Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[OH2:16]>O.O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O>[CH:2]([C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:16]
Reactant: COc1ccc(CC(=O)O)cc1CBr
Reactant: O
Agent: [Cu+2]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Product: COc1ccc(CC(=O)O)cc1C=O

Procedure:
Copper(II) nitrate trihydrate (3.3 g) was added to (3-bromomethyl-4-methoxy-phenyl)-acetic acid (1.4 g) in water (50 mL) and heated to reflux for 75 minutes. On cooling the reaction mixture was acidified with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was separated and washed sequentially with 2M aqueous hydrochloric acid (2×50 mL), brine (50 mL), dried (magnesium sulfate) and concentrated. Purification on silica, eluting iso-hexane/ethyl acetate [4:1 to 1:1 to 0:1], to give the subtitle compound as a solid (0.26 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1.[OH-].C[Sn+](C)C>ClCCCl.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccccc1
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(O)c1nc(-c2c(F)cccc2F)oc1Nc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of ethyl 2-(2,6-difluorophenyl)-5-(phenylamino)oxazole-4-carboxylate (0.080 g, 0.23 mmol) in DCE (8 mL) was added trimethyltin hydroxide (0.300 g, 1.66 mmol) and the resulting solution stirred at 80° C. overnight. A further portion of trimethyltin hydroxide (0.168 g, 0.93 mmol) was added and the solution stirred at 80° C. overnight. The reaction was diluted with DCM and washed with 1M aqueous HCl and brine. The organic phase was dried over MgSO4 and solvent removed in vacuo. The residue was purified by silica gel column chromatography using an 8% to 50% EtOAc in hexanes gradient followed by a 5% to 50% MeOH in DCM gradient to afford 2-(2,6-difluorophenyl)-5-(phenylamino)oxazole-4-carboxylic acid (0.030 g, 0.095 mmol, 41% three steps). LCMS (1) Rt: 1.46 min; m/z (ES+) 317.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([CH3:57])[CH:51]=1>CN(C=O)C.C(O)=O>[OH:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[CH:51][C:52]=1[CH3:57]
Reactant: Cc1cc(CN)ccc1O
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)ccc1O
Reaction time: 0.33 h
Yield: 50.4 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (177 mg, 0.55 mmol) and ethyl-diisopropylamine (282 μL, 1.65 mmol) in DMF (15 mL) is allowed to stand at rt for 20 min. A solution of 4-aminomethyl-2-methyl-phenol hydrochloride (96 mg, 0.55 mmol) and ethyl-diisopropylamine (94 μL, 0.55 mmol) in DMF (1.5 mL) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 mL), the mixture is separated by HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3-methyl-benzylamide (86 mg) as a colourless oil. LC-MS: tR=0.99 min, [M+1]+=342.17.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([C:11]([NH2:13])=[O:12])[CH2:5]2.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22].O>C(Cl)Cl>[C:21]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH2:5][CH:6]1[C:11]([NH2:13])=[O:12])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: NC(=O)C1Cc2cc(F)ccc2N1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc(F)cc2CC1C(N)=O
Reaction time: 6 h
Yield: 75.6 %

Procedure:
To a mixture of intermediate (17) (0.0094 mole) in DCM (30 ml), cooled in an ice bath under argon, was added triethylamine (0.031 mole) followed by acetyl chloride (0.031 mole). The resulting mixture was allowed to return to room temperature. After stirring for 6 hours, the mixture was cooled in an ice bath and 50 ml of water was added. The mixture was allowed to stir about 20 minutes, was filtered and the solid was allowed to dry to obtain 1.58 g of 1-acetyl-5-fluoro-2,3-dihydro-1H-indole-2-carboxamide (intermediate 18, mp. 232–235° C.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:27])[C:18]1[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:20](Cl)=[O:21]>O1CCCC1.CCCCCC>[C:12]([C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[O:16][C:17](=[O:27])[C:18]1[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:20]([O:16][C:6]1[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C(C)(C)C)c(OC(=O)c2ccccc2C(=O)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred, ice-cold solution of 11.6 g (0.05 mol) 2,6-di-tert-butyl-4-methylphenol in 100 mL dry tetrahydrofuran was added dropwise under argon 25 mL 23M n-butyllithium in hexane. After 2.5 hours, 5.3 g (0.026 mol) fresh phthaloyl chloride was added dropwise and the mixture stirred overnight at room temperature. Product was isolated by extraction, washed with ligroin and recrystallized from acetonitrile to give 4 g nearly pure Compound 6, as white crystals, m.p. 262°-5° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:23]>>[ClH:23].[Cl:23][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH+:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: OCc1ccc(C=Cc2ccnc3ccccc23)cc1
Reactant: O=S(Cl)Cl
Product: Cl
Product: ClCc1ccc(C=Cc2cc[nH+]c3ccccc23)cc1
Reaction time: 3 h

