Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=2)=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[BH4-].[Na+]>ClCCl.C(O)C>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCc1ccc(C(=O)c2ccc([N+](=O)[O-])cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(C(O)c2ccc([N+](=O)[O-])cn2)cc1
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-[4-(5-nitropyridine-2-carbonyl)phenyl]propionate (1.52 g, 4.63 mmol) in dichloromethane (15 mL) and ethanol (15 mL) was added sodium borohydride (0.175 g, 4.63 mmol) under ice cooling, and the resulting solution was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in water and ethyl acetate. To the solution was added acetic acid and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 0.264 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[I:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([I:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1cccc(I)c1
Product: Nc1cc2ncnc(Nc3cccc(I)c3)c2cn1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (72 mg, 0.37 mmol) and 3-iodoaniline (1.25 g, 5.71 mmol) is stirred at 160° C. for 30 min. The resulting product is chromatographed over silica gel (5-7% MeOH/CH2Cl2) to give 7-amino-4-(3-iodoanilino)pyrido[4,3-d]pyrimidine (83 mg, 61%) as a light brown rosettes. 1H NMR (DMSO) δ 9.84 (1H, brs), 9.34 (1H, s), 8.44 (1H, s), 8.30 (1H, brs), 7.90 (1H, dd, J=7.9, 0.8 Hz), 7.47 (1H, d, J=7.7 Hz), 7.18 (1H, t, J=8.0 Hz), 6.66 (2H, brs), 6.46 (1H, s).
Reaction SMILES: C([O:4][CH:5]=[CH2:6])(=O)C.[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[C:9]1([C@@H:5]([OH:4])[CH3:6])[CH:8]=[CH:7][CH:12]=[CH:11][CH:10]=1
Reactant: C=COC(C)=O
Reactant: CCCCCC
Product: C[C@H](O)c1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
(R, S)-1-phenylethanol (0.276 gram, 2 mmol) and vinyl acetate (0.17 gram, 2 mmol) were dissolved in 10 ml of n-hexane dried in advance on Molecular Sieve 4A for one day. To the resulting solution was added 1 gram of PPL (porcine pancrea lipase: Product of Sigma), and the mixture was stirred at 25° C. and 150 r.p.m. to give (S)-1-phenylethanol in an optical purity of 90% with a theoretical yield of 85%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][C:15](=[O:17])[CH:14]=[CH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H].Cl.C(OCC)(=O)C>C(O)C.C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC=CC(=O)C2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCCC(=O)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
5-(3,4-Dimethoxyphenyl)-2-cyclohexen-1-one (6.76 g) was dissolved in ethanol (100 ml), and 10% palladium-carbon (684 mg) was added thereto. After substituting the reaction vessel with hydrogen gas, hydrogen addition was effected for 30 minutes at normal pressure and room temperature. After the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to produce an oily substance which was dissolved in ethyl acetate (50 ml), and then 4 N HCl-ethyl acetate solution (2 ml) was added and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure to produce crude crystals which were then washed with n-hexane to give 6.72 g of 3-(3,4-dimethoxyphenyl)cyclohexanone (98.5%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:11][C:12]1[C:13]([I:26])=[C:14]([C:23]([Cl:25])=[O:24])[C:15]([I:22])=[C:16]([C:20]=1[I:21])[C:17]([Cl:19])=[O:18]>CN(C=O)C>[CH3:1][O:2][CH2:3][C:4]([NH:11][C:12]1[C:20]([I:21])=[C:16]([C:17]([Cl:19])=[O:18])[C:15]([I:22])=[C:14]([C:13]=1[I:26])[C:23]([Cl:25])=[O:24])=[O:6]
Reactant: COCC(=O)O
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COCC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Temperature: 10 °C
Reaction time: 1 h

Procedure:
121.2 g. (1.6 mole) of methoxyacetic acid is dissolved in 400 ml. of dry DMF, cooled to 0° C., and within 60 minutes 116 ml. (1.6 mol) of thionyl chloride is added dropwise thereto. The mixture is stirred for 30 minutes at 10° C. and 138.3 g. (0.4 mol) of 5-amino-2,4,6-triiodoisophthalic acid dichloride is introduced into the reaction mixture and the latter is stirred for 20 hours at room temperature. The reaction solution is stirred into 10 l. of water, the precipitate is vacuum-filtered, washed with water, again stirred with water, vacuum-filtered, and dried at 50° C. under vacuum. Yield: 198 g. (0.296 mol)=74% of theory.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:17])[NH:15][NH2:16])=[N:6]1.[NH2:22][C:23](=S)[C:24](OCC)=[O:25].C(N(CC)CC)C>CO>[NH2:22][C:23]1[N:16]=[N:15][C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[F:1])[N:6]=2)=[N:17][C:24]=1[OH:25]
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: CCOC(=O)C(N)=S
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Reaction time: 8 h

