Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C([N+]([O-])=O)=C(Cl)C=CC=1C([O-])=O.[Na+].[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][C:18]=1[C:19]([O-:21])=[O:20].[Na+].Cl>O>[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: O=C([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])c1ccc(Cl)c([N+](=O)[O-])c1Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Yield: 72 %

Procedure:
2,4-Dichlorobenzoic acid 1-1 (1.0 g, 5.34 mmol) was added in one portion to a stirred solution of concentrated nitric acid (0.26 mL, 5.75 mmol) in concentrated sulphuric acid (7 mL). After 3 hours at room temperature the solution was poured onto ice. The resulting white solid was isolated via filtration and washed with H2O (×3). The white solid was then stirred with 1% Na2CO3 (aq) (20 mL) for 1 h at room temperature. Remaining insoluble material was filtered off and the resulting clear filtrate was concentrated to a pale yellow solid. Recrystallisation from H2O afforded the sodium salt as pale yellow crystals. (Note: the other minor product, sodium 2,4-dichloro-3-nitrobenzoate, remained in solution). The yellow crystals of sodium 2,4-dichloro-5-nitrobenzoate was dissolved in a minimum amount of H2O and acidified by the slow addition of concentrated HCl until a white precipitate formed. After isolation by filtration and washing with H2O 2,4-dichloro-5-nitrobenzoic acid 1-2 was obtained as a white solid (0.91 g, 72%). 1H NMR (400 MHz, CDCl3) δ7.73 (s, 1H), 8.60 (s, 1H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][N:9]=1.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH2:1])=[CH:10][N:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(Cl)nc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Cl)nc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To a cooled (5° C.), stirred slurry of methyltriphenylphosphonium bromide (75.7 g) in tetrahydrofuran (530 mL) was added potassium t-butoxide (23.8 g) portionwise over a 5-min period to produce a yellow slurry. After 30 min, 2-chloro-5-formylpyridine (25.0 g) was added in one portion to produce a purple colored slurry. After an additional 30 min, the reaction mixture was treated with saturated aqueous ammonium chloride (200 mL) and a majority of the tetrahydrofuran was removed in vacuo. The resulting mixture was washed with ethyl acetate, the combined organic layers washed with saturated aqueous brine, stirred over activated charcoal for 20 min, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting semi-solid was stirred for 30 min with a solution of 2:1 diethyl ether/petroleum ether (375 mL), filtered and the solids washed with an additional portion of 2:1 diethyl ether/petroleum ether (300 mL). The combined filtrates were concentrated in vacuo, pre-loaded on 60 g of silica gel and chromatographed over 700 g of silica gel eluting with a gradient of ethyl acetate (0-8%)/hexanes to afford 15.2 g of the title compound (I-2b) as a colorless oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].O.[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24]>O1CCCC1>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(Br)c1
Yield: 64.7 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and using a mixture of 7 ml of water and 1.5 ml of tetrahydrofuran in place of the methanol, and 190 mg of 3-bromo-4-fluoroaniline in place of the 3-(tert-butyl)aniline. 266 mg of N-(3-bromo-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([C@@H:3]([NH:20]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([F:19])[CH:12]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[NH2:20][C@H:3]([C:1]#[N:2])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([F:19])[CH:12]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C#N)Cc1ccc(-c2ccc(C#N)c(F)c2)cc1
Solvent: O=CO
Product: N#Cc1ccc(-c2ccc(C[C@H](N)C#N)cc2)cc1F
Temperature: 50 °C
Yield: 79.6 %

