Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:32]C(=O)OC(C)(C)C)[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23](C3CN(C)CCC=3)[S:24][C:17]=12>>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:16]3[CH2:17][CH2:18][N:19]([CH3:20])[CH2:1][CH:3]=3)[S:24][C:17]=12)[NH2:32]
Reactant: CN1CCC=C(c2cc3nccc(Oc4ccc(NC(=O)OC(C)(C)C)cc4F)c3s2)C1
Reactant: O=C(O)C(F)(F)F
Product: CN1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
TFA (1 mL) was added to tert-butyl 3-fluoro-4-(2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamate (229) (105 mg, 0.23 mmol) and the mixture was stirred for 1 h at room temperature. The solution was concentrated under reduced pressure, the residue co-distilled with MeCN, redissolved in MeOH and purified by preparative HPLC (gradient 40% to 95% MeOH in water, 45 min) giving 230 (50 mg, 0.1 mmol, 48% yield) as a white solid. MS (m/z): (M+1) 356.1 (100%).
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](OCCCl)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CC12CC([NH:37]C1)CC(C)(C)C2>C(#N)C>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:37]
Reactant: CC1(C)CC2CC(C)(CN2)C1
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1cc2ccccc2[nH]1
Yield: 52.2 %

Procedure:
5-(2-Chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.500 g, 1.450 mmol, 1 eq, Example 1, Step A) was suspended in dry acetonitrile (30 mL) under Ar. K2CO3 (0.400 g, 2.900 mmol, 2 eq) and KI (0.025 g, 0.145 mmol, 0.1 eq) were added followed by the addition of 1,3,3-trimethyl-6-azabicyclo-[3,2,1]octane (0.334 g, 2.180 mmol, 1.5 eq). The reaction mixture was stirred and heated to reflux for 24 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.100 g (15%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 461 (M+1); Anal. Calcd for C29H36N2O3.1 HCl.0.75H2O: C, 68.22; H, 7.60; N, 5.49; Found: C, 68.25; H, 7.41; N, 5.56.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:7]([C:8]([O:10]C)=O)=[C:6]([CH:16]=[O:17])[CH:5]=1)[CH:2]=[CH2:3].[BH4-].[Na+]>CO.CCOC(C)=O>[CH2:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:7]2[C:8](=[O:10])[O:17][CH2:16][C:6]=2[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=O)c(C(=O)OC)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCc1cc2c(c(OC)c1)C(=O)OC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a flask charged with methyl 4-allyl-2-formyl-6-methoxybenzoate (0.77 g, 1 mmol) was added sodium borohydride (0.36 g, 9.33 mmol); the mixture was then dissolved in MeOH (10 mL) and stirred for 18 h at room temp. LC indicated completion of the reaction. The mixture was diluted with EtOAc (150 mL) and washed with brine (2×100 mL). The organic layer was then separated, dried(Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by MPLC (hexanes/EtOAc=1/0.5) to provide 5-allyl-7-methoxy-2-benzofuran-1(3H)-one.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:18][C:19]2[C:20]([CH3:26])=[N:21][N:22]([CH3:25])[C:23]=2[CH3:24])[CH:17]=1)[C:13]#[N:14].N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:24][C:23]1[N:22]([CH3:25])[N:21]=[C:20]([CH3:26])[C:19]=1[O:18][C:16]1[CH:15]=[C:12]([CH:11]=[C:10]([Cl:9])[CH:17]=1)[C:13]#[N:14]
Reactant: Cc1nn(C)c(C)c1Oc1cc(Cl)cc(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nn(C)c(CBr)c1Oc1cc(Cl)cc(C#N)c1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
N-Bromosuccinimide (340 mg, 1.90 mmol) was added to a stirred solution of the pyrazole of Example 112 (500 mg, 1.90 mmol) in carbon tetrachloride (10 ml) and azobisisobutyronitrile (20 mg) at room temperature under nitrogen. The reaction was heated under reflux for 1 hour, cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (80:20, by volume) to provide the title compound (340 mg) as a white solid, m.p. 76–78° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH:27]([OH:33])[C:28](=[NH:32])[O:29]CC)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O:34]1CCC[CH2:35]1>C1(C)C=CC=CC=1>[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH:27]1[O:33][C:35](=[O:34])[NH:29][C:28]1=[O:32])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1c(OCc2ccccc2)ccc2ccccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(c2c(OCc3ccccc3)ccc3ccccc23)O1

