Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[N:23]=[C:22]([N:24]5[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]5)[CH:21]=[CH:20][CH:19]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:5][CH:4]=1)=[CH2:2].[OH2:37].C[N+]1([O-])CCOCC1.[OH2:46]>CC(C)=O.[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[OH:37][CH:1]([C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[N:23]=[C:22]([N:24]5[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]5)[CH:21]=[CH:20][CH:19]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:5][CH:4]=1)[CH2:2][OH:46]
Reactant: O
Reactant: C=Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cncc(C(O)CO)n5)cc43)n2)CC1
Yield: 67 %

Procedure:
A mixture of tert-butyl 4-[6-[6-(6-vinylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]piperazine-1-carboxylate (513 mg; 1.06 mmol), N-methylmorpholine-N-oxide monohydrate (744 mg, 6.35 mmol) and 2.5% solution of osmium tetroxide in tert-butanol (0.6 ml, 0.04764 mmol) in 20 ml of acetone and 2.5 ml of water was stirred at room temperature for 24 hours. The mixture was filtered, mixed with water and extracted with EtOAc. The organic extracts were washed with water, 5% aq. citric acid, sat. aq. NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was triturated with ethyl ether, the precipitate was collected by filtration and washed with ethyl ether affording tert-butyl 4-(6-(6-(6-(1,2-dihydroxyethyl)pyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate (424 mg, 67%). MS (ESI) m/z: 519.3 [M+H]+
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)C.Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])=[CH:25][CH:24]=1>>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][CH2:19][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:15][CH3:16])[C:4]([OH:3])=[O:17])=[CH:8][C:9]=2[CH3:14])=[CH:28][CH:27]=1)(=[O:30])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OC
Reactant: O=C(c1ccccc1)c1ccc(OCCCBr)cc1
Product: COC(Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)c(C)c1)C(=O)O

Procedure:
A mixture of 3-(4-Hydroxy-3-methyl-phenyl)-2-methoxy-propionic acid ethyl ester and from Example 162, Step E and [4-(3-Bromo-propoxy)-phenyl]-phenyl-methanone were treated under standard condition I to give the title product.
Reaction SMILES: [N:1]([CH:4]([CH2:9][C:10]([CH3:12])=[CH2:11])[C:5]([O:7][CH3:8])=[O:6])=[C:2]=[O:3].[N:13]1C=CC=CC=1.Cl.NO.C(OC)(OC)OC>C1COCC1.CO>[CH3:8][O:7][C:5]([CH:4]([NH:1][C:2]([NH2:13])=[O:3])[CH2:9][C:10]([CH3:12])=[CH2:11])=[O:6]
Reactant: c1ccncc1
Reactant: C=C(C)CC(N=C=O)C(=O)OC
Agent: Cl
Agent: NO
Solvent: CO
Solvent: COC(OC)OC
Solvent: C1CCOC1
Product: C=C(C)CC(NC(N)=O)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.1 mol of p-aminobenzaldehyde ethylene glycol acetal in 100 mL of anhydrous THF is added dropwise over 10 minutes to a solution of 0.1 mol of methyl 2-isocyanato-4-methyl-4-pentenoate and 0.35 mol pyridine in 100 mL THF at room temperature under N2. The reaction mixture is stirred at room temperature for 2 hours. After 2 hours the solvent is removed by rotary evaporator. A solution of 0.11 mmol hydroxylamine hydrochloride and 0.1 mol trimethyl orthoformate in CH3OH is added, and the reaction mixture is heated to reflux under N2 for 1 hour. The reaction mixture is reduced to about 1/4 volume by rotary evaporator, and water is added. The product, N-[4-(hydroxyiminomethyl)phenyl]-N'-[1-(1-methoxycarbonyl-3-methyl-3-butenyl]urea, is isolated by filtration and dried in vacuo.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[C:6]=2[N:7]=1.[OH:27][CH:28]([CH3:31])[CH2:29][NH2:30]>>[CH2:16]([N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([NH:30][CH2:29][CH:28]([OH:27])[CH3:31])[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[CH3:17]
Reactant: CC(O)CN
Reactant: CCN(CC)CCSc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Product: CCN(CC)CCSc1ncnc2c(N3CCS(=O)CC3)nc(NCC(C)O)nc12

