Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>CC#N.O>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@@H:2]([NH:1][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1
Reactant: N[C@H](Cc1ccc(Br)cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
To a solution of (R)-2-amino-3-(4-bromophenyl)propionic acid (50 g, 0.2 mol) in MeCN (700 mL) was added a solution of NaOH (16.4 g, 0.4 mol) in water (700 mL) at −5° C. After stirring for 10 minutes, a solution of (BOC)2O (44.7 g, 0.2 mol) in MeCN (100 mL) was added. The mixture was warmed to room temperature and stirred overnight. After evaporation of the MeCN, the residue was diluted with DCM (800 mL) and acidified with 1 M HCl to pH 2 at −5° C. The aqueous layer was extracted with DCM (3×200 mL). The combined organic layers were washed with saturated aqueous NaCl (500 mL), dried over anhydrous Na2SO4 and concentrated to yield the title compound as a white solid (64.2 g). LC-MS: [M+Na]:366, [2M+Na]:709.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[N:11](C(OC(C)(C)C)=O)[C:10]=2[CH2:9][CH2:8]1)#[CH:2].FC(F)(F)C(O)=[O:32]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1)(=[O:32])[CH3:2]
Reactant: C#Cc1cccc(CC2CCc3c2cc(C(=O)OC)n3C(=O)OC(C)(C)C)c1
Reactant: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(C(C)=O)c1
Reaction time: 2 h

Procedure:
The title compound was synthesized from 1-tert-butyl 2-methyl 4-(3-ethynylbenzyl)-5,6-dihydrocyclopenta[b]pyrrole-1,2(4H)-dicarboxylate (see Example 2.51). 1-tert-Butyl 2-methyl 4-(3-ethynylbenzyl)-5,6-dihydrocyclopenta[b]pyrrole-1,2(4H)-dicarboxylate (0.016 g, 0.042 mmol) was dissolved in trifluoroacetic acid (1 mL) and stirred for 2 h. The reaction was then quenched with bicarbonate solution and extracted three times with ethyl acetate. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-25% EtOAc/heptane to afford the title compound. 0.006 g. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.07-2.16 (m, 1H) 2.49-2.55 (m, 1H) 2.57 (s, 3H) 2.61-2.68 (m, 2H) 2.88 (d, J=7.40 Hz, 2H) 3.29-3.37 (m, 1H) 3.70 (s, 3H) 6.28 (d, J=1.59 Hz, 1H) 7.41-7.50 (m, 2H) 7.82-7.87 (m, 2H) 10.48 (br. s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([CH:11](O)[CH3:12])=[CH:7][C:8]=1[CH2:9][CH3:10].S(Cl)([Cl:16])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([CH:11]([Cl:16])[CH3:12])=[CH:7][C:8]=1[CH2:9][CH3:10]
Reactant: CCc1cc(C(C)O)ncc1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCc1cc(C(C)Cl)ncc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A solution of 3-methoxy-4-ethyl-6-(1-hydroxyethyl)-pyridine (236 mg, 1.3 mmol) in 5 mL of methylene chloride at 0° C. is treated with thionyl chloride (0.141 mL, 1.95 mmol) and stirred at room temperature for 1 h. The reaction is quenched with 12 mL of saturated sodium bicarbonate. The aqueous layer is extracted with 3×10 mL of methylene chloride. The combined organics are dried over potassium carbonate and concentrated in vacuo to provide 249 mg (96%) of 3-methoxy-4-ethyl-6-(1-chloroethyl)-pyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1C=C(C=CC=1O)C=O)C1C=CC=CC=1.[Cl:18][C:19]1[C:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:25]([OH:35])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>>[Cl:18][C:19]1[C:26]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:25]([O:35][CH2:1][O:8][CH3:9])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]
Reactant: O=Cc1ccc(O)c(OCc2ccccc2)c1Cl
Reactant: O=Cc1ccc(O)c(OCc2ccccc2)c1
Product: COCOc1ccc(C=O)c(Cl)c1OCc1ccccc1