Procedure:
2.000 g (7.035 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidohydrazide in 50 ml of methanol were initially introduced and admixed with 0.937 g (7.035 mmol) of ethyl amino(thioxo)acetate, and 1.424 g (14.070 mmol) of triethylamine were admixed and the mixture was heated under reflux for 5 h. The reaction mixture was left to stand overnight, and the precipitate was filtered off with suction, washed with a little ethanol and dried under high vacuum. This gave 1.892 g of the target compound (purity 94%; 75% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH2:14][N:15]2[C:19](=[O:20])[N:18]([CH2:21][C@H:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:17]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[N:16]2)[CH:11]=[C:10]([C:35]([O:37]C)=[O:36])[CH:9]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH2:14][N:15]2[C:19](=[O:20])[N:18]([CH2:21][C@H:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:17]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[N:16]2)[CH:11]=[C:10]([C:35]([OH:37])=[O:36])[CH:9]=1
Reactant: COC(=O)c1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc(-c2ccccc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc(-c2ccccc2Cl)c1

Procedure:
Analogously to the preparation of Example 141, 244 mg (0.43 mmol) of the compound from Example 146 were reacted with 2 N aqueous sodium hydroxide solution. This gave 242 mg (100% of theory) of the target compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][OH:15].CN(C=O)C>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][OH:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: OCCBr
Reactant: Cc1cc(I)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(I)ccc1OCCO
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Under an N2 atmosphere 2.34 g (10 mmol) 4-iodo-2-methyl-phenol are added to a suspension batchwise, cooled to 0° C., of 0.48 g (11 mmol) NaH in 50 mL THF and stirred for a further 30 min at this temperature. Then 0.85 mL (12 mmol) 2-bromoethanol, dissolved in 5 mL THF, are added dropwise and the mixture is stirred for 18 h at RT. 5 mL of DMF are added and the reaction mixture is heated to 70° C. for 8 h. The mixture is evaporated down i. vac., the residue is taken up in water, extracted exhaustively with EtOAc and dried with Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography on silica gel (cyc/EtOAc 7:3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[F:19].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[F:19])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Nc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Nc2ccnc(Cl)c2)c(F)c1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
Add 2-chloropyridin-4-amine (500 mg, 3.9 mmol), 1,2-difluoro-4-nitrobenzene (620 mg, 3.9 mmol), Cs2CO3 (3.2 g, 9.8 mmol) to DMF (15 mL). Stir the reaction at 110° C. for 16 hrs. Cool to room temperature, add water (100 mL), extract with EtOAc (15 mL×3). Combine the organic layers and wash with brine, dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (280 mg, 27%). MS: (M+1): 268.1.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](Cl)(=[O:13])[C:10]([Cl:12])=[O:11]>>[C:10]([Cl:12])(=[O:11])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)C(=O)OCc1ccccc1
Yield: 92.1 %

Procedure:
In this example the product was prepared in two synthetic steps. In the first step benzyl alcohol was reacted with 50% molar excess of oxalyl chloride. Upon completion of the reaction the excess oxalyl chloride was stripped from the product at reduced pressure to produce benzyl chlorooxalate having an assay of 96.6% and in a corrected yield of 92.1%. In the second step benzyl chlorooxalate was reacted with 2,5-dimethyl-2,5-dihydroperoxyhexane, in the presence of pyridine, to yield the product as described below:
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:25][C:26]([F:39])([F:38])[C:27]1[CH:37]=[CH:36][C:30]([CH2:31][C:32]2([NH2:35])[CH2:34][CH2:33]2)=[CH:29][CH:28]=1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:35][C:32]2([CH2:31][C:30]3[CH:36]=[CH:37][C:27]([C:26]([F:25])([F:38])[F:39])=[CH:28][CH:29]=3)[CH2:33][CH2:34]2)=[CH:11][CH:10]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: NC1(Cc2ccc(C(F)(F)F)cc2)CC1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(C(O)CNC3(Cc4ccc(C(F)(F)F)cc4)CC3)ccc(O)c2N1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 215 mg (1 mmol) 1-(4-trifluoromethyl-benzyl)-cyclopropylamine. Yield: 18 mg (3%, trifluoroacetate); mass spectroscopy: [M+H]+=423.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[C:14](Cl)(=O)C>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:14])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reaction time: 144 h