Procedure:
(S)-tert-Butyl 1-cyano-2-(4′-cyano-3′-fluorobiphenyl-4-yl)ethylcarbamate (0.580 g) was stirred in formic acid (8 mL) and heated at 50° C. for 10 min. The cooled mixture was evaporated, dissolved in methanol and applied to a 10 g SCX column. The column was washed with methanol then eluted with 10% ammonia in methanol. The eluate was evaporated to give a solid (0.335 g).
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]3[N:28]([CH3:29])[N:27]=[N:26][CH:25]=3)[CH:15]=2)[C@@H:7]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CS(C)=O>[N:36]([CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]3[N:28]([CH3:29])[N:27]=[N:26][CH:25]=3)[CH:15]=2)[C@@H:7]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:37]=[N-:38]
Reactant: Cn1nncc1-c1cc(CO[C@H]2CCCN(CC#CCCl)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1nncc1-c1cc(CO[C@H]2CCCN(CC#CCN=[N+]=[N-])[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Yield: 83.4 %

Procedure:
To a solution of [2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol-5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine (142 mg) in dimethyl sulphoxide (3.0 ml) was added sodium azide (20.1 mg). The solution was stirred for 3 hours at room temperature at which time aqueous ammonium chloride and ethyl acetate were added. The organic phase was separated, washed with water (20 ml), saturated brine (20 ml) dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by MPLC (20% ethyl acetate/hexane) gave [2S,3S]-1-(4-azidobut-2-yn-1-yl)-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a white solid (120 mg). 1H NMR (360 MHz,CDCl3) δ 1.20-1.60 (2H, m), 2.22 (2H, m), 2.67 (1H, m), 2.98 (1H, m), 3.27 (2H, m), 3.47 (1H, br s), 3.62 (1H, br s), 3.92 (2H, s), 3.98 (3H, s), 4.47 (1H, d, J=11.0 Hz), 4.81 (1H, d, J=11.0 Hz), 7.26-7.35 (4H, m), 7.44-7.47 (4H, m), 7.69 (1H, s).
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][C:3]=1[CH2:16]Br.BrC1C(CBr)=CC([O:23][CH:24]2[CH2:29]CCC[O:25]2)=CC=1CBr.CN(C=O)C.CC([O-])=O.[K+]>C(Cl)Cl.O>[C:24]([O:25][CH2:16][C:3]1[CH:4]=[C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:13]=[C:14]([CH3:15])[C:2]=1[Br:1])(=[O:23])[CH3:29]
Reactant: BrCc1cc(OC2CCCCO2)cc(CBr)c1Br
Reactant: Cc1cc(OC2CCCCO2)cc(CBr)c1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)OCc1cc(OC2CCCCO2)cc(C)c1Br
Temperature: 60 °C
Yield: 52 %

Procedure:
Intermediates 2-(4-bromo-3-(bromomethyl)-5-methylphenoxy)tetrahydro-2H-pyran and 2-(4-bromo-3,5-bis(bromomethyl)phenoxy)tetrahydro-2H-pyran from above reaction was made into a solution with 33 mL of DMF. The reaction mixture was then treated with KOAc (6.95 g, 70.83 mmol) before heating to 60° C. for 2 hr. The reaction was worked-up with equal volumes of water and CH2Cl2 (1:1, 50 mL). The layers were separated and the water phase was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 2-bromo-3-methyl-5-(tetrahydro-2H-pyran-2-yloxy)benzyl acetate (2.24 g, two steps 52%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[C:9](/[O-])=[CH:10]/[C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Li+].Cl.[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][NH2:29])[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(=O)/C=C(\[O-])c1cccc(C#N)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Agent: [Li+]
Product: CCOC(=O)c1cc(-c2cccc(C#N)c2)n(-c2cccc(Cl)c2)n1
Yield: 35 %

