Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[C:24]([CH:28]1[CH2:33][CH2:32][CH:31](O)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:24]([C@H:28]1[CH2:33][CH2:32][C@H:31]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CC(C)(C)C1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1

Procedure:
(R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (2.0460 g, 0.0084108 mol) was dissolved in tetrahydrofuran (20 mL, 0.2 mol) in a 100 mL RBF equipped with a magnetic stir bar. 4-tert-Butyl-cyclohexanol (1.58 g, 0.0101 mol) was added, followed by triphenylphosphine (3.53 g, 0.0134 mol) and the mixture was stirred for a few minutes. Diisopropyl azodicarboxylate (2.65 mL, 0.0134 mol) was then slowly added and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The resulting product was adsorbed to silica gel and purified by flash chromatography (0-55% EtOAc in hexanes) to give 2.07 g of the title compound (64% yield). MS: m/z=382.23 [M+1] 1H NMR (MeOD) δ: 7.77-7.85 (m, 3H), 7.48 (dd, J=8.5, 2.0 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.16 (dd, J=8.8, 2.5 Hz, 1H), 4.49-4.54 (m, 1H), 4.41-4.46 (m, 1H), 4.32-4.41 (m, 1H), 2.25-2.35 (m, 2H), 1.94 (d, J=13.3 Hz, 2H), 1.81 (s, 3H), 1.38-1.52 (m, 2H), 1.16 (d, J=11.8 Hz, 2H), 0.92-0.98 (m, 9H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[Cl:9][C:10]1[CH:15]=[C:14](B(O)O)[CH:13]=[CH:12][N:11]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:9])[CH:15]=2)[CH:5]=[N:4][CH:3]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Brc1cncc(I)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(-c2cncc(Br)c2)ccn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of 9.63 g (33.9 mmol) 3-bromo-5-iodopyridine, 4.85 g (30.8 mmol) 2-chloro-pyridine-4-boronic acid and 3.11 g (37.0 mmol) sodium bicarbonate in 120 ml DMF and 30 ml water is heated to 80° C. under nitrogen. 433 mg (0.616 mmol) bis-(triphenylphosphine)-palladium(II)-chloride are added and the mixture is stirred for 4 hrs at 80° C. Water is added to the reaction mixture and the resulting precipitate is filtered off and washed well with water. The residue is dried under vacuum and recrystallized from 2-propanol yielding 5-bromo-2′-chloro-[3,4′]bipyridinyl as brown crystals; HPLC-MS: 2.16 min, [M+H] 271.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]1[CH:17]([N:18](CC2C=CC=CC=2)CC2C=CC=CC=2)[C:16](=[O:33])[NH:15][C:14]2[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:13]=2[O:12]1)C1C=CC=CC=1>CO.[Pd]>[NH2:18][CH:17]1[C:16](=[O:33])[NH:15][C:14]2[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:13]=2[O:12][CH:11]1[CH2:10][CH2:9][OH:8]
Reactant: O=C1Nc2cc(F)ccc2OC(CCOCc2ccccc2)C1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1C(=O)Nc2cc(F)ccc2OC1CCO
Yield: 96 %

