Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][C:24]2[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:19][CH:18]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([NH:30][C:25]1[C:24]([NH:23][C:21](=[O:22])[C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:32][CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:9])([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(OC)c([N+](=O)[O-])c2)cc1
Yield: 83.3 %

Procedure:
Using the procedure described in Example 102, Part A, 3-nitro-4-methoxybenzoic acid (3.1 mmol) and N1-(4-methoxybenzoyl)-1,2-benzenediamine (2.1 mmol) yielded 737 mg (83%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:10](=[O:19])[O:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=O)=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1.C([O-])(=O)C.[NH4+].C(OCC)C>C(O)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]2[N:22]=[C:23]3[NH:24][N:25]=[C:26]([CH3:28])[C:27]3=[C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][C:10](=[O:19])[C:9]=23)=[CH:5][CH:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1ccc(C(=O)c2cc3ccccc3oc2=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(-c2nc3[nH]nc(C)c3c3c2c(=O)oc2ccccc23)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 30.3 %

Procedure:
A mixture of 2.1 g (7.49 mmol) of 3-(4-methoxybenzoyl)-2H-chromen-2-one with 728 mg (7.49 mmol) of 3-amino-5-methyl-pyrazole in 15 ml of acetic acid is heated at 110° C. for 10 minutes. 2.3 g (30 mmol) of ammonium acetate is then added and then the mixture is carried at 150° C. for 3 h. The solution is placed at room temperature and then 30 ml of ethyl ether and 5 ml of methanol are added. The white solid formed is filtered and then rinsed with diethyl ether to yield 810 mg of 5-(4-methoxyphenyl)-1-methylchromeno[4,3-d]pyrazolo[3,4-b]pyridin-6(3H)-one.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:29])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:19]([NH:21][CH:22]3[CH2:24][CH2:23]3)=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.BrCCOC1C=C2C(C(C)=[CH:39][N:40]([C:45]3[CH:46]=C(C=C[C:56]=3C)C(NC3CC3)=O)C2=O)=CC=1.[I-].[K+].CNC(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH:22]1([NH:21][C:19](=[O:20])[C:18]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:16]([N:11]3[CH:10]=[C:9]([CH3:29])[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:40]([CH:45]([CH3:46])[CH3:56])[CH3:39])=[CH:6][CH:7]=4)[C:12]3=[O:15])[CH:17]=2)[CH2:24][CH2:23]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C)c2ccc(OCCCl)cc2c1=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C)c2ccc(OCCBr)cc2c1=O
Agent: CNC(C)C
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C)c2ccc(OCCN(C)C(C)C)cc2c1=O
Temperature: 150 °C

Procedure:
A mixture of 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-N-cyclopropyl-4-methylbenzamide and 3-[7-(2-bromoethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-N-cyclopropyl-4-methylbenzamide (4:1, 225 mg), potassium iodide (182 mg), and N-methylisopropylamine (0.34 ml) were stirred in DMA (3 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting using initially 10% methanol/ethyl acetate and then a 99:1 mixture of 10% methanol/ethyl acetate and aqueous ammonia solution gave N-cyclopropyl-3-[7-{2-[isopropyl(methyl)amino]ethoxy}-4-methyl-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzamide (105 mg) as a pale yellow foam; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 0.97 (d, 6H), 2.10 (s, 3H), 2.24 (s, 3H), 2.27 (s, 3H), 2.76 (t, 2H), 2.80-2.89 (m, 2H), 4.14 (m, 2H), 7.09 (s, 1H), 7.45-7.51 (m, 2H), 7.70-7.75 (m, 3H), 7.86 (d, 1H), 8.45 (d, 1H); Mass Spectrum: M+H+ 448.
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]([O:21][CH3:22])=[O:20]>O>[CH3:22][O:21][C:19]([NH:1][C@@H:2]([CH:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)[C:3]([OH:5])=[O:4])=[O:20]
Reactant: N[C@H](C(=O)O)C1CCOCC1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reaction time: 18 h