Procedure:
Starting from 10 g (39.81 mmol) of lithium (1Z)-1-(3-cyanophenyl)-4-ethoxy-3,4-dioxobut-1-en-1-olate from example 10A and 9.7 g (54.15 mmol) of 3-chlorophenylhydrazine hydrochloride, 4.97 g (14 mmol, 35% yield of theory) of product are obtained according to the method described in example 4A.
Reaction SMILES: CO[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].C[O-].[Na+]>C1(C)C(C)=CC=CC=1.CO>[C:11]([CH2:12][C:3](=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
Methylbenzoate (136.0 grams; 1.0 mol), acetophenone (30.0 grams; 0.25 mol), sodium methoxide (17.3 grams; 0.3 mol) and xylene (300 ml) were placed into a four-necked, round bottom, one liter flask equipped with stirrer, nitrogen addition adapter, thermometer and Oldershaw column connected with distillation head and a trap. The mixture was heated with stirring to 135°-140° C. and maintained there for 6 hours while under a blanket of nitrogen. At 110°-120° C. methanol started to evolve and the reaction mixture became semi-solid. After two hours of heating the contents of the flask somewhat liquified. Towards the end of the reaction, nearly 25 ml of liquid consisting of methanol and xylene had been collected in the trap. The reaction mixture was cooled to room temperature and acidified with hydrochloric acid (500 ml of 6N). Stirring was continued for about 30 minutes until all the solid was dissolved. The xylene layer was separated and washed twice with water, then twice with aqueous sodium carbonate and then twice again with water. The xylene layer was removed by evaporation from the dibenzoylmethane (53.1 grams; 95% yield). Analysis by GLC showed the product to be 95% pure. This product after recrystallized from methanol had a melting point of 77°-78° C. The distillate (347.0 grams) containing xylene, methylbenzoate and water was subjected to azeotropic distillation.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1C(N)=[O:6])#N.[OH2:12].[OH2:13].O.O.O.O.[Co:18]([Cl:20])[Cl:19].O.O.O.O.O.O.[Co](Cl)[Cl:28].C(C1C=CC=CC=1C(N)=[O:35])#N>>[OH2:6].[OH2:35].[OH2:12].[OH2:6].[OH2:6].[OH2:6].[Co:18]([Cl:20])[Cl:19].[CH:10]1[CH:11]=[C:3]([C:1]([OH:13])=[O:12])[C:4]([Cl:28])=[CH:8][CH:9]=1
Reactant: N#Cc1ccccc1C(N)=O
Agent: Cl[Co]Cl
Solvent: O
Product: O=C(O)c1ccccc1Cl

Procedure:
To 5.13 g of 2-cyanobenzamide (2-CBA) (from Tokyo Chemical Industry Co., Ltd.) is added 1.39 g of cobalt (II) chloride hexahydrate (from Wako Pure Chemical Industries, Ltd.) and mixed in an agate mortar to prepare a cobalt (II) chloride hexahydrate/2-CBA mixture (18A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][N:17]([CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[C:18]3=[O:23])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4ccc(Cl)cc4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
4-Chlorophenyl isocyanate (0.4 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL) and concentrated. The residue was stirred with 1NHCl (30 mL) for 30 minutes. The mixture was filtered, and the solid was slurried with hot acetone (10 mL) to give 1-(4-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.7 g, 73%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.33-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.36-4.58 (m, 4H, 2CH2), 5.11-5.18 (dd, J=5.0 and 12.5 Hz, 1H, CH), 6.77 (t, J=5.0 Hz, 1H, NH), 7.27 (d, J=10.0 Hz, 2H, Ar), 7.40 (d, J=10 Hz, 2H, Ar), 7.47-7.64 (m, 3H, Ar), 8.77 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.18, 39.68, 45.19, 51.58, 119.29, 121.56, 124.66, 128.30, 128.44, 130.35, 131.64, 135.46, 139.31, 139.92, 155.08, 168.07, 171.00, 172.84; Anal. calcd. for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 58.85; H, 4.35; N, 12.97; Cl, 8.19.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([OH:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@H:17]([O:34][C:35]([CH2:39][F:40])([CH3:38])[CH2:36][F:37])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([OH:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@H:17]([O:34][C:35]([CH2:36][F:37])([CH3:38])[CH2:39][F:40])[CH2:16]1)=[O:14])([CH3:10])([CH3:11])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OC(C)(CF)CF)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(O)cc(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)[C@H]1CO[C@H](OC(C)(CF)CF)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
Add acetic anhydride (2.13 mmoles; 201.52 μL) to a solution of (2R,5R)-5-[(1S,2S)-2-amino-3-(3-fluoro-5-hydroxy-phenyl)-1-hydroxy-propyl]-2-(2-fluoro-1-fluoromethyl-1-methyl-ethoxy)-morpholine-4-carboxylic acid tert-butyl ester (2.03 mmoles; 1.00 g) and triethylamine (2.23 mmoles; 311.29 μL) in 10 mL dichloromethane at 0° C. (ice bath) and stir the mixture at 0° C. for 1 h. Concentrate under reduced pressure and subject residue to silica gel chromatography eluting with 40:60 to 0:100 hexane/ethyl acetate gradient to give the desired compound as white solid (950.00 mg, 87.53%).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.CO.[H][H].NC1C=CC=C(C(O)=O)C=1OOC1C=CC=CC=1>C(O)C.[Ni].CC(N(C)C)=O>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(O)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1O
Agent: [Ni]
Agent: Nc1cccc(C(=O)O)c1OOc1ccccc1
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: Nc1ccc(Oc2ccc(O)c(C(=O)O)c2)cc1