Procedure:
Proceeding as in example 63, but replacing for 3-benzyloxy-4-hydroxybenzaldehyde an equivalent quantity of 2-chloro-3-benzyloxy-4-hydroxybenzaldehyde obtained as described in example 85, 2-chloro-3-benzyloxy-4-methoxymethoxybenzaldehyde was obtained, m.p. 66°-67° C. (from petroleum ether, b.p. 30°-70° C.).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>ClCCl>[CH2:16]([O:15][C:13]([CH2:12][CH2:11][CH2:10][O:9][C:8]1[CH:18]=[C:19]([CH3:23])[C:20]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:21]([CH3:22])[C:7]=1[CH3:6])=[O:14])[CH3:17]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)CCCOc1cc(C)cc(C)c1C
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of chlorosulfonic acid (4.78 ml) and CH2Cl2 (25 ml) was added dropwise into a mixture of ethyl 4-(2,3,5-trimethylphenoxy)butyrate (6.00 g) and dichloromethane (CH2Cl2, 500 ml) under ice-water cooling over 10 minutes, and was stirred at room temperature for 2.5 hours. The reaction mixture was poured into a mixture of ice and sat. NaHCO3aq. The separated organic phase was washed with sat. NaHCO3aq., water, and brine, and was dried over MgSO4. After filtration, the filtrate was evaporated to give 4-(3-ethoxycarbonylpropoxy)-2,3,6-trimethylbenzenesulfonyl chloride (16.35 g) as an oil compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: N#CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
4-Hydroxybenzyl cyanide (2.5 g, 18.77 mmol), benzyl bromide (3.8 g, 22.5 mmol) and potassium carbonate (45 mmol) were combined in acetone (50 mL) and heated to reflux for 8 h. The reaction was allowed to cool to rt, diluted with ethyl acetate and filtered to remove the solids. The organic layer, was concentrated in vacuo to give an oil. The crude benzyl ether was purified by chromatography on silica gel eluting hexane: ethyl acetate (90:10, v:v) to give 4-benzyloxybenzyl cyanide (4.0 g, 95%) which solidified. MS (M+NH4)+=241.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([CH2:16][CH:17]=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:19].[Na+].Cl>C1COCC1.[Ag]=O>[CH2:1]([O:8][C:9]([C:11]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=CCC1(C(=O)OCc2ccccc2)CCCC1
Agent: O=[Ag]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CC1(C(=O)OCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Next, to a solution of 1-(2-oxo-ethyl)-cyclopentanecarboxylic acid benzyl ester (200 mg, 0.81 mmol) in THF (5 mL) is added silver(II) oxide (201 mg, 1.62 mmol) and aqueous 1M NaOH (0.81 mL of 1.0 N, 0.81 mmol) and the suspension is stirred at room temperature for 18 hours. The mixture is acidified to pH 3 with aqueous 1M HCl and is extracted with ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure to furnish 1-carboxymethyl-cyclopentanecarboxylic acid benzyl ester MS 263.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[OH-].[K+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH:9]=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 1-(3-chlorophenyl)ethanone (1.54 g, 10 mmol), 4-chlorobenzaldehyde (1.4 g, 10 mmol) in EtOH (25 mL) was added aq. KOH (50% wt, 10 mmol, 0.56 mL). The reaction was stirred at RT for 2 h then filtered the insoluble white solid. The solid was dried and washed with PE/EA (5:1, 10 mL) to give 1-(3-chlorophenyl)-3-(4-chlorophenyl)prop-2-en-1-one (2.3 g, 83% yield) as a white solid. LCMS: MH+ 277 and TR=2.050 min. Used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(O)(=O)=O)=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:20])[CH2:18][CH3:19])=[C:5]2C.[CH2:27]([NH2:30])[C:28]#[CH:29]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:20])[CH2:18][CH3:19])=[C:5]2[NH:30][CH2:27][C:28]#[CH:29]
Reactant: CCC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C(F)(F)F)c2[nH]c1=O
Reactant: C#CCN
Product: C#CCNc1c(C(=O)CC)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12
Yield: 86.9 %