Procedure:
To (S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetic acid (505 mg; 3.18 mmol; obtained from Astatech) in water (15 ml) was added sodium carbonate (673 mg; 6.35 mmol), and the resultant mixture was cooled to 0° C. and then methyl chloroformate (0.26 ml; 3.33 mmol) was added dropwise over 5 minutes. The reaction was allowed to stir for 18 hours while allowing the bath to thaw to ambient temperature. The reaction mixture was then partitioned between 1N HCl and ethyl acetate. The organic layer was removed and the aqueous layer was further extracted with 2 additional portions of ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford Cap-170 a colorless residue. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.65 (1 H, br s), 7.44 (1 H, d, J=8.24 Hz), 3.77-3.95 (3 H, m), 3.54 (3 H, s), 3.11-3.26 (2 H, m), 1.82-1.95 (1 H, m), 1.41-1.55 (2 H, m), 1.21-1.39 (2 H, m); LC/MS: Anal. Calcd. for [M+H]+ C9H16NO5: 218.1; found 218.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH2:24][OH:25])[CH2:19]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1.[ClH:36]>C(Cl)Cl.CO>[ClH:36].[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:21]2[CH2:22][CH2:23][N:18]([C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][N:10]=3)[CH2:19][C@@H:20]2[CH2:24][OH:25])=[O:35])=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: OC[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2nnc(-c3ccc(F)cc3)c3ccccc23)C[C@@H]1CO
Yield: 97.7 %

Procedure:
Treat a solution of (R)-(4-(4-(4-fluorophenyl)phthalazin-1-yl)piperazin-2-yl)-methanol (0.15 g, 0.44 mmol) in CH2Cl2 (3 ml) with 1-fluoro-4-isocyanatobenzene (0.04 g, 0.31 mmol). Stir the reaction at ambient temperature for 30 min and then concentrate the reaction mixture. Purify the resulting residue by flash silica gel chromatography (0-50% EtOAc in hexanes, then switch to 3% MeOH in CH2Cl2) to yield a solid. Dissolve the solid in MeOH (1 mL) and treat with 1 N aqueous HCl (0.13 mL, 0.13 mmol). Concentrate the solution to obtain the title compound as a solid (0.065 g, 29%). ES/MS m/z 476.0 (M+1).
Reaction SMILES: [C:1]([O:20]C(C)C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]CCCCCCCCC.[CH3:24]C(C)=O>>[CH3:24][C@@H:1]([OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(C)C
Reactant: CC(C)=O
Product: CCCCCCCC[C@@H](C)O
Temperature: 5 °C
Yield: 72 %

Procedure:
In a 300 ml separable flask were put 1 g of Lipase QL and 40 g of (R,S)-2-decanol, and the mixture was subjected to ultrasonication with the same ultrasonic wave generating equipment as used in Example 1 at room temperature and 90 kHz for 1 minute. To the dispersion was added 60 g of isopropyl stearate, followed by stirring at 95° C. and 250 rpm for 20 hours to carry out interesterification while evaporating by-produced isopropyl alcohol under reduced pressure. The water content of the reaction system was 0.02% by weight, and 96% of the lipase particles had a particle size of 10 to 40 μm. Gas chromatographic analysis of the reaction mixture revealed that 58 mol % of (R,S)-2-decanol had been converted to 2-decyl stearate. Lipase was removed by filtration in the same manner as in Example 1, and the filtrate was subjected to simple distillation at 70° C. under reduced pressure of 5 mmHg to give (S)-(+)-2-decanol (yield: 73.5%; chemical purity: 99.9%; optical purity: 98.5% ee). The residue, i.e., a mixture of (R)-(-)-2-decanol stearic acid ester and unreacted isopropyl stearate was acid-hydrolyzed in the same manner as in Example 2, and 1000 ml of acetone was added to the reaction mixture, followed by cooling to 5° C. The precipitated stearic acid was removed by filtration, and methanol was evaporated from the filtrate under reduced pressure to give (R)-(-)-2-decanol (yield: 72%; chemical purity: 99.6%; optical purity: 84% ee).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([OH:14])[CH:3]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([O:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@H](Oc1ccc(Cl)cc1O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: C[C@H](Oc1ccc(Cl)cc1Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 90 °C