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(2-diethylaminoethyl-thio)-4-(1-oxidothiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 146°-148° C.) and 2-hydroxypropyl-amine. Resin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].S(Cl)(Cl)=O.[OH-].[NH4+:36].O>C1COCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([NH2:36])=[O:30])[CH:26]=3)[CH:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2cc3nccc(-c4cnn(CC(=O)O)c4)c3o2)cc(OC)c1OC
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2cc3nccc(-c4cnn(CC(N)=O)c4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
2-[4-[2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridin-7-yl]pyrazol-1-yl]acetic acid (0.040 mmol) is dissolved in THF and thionylchloride (0.234 mmol) is added. The mixture is stirred 24 h at RT. Additional thionylchloride (0.234 mmol) is added and the reaction is stirred 24 h at RT. Additional Thionylchlorid (2.343 mmol) is added and the reaction is stirred 48 h. The solvent is removed in vacuo and ammonium hydroxide (32%, 1.205 mmol) is added. Water (3 ml) is added and the precipitate is filtered and resuspended in MeOH and filtered and dried at 50° C. in vacuo. The product is isolated as beige solid in a yield of 92%). HPLC (method A): Rt 2.40 min (purity 95%); LCMS (ESI+) (method E): Rt 1.49 min, M+H+ 409.1 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.67 (s, 1H), 8.45 (d, J=4.4, 1H), 8.32 (s, 1H), 7.75-7.51 (m, 3H), 7.47-7.26 (m, 3H), 4.93 (s, 2H), 3.95 (s, 6H), 3.74 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][C:5](Cl)=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C>[Pd].C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:4][CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c(N)c1C(=O)OCC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(-c2ccccc2)c(N)c1C(=O)OCC

Procedure:
A mixture of 100 mg of 3-amino-6-chloro-4,5-diethoxycarbonyl-2-phenylpyridine, 0.08 ml (2.0 eq.) of triethylamine amd 8 ml of ethyl acetate was subjected to catalytic reduction for 7 hours with 100 mg of 10% Pd-C (50% wet). The catalyst was removed by filtration, and the solvent was distilled off. Yield: 86 mg(95.4%).
Reaction SMILES: C1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)C=CC=1C(O)=O.[C:17](O)(=O)C1C=CC(C(O)=O)=CC=1.[N+]([O-])(O)=O>C1(C)C(C)=CC=CC=1>[CH3:17][C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][C:7]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O=[N+]([O-])O
Product: Cc1ccccc1C(=O)O