Procedure:
The title compound was prepared in 96% yield by hydrogenation of (+)-(6R,7R or 6S,7S)-6-(2-benzyloxy-ethyl)-7-dibenzylamino-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 241.3 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][O:17][C:18]4[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=4)[C:21]([O:23]CC)=[O:22])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[OH-].[Na+].CO.Cl>O>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][O:17][C:18]4[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=4)[C:21]([OH:23])=[O:22])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cccc(OCCC2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(OCCC2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of Ethyl 3-{2-[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]ethoxy}benzoate (0.30 g; 6.671 mmol), 2N-aqueous sodium hydroxide (1.5 ml) and methanol (3 ml) was stirred at 60° C. for 1 hour. The reaction solution was condensed under reduced pressure. To the residue were added water and 2N aqueous hydrochloric acid to be neutral. The precipitate was collected and washed with water and diisopropyl ether to give 3-{2-[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]ethoxy}benzoic acid as colorless crystal (0.26 g; 93%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]=1[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:2][CH2:3][CH3:4].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O.CO>[C:30]([O:29][C:27](=[O:28])[NH:26][CH2:25][C:7]1[N:8]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:9](=[O:19])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(C(=O)O)cc12
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(CO)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
To a solution of 4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (4.60 g, 10 mmol) and N-methylmorpholine (1.3 mL, 12 mmol) in tetrahydrofuran (30 mL) was added ethyl chloroformate (1.2 mL, 12 mmol) at 0° C. and the mixture was stirred at 0° C. for 10 min. To the obtained mixture were added sodium tetrahydroborate (1.13 g, 30 mmol) and methanol (5 mL), and the mixture was stirred at 0° C. for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl(4-butoxy-6-hydroxymethyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (2.89 g, 64.8%) as crystals.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[O:32]1C=CC[CH2:34][CH2:33]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[O:31][C:33](=[O:32])[CH3:34])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)CCC(=O)O)cc2)ccc(C(C)=O)c1O
Reactant: C1=COCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CCCc1c(OCCCSc2ccc(C(=O)CCC(=O)O)cc2)ccc(C(C)=O)c1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of the compound of Example 6, (1.2 g, 2.7 mmoles) and dihydropyran (0.8 ml, 4.4 mmoles) in methylene chloride (20 ml) was added p-toluenesulfonic acid monohydrate (5 mg) The reaction mixture was stirred at room temperature for two hours. The solution was cooled to 0° and triethylamine (6 ml), 4-dimethylaminopyridine (DMAP) (15 mg) and acetic anhydride (5 ml) were added. The resulting solution stirred at room temperature for two hours. The solution was washed with 5% NaHCO3 (2×), water, 1N HCl and concentrated in vacuo. The residue was dissolved in THF (6 ml) and stirred with 1N HCl (1 ml) at room temperature for one hour. Dichloromethane (50 ml) and water (50 ml) were added to the solution and the organic layer was collected, washed with brine (4×) dried (Na2SO4) and concentrated in vacuo. The crystalline residue was washed with hexane and recrystallized to afford the title compound, m.p. 121°-123°.
Reaction SMILES: [C:1]12([C:11](=O)/[CH:12]=[C:13]3/[C:14](=O)[C@:15]4([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:18]/3[CH2:17][CH2:16]4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[NH2:26][NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]12([C:11]3[CH:12]=[C:13]4[C:14]([C@:15]5([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:18]4[CH2:17][CH2:16]5)=[N:27][N:26]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NN
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)/C2=C/C(=O)C12CC3CC(CC(C3)C1)C2
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)[C@H]2CC[C@]1(C)c1nnc(C34CC5CC(CC(C5)C3)C4)cc12

Procedure:
This material was prepared according to example 1 step C] (1S,4R)-3-[2-adamantan-1-yl-2-oxo-eth-(E)-ylidene]-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-one (0.2 g) and hydrazine monohydrate (0.117 g) with the following modifications: toluene as solvent (5 ml) in the presence of p-toluene sulfonic acid (0.117 g), heating for 12 h at reflux temperature and isolation of desired product by chromatography (no further NaOMe treatment as in example 1 step C]. This gave (1S,8R)-5-adamantan-1-yl-1,11,11-trimethyl-3,4-diaza-tricyclo[6.2.1.02,7]undeca-2,4,6-triene (0.027 g) as an amorphous light yellow solid. MS (EI): 322.4 (M+).
Reaction SMILES: FC1C(F)=C(F)[C:5]2=[N:6][C:7]3[N:8](C)[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=O)[C:12]=3[CH:13]=[C:4]2C=1.CN1CCNCC1.O.C(O)(=O)C>CS(C)=O>[N:8]1[C:7]2[C:12](=[CH:13][CH:4]=[CH:5][N:6]=2)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)c(F)c3nc21
Agent: CN1CCNCC1
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cnc2ncccc2c1
Temperature: 80 °C