Procedure:
By the procedure of Example 27, except that 2.1 equivalents rather than 3.2 equivalents of triethylamine were employed, ethyl 1-(2-benzyloxy-1-naphthyl)-1-hydroxymethanecarboximidate hydrochloride (4.0 g., 0.011 mole) in 180 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2-benzyloxy-1-naphthyl)-oxazolidine-2,4-dione (1.61 g., m.p. 197°-199.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([C:18]([OH:20])=O)=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].N.C1C[N:25]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([C:18]([NH2:25])=[O:20])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Cl)c(Cl)c2)cc1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Product: Cn1cc(C(N)=O)c(Nc2ccc(Cl)c(Cl)c2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
The product of step A (234 mg) was dissolved in dichloromethane (5 mL) and ethanolic ammonia (2 M, 2.0 mL, 4.0 mmol): PyBOP (579 mg, 1.10 mmol) was added in one portion and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was quenched with acetic acid (ca. 0.5 mL), diluted with ethyl acetate (40 mL) and washed with water (2×10 mL) and saturated brine (10 mL). The organics were dried over magnesium sulfate, concentrated in vacuo and chromatographed on silica gel. Elution with dichloromethane-methanol (4:1) afforded 4-(3,4-Dichloro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid amide (28 mg, 12% yield) as a dark yellow-colored solid. An analytical sample was prepared by crystallization from methanol: m.p. >250° C.; 1H NMR (DMSO-d6, 400 MHz) δ10.38 (s, 1H), 8.30 (s, 1H), 7.85 (br s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.45 (br s, 1H), 7.23 (dd, J=8.8, 2.4 Hz, 1H), 5.70 (s, 1H), 3.33 (s, 3H). Anal. Calcd./Found for C13H11Cl2N3O2: C, 50.02/50.02; H, 3.55/3.19; N, 13.46/13.21.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]([NH2:16])=[O:15])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].C1(C2[O:25]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]1[N:11]=[C:10]([S:12]([CH3:13])=[O:25])[C:9]([C:14]([NH2:16])=[O:15])=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(NC(C)(C)C)ncc1C(N)=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(NC(C)(C)C)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a stirring solution of 2-(tert-butylamino)-4-(methylthio)pyrimidine-5-carboxamide (0.1 g, 0.416 mmol) in chloroform (12 mL) was added portion-wise 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.130 g, 0.499 mmol). The resulting pale yellow solution was stirred at ambient temperature overnight. The reaction solution was concentrated under reduced pressure to give the crude product as a white solid. Ethyl acetate (1 mL) was added and the slurry was stirred at room temp for 1 h. The solids were filtered, washed with ethyl acetate, and dried under vacuum to afford 2-(tert-butylamino)-4-(methylsulfinyl)pyrimidine-5-carboxamide (0.092 g, 0.359 mmol, 86% yield). MS (ESI) m/z 257.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:28][CH2:27][CH:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]2[OH:29])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:12]([O:16][C:17]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:29][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N+:8]([O-:10])=[O:9])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC2C(=CC=CC2O)C1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2Oc2cc(Cl)ccc2[N+](=O)[O-])C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (1.93 g, 11 mmols), 2-tert-butoxycarbonyl-5-hydroxy-tetrahydroisoquinoline (2.74 g, 11 mmols), potassium carbonate (1.53 g, 11 mmols) and N,N-dimethylformamide (20 ml) was stirred at 60° C. for 24 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give an oil of 2-tert-butoxycarbonyl-5-(5-chloro-2-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline (4.35 g, 97.7%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[N:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH:21]=O)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1.[CH2:32](P(=O)(OCC)OCC)[P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36].CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:20](/[CH:21]=[CH:32]/[P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[CH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2ncccc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cccnc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 63.2 %

Procedure:
To a mixture of 2-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]nicotinaldehyde (0.30 g), tetraethyl methylenediphosphonate (0.21 g) and N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (3:1, v/v) to give diethyl (E)-2-{2-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]pyridin-3-yl}ethenylphosphonate as a colorless oil (0.25 g, yield 64%).
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:13][O:14][C:15]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:16]=1[CH2:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)=[O:28]>ClCCl>[C:1]([CH2:3][C:4]([N:18]([CH2:17][C:16]1[CH:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:15]=1[O:14][CH3:13])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)=[O:5])#[N:2]
Reactant: N#CCC(=O)O
Reactant: COc1ccc(CNc2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)CC#N)c2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1