Procedure:
Organic acids, such as naphthalene-2,6-dicarboxylic acid or terephthalic acid, are highly useful in the manufacture of polyester-type and polyamide-type resins, including polyethyleneterephthalate. Such organic acids customarily have been prepared by a liquid phase oxidation of an alkyl-substituted aromatic precursor in the presence of an aqueous acidic reaction medium, and usually in the presence of a metal catalyst. For example, U.S. Pat. No. 2,766,281 discloses the preparation of phthalic acids, including terephthalic acid, by a step-wise oxidation of a corresponding xylene with concentrated nitric acid at atmospheric pressure and in the presence of an inert organic reaction medium that is liquid at the reaction temperatures. In the first step, the xylene starting material is reacted with the nitric acid at a temperature of from about 120 ° C. up to the boiling point of the xylene starting material, while removing water by distillation, to form a toluic acid. In the second step, nitric acid is slowly added to the toluic acid at a temperature in excess of about 140 ° C., while removing water by distillation, to form the product phthalic acid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]1[C:4]([CH3:9])=[N+:5]([O-:18])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ncccc1CCl
Solvent: ClC(Cl)Cl
Product: Cc1c(CCl)ccc[n+]1[O-]
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-chloromethyl-2-methylpyridine (0.50 g, 3.5 mmol) from step 2 above in CHCl3 (40 mL) was added MCPBA (1.1 g of 50% MCPBA by weight; 3.5 mmol). After 1.5 h, the solution was extracted with saturated aqueous NaHCO3 (40 mL), water (40 mL), dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 97:3 CH2Cl2 :MeOH as eluant. 3-Chloromethyl-2-methylpyridine-N-oxide was obtained as a solid (TLC: Rf = 0.30 (97:3 CH2Cl2 :MeOH); FAB MS m/z 158 (M+ +H)).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[N:12]1([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C@@H:24]([NH2:28])[C:25]([NH2:27])=[O:26])=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.CCN(C(C)C)C(C)C>CS(C)=O>[N:12]1([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][C@@H:24]([NH:28][C:8]3[CH:9]=[C:2]([Br:1])[C:3]([C:4]#[N:5])=[CH:6][C:7]=3[F:11])[C:25]([NH2:27])=[O:26])=[CH:21][CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: NC(=O)[C@H](N)Cc1ccc(-n2ccnc2)cc1
Reactant: N#Cc1cc(F)c(F)cc1Br
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(F)c(N[C@H](Cc2ccc(-n3ccnc3)cc2)C(N)=O)cc1Br
Yield: 31.7 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (100 mg, 0.458 mmol), ((R)-3-(4-(1H-imidazol-1-yl)phenyl)-2-aminopropanamide (100 mg, 0.434 mmol) and DIEA (0.100 mL, 0.575 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. The mixture was purified by HPLC to give (R)-3-(4-(1H-imidazol-1-yl)phenyl)-2-(5-bromo-4-cyano-2-fluorophenylamino)propanamide (59 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]([C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[CH:17]=3)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH:26]([C@H:28]([C:30]1[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1)[CH3:29])[NH2:27].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[CH:17]=4)[N:26]([C@H:28]([C:30]3[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=3)[CH3:29])[N:27]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H](C)NN)cc1
Reactant: COc1ccc2cc(C(=O)C#Cc3cc(Cl)cc(Cl)c3)cnc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2cnc3cc(OC)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from step F (118 mg, 0.33 mmol) in DMF was added the ethyl 4-[(1S)-1-hydrazinoethyl]benzoate hydrochloride (89 mg, 0.36 mmol) and triethyl amine (55 μL, 0.39 mmol). After stirring the reaction mixture at room temperature for 18 hours it was concentrated in vacuo. The residue was diluted with water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 25% ethyl acetate-hexanes. This material was then re-purified with 3% acetonitrile-dichloromethane to give the desired compound. 1H NMR (500 MHz, CDCl3): 8.76 (d, J=2.0 Hz, 1H), 8.04 (d, J=8.2 Hz, 2H), 7.92 (1.8 Hz, 1H), 7.85 (d, J=1.8 Hz, 2H), 7.68 (d, J=8.9 Hz, 1H), 7.5 (d, J=2.1 Hz, 1H), 7.36 (t, J=1.8 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 6.76 (s, 1H), 4.42 (q, J=7.0 Hz, 1H), 4.03 (s, 3H), 2.04 (s, 3H), 2.01 (t, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). LC-MS: 4.28 min; (M+H)=546.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH2:15][CH:16]([F:18])[F:17])=[CH:4][N:3]=1.[F-:19].[Cs+]>CS(C)=O>[F:17][CH:16]([F:18])[CH2:15][O:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[C:2]([F:19])=[N:3][CH:4]=1
Reactant: COc1ccc2c(Cl)ncc(OCC(F)F)c2c1
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1ccc2c(F)ncc(OCC(F)F)c2c1
Temperature: 140 °C

