25][C@H:26]([C:31]([OH:33])=O)[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:24])[CH3:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(CC)CC)C>CN(C=O)C.O>[CH:18]([C:8]1([CH:9]=[CH:10][CH:11]=[CH:12][CH2:13]1)[CH2:7][CH2:5][NH:6][C:31](=[O:33])[C@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:25][C:22](=[O:24])[CH3:23])=[O:19]
Reactant: CN1CCOCC1
Reactant: CC(=O)N[C@@H](CC(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](CC(C)C)C(=O)NCCC1(C=O)C=CC=CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
In 100 ml of DMF was dissolved 5.0 g of L-phenylalanine methyl ester hydrochloride, and 2.4 g of N-methylmorpholine was added thereto. To the solution were added 4.0 g of N-acetyl-L-leucine, 5.0 g of 1-hydroxybenzotriazole, and 5.5 g of 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with a 10% citric acid solution, a saturated brine, a saturated sodium bicarbonate solution, and a saturated brine and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 6.7 g of the titled compound as a colorless crystal.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:46])=[C:11]([CH:43]=[CH:44][CH:45]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:41][CH3:42])=[C:20]([O:23][C@@H:24]3[CH2:28][N:27](C(OC(C)(C)C)=O)[C@H:26]([C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:46])=[C:11]([CH:43]=[CH:44][CH:45]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:41][CH3:42])=[C:20]([O:23][C@@H:24]3[CH2:28][NH:27][C@H:26]([C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CN[C@H](C(=O)N(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline (0.17 g) in methylene chloride (10 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was evaporated under vacuum and the residue dissolved in methanol (saturated with ammonia)/methylene chloride, adsorbed onto silica and purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 85/15). The fractions containing the required product were combined and evaporated under vacuum to give the title product as a colourless gum which crystallised on standing (0.13 g); 1H NMR Spectrum: (DMSO d6 and CD3COOD) 1.85-1.96 (m, 1H), 2.84-2.95 (m, 4H), 3.00 (s, 3H), 3.24-332 (m, 1H), 3.40-3.48 (m, 1H), 3.95 (s, 3H), 4.31 (m, 1H), 5.21 (m, 1H), 7.20-7.30 (m, 2H), 7.47-7.55 (m, 2H), 7.76 (s, 1H), 8.37 (s, 1H); Mass Spectrum: (M+H)+ 460.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1)=[NH:4].[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[C:13]=1[C:14]([OH:16])=O.C(O)(=O)C>CO>[Br:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:12]2[C:13]=1[C:14]([OH:16])=[N:4][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1)=[N:11]2
Reactant: COC(=N)c1cncnc1
Reactant: Nc1cccc(Br)c1C(=O)O
Solvent: CC(=O)O
Solvent: CO
Product: Oc1nc(-c2cncnc2)nc2cccc(Br)c12
Reaction time: 16 h
Yield: 27.3 %

Procedure:
To a stirred suspension of methylpyrimidine-5-carbimidate (2.00 g, 14.5 mmol) in methanol (20 mL) was added 2-amino-6-bromobenzoic acid (3.1 g, 14.5 mmol). The mixture was heated to reflux where it stirred for 16 h under the nitrogen atmosphere. At the conclusion of this period, acetic acid (2.72 ml, 47 mmol) was added drop wise. Upon completion of addition, methanol was evaporated under reduced pressure to yield a residue. The residue was triturated with ether (100 mL), ethyl acetate (50 mL) and the resulting solid was dried to yield 5-bromo-2-(pyrimidin-5-yl)quinazolin-4-ol (1.2 g, 27%) as an off-white solid. The crude product was used without further purification. 1H NMR (400 MHz, DMSO-d6, δ): 7.64 (dd, J=7.2 Hz, 8.4 Hz, 1H); 7.73-7.75 (m, 2H); 9.35 (s, 1H); 9.46 (s, 2H); 12.9 (br s, 1H). ES-MS: [M++1]=303 and [M++3]=305.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:7])=[N:4][NH:5][CH:6]=1.[P:8](=[O:12])([OH:11])([OH:10])[OH:9]>O>[P:8]([O-:12])([OH:11])([OH:10])=[O:9].[Cl:1][C:2]1[CH:6]=[NH+:5][NH:4][C:3]=1[CH3:7]
Reactant: Cc1n[nH]cc1Cl
Reactant: O=P(O)(O)O
Solvent: O
Product: Cc1[nH][nH+]cc1Cl
Product: O=P([O-])(O)O
Yield: 98 %

Procedure:
116 g (1.0 mol) of 4-chloro-3-methylpyrazole were dissolved in 115 g (1.0 mol) of phosphoric acid (85%) at room temperature. The water contained in the phosphoric acid was evaporated. After a few hours, the title compound crystallized out of the oil initially present (yield 98%).