Procedure:
71 g of 5-(4-nitrophenoxy)-salicylic acid prepared in accordance with Example 1a were hydrogenated at 90° C/100 atms. in 400 ml of ethanol or methanol in the presence of 2.8 g of Raney nickel. The adsorption of hydrogen ceased after 3 hours at the longest. Following the addition of 100 ml of dimethyl acetamide, the catalyst was separated off under heat, water was added at 100° C until a haze began to form, after which the solution was heated for 20 minutes in the presence of 20 g of active carbon and the free aminophenoxy salicylic acid allowed to crystallise out after filtration, being obtained in a yield of 50 g (79% of the theoretical yield), m.p. 223° - 224° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[N:49](C)[N:48]=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:46]([CH3:45])[N:47]=[N:48][N:49]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nnnc1CCl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cn1nnnc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as white solid. MS (m/e): 379.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][CH:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[N:6]=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C:2]1[O:3][CH2:4][CH:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[N:6]=1
Reactant: NC1=NC(c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)CO1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NC1=NC(c2ccc(NC(=O)c3ccccc3)cc2)CO1
Temperature: 60 °C
Yield: 44.9 %

Procedure:
To a stirred suspension of (RS)—N-[4-(2-amino-4,5-dihydro-oxazol-4-yl)-phenyl]-4-chloro-benzamide (50 mg) in methanol (3 ml) were added ammonium formate (100 mg) and palladium on charcoal (13 mg, 10 wt %) and the mixture was heated at 60° C. for 2 hours. The mixture was then cooled to room temperature, filtered through celite and the filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate/THF (1:1) and this solution was washed sequentially with saturated aq. sodium bicarbonate solution and saturated brine. The organic phase was then separated, dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/dichloromethane/methanol) to give (RS)—N-[4-(2-amino-4,5-dihydro-oxazol-4-yl)-phenyl]-benzamide (20 mg, 45%) as a white solid. MS (ISP): 282.1 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:10][C:11](=[O:17])[CH2:12][O:13]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([C:7]#[C:8][CH:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:10][C:11](=[O:17])[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)COC(C)=O)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(C#Cc2ccccc2)CC(=O)CO)cc1OC1CCCC1
Reaction time: 3.5 h
Yield: 24.9 %