Procedure:
To a solution of 1-chloro-4-(2,2-difluoroethoxy)-6-methoxyisoquinoline (538 mg, 1.966 mmol) in DMSO (5 mL) was added CsF (597 mg, 3.93 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with ethyl acteate and washed with water, and brine. The organic phase was collected, dried over MgSO4, and concentrated under vacuum to give the crude product as a reddish brown solid. The crude material was purified via silica gel chromatography (5-50% EtOAc:Hex) to give the product 4-(2,2-difluoroethoxy)-1-fluoro-6-methoxyisoquinoline (237 mg, 0.921 mmol, 46.9% yield) as a light yellow solid. MS: MS m/z 258.2(M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([Cl:20])=[C:18]([C:21]([F:24])([F:23])[F:22])[N:17]([CH3:25])[N:16]=2)=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[CH3:32][NH2:33]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([Cl:20])=[C:18]([C:21]([F:24])([F:23])[F:22])[N:17]([CH3:25])[N:16]=2)=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([NH:33][CH3:32])=[O:7]
Reactant: CN
Reactant: CC(Oc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)C(C)Oc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Yield: 99 %

Procedure:
To a solution of 0.8 g (2.0 mmole) of the product of step A in 100 mL methylene chloride was added 0.5 mL (6.0 mmole) oxalyl chloride over 5 minutes, causing the evolution of gas. When this evolution ceased, one drop of DMF was added and the solution stirred until the gas evolution ceased. The solution was stripped to dryness in vacuo. The residue was dissolved in 10 mL THF and added to a solution of 5 mL 40% aqueous methyl amine and 10 mL THF at 0° C. over 5 minutes. The reaction mixture was allowed to stir for 30 minutes at room temperature. The solution was diluted with 100 mL cold water and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The solid was recrystallized from methylcyclohexane to give 0.83 g (99%) of 2-(2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)- 1H-pyrazol-3-yl)-4-fluorophenoxy)-N-methyl-propanamide as a white solid, mp 134.5°-135.5° C.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=2)O1>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:32]5[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cnc(N)nc3)cc1OCC2
Yield: 73 %

Procedure:
Following the same procedure as for 182, 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine provided 223 in 73% yield. LS/MS (ESI+): m/z 389 (M+H). 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.45 (d, J=8.4, 1H), 7.93 (d, J=9.7, 2H), 7.46 (dd, J=8.5, 1.9, 1H), 7.35 (d, J=1.8, 1H), 6.86 (s, 1H), 5.91 (hept, J=6.4, 1H), 4.61-4.44 (m, 4H), 1.50 (d, J=6.6, 6H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([NH2:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:31][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(C)(C)CN
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and neopentylamine.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(N(CC)CC)C>C(O)C>[OH:16][C:9]1[CH:10]=[CH:11][C:12]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:14]=1
Reactant: CNc1ccccc1
Reactant: O=C1CCC(=O)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(c1ccccc1)c1ccc(O)cc1
Yield: 32.2 %

Procedure:
1.07 g of N-methylaniline, 2.24 g of 1,4-cyclohexanedione and 1.4 ml of triethylamine were heated with stirring in 15 ml of ethanol at 50° C. to 60° C. and reacted in air for 8 hours. During the reaction, ethanol was added as needed. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resultant was separated by silica gel column chromatography (n-hexane:ethyl acetate=3:1) and 0.64 g of N-(4-hydroxyphenyl)-N-methylaniline was obtained (yield 32.1%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Br:18][C:19]1[C:24](F)=[C:23]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:21][C:20]=1[F:29]>C1COCC1>[Br:18][C:19]1[C:20]([F:29])=[CH:21][CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[C:24]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(Br)c1Nc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
LiHMDS (1.0M in THF, 16.8 mL, 16.8 mmol) was added dropwise to a stirred solution of aniline (821 mg, 8.80 mmol) in anhydrous THF (20 mL) under a nitrogen atmosphere at −78° C. After 10 min stirring at −78° C., a solution of 2-bromo-1,3-difluoro-4-nitrobenzene (2.0 g, 8.40 mmol) in THF (10 mL) was added and stirring at −78° C. was continued for 30 min. The reaction mixture was quenched by addition of water and extracted with EtOAc (×3). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% DCM in cyclohexane) to afford the title compound (2.4 g, 91%). 1H NMR (CDCl3, 400 MHz): δ 8.48 (1H, s), 8.19-7.12 (1H, m), 7.33-7.25 (2H, m), 7.09 (1H, t, J=7.41 Hz), 6.93-6.83 (3H, m).
Reaction SMILES: CN(C)/C=[CH:4]/[C:5](C1N(C(C)C)C(C)=NC=1)=[O:6].S([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:49]=[CH:48][C:30]([NH:31][C:32]3[N:37]=[C:36]([C:38]4[N:42]([CH:43]([CH3:45])[CH3:44])[C:41]([CH3:46])=[N:40][CH:39]=4)[C:35](Cl)=[CH:34][N:33]=3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)(C)(=O)=O>COCCO>[C:5]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:28]=[CH:29][C:30]([NH:31][C:32]3[N:37]=[C:36]([C:38]4[N:42]([CH:43]([CH3:45])[CH3:44])[C:41]([CH3:46])=[N:40][CH:39]=4)[CH:35]=[CH:34][N:33]=3)=[CH:48][CH:49]=2)[CH2:25][CH2:26]1)(=[O:6])[CH3:4]
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C(C)C
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)ncc2Cl)n1C(C)C
Solvent: COCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1