Procedure:
1 mM of (1) was added to an excess of SOCl2 and stirred for three hours. Product was precipitated with Et2O, filtered and dried in vacuo. Yield of the yellow crystals was 0.242 g (86%) mp=260° C. (decomposed). Elemental analysis (Theoretical: C=68.37, H=4.78. N=4.43 and Cl=22.42. Actual: C=67.21, H=4.69, N=4.33, and Cl=22.00) and NMR(CDCl3 /CD3OD; 200 MHz) confirmed structure. The resulting product (2) was exposed to light (OLITE AL 53/100, 5 kw, L1261 lamp at 40 in).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[NH:45])[NH:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])=[CH:29][CH:28]=1>CN(C)C=O>[CH2:38]([O:37][C:35]([NH:34][C:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][N:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[C:7](=[O:13])[C:8]2=[O:12])=[CH:32][CH:31]=1)=[NH:45])=[O:36])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCBr)cc1
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(CCCOc3ccc(C(=N)NC(=O)OCc4ccccc4)cc3)C(=O)C2=O)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 1.00 g of 1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, and 0.17 g of sodium hydride (60%, oil) was added to the solution, followed by stirring at 50° C. for 30 minutes. Then, the reaction mixture was cooled to room temperature, after which 1.48 g of 1-bromo-3-(4-benzyloxycarbonylamidinophenoxy)propane was added thereto and the resulting mixture was stirred overnight at the same temperature. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=20:1) to obtain 1.76 g of 4-(3-(4-benzyloxycarbonylamidinophenoxy)propyl]-1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[C:25]([Cu])#[N:26].O.Cl>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(I)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-1-iodo-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (136 mg, 0.31 mmol) and CuCN (56 mg, 0.62 mmol) in 5 mL of DMF was refluxed for 8 min. The mixture was cooled to r.t. and poured into a mixture of water and CH2Cl2. 4 M HCl was added to the mixture with vigorous stirring until no solid was present. The aqueous layer was extracted with additional CH2Cl2, and the combined organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-10% EtOAc/CH2Cl2) to give 88 mg of the title compound. MS: (+) m/z 336.00 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[CH:4][C:3]=1[NH:19][C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].O>CN(C)C=O>[C:20]([NH:19][C:3]1[C:2]([F:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([CH:4]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:30][C:31]([O:33][CH3:34])=[O:32])(=[O:22])[CH3:21]
Reactant: COC(=O)CBr
Reactant: CC(=O)Nc1cc(Oc2ccccc2O)c([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
3.02 g of N-[2-fluoro-5-(2-hydroxyphenoxy)-4-nitrophenyl]acetamide was dissolved in 20 ml of N,N-dimethylformamide, then, 1.5 g of potassium carbonate was added, and the mixture was stirred for 1 hour at room temperature. Then, 1.6 g of methyl bromoacetate was added at room temperature. The mixture was stirred for 2 hours under the same condition, poured into water, extracted with ethyl acetate, and the organic layer was washed with dilute hydrochloric acid, washed with water, dried over magnesium sulfate and concentrated, and the resulted crystal was washed with t-butyl methyl ether to obtain 3.01 g of methyl [2-(5-acetylamino-4-fluoro-2-nitrophenoxy)phenoxy]acetate.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[CH:11][C:10]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32](Cl)(=[O:36])[CH2:33][CH2:34][CH3:35]>O1CCCC1.O>[CH2:25]([O:24][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][N:17]([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])[CH:13]=[CH:14][C:9]=1[NH:8][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCC(=O)Cl
Reactant: CCCN(CCC)CCc1ccc(N)c(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1ccc(CCN(CCC)CCC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.3 ml of triethylamine is added to 0.65 g of N-[2-(4-amino-3-benzyloxyphenyl)ethyl]-N,N-dipropylamine in 10 ml of tetrahydrofuran, and then 0.23 ml of butyryl chloride is added dropwise thereto. The reaction mixture is stirred for one hour at room temperature, diluted with water, and the product extracted by shaking with methylene chloride, isolating 770 mg of N-[2-benzyloxy-4-(2-dipropylaminoethyl)phenyl]butyramide as an oil from the methylene chloride solution.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39]C)=[O:37]>C1COCC1>[C:36](=[O:37])([O:38][CH3:39])[O:15][C:14](=[O:16])[CH2:13][C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)O)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)OC(=O)C[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2 g (5.26 mmol) of (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl) amino]hexanoic acid and 0.56 g (5.73 mmol) of triethylamine are dissolved in 30 ml of THF under argon and cooled to 0° C. 0.59 g (5.73 mmol) of ethyl chloroformate are added, and the mixture is stirred at 0° C. for 3 hours. The reaction mixture is filtered through kieselguhr, and the filtrate is reacted directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[C:5]([CH3:22])[CH:4]=1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>>[CH2:27]([N:10]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:22])=[C:17]2[C:12]([C:13]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=[CH:16]2)=[N:11]1)[CH:26]=[CH2:25]
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(C)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(OC)cc1C
Yield: 32.4 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxy-2-methylphenyl)-7-(trifluoromethyl)-1H-indazole (0.150 g, 0.49 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and allyl bromide (0.07 mL, 0.74 mmol) to give the title compound (0.055 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[OH:18][CH2:19][CH2:20][O:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([C:29]2[NH:38][C:37](=[O:39])[C:36]3[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=3[O:40][CH3:41])[N:30]=2)=[CH:24][C:23]=1[CH3:44]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[O:18][CH2:19][CH2:20][O:21][C:22]2[C:27]([CH3:28])=[CH:26][C:25]([C:29]3[NH:38][C:37](=[O:39])[C:36]4[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=4[O:40][CH3:41])[N:30]=3)=[CH:24][C:23]=2[CH3:44])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCOC(=O)Nc4ccc(F)cc4)c(C)c3)nc2c1
Yield: 74 %