Procedure:
To a solution of (2S)-2-(4-chloro-2-hydroxyphenoxy)-propanoic acid (0.216 g) and 1-fluoro-4-nitro-benzene (0.127 g) in NUT (3 ml) was added potassium carbonate (0.276 g) and the reaction heated at 90° C. for 2 h. After cooling to RT, water and diethylether were added. The aqueous layer was separated and extracted again with diethylether. The aqueous layer was isolated, acidified to pH 2 and extracted with diethylether. This later extract was dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 30-50% ethylactate/isohexane+1% AcOH, yield 0.2 g
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[C:14](=O)([O-])[O-].[K+].[K+].[CH3:20][CH2:21][OH:22].C1COCC1>O>[Cl:13][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:22][CH2:21][CH3:20])=[CH:12][C:7]=1[C:8]([O:10][CH2:11][CH3:14])=[O:9]
Reactant: CCO
Reactant: COC(=O)c1cc(CBr)ccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCc1ccc(Cl)c(C(=O)OCC)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The mixture of methyl 5-(bromomethyl)-2-chlorobenzoate (prepared as described in WO2010/132999) (0.2 g), potassium carbonate (0.21 g), EtOH (3 mL) and THF (3 mL) was stirred at 80° C. for 4 hours. The reaction mixture was cooled to room temperature, water was then added, and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with brine, and dried over magnesium sulfate and concentrated in vacuo. The residue was purified on column chromatography to obtain ethyl 2-chloro-5-(ethoxymethyl)benzoate (0.15 g). This was dissolved in THF-MeOH—H2O (3:3:2, 8 mL), and lithium hydroxide hydrate (0.15 g) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to obtain the titled compound (0.12 g) as pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@:12]([CH3:16])([C:13]([OH:15])=O)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([NH:22][NH2:23])(=[O:21])[CH3:20].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O.CN(C=O)C>[C:19]([NH:22][NH:23][C:13]([C@:12]1([CH3:16])[CH2:11][O:10][C:9]([CH3:18])([CH3:17])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])(=[O:21])[CH3:20]
Reactant: CC(=O)NN
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)[C@]1(C)COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
To a mixture of 1.00 g of (4S)-3-(tert-butoxycarbonyl)-2,2,4-trimethyl-1,3-oxazolidine-4-carboxylic acid, 400 mg of acetohydrazide, 850 mg of 1-hydroxybenzotriazole, 2.0 ml of diisopropylethylamine, and 20 ml of DMF was added 1.2 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, followed by stirring at room temperature for 5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.11 g of tert-butyl (4S)-4-[(2-acetylhydrazino)carbonyl]-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: [S:1]([N:11]=[N+:12]=[N-:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]#[CH:22].N1C(C)=CC=CC=1C>C(Cl)(Cl)Cl.[Cu]I>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:13]=[N:12][N:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])[CH:22]=1
Reactant: C#Cc1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3Cl)nn2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of tosyl azide (16) (1.0 equiv) in CHCl3 (0.5M) cooled to 0° C. was treated with 2-chlorophenyl acetylene (15) (1.2 equiv), 2,6-lutidine (1.2 equiv) and CuI (0.1 equiv). The resulting mixture was stirred at 0° C. for 24 h, quenched with 10% HCl, the layers separated and the aqueous one washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Hexane/AcOEt 5:1, 3:1 and 1:1) to provide 4-(2-chlorophenyl)-1-tosyl-1H-1,2,3-triazole (17) as a pale yellow crystalline solid.
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].Br[C:31]1[CH:32]=[CH:33][C:34]([CH:37]([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH3:38])=[N:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O1CCOCC1.O>[F:29][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:31]3[CH:32]=[CH:33][C:34]([CH:37]([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH3:38])=[N:35][CH:36]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CC(NC(=O)OCc1ccccc1)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(NC(=O)OCc1ccccc1)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 80 °C