Procedure:
3-Hydroxy-4-nitrobenzoic acid (I) (100.3 g, 95% pure, 0.53 mole) was added to methanol (1250 ml) to which had been added acetyl chloride (25 ml). The solid dissolved over a period of two days. After six days, the solution was filtered to remove undissolved impurities. The crude ester was obtained by evaporation of the solution. Several crops of crystals were taken, the last from a 50 ml volume. The combined crops were recrystalized from methanol (150 ml). Two crops of the ester (II) as yellow-brown crystals, m.p. 89°-91°, (98.7 g, 0.50 mole) were obtained.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:1]1([N:6]2[C:10]3=[N:11][C:30]([C:29]4[CH:32]=[CH:33][C:26]([O:25][CH2:24][CH2:23][N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[CH:27][CH:28]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(OCCN4CCOCC4)cc3)nc(=O)c1-2
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.19 g, 9.86 mmol), 4-[2-(4-morpholinyl)ethoxy]benzaldehyde (3.5 g) and xylenes (10 ml) was heated at 160° C. overnight. p-Toluenesulfonic acid (0.2 g) was added and the mixture was heated at 160° C. overnight. The reaction mixture was cooled to room temperature, and the precipitate which formed was slurried with methanol, collected by filtration and washed with methanol, and then ether. The product was recrystallized from acetonitrile to afford 1-cyclopentyl-3-ethyl-6-[4-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:26]=[CH:25][C:15]([CH:16]([NH2:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:24][CH:16]([C:15]1[CH:25]=[CH:26][C:12]([F:11])=[CH:13][CH:14]=1)[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC(c1ccc(F)cc1)c1ccc(F)cc1
Product: Fc1ccc(C(Nc2nc3ccccc3[nH]2)c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4,4′-difluoro-benzhydrylamine (prepared by Procedure B from 4,4′-difluorobenzophenone) by Procedure A. The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 241-243° C.). MS(ES+) m/z 336 ([M+1]+, 100). 1NMR (DMSO-d6) δ 6.20 (d, 1H), 6.80-6.91 (m, 2H), 7.09-7.20 (m, 6H), 7.38-7.43 (m, 4H), 7.69 (d, 1H), 10.6 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][C:13]([N:20]([CH3:22])[CH3:21])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][NH2:15].[OH-].[Na+]>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:15][CH2:14][C:13]([CH3:12])([N:20]([CH3:22])[CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:6]
Reactant: CCCCC(C)(CN)N(C)C
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCC(C)(CNC(=O)c1ccc(Cl)c(Cl)c1)N(C)C

Procedure:
A solution of 3,4-dichlorobenzoyl chloride (2.1 g.,) in dry benzene (25 ml.) was added to a solution of 2-methyl-2-dimethylamino-hexylamine (1.58 g.,) in dry benzene (25 ml.) and the mixture heated under reflux for 1.5 hrs. The mixture was diluted with water, basified with 2N sodium hydroxide solution, and extracted with benzene (4 × 100 ml.). The combined benzene extracts were washed with water (4 × 50 ml.), dried (Na2SO4) and evaporated affording 3,4-dichloro-N-[2-methyl-2-dimethylamino-hexyl]benzamide as a colourless oil (3.6 g., ca 100%) which slowly crystallised.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH3:24][C:25]1([CH3:37])[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:27]=2[O:26]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:33]3[C:27]4[O:26][C:25]([CH3:37])([CH3:24])[CH2:29][C:28]=4[CH:30]=[CH:31][CH:32]=3)=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: CC1(C)Cc2cccc(C(=O)O)c2O1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OC(C)(C)C4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,2-dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid. LC-MS (basic): tR=0.96 min; [M+H]+=506.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:16]=1[NH2:17].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([NH:17][C:16]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=1[Cl:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cl)c(NC(=O)COCc2ccccc2)c1
Temperature: 25 °C
Yield: 103 %

Procedure:
Benzyloxy acetyl chloride (1) (11.0 g, 60.0 mmol) and 2-chloro-5-methoxyaniline hydrochloride (11.7 g, 60.2 mmol) in dichloromethane (100 mL) at 0° C., was stirred and triethylamine (13.0 g 126.0 mmol, 18.0 mL) added slowly over 15 min. The stirred reaction was allowed to warm to RT over 18 h. There was a heavy precipitation of triethylamine hydrochloride. The dichloromethane solution was washed with 10% aqueous potassium carbonate (50 mL), dried over magnesium sulfate and concentrated in vacuo to afford 18.9 g (quantitative) of 2-Benzyloxy-N-(2-chloro-5-methoxy-phenyl) acetamide (2) as a gum. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 55.6, 69.6, 73.6, 106.2, 111.1, 114.1, 127.7, 128.3, 128.6, 129.2, 134.6, 136.5, 158.9, and 167.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH3:9][Si:10](Cl)([CH3:12])[CH3:11].C([Li])CCC>>[F:1][C:2]1[C:3]([F:8])=[C:4]([Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:5]=[CH:6][C:7]=1[Si:10]([CH3:12])([CH3:11])[CH3:9]
Reactant: C[Si](C)(C)Cl
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Product: C[Si](C)(C)c1ccc([Si](C)(C)C)c(F)c1F