Procedure:
A mixture of 4-fluorophenylisocyanate (0.138 mL, 1.14 mmol), Et3N (0.185 mL, 1.32 mmol) and 4 (0.0700 g, 0.189 mmol) in THF (1.00 mL) was heated at reflux for 8 hours. The mixture was cooled, diluted with EtOAc (200 mL), washed with saturated aqueous NH4Cl (3×75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified on silica gel (12 g, CH2Cl2/MeOH) and the product was freeze-dried from MeCN/H2O to provide 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl 4-fluoro-phenylcarbamate (5) (0.0710 g, 74%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.78 (s, 1H), 7.91 (s, 2H), 7.54-7.44 (m, 2H), 7.18-7.08 (m, 2H), 6.73 (d, J=2.31 Hz, 1H), 6.51 (d, J=2.31 Hz, 1H), 4.47-4.38 (m, 2H), 4.12-4.03 (m, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 2.31 (s, 6H); MS (APCI) m/z 508 [C27H26FN3O6+H]+.
Reaction SMILES: [C:1]1([O:7]C)C=CC=CC=1.[C:9]([NH:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)(=[O:11])[CH3:10]>>[OH:19][C:15]1[CH:14]=[C:13]([NH:12][C:9](=[O:11])[CH3:10])[CH:18]=[CH:17][C:16]=1[CH:1]=[O:7]
Reactant: COc1ccccc1
Reactant: CC(=O)Nc1cccc(O)c1
Product: CC(=O)Nc1ccc(C=O)c(O)c1