Procedure:
A suspension of 4 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid in 60 cm3 of dimethyl sulphoxide and 3 g of 1-methylpiperazine is heated at 80° C. for 1 hour and a half. After cooling to about 20° C., 150 cm3 of water are added. 18 cm3 of 10% acetic acid are added to the solution obtained. The precipitate formed is drained, washed with 3 times 50 cm3 of water and recrystallized from 50 cm3 of dimethylformamide. 4 g of 7,9-difluoro-1-methyl-8-(4-methyl-1-pip-erazinyl)-4-oxo-1,4-dihydrobenzo[b]1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 316° C..
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[CH2:11]([CH2:13][NH2:14])[OH:12]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH:14][CH2:13][CH2:11][OH:12]
Reactant: Fc1cccc(F)c1CBr
Reactant: NCCO
Solvent: CCO
Product: OCCNCc1c(F)cccc1F
Temperature: 75 °C
Yield: 97.5 %

Procedure:
A mixture of 2,6-difluorobenzyl bromide (3.7 g, 17.8 mmol) and ethanolamine (6.46 mL, 107 mmol) in ethanol (18 mL) was heated at 75° C. for 16 h. The reaction mixture was concentrated and the resulting residue was diluted with dichloromethane (50 mL). The organic layer was partitioned with water (75 mL) and the aqueous layer extracted with dichloromethane (50 mL). Combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound as a yellow solid (3.25 g). (m/z): [M+H]+ calcd for C9H11F2NO, 188.08; found, 188.1. 1H NMR (d6-DMSO, 300 MHz) δ (ppm): 7.37-7.34 (m, 1H), 7.10-7.05 (m, 2H), 4.47 (t, J=5.4 Hz, 1H), 3.75 (s, 2H), 3.42 (q, J=5.5 Hz, 2H), 2.25 (t, J=5.7 Hz, 2H), 1.82 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N:25]1([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[N:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:34][C:33]3[CH:32]=[CH:31][C:30]([N:25]4[CH:29]=[CH:28][CH:27]=[N:26]4)=[CH:37][CH:36]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ccc(-n4cccn4)cc3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by coupling 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 of Example B(13), to 4-Pyrazol-1-yl-benzaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31). ESIMS (MH+): 508.1
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[K+]>CS(C)=O.C(OCC)(=O)C.O>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: Brc1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Nc2ccccn2)cc1
Temperature: 100 °C
Yield: 9 %

Procedure:
To a solution of 4-nitro aniline (2 g, 14.48 mmol) and 2-bromo pyridine (3.43 g, 21.72 mmol) in DMSO (12 ml) was added powdered potassium hydroxide (3.24 g, 57.92 mmol) at room temperature and the reaction mixture was heated at 100° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, and water added. The organic layer was separated, washed with brine, dried and evaporated to give crude material. Purification by column chromatography using hexane/ethyl acetate (96:4) yielded (4-nitro-phenyl)-pyridin-2-yl-amine (0.28 g, 9%).
Reaction SMILES: [ClH:1].C[C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.BrC1C([C:32]([F:35])([F:34])[F:33])=CC2C(=O)OCC=2C=1>>[ClH:1].[N:15]1([CH2:14][CH2:13][C:4]2[C:5]([C:32]([F:35])([F:34])[F:33])=[CH:6][C:7]3[C:8](=[O:12])[O:9][CH2:10][C:11]=3[CH:3]=2)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Reactant: O=C1OCc2cc(Br)c(C(F)(F)F)cc21
Agent: Cl
Product: O=C1OCc2cc(CCN3CCNCC3)c(C(F)(F)F)cc21

Procedure:
5-[2-(piperazin-1-yl)ethyl]-6-(trifluoromethyl)-2-benzofuran-1(3H)-one hydrochloride was prepared in an analogous fashion to that described for the synthesis of 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride above starting from 5-bromo-6-(trifluoromethyl)-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 315 [M+1]+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.N([O-])=[O:14].[Na+].S(=O)(=O)(O)O>>[O:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([OH:14])=[CH:3][CH:4]=1
Reactant: Nc1ccc(-c2ncco2)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1ccc(-c2ncco2)cc1
Yield: 47.9 %