Procedure:
4-Alkoxy-2-fluoro-3-phenoxyphenylacetic acid compounds were prepared from o-difluorobenzene (SCHEME 5). A mixture ortho-difluorobenzene (23a) and trimethylsilylchloride was treated with butyl lithium to produce 2,3-difluoro-1,4-bis-trimethylsilanyl-benzene (23b) which was brominated to afford 23c. Selective monometallation of 23c with iso-propylmagnesium chloride-lithium chloride complex and quenching the organomagnesium compound with DMF afforded 23d. Reaction of 23d with a phenol in the presence of K2CO3 resulted in displacement of the fluorine atom adjacent to the aldehyde to afford 24a. The aldehyde was subjected to a Baeyer-Villiger oxidation with trifluoroperacetic acid which underwent concomitant hydrolysis to the phenol 24b which was alkylated with Cs2CO3 and methyl iodide to afford the methoxy substituted analog 24c. Metallation of the remaining bromine substituent with iso-PrMgCl/LiI/THF and allylation of the resulting Grignard reagent afforded 25a which was oxidatively cleaved with NaIO4/Ru(III)Cl3 to produce the phenylacetic acid 25b.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:34]([NH:41][C@H:42]([C:45]([OH:47])=[O:46])[CH2:43]O)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCOCC>CC#N>[C:37]([O:36][C:34](=[O:35])[NH:41][C@H:42]1[CH2:43][O:47][C:45]1=[O:46])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1COC1=O
Temperature: -35 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of dry PPh3 (72 h under vacuum in the presence of P2O5) (5 mmol) in dry CH3CN (31 mL), kept at −50° C. under N2, dimethylazodicarboxylate (5 mmol) and, after 20 min, a solution of 1 (4.47 mmol) in CH3CN (10.4 mL), were added dropwise. The mixture was stirred for 1.5 h at −50/−35° C. and concentrated. Purification of the residue by flash-chromatography (cyclohexane/EtOAc 8:2 to 6:4) gave crude 2, which was finally washed and triturated to afford a white solid. Mp 120-122° C. (Et2O). [α]D20=−27° (c 0.1, CH3CN). 1H NMR is in accordance with literature (Arnold, et al., 1985).
Reaction SMILES: [CH2:1]([O:7][CH2:8][CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][NH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([F:28])=[C:24](F)[CH:25]=2)[C:20](=[O:29])[C:19]([C:30]([OH:32])=[O:31])=[CH:18]1)[CH3:16]>N1C=CC=CC=1>[CH2:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([F:28])=[C:24]([N:13]3[CH2:12][CH2:11][NH:10][CH:9]([CH2:8][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:14]3)[CH:25]=2)[C:20](=[O:29])[C:19]([C:30]([OH:32])=[O:31])=[CH:18]1)[CH3:16]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: CCCCCCOCC1CNCCN1
Solvent: c1ccncc1
Product: CCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1

Procedure:
A 3 g portion of 2-[(hexyloxy)methyl]piperazine was added to 20 ml of pyridine in a pressure bottle, under argon. A 1.26 g portion of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added, the bottle sealed and the mixture heated at 80°-90° C. for 4 hours, then evaporated. The residue was evaporated twice from toluene, the residue triturated with ether and the solid collected, giving 2.03 g of the desired product, mp 121°-124° C.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=Cc1ccc2nnn(O)c2c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=Cc1ccc2nnn(OS(=O)(=O)c3ccc(C)cc3)c2c1
Temperature: 10 °C
Yield: 64.5 %

Procedure:
In dry benzene (300 ml) are dissolved 1-hydroxy-6-vinyl-1,2,3-benzotriazole (4.83 g) and triethylamine (3.2 g) under stirring, and thereto is added dropwise a solution of p-toluenesulfonyl chloride (5.8 g) in benzene (50 ml) under cooling at 10° C. The mixture is stirred at room temperature for 2 hours. The reaction mixture is poured onto ice-water (200 ml) and extracted with ethyl acetate (60 ml, three times). The combined extracts are washed with an aqueous sodium hydrogen carbonate and then water, dried over anhydrous magnesium sulfate, treated with charcoal and then concentrated under a reduced pressure. The resulting residue is recrystallized from ethyl acetate-n-hexane to give colorless crystals of 1-(p-toluenesulfonyloxy)-6-vinyl-1,2,3-benzotriazole (6.1 g), melting point: 90°-91° C. The filtrate is further concentrated, and the resulting residue is recrystallized from benzene-n-hexane to give additionally the desired product (1.9 g).