Procedure:
6-Chloro-4-methylsulfoxy-3-propionyl-8-trifluoromethyl-2-quinolinone (365 mg, 1 mmol) and propargylamine (55 mg, 1 mmol) were used and the reaction was carried out as in the above process of example 1 to obtain the desired product (310 mg, yield: 87%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>C1COCC1>[Cl:11][C:9]1[C:10]2[C:2]([CH:20]=[O:21])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (G-1) (2.33 g, 10.0 mmol, 1.0 eq) in anhydrous THF (100 mL) at −78° C. under argon, n-BuLi solution (2.5 M in THF, 8.8 mL, 22.0 mmol, 2.2 eq) is added dropwise (over 10 min). The resulting mixture is stirred at −78° C. for 1 h and then DMF (2.0 g, 11.0 mmol, 1.1 eq) is added dropwise (over 10 min). The mixture is stirred at −78° C. for an additional 30 min and then stirred at RT overnight. The reaction mixture is quenched with H2O (50 mL) and then concentrated in vacuo. The residue is triturated with saturated aqueous NH4Cl solution. The solid is collected by filtration, rinsed with ethyl acetate, and dried in vacuo to afford the product, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (G-2).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9](C(OCC)=O)=[CH:8][CH:7]=[CH:6][N:5]=1.[C:15]([O-])(O)=O.[Na+]>>[CH:3]1[N:2]=[CH:15][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=12
Reactant: CCOC(=O)c1cccnc1CN
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: c1ccn2cncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 67.2 mL of acetic anhydride and 28.8 mL of formic acid was heated at 50-60° C. oil bath temperature for 3 h and then cooled to rt to give formic-acetic anhydride, which was then slowly added into the solid ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl and then stirred at rt for 8 h. Excess reagent was evaporated to give a residue, which was neutralized by very slow addition of sat NaHCO3 solution. Solution was extracted with DCM, dried and evaporated to provide imidazo[1,5-a]pyridine as a yellow solid. MS: exact mass calculated for C10H10N2O2, 190.07; m/z found, 191 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C([N:17](CC)CC)C.ClC(OCC)=O.N>C(OCC)(=O)C.C1COCC1>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH2:17])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)O)cc(OC)c1Br
Agent: CCOC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(N)=O)cc(OC)c1Br
Yield: 78.8 %

Procedure:
To a mixture of 4-bromo-3,5-dimethoxybenzoic acid (15 g, 57.6 mmol) and THF (200 mL) were added triethylamine (9.63 mL, 69.0 mmol) and ethyl chloroformate (5.79 mL, 60.6 mmol) while stirring on ice, and the resulting mixture was stirred for 20 minutes while cooling on ice. After adding 28% aqueous ammonia to the mixture and stirring at room temperature for 2 hours, ethyl acetate was further added. After then thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and the solvent in the filtrate was distilled off under reduced pressure. The obtained residue (solid) was washed with diethyl ether and collected by filtration to obtain the title compound (11.8 g, 45.4 mmol).
Reaction SMILES: [CH3:1][C@@H:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:12]([OH:14])=O.S(Cl)([Cl:17])=O>>[CH3:1][C@@H:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:12]([Cl:17])=[O:14]
Reactant: Cc1cccc2c1C[C@H](C(=O)O)[C@@H]2C
Reactant: O=S(Cl)Cl
Product: Cc1cccc2c1C[C@H](C(=O)Cl)[C@@H]2C
Yield: 92 %

Procedure:
cis-2,3-Dihydro-1,4-dimethyl-1H-indene-2-carboxylic acid is converted to its acid chloride by treatment with thionyl chloride. Yield 92%.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[PH:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].C[O-].[Na+]>CO>[OH:9][CH:8]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCO[PH](=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(OCC)C(O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.8 %