Procedure:
(2E)-3-(Dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 24 of WO 03/076436; 140 mg 0.63 mmol) and N-[4-(4-acetylpiperazin-1-yl)phenyl]guanidine bicarbonate salt (Method 2; 240 mg 0.74 mmol) in 2-methoxyethanol (4 ml) were reacted under nitrogen under microwave conditions at 200° C. for 30 minutes. After evaporation under reduced pressure, chromatography on silica gel with MeOH:DCM (2:98 to 6:94) gave the title compound, after ether trituration, as a yellow solid. (85 mg 31.5%). NMR: 1.39 (d, 6H), 2.02 (s, 3H), 2.45 (s, 3H), 3.00 (b t, 2H), 3.06 (b t, 2H), 3.56 (b q, 4H), 5.70 (septuplet, 1H), 6.91 (d, 2H), 6.95 (d, 1H), 7.38 (s, 1H), 7.46 (d, 2H), 8.31 (d, 1H), 9.15 (s, 1H); m/z 420.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH:20]([C:28]#[N:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].O.[OH-].[Na+]>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:28][NH2:29])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)c2ccccc2F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2F)CC1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
1M LAH in THF (250 mL, 250 mmol) was cooled to −40° C. and 4-[Cyano-(2-fluoro-phenyl)-methyl]-piperazine-1-carboxylic acid tert-butyl ester (7) (20 g, 62.66 mmol) in THF (100 mL) was added slowly via addition funnel. The reaction mixture was allowed to stir for 2 h at −40° C. and then allowed to warm to 0° C. Reaction progress was monitored by H1 NMR. The reaction mixture was then cooled to −40° C. again and H2O (9.5 mL) was added. The reaction mixture was then diluted with THF (1 L) followed by the addition of 15% NaOH (9.5 mL) and H2O (28.5 mL). The solution was then allowed to warm to room temperature. The aluminum salts were removed by filtration and the filtrate was concentrated to dryness. The resulting residue was taken up in EtOAc (500 mL) and H2O (500 mL) and the aqueous layer was made acidic (pH=4) by cautious addition of a 25% aqueous solution of KHSO4. The aqueous phase was then made basic (pH=10) with SN NaOH and the product was extracted into EtOAc (500 ml) and concentrated to dryness. The starting material (nitrile) can be recovered by concentration of the original organic phase and purified by recrystallization from MeOH. The yield was 9.2 g (466) pure product.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:25])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)=[O:7])(C)(C)C.[C:26]([O:30][C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1C(O)=O)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:25])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)=[O:7])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc2c(c1)OCO2
Yield: 68.1 %

Procedure:
By the same procedure as in Example 26-D), while using (2S)1-(tert-butoxycarbonyl)-2-{1-hydroxy-2-[(3,4-methylenedioxy)phenoxy]ethyl} pyrrolidine (2.38 g) and N-(tert-butoxycarbonyl)-L-proline (1.60 g), there was obtained 2.07 g of the title compound.