Procedure:
2-(4-Aminophenyl)oxazole [m.p. 121°-123° C.; Rosenbaum et al., J. Am. Chem. Soc. 64, 2444 (1942)] (10.3 g) was diazotized with 4.93 g of sodium nitrite and 215 ml of 2N sulfuric acid. The resulting diazonium salt was heated until no more nitrogen was evolved, and the product was isolated and recrystallized from ethylene dichloride to give 4.96 g of 4-(2-oxazolyl)phenol, yellow crystals, m.p. 167°-168° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1)[C:5]([OH:7])=[O:6].F[C:18]1[CH:30]=[CH:29][C:21]2[S:22](=[O:28])(=[O:27])[CH2:23][CH2:24][CH2:25][O:26][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:28]=[S:22]1(=[O:27])[C:21]2[CH:29]=[CH:30][C:18]([O:1][C:2]3[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=3)[C:5]([OH:7])=[O:6])=[CH:19][C:20]=2[O:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)O)c1
Reactant: O=S1(=O)CCCOc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCCS3(=O)=O)cc(C(=O)O)c1
Temperature: 160 °C
Yield: 48.7 %

Procedure:
A mixture of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (0.245 g, 1.08 mmol), 8-fluoro-3,4-dihydro-2H-1,5-benzoxathiepine 5,5-dioxide (235 mg, 1.08 mmol) and potassium carbonate (299 mg, 2.17 mmol) in acetonitrile (7.8 mL) was heated in a microwave reactor at 160° C. for 5 hours. The mixture was reduced in vacuo and the residue purified by preparative HPLC (on a C18 reversed phase using 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA) as eluant) to give the desired compound as a beige solid (222 mg). 1H NMR δ (d6-DMSO): 1.22 (d, 3H), 2.22-2.24 (m, 2H), 3.17 (s, 3H), 3.43-3.58 (m, 4H), 4.03-4.16 (m, 1H), 4.16-4.25 (m, 2H), 4.63-4.73 (m, 1H), 6.80-6.85 (m, 1H) 6.90-7.01 (m, 2H), 7.15 (s, 1H), 7.35 (s, 1H), 7.83 (d, 1H); m/z 421 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=O.Cl.[NH2:21][OH:22].C([O-])(=O)C.[NH4+].C(O)C>O>[C:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4](=[N:21][OH:22])[C:3]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=2[Cl:1])[CH2:7][CH2:8]1)(=[O:14])[CH3:13]
Reactant: NO
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Cl)cc2Cl)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCC(C(=NO)c2ccc(Cl)cc2Cl)CC1
Yield: 31.1 %