Procedure:
To a solution of cyanoacetic acid (43.0 mg, 0.511 mmol) in 1 mL of dichloromethane at room temperature was added PCl5 (106 mg, 0.511 mmol). The mixture was heated to reflux for 10 minutes. A solution of {2-[(2,4-dimethoxybenzyl)amino]-5-methoxyphenyl}(3-fluorophenyl)methanone (101 mg, 0.255 mmol) in 1 mL dichloromethane was added, and the reaction was refluxed for an additional 1.5 hours. The reaction was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The titled product was isolated as a yellow foam (117 mg, 99% yield) which was used in the next step without further purification. Proton NMR for the product was consistent with the titled compound. ESI+MS: 463.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:30][C:28](=[O:29])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)cc1)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
In a reaction vessel were placed 0.20 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.10 g of 4-chlorophenylacetic acid, 0.08 g of potassium carbonate and 5 ml of N,N-dimethylformamide, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into water, and extracted twice with 30 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.22 g of 3,5-dichloro-4-(3-(4-chlorophenylacetyloxy)propyloxy)-1-(3,3-dichloro-2-propenyloxy) benzene (90% yield), nD22.0 1.5698.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[OH:22].C(=O)([O-])[O-].[Ca+2]>O1CCOCC1>[CH2:5]([O:4][C:2]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[OH:22])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)OCc1ccccc1

Procedure:
3.58 moles (536 ml) of benzyl chloroformate (95%) are added in the course of 45 minutes to 3.25 moles (500 g) of 2-amino-5-nitrophenol and 204.5 g of calcium carbonate in 1.5 liter of dioxane brought to 70° C., the temperature being maintained at between 70° C. and 80° C. When the addition is complete, heating is maintained for a further 30 minutes. The inorganic salts present in the reaction medium are removed by filtration while hot. After the addition of ice-cold water to the filtrate, the expected product crystallizes. After filtration and drying, the product obtained is recrystallized from acetic acid. It melts at 200° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[NH2:3][C:4]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccc(O)cc1N
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCc2ccccc2)cc1N
Temperature: 15 °C
Reaction time: 20 h
Yield: 42.1 %

Procedure:
To a solution of 95% NaH (1.82 g, 72.30 mmol) in DMF (100 mL) at 10° C. was added 2-amino-4-hydroxybenzamide (10.0 g, 66.72 mmol) in portions, maintaining the internal temperature at ca. 15° C. The cooling bath was removed, and the solution was allowed to warm to 40° C. over 25 min. The mixture was cooled to 10° C. and a solution of benzyl bromide (7.8 mL, 66.72 mmol) in DMF (20 mL) was added dropwise, and the mixture was allowed to warm to rt. After stirring for 20 h at rt, the mixture was cooled in an ice bath and quenched by addition of aq ammonium chloride. The solution was concentrated and diluted with water. The precipitate was collected by filtration, and the filtrate was extracted with EtOAc. The precipitate from above and the ethyl acetate extracts were combined and chromatographed on silica gel eluting with 20-80% EtOAc/DCM to afford 2-amino-4-(benzyloxy)benzamide as a solid (6.8 g, 43%). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.04 (s, 2 H) 6.14 (dd, J=8.76, 2.54 Hz, 1 H) 6.27 (d, J=2.64 Hz, 1 H) 6.71 (bs, 2 H) 7.26-7.58 (m, 6 H). LC-MS (ESI) m/z 243 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:35])[CH2:19][O:20][CH2:21][C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:25]([NH:24][C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18](=[O:35])[NH:17][C:13]2[CH:12]=[CH:11][CH:16]=[C:15]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:14]=2)=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28]
Reactant: OB(O)c1cccnc1
Reactant: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2cccnc2)c1