Procedure:
A mixture of the product of Example 22, Step 3, benzyl (1-(5-bromopyridin-2-yl)ethyl)carbamate, 2.0M sodium carbonate in water (3.1 mL, 6.2 mmol) in dioxane is degassed with nitrogen. 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium(ii) complex with dichloromethane (169 mg, 0.21 mmol) is added and the mixture heated to 80° C. overnight. After cooling to room temperature the reaction mixture is diluted with water (25 mL) and extracted with ethylacetate. The organic phase is separated, dried over MgSO4, and concentrated under reduced pressure. The crude material is purified using silica chromatography eluting from 25% ethylacetate/heptane to 35% ethylacetate/heptane to give the title product (1.00 g): m/z: 541.22.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([C:13]([CH3:17])=[C:14]([OH:16])[CH:15]=1)[C:5]([O:7][CH2:8][C:9]([Cl:12])([Cl:11])[Cl:10])=[O:6]>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:2]([O:1][C:2]1[C:3]([CH3:18])=[C:4]([C:13]([CH3:17])=[C:14]([O:16][C:5](=[O:6])[CH3:4])[CH:15]=1)[C:5]([O:7][CH2:8][C:9]([Cl:10])([Cl:11])[Cl:12])=[O:6])(=[O:1])[CH3:15]
Reactant: Cc1c(O)cc(O)c(C)c1C(=O)OCC(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(OC(C)=O)c(C)c(C(=O)OCC(Cl)(Cl)Cl)c1C

Procedure:
A solution of 6.27 g of 2,2,2-trichloroethyl 3,5-dihydroxy-2,6-dimethylbenzoate in 15 ml of acetic anhydride and 0.3 ml of pyridine was heated under reflux for 3 hours. The solution was cooled and the solvent removed under reduced pressure. The residue was dissolved in 20 ml of ethyl acetate and crystallized by the addition of 120 ml of n-hexane to yield 2,2,2-trichloroethyl 3,5-diacetoxy-2,6-dimethylbenzoate as white crystals with mp 127°-128° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[C:4]([OH:9])[CH:3]=1.[NH3:10]>O>[OH:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([OH:9])[CH:3]=1)[NH2:10]
Reactant: N
Reactant: Oc1cc(O)cc(O)c1
Solvent: O
Product: Nc1cc(O)cc(O)c1
Reaction time: 18 h
Yield: 37 %