Procedure:
A mixture of 13.0 g of 4-(2,4-dichlorobenzoyl)-N-acetylpiperidine, 6.8 g of hydroxylamine hydrochloride, 13.5 g of ammonium acetate, 127 ml of ethanol and 43 ml of water was stirred and heated at 130° for 24 hrs. The reaction mixture was evaporated and 1.3 l of water was added to the residue. The water was decanted from the oil and the oil was dissolved in about 150 ml dichloromethane. After washing with about 150 ml of water, drying over anhydrous magnesium sulfate and evaporating the solvent, an oil was obtained, which after crystallization from methanol/ether gave 4.25 g (31.1%) of product, mp, 167°-168°.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1([F:22])[CH2:19][C@H:18]2[CH2:20][C@@H:15]1[CH2:16][C@H:17]2O.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:13][C:14]1([F:22])[CH2:19][C@H:18]2[CH2:20][C@@H:15]1[CH2:16][C@@H:17]2[N:27]1[C:23](=[O:33])[C:24]2[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:26]1=[O:28]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O[C@@H]1C[C@H]2C[C@@H]1CC2(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@H]1C[C@H]2C[C@@H]1CC2(F)F
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A solution of diethyl azodicarboxylate (0.56 mL, 3.6 mmol) in anhydrous THF (3.0 mL) was added drop-wise to a mixture of (1R,2R,4R)-5,5-difluorobicyclo[2.2.1]heptan-2-ol (0.44 g, 3.0 mmol), phthalimide (0.50 g, 3.4 mmol), and triphenyl phosphine (0.78 mL, 3.4 mmol) in anhydrous tetrahydrofuran (15.0 mL) at r.t. under nitrogen. After stirring at ambient temperature for 66 h, the solvents were removed in vacuo. The residue was partitioned between ethyl acetate and water, and the organic portion was separated, washed with brine, and conc. in vacuo. Flash column chromatography (0 to 35% of ethyl acetate in hexanes) gave the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:24]=O.O>C(O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: Cc1ccc(N2CCN(C(=O)OCC3CCNCC3)CC2)cc1
Solvent: O=CO
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)OCC3CCN(C)CC3)CC2)cc1
Temperature: 95 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
(1-piperidin-4-yl)methyl 4-(4-methylphenyl)piperazine-1-carboxylate (Example 3; 9.75 g, 30.7 mmol) was dissolved in formic acid (3 mL), 35% aqueous formaldehyde solution (3 mL) and water (20 mL). The reaction mixture was heated at 95° C. for 45 minutes, and then cooled to room temperature. The reaction mixture was quenched by slowly pouring it onto 1M aq Na2CO3 solution (400 mL) and extracted with EtOAc (4×150 mL). The combined organic layers were washed with brine (75 mL), dried (MgSO4) and concentrated in vacuo. The residue was recrystallised from heptane and then purified by reverse phase column chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo. The residue was recrystallised from heptane to give (1-methylpiperidin-4-yl)methyl 4-(4-methylphenyl)-piperazine-1-carboxylate (4.38 g, 43.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23]OS(C)(=O)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[N:29]([CH2:23][C@H:10]1[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)=[N+:30]=[N-:31]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN=[N+]=[N-])C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (1.43 g) in DMF (15 mL) was added sodium azide (322 mg), and the mixture was stirred at 70° C. overnight. The solvent was evaporated under reduced pressure, distilled water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.23 g).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH2:26][C:27]4[CH:32]=[C:31]([NH2:33])[N:30]=[CH:29][N:28]=4)=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:9][C:8]=1[C:34]([F:37])([F:36])[F:35]>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O.O>[CH3:5][O:4][C:2](=[O:3])[NH:33][C:31]1[CH:32]=[C:27]([CH2:26][C:22]2[CH:23]=[CH:24][C:25]3[C:20](=[CH:19][CH:18]=[CH:17][C:16]=3[C:14](=[O:15])[NH:13][C:10]3[CH:11]=[CH:12][C:7]([F:6])=[C:8]([C:34]([F:37])([F:36])[F:35])[CH:9]=3)[CH:21]=2)[N:28]=[CH:29][N:30]=1
Reactant: Nc1cc(Cc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)ncn1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1cc(Cc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)ncn1
Reaction time: 20 h

Procedure:
0.4 ml (5 mMol) methyl chloroformate are added to a solution of 54 mg (0.123 mMol) 6-(6-amino-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide in 1 ml CH2Cl2 and 1.5 ml pyridine. After 20 h, the solution is diluted with EtOAc and water, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; CH2Cl2→CH2Cl2/MeOH 92:8) gives the title compound: MS: [M+1]+=499; TLC (CH2Cl2/MeOH 85:15): Rf=0.54; 1H-NMR (DMSO-d6): δ ppm 10.86 (s, HN), 10.65 (s, HN), 8.69 (s, 1H), 8.30 (d, 1H), 8.13 (d, 1H), 8.03 (m, 2H), 7.90 (s, 1H), 7.74 (m, 2H), 7.58 (t, 1H), 7.50 (m, 2H), 4.22 (s, H2C), 3.64 (s, H3C).