Procedure:
The title compound was prepared as described in Taylor, W P, et. Al, Bioorg. Med. Chem. 4:1515-1520 (1996). 4-Nitrobenzaldehyde (3.0 g, 19.85 mmol) and diethyl phosphonate (2.74 g, 19.85 mmol) were combined and treated with a 0.5N solution of sodium methoxide in methanol (0.993 mL, 0.496 mmol). The resulting red-orange solution was stirred 12 h at room temperature. The reaction mixture was extracted with dichloromethane (20 mL) followed by half saturated ammonium chloride (20 mL). The organic layer was separated, dried and concentrated under vacuum to provide the title compound as a semi-solid (5.1 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]1[O:14][CH2:13][CH2:12][O:5]1
Reactant: OCCO
Reactant: COc1ccc(C=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2OCCO2)c(F)c1
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a solution of 2-fluoro-4-methoxy-benzaldehyde (13.98 g, 90.7 mmol) in toluene (100 mL) was added ethylene glycol (101 mL, 1.81 mol) and p-toluenesulfonic acid monohydrate (1.04 g, 5.44 mmol). The reaction mixture was heated at reflux for 16 hrs. The water was removed using a Dean Starck apparatus. After cooling, aqueous potassium carbonate (10%, 200 mL) was added and the mixture stirred for 30 minutes. The solution was extracted with ethyl acetate. The organic phase was washed successively with 10% aqueous potassium carbonate, brine and dried (MgSO4). The residue was purified on silica gel (eluent: 10% ethyl acetate in hexane) to give 9.187 g of 2-(2-fluoro-4-methoxy-phenyl)-[1,3] dioxolane (51%). 1H NMR (300 MHz; CDCl3): 3.81 (s, 3 H), 4.06 (m, 2 H), 4.15 (m, 2 H), 6.03 (s, 1 H), 6.60 (dd, J=12.3 and 2.7 Hz, 1 H), 6.72 (d, J=8.4 Hz, 1 H), 7.44 (t, J=8.4 Hz, 1 H).
Reaction SMILES: NC1C=CC=CC=1C1C([C:14]([C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH2:28])=[CH:20][CH:19]=[CH:18][N:17]=2)=O)=NC=CC=1.[NH2:29][C:30](N)=[O:31]>C(O)(=O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:14][C:16]=1[C:21]1[C:22]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:28][C:30](=[O:31])[N:29]=1
Reactant: Nc1ccccc1-c1cccnc1C(=O)c1ncccc1-c1ccccc1N
Reactant: NC(N)=O
Solvent: CC(=O)O
Product: O=c1nc(-c2ccccn2)c2ccccc2[nH]1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
A solution of 2-aminophenyl-2-pyridyl ketone (0.95 g, 4.8 mmol), urea (500 mg, 8.3 mmol) and acetic acid (10 mL) was stirred at 110° C. for 18 h. The reaction mixture was cooled to rt and filtered. The solid was washed with water and dried under reduced pressure to give 4-(pyridin-2-yl)quinazolin-2(1H)-one as a yellow solid (0.83 g, 78%), which was dissolved in phosphorous oxychloride (3 mL) and the mixture was stirred at reflux for 30 min. The reaction mixture was cooled to rt and slowly poured over an ice/water mixture. The mixture was filtered and the solid was dried under reduced pressure to give 2-chloro-4-(pyridin-2-yl)quinazoline as an off-white solid (56 mg, 6%).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH3:14][C:15]1[C:16]2[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=2[S:18][C:19]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)O>>[OH:6][C:5]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:7])[C:4]=1[CH:20]([C:19]1[S:18][C:17]2[CH:28]=[CH:29][CH:30]=[CH:31][C:16]=2[C:15]=1[CH3:14])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(C(O)c2ccccc2)sc2ccccc12
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Product: Cc1c(C(C2=C(O)C(C)(c3ccccc3)C2=O)c2ccccc2)sc2ccccc12

Procedure:
Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with (3-methyl-benzo[b]thiophen-2-yl)-phenyl-methanol to give the title compound as a colorless solid. MS: 409.5 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:9])=[C:4](Cl)[CH:5]=[CH:6][CH:7]=1.[CH3:10][O-:11].[Na+]>CC(N(C)C)=O.CO>[Cl:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][CH3:10]
Reactant: C[O-]
Reactant: Clc1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COc1cccc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
Trichlorobenzene (363 g, 2 moles) was dissolved in 600 ml of dimethyl acetamide and 650 ml of 25% sodium methoxide in methanol solution added all at once. The solution was stirred and heated to 166° as the methanol slowly distilled out. The solution was held at 166° for 30 minutes, * cooled and quenched with 5 times its volume of water and extracted with toluene (2 × 1000 ml). The toluene extracts were washed with water (1 L) and dried over sodium sulfate. The toluene was removed by distillation under reduced pressure and the residue fractionated to yield the pure 2,3-dichloroanisole, bp 140°/28 mm. Yield 212 g (60%). Considerable material remains in the aqueous DMAC layer and can be recovered by repeated extractions with methylene chloride.
Reaction SMILES: [C:1]1([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[C:20]([O:22]CC3C=CC=CC=3)[C:19]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:18][C:17]=2[CH2:37][CH3:38])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:39]=[N+:40]=[N-:41].[Na+].Cl.C(N(CC)CC)C.Cl>CN(C)C=O>[C:1]1([CH:7]([C:8]2[NH:9][N:41]=[N:40][N:39]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[C:20]([OH:22])[C:19]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:18][C:17]=2[CH2:37][CH3:38])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C#N)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCCCC(c1ccccc1)c1nnn[nH]1
Temperature: 110 °C
Yield: 107 %

