Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[F:31][C:32]1[CH:33]=[N:34][C:35]2[C:40]([C:41]=1I)=[CH:39][CH:38]=[CH:37][CH:36]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.[Cl-].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[Pd+2].[Cl-]>[F:31][C:32]1[CH:33]=[N:34][C:35]2[C:40]([C:41]=1[CH2:3][CH2:2][CH2:1][C:4]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[CH:39][CH:38]=[CH:37][CH:36]=2
Reactant: Fc1cnc2ccccc2c1I
Reactant: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccccc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 56.9 %

Procedure:
17.7 g of ethyl 4-allyl-1-(tert-butyloxycarbonyl)piperidine-4-carboxylate in 200 cm3 of tetrahydrofuran were cooled to a temperature in the region of −30° C. and 135 cm3 of a 0.5M solution of 9-borabicyclo-[3.3.1]nonane in tetrahydrofuran were added with stirring and under an inert atmosphere. After the addition, the temperature of the mixture was returned to about 20° C. and the mixture was stirred for 2 hours. 14.8 g of 3-fluoro-4-iodoquinoline in 430 cm3 of tetrahydrofuran, 1.3 g of palladium diphenylphosphinoferrocene chloride and 29.8 g of tribasic potassium phosphate were added. The reaction mixture was then heated at a temperature in the region of 70° C. for 20 hours. After cooling to a temperature in the region of 20° C., the reaction mass was filtered and washed with 3 times 100 cm3 of tetrahydrofuran. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue was taken up in 500 cm3 of diethyl ether, the insoluble material was washed with 3 times 100 cm3 of diethyl ether and the filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The oil obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 6 cm; height 45 cm), eluting with a dichloromethane/ethyl acetate mixture (90/10 by volume) and collecting 120-cm3 fractions. Fractions 30 to 76 were combined and then concentrated to dryness under the same conditions as above. 13.7 g of ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)-piperidine-4-carboxylate were obtained in the form of a viscous orange-colored oil.
Reaction SMILES: C([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH:29][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])(C)C.[I-].[Na+]>CC(=O)CC>[C:30]([NH:29][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([OH:28])=[C:17]([N:18]=[N:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:8]([S:5]([OH:7])(=[O:6])=[O:4])=[CH:9]2)=[CH:14][CH:13]=1)(=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(NC(=O)c4ccccc4)ccc3c2O)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1ccc(N=Nc2c(S(=O)(=O)O)cc3cc(NC(=O)c4ccccc4)ccc3c2O)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
7-Benzoylamino-4-hydroxy-3-(4-methoxy-phenylazo-napthalene-2-sulfonic acid isopropyl ester (Example 15, 49 mg, 0.09 mmol) was suspended in 2-butanone (3 mL) and sodium iodide (57 mg, 0.38 mmol) was added. The reaction mixture was allowed to stir under nitrogen at 60° C. for 24 h. The solvent was removed under a stream of nitrogen, acetone was added and the suspension was filtered to provide the title compound (51 mg, 0.08 mmol, 91%) as a red solid: NMR (DMSO-d6): δ 16.30 (s, 1H), 10.68 (s, 1H), 8.26 (d, J=9 Hz, 1H), 8.19 (m, 1H), 8.01 (m, 3H), 7.83 (d, 4H), 7.10 (d, J=9 Hz, 2H), 3.92 (s, 3H); Analytical BPLC: 99% pure; MS (ES-NEG): [M−H] 476; Anal. Calc. for C27H25N3O6S: C, 57.71, H, 3.63, N, 8.41. Found: C, 52.85, H, 4.44, N, 6.66.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][CH:7]=1.[CH:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24].CP(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.CC1CCCO1.ClCCl>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]([C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(n1Cc1cccc(I)c1)C(O)CCC2
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CC1CCCO1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCCc2nc(C(C)C)n(Cc3cccc(I)c3)c21
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of Intermediate 91 (5.7 g) in Toluene (50 mL) and 2-Methyltetrahydrofuran (2-MeTHF) (50 mL) under nitrogen was added triethyl methanetricarboxylate (6.14 mL) followed by trimethylphosphine (2.54 mL). The reaction mixture was then cooled to −78° C. and DIAD (5.68 mL) was added dropwise over 12 min. The reaction mixture was allowed to continue stirring at −78° C. and under nitrogen for a further 40 min. The reaction mixture was then allowed to warm to room temperature and allowed to stir for a further 2 hours while still under nitrogen. The reaction mixture was then concentrated in vacuo before being partitioned between DCM (50 mL) and water (50 mL). The phases were separated and the aqueous layer was washed with further DCM (2×50 mL). The organic phases were combined, filtered through a hydrophobic frit and concentrated in vacuo to give 19.8 g of crude product as an orange oil. The sample was loaded in dichloromethane and purified on by column chromatography (silica) using a 0-100% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product 7.67 g as an off-white solid. LC/MS MH+ 611, Rt 3.54 min (5 min run).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[N+:6]([O-])[CH:7]=1.C[Si]([C:14]#[N:15])(C)C.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:7]([C:14]#[N:15])=[N:6][C:5]([Cl:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cc(Br)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1nc(Cl)ccc1Br
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-2-chloropyridine 1-oxide (from step 1) (1.0 eq.) in acetonitrile (0.2 M) was added trimethylsilyl cyanide (TMSCN) (4.0 eq.) and triethylamine (3.0 eq.). The reaction was heated at 100° C. overnight. After cooling to room temperature, the solvent was concentrated en vacuo, and the residue was purified by a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in hexane