Procedure:
A solution of (+/-)-1-phenyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-5-oxo-6-acetoxyhexyne (130 mg, 0.34 mmol) in MeOH (2 ml) was treated with NaOH (0.1 ml of a 2.5N solution), and the mixture was stirred at 23° for 3.5 hr. The reaction was diluted with H2O, and extracted with Et2O. The extracts were washed with H2O, dried, and the solvent removed. Purification by flash chromatography (silica gel, 50% Et2O in CH2Cl2) gave the titled compound as an oil (32 mg, 28%). 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 2 H), 7.32 (m, 3 H), 6.98 (m, 2 H), 6.86 (d, 1 H), 4.80 (m, 1 H), 4.38 (t, 1 H), 4.32 (d, 1 H), 4.14 (d, 1 H), 3.84 (s, 3 H), 3.00 (d of d, 1 H), 2.86 (d of d, 1 H), 1.68-2.00 (m, 6 H), 1.62 (m, 2 H).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([CH2:4][C:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:11]#N)[CH2:6][CH2:7]2)[O:2]1.CC(C[AlH]CC(C)C)C.Cl.C(=O)(O)[O-:30].[Na+]>C1(C)C=CC=CC=1>[CH2:1]1[CH2:10][O:9][C:3]2([CH2:8][CH2:7][CH2:6][C:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([CH:11]=[O:30])[CH2:4]2)[O:2]1
Reactant: O=C([O-])O
Reactant: N#CC1(c2ccccc2)CCC2OCCOC2C1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=CC1(c2ccccc2)CCCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
At −78° C., 3-ethylenedioxy-1-phenylcyclohexanecarbonitrile (1.66 g, 6.83 mmol) in toluene (20 mL) was added DIBAL-H (1.0 M solution in toluene, 8.88 mL) slowly and was stirred for 1 hr. The reaction mixture was warmed up to room temperature and was added 1N HCl solution (2.60 mL) and was stirred for 1 hr. Saturated sodium bicarbonate was added to quench the reaction and the organic layer was separated. The aqueous layer was extracted with dichloromethane 3 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude material was purified by filtering through a short silica gel pad with dichloromethane to give the title compound as a white sticky oil (1.43 g, 85% yield). 1H NMR (400 MHz, CDCl3) δ 1.32–1.40 (1H, m), 1.46–1.54 (1H, m), 1.72–1.86 (3H, m), 2.08 (1H, d, J=16 Hz), 2.59–2.67 (2H, m), 3.94–4.07 (4H, m), 7.15–7.36 (5H, m), 9.36 (1H, d, J=4 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]([OH:12])=[O:11].[CH3:13][C:14](O)([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.O>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][C:14]([CH3:16])([CH3:15])[CH3:13])=[O:11]
Reactant: CC(C)(C)O
Reactant: Cc1cc(O)c(C(=O)O)c(=O)o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(O)c(C(=O)OC(C)(C)C)c(=O)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.4 %

Procedure:
In 18 ml of toluene, 0.51 g of 4-hydroxy-6-methyl-2-oxo-2H-pyrane-3-carboxylic acid, 0.67 g of 2-methyl-2-propanol and 0.07 g of 4-dimethylaminopyridine were dissolved, and 0.58 g of WSC was added and the mixture was stirred at room temperature for 16 hours. Subsequently, water was poured into the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The resultant organic layer was washed with a saturated solution of sodium chrolide, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography to obtain 0.22 g of tert-butyl 4-hydroxy-6-methyl-2-oxo-2H-pyrane-3-carboxylate (Compound No. 7).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH2:11])[CH3:8])([CH3:4])[CH3:3].Cl[C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][C:18]([F:25])=[C:19]([F:24])[CH:20]=2)[N:15]=1.C(N(CC)C(C)C)(C)C>C1(C)C(C)=CC=CC=1>[CH3:4][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH:11][C:23]1[CH:14]=[N:15][C:16]2[C:21](=[CH:20][C:19]([F:24])=[C:18]([F:25])[CH:17]=2)[N:22]=1)[CH3:8])([CH3:1])[CH3:3]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: Fc1cc2ncc(Cl)nc2cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: CN(CCNc1cnc2cc(F)c(F)cc2n1)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of (2-amino-ethyl)-methyl-carbamic acid dimethyl-ethyl ester (1.01 g, 5.8 mmol), 2-chloro-6,7-difluoro-quinoxaline (1.00 g, 5.8 mmol) and N,N-diisopropylethylamine (3.02 ml, 17.4 mmol) in xylene (10 ml) was heated under argon at 80° C. for 18 h. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with diethyl ether/pentane to afford the title compound as a pale orange solid.