Procedure:
To a 200-mL, 2-necked flask was added 31.5 g (250 mmol) of 1,3,5-trihydroxybenzene. After replaced with argon, 25 mL of 28% ammonia and water were added thereto, and the resulting mixture was stirred in a water bath for 18 hours. Water was removed away in vacuo and 50 mL of isopropanol was added. The obtained mixture was ice-cooled for 2 hours to precipitate a solid and the precipitated solid was obtained by filtration. The solid was washed with isopropanol and then vacuum-dried, whereby a desired product was obtained (Quantity: 11.4 g, 91.3 mmol, Yield: 37%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:17]2[C:12](=[C:13]([F:18])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10][C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].ClC([O:24][C:25](Cl)(Cl)Cl)=O.C(N(C(C)C)CC)(C)C.[NH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([N:48]2[CH2:54][CH2:53][CH2:52][CH2:51][C:50]3[CH:55]=[CH:56][CH:57]=[CH:58][C:49]2=3)=[O:47])=[CH:42][C:41]=1[CH3:59]>C1(C)C=CC=CC=1.C1COCC1>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:17]2[C:12](=[C:13]([F:18])[CH:14]=[CH:15][CH:16]=2)[N:11]([C:25](=[O:24])[NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([N:48]3[CH2:54][CH2:53][CH2:52][CH2:51][C:50]4[CH:55]=[CH:56][CH:57]=[CH:58][C:49]3=4)=[O:47])=[CH:42][C:41]=2[CH3:59])[CH2:10][C:9]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)CN1C(=O)CNc2c(F)cccc21
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CN
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CC(=O)OC(C)(C)C)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5-fluoro-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl)acetic acid tert-butyl ester from Example 7A (84 mg, 0.30 mmol) in toluene (4.0 ml) were added trichloromethyl chloroformate (36 μl, 0.30 mmol), diisopropylethylamine (54 μl, 0.30 mmol) and a spatula full of activated carbon. The mixture was heated at reflux for 2 h, cooled, filtered through Celite®, washed with EtOAc and evaporated in vacuo. The residue was taken up in THF (3.0 ml) and added to a solution of (4-aminomethyl-3-methylphenyl)-(2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)methanone from Example F (85 mg, 0.29 mmol) in THF (3.0 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature, stirred for 1 h and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 75:25) to afford a white solid; yield 120 mg, 66%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][C@@H:29]([NH2:31])[CH3:30]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][C@H:29]([CH2:28][CH2:27][O:26][CH3:25])[CH3:30])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: COCC[C@H](C)N
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCC[C@H](C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-4-methoxybutan-2-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.82 Hz, 3 H) 1.67-1.77 (m, 1 H) 1.77-1.88 (m, 1 H) 2.44 (s, 3 H) 3.23 (s, 3 H) 3.39 (t, J=6.57 Hz, 2 H) 4.06-4.20 (m, 1 H) 7.67 (d, J=8.08 Hz, 1 H) 7.73 (s, 1 H) 7.78 (br. s., 1 H) 8.17 (br. s., 1 H) 8.43 (d, J=7.33 Hz, 3 H) 8.89-8.95 (m, 1 H) 13.16 (br. s., 1 H); ESI-MS m/z [M+H]+ 406.2.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH:18]([OH:20])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH:18]([O:20][C:35](=[O:37])[CH3:36])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OC(C)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1

Procedure:
A solution of 0.026 g (0.057 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxyethyl)pyrrolidine (diastereomer 2, Example 18), 0.027 mL (0.28 mmol) of acetic anhydride, 0.046 mL of pyridine and 3.4 mg of DMAP in 2 mL of THF was stirred at rt for 18 h. The reaction mixture was concentrated and purified by chromatography (silica, hexanes:ethylacetate:(2N NH3 in MeOH), 15:15:1) to give the title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[F:27][C:28]1([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([N:31]4[CH2:32][CH2:33][C:28]([F:34])([F:27])[CH2:29][CH2:30]4)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)O
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)N1CCC(F)(F)CC1
Yield: 67 %

Procedure:
As described for example 107, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.28 mmol) was converted, using 4,4-difluoropiperidine hydrochloride instead of 2-amino-2-methyl-1-propanol, to the title compound (87 mg, 67%) which was obtained as a colorless gum. MS: m/e=467.2 [M+H]+.
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:15]C(=O)OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)#[N:2].[NH:21]([C:23](=[O:27])C(O)=O)[NH2:22].O.[C:29](OCC)(=O)C>CN1C(=O)CCC1>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([C:4]2[N:15]=[C:23]([OH:27])[N:21]3[N:22]=[CH:29][N:2]=[C:1]3[CH:3]=2)=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: NNC(=O)C(=O)O
Reactant: CCOC(=O)NC(=CC#N)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Oc1nc(-c2ccc(C(F)(F)F)cc2)cc2ncnn12
Temperature: 160 °C
Reaction time: 4 h

Procedure:
2.00 g (7.0 mmol) of ethyl [2-cyano-1-(4-trifluoromethylphenyl)ethenyl]carbamate (Example 129A) and 0.73 g (7.0 mmol) of hydrazino(oxo)acetic acid are dissolved in NMP (7 ml) under argon and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 4 h. The reaction mixture is cooled to RT, mixed with water (20 ml) and stirred for 20 min. Ethyl acetate (150 ml) and water (100 ml) are added, and the organic phase is separated off, dried with magnesium sulphate and concentrated. The residue is suspended in water in an ultrasonic bath for 10 min. and then stirred for 30 min. The solid is filtered off and dried. 0.97 g (38% of theory) of the product are obtained.