Procedure:
2-Phenyl-7-(2-ethyl-4-(4-fluorophenyl)-5-benzyloxyphenoxy)heptanenitrile (700 mg, 1.38 mmol) was dissolved in dimethylformamide (20 mL) and sodium azide (0.6 g) and triethylamine hydrochloride added (1.2 g) and the stirred suspension heated at 110° C. for 3 days. The suspension was then added to 1M hydrochloric acid (100 mL) and the solution extracted 4 times with chloroform. The combined chloroform extracts were washed with water and dried with magnesium sulfate. On evaporation the solution yielded 680 mg (72%) of the title compound as a crude oil which was then directly deprotected.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.CC(C)=[O:20]>>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([OH:20])=[O:10])=[CH:7][CH:6]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Oc2c(F)cccc2F)cc1
Product: O=C(O)c1ccc(Oc2c(F)cccc2F)cc1
Yield: 70 %

Procedure:
To a cold solution of 4-(2,6-difluoro-phenoxy)-benzaldehyde (1 g, 4.2 mmol) in acetone (10 mL) was added the Jone's reagent slowly drop wise at 0° C. until the reaction completes. The acetone was removed completely and the residue was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with water and brine, then dried over sodium sulphate and concentrated to obtain the title compound (0.75 g, 70%)
Reaction SMILES: [NH:1]([C:31]([O:33]C(C)(C)C)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1)=[O:20])[CH2:15][C:16](=[O:18])[OH:17])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:38]C(ON1C(=O)CCC1=O)=O.C([O-])(O)=O.[Na+].CN(C=O)C>C(O)(C(F)(F)F)=O.Cl>[NH:1]([C:31]([CH3:38])=[O:33])[C@H:2]([C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1)=[O:20])[CH2:15][C:16](=[O:18])[OH:17])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)Nc1ccc([N+](=O)[O-])cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-BOCValAlaAsp-p-nitroanilide (174 mg, 0.33 mmole) was dissolved in neat TFA (5 mL) and stirred at room temperature for 1 hour. The TFA was removed in vacuo and the residue was then dissolved in 5 mL of CH2Cl2 which was then evaporated in vacuo. This dissolution with CH2Cl2 and subsequent evaporation repeated two more times. The residue was dissolved in dioxane/water (5 mL, 4:1 ) and treated with acetic acid N-hydroxysuccinimide ester (63 mg, 0.40 mmole) and NaHCO3 (139 mg, 1.65 mmole). After 18 hours, the mixture was diluted with 1N HCl (25 mL) and extracted three times with ethyl acetate. The combined extracts were dried with MgSO4, filtered and concentrated to a yellow solid which was recrystallized from ethyl acetate/ethanol to give 33 mg (21%) of light yellow powder: mp 196°-200° C. (dec.); 1H NMR (DMSO-d6) δ 0.80 (d, J=6.6 Hz, 3H), 0.82 (d, J=5.1 Hz, 3H), 1.20 (d, J=7.2 Hz, 3H), 1.85 (s, 3H), 1.85-2.0 (m, 1H), 2.60 (dd, J=7.5, 16.6 Hz, 1H), 2.75 (dd, J=6.2, 16.6 Hz, 1H), 4.1-4.2 (m, 1H), 4.2-4.3 (m, 1H), 4.6-4.7 (m, 1H), 7.8-7.9 (m, 3H), 8.11 (d, J=6.8 Hz, 1H), 8.21 (d, J=9.3 Hz, 2H), 8.27 (d, J=7.2 Hz, 1H), 10.51 (s, 1H), 12.45 (br s, 1H); MS (LSIMS) m/e 488 (6, M+ +Na), 466 (23, M+ 1), 449 (7) 328 (15), 213 (44), 142 (100); [α]D20 -24.9° (c=1.0, DMF); Analysis calculated for C20H27N5O8 : C, 51.60; H, 5.85; N, 15.05; found: C, 50.16; H, 5.79; N, 14.06.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[O:5][CH3:6].[H-].[Na+].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br.O>CN(C)C=O>[CH3:1][O:2][N:3]([CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([Br:10])[CH:12]=1)[C:4](=[O:7])[O:5][CH3:6]
Reactant: BrCc1cccc(Br)c1
Reactant: CONC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1cccc(Br)c1)OC
Reaction time: 3 h
Yield: 455 %

Procedure:
2.52 g of methyl N-methoxycarbamate in N,N-dimethylformamide (30 ml) was stirred together with 1.15 g of 60% sodium hydride at room temperature for 30 minutes. 1.00 g of 3-bromobenzyl bromide was added dropwise at room temperature, and the resulting solution was stirred for 3 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 4.99 g of methyl N-methoxy-N-(3-bromobenzyl)carbamate as a transparent viscous liquid.