Procedure:
By operating according to Example 13, but using anisole as the solvent and a temperature of 100° C., and starting from 15.1 g of 3-acetylaminophenol, 9.0 g of a product (yield on the theoretical value=50%) having a melting point at 185°-186° C. were obtained.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].C([Li])CCC.IC>C1COCC1>[F:7][C:8]1[CH:16]=[C:15]([CH3:1])[C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COc1ccc(F)c(C(=O)O)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c(F)cc1C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Potassium tert-butoxide (7.92 g, 70.5 mmol) was dissolved in THF (150 mL) and cooled to −78° C. 2-Fluoro-5-methoxybenzoic acid (3.00 g, 17.6 mmol) in THF (100 mL) was added followed by n-butyl lithium (2.5 N in hexanes, 28.2 mL, 70.5 mmol). After 40 minutes, iodomethane (2.2 mL, 35.4 mmol) was added and allowed to stir at −78° C. for 70 minutes before warming to room temperature. The reaction was quenched with saturated ammonium chloride (100 mL) and extracted with ether. The aqueous layer was acidified using 6 N HCl then extracted with ether. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by Gilson reverse-phase HPLC (acidic mobile phase) to yield 2-fluoro-5-methoxy-4-methylbenzoic acid as a white solid. MS m/z=185 [M+1]+. Calc'd for CgHgFO3: 184.20.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(C(C)C)C(C)C)C.Cl.[NH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([NH:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[O:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CN
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.75 g (0.006 mol) of 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid and 0.95 g (0.006 mol) of 1,1'-carbonyldiimidazole are stirred at room temperature in 15 ml of tetrahydrofuran and 1.0 ml (0.006 mol) of N-ethyldiisopropylamine and 0.82 g (0.006 mol) of ethyl glycinate hydrochloride are then added thereto. After stirring at room temperature for 1 hour, the solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on aluminum oxide with ethyl acetate-ethanol (9:1) and crystallization from methylene chloride/t-butyl methyl ether gives ethyl N-[2-(4-acetamidobutyryl)-5-chlorohydrocinnamoyl]-glycinate as white crystals with melting point 96°.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[O:26][CH3:27]>CCO.N1CCCCC1>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]([NH2:16])=[O:15])=[CH:20][C:19]=1[O:26][CH3:27]
Reactant: COc1cc(C=O)ccc1F
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C=Nc2[nH]nc(Nc3cccnc3)c2C(N)=O)ccc1F

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (100 mg) was suspended in EtOH (3 mL) and 4-Fluoro-3-methoxybenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-fluoro-3-methoxybenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][O:10][CH:11]([C:17]([O-])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:18])[CH:11]([O:10][CH3:9])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)C(OC)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(OC)C(=O)Nc1cccc(Cl)c1
Yield: 30 %

Procedure:
3-Chloroaniline (2.82 grams, 0.02 mole), mono-ethyl methoxymalonate (3.58 grams, 0.02 mole), prepared in Example LIII Part B, and 1,3-dicyclohexylcarbodiimide (4.50 grams, 0.02 mole) were reacted in a manner similar to that described in Example LVII to give 1.60 grams (0.006 mole) of ethyl 3-[(3-chlorophenyl)amino]-2-methoxy-3-oxopropanoate having melting point of 43.50° C.-46.50° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.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.[NH2:42][CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][CH2:55][C:56]2[CH:61]=[C:60]([Cl:62])[CH:59]=[C:58]([Cl:63])[CH:57]=2)=[O:53])[CH2:48][CH2:47]1>CN(C=O)C.CCOC(C)=O>[NH:1]1[CH:5]=[C:4]([C:6]([NH:42][CH2:43][CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][CH2:55][C:56]3[CH:61]=[C:60]([Cl:62])[CH:59]=[C:58]([Cl:63])[CH:57]=3)=[O:53])[CH2:48][CH2:47]2)=[O:8])[N:3]=[N:2]1
Reactant: O=C(O)c1c[nH]nn1
Reactant: NCCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(NCCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)c1c[nH]nn1
Reaction time: 0.17 h

Procedure:
To 1H-1,2,3-triazole-4-carboxylic acid (32.7 mg, 0.289 mmol) in DMF (2 ml) was added HATU (110 mg, 0.289 mmol) and DIPEA (0.050 ml, 0.289 mmol). The resulting yellow solution was stirred for 10 mins and treated with 3,5-dichlorobenzyl 4-(3-amino propyl)piperazine-1-carboxylate (step 2) (100 mg, 0.289 mmol). After stirring at ambient temperature for 4 hrs, the mixture was diluted with EtOAc (50 ml) and washed with water (2×10 ml). The organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in DCM and applied to a 20 g silica cartridge eluting with 10% MeOH/DCM containing 1% aqueous 880 ammonia. The product fractions were concentrated to give 3,5-dichlorobenzyl 4-(3-(1H-1,2,3-triazole-4-carboxamido)propyl)piperazine-1-carboxylate as a white foam;