Procedure:
0.48 g (3.88 mmol) of 3-pyridineboronic acid, 1.3 g (2.85 mmol) of 2-[((2-[(3-bromophenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester, 95.9 mg (0.08 mmol) of tetrakis(triphenyl phosphine)palladium (0), and 0.41 g (3.88 mmol) of 2N sodium carbonate were heated under reflux for 8 hours in 9.2 mL of toluene and 2.6 mL of methanol. After completion of the reaction, the solvent was distilled off under reduced pressure, and ethyl acetate was added to separate the solid by filtration. Thereafter, the organic layer was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography to give 5-chloro-2-([(2-oxo-2-([3-(pyridin-3-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 62%).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:8]=1.[Cl:18][CH2:19][C:20](N(C)C)=[O:21].Cl>O1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:14][C:15]([C:20](=[O:21])[CH2:19][Cl:18])=[CH:16][CH:17]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-c2ccco2)cc1
Reactant: CN(C)C(=O)CCl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCl)c1ccc(-c2ccc(F)cc2)o1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.60 g (21.98 mmol) of n-butyllithium (2.5N in n-hexane) are added dropwise to 4.44 g (27.41 mmol) of 2-(4-fluorophenyl)furan in 40 ml of absolute tetrahydrofuran at -75° C. After stirring for 45 min, 5.21 g (42.86 mmol) of 2-chloro-N,N-dimethylacetamide in 20 ml of absolute tetrahydrofuran are added at -75° C. After 60 min, the mixture is poured into 200 ml of ice-water, neutralized at 0° C. with 2N hydrochloric acid and extracted 6× with 60 ml of ethyl acetate each time, the combined organic phases are washed 2× with 20 ml of water each time, dried over sodium sulphate and filtered, and the solvent is stripped off. The product is purified by column chromatography (280 g of silica gel 60; solvent: PE/EA 20:1), recrystallized from ethanol and digested with diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(Cl)nn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(Oc2ccc(Cl)nn2)cc1
Yield: 75.7 %

Procedure:
3-Chloro-6-(4-formylphenoxy)pyridazine (4.06 g, 17.3 mmol) and 200 mL of methanol were mixed, and after sodium borohydride (654 mg, 17.3 mmol) was added under cooling with ice and stirring, the mixture was stirred for 15 minutes. Water was added to the reaction mixture and methanol was distilled off. The residue was poured into water, which was extracted with ethyl acetate. The extracted solution was washed with saturated brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=1:2 v/v) to obtain 3.10 g (76%) of the title compound as a colorless oily product.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].Cl>O.CN(C=O)C>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:3]2[CH2:7][CH2:6][NH:5][C:4]2=[O:8])=[CH:19][CH:20]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: O=C1NCCN1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN2CCNC2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium hydride (approximately 60% strength suspension in oil, 1.2 g, approximately 30 mmol) was added portionwise to a solution of imidazolidin-2-one (2.58 g, 30 mmol) in abs. DMF (40 mL) under a blanket of argon within 10 min. The reaction mixture was stirred for 90 min at RT and a solution of 4-tert-butylbenzyl bromide (3.7 mL, 20.1 mmol) in abs. DMF (3 mL) was then added. The reaction mixture was stirred at RT over a period of 3 h and then added to a mixture of H2O (100 mL) and 2N hydrochloric acid solution in H2O (10 mL). The resulting mixture was stirred for 30 min, and the resulting crystals were separated with the aid of a frit and washed with H2O (3×30 mL). The isolated solid matter was recrystallized from a mixture of H2O (100 mL) and EtOH (120 mL). The substance formed (1.4 g, mp: 122-127° C.) is compound D.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]1([C@H:17]([CH2:19][OH:20])[NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:18][C@H:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:19][OH:20])=[O:6]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(Cl)c1cccc(I)c1
Solvent: ClCCl
Product: O=C(N[C@@H](CO)c1ccccc1)c1cccc(I)c1
Reaction time: 3 h
Yield: 63.7 %

Procedure:
To a vigorously stirred solution of 3-iodobenzoyl chloride (16.79 g, 63 mmol) in dichloromethane (300 ml) was rapidly added a solution of (R)-(-)-2-phenylglycinol (8.64 g, 63 mmol) in dichloromethane (50 ml). The reaction mixture was stirred for 3 hours and crude product collected by filtration. Recrystallization from isopropyl alcohol gave (+)-2-(3-iodobenzamido)-2(R)-phenylethan-1-ol as white needles (14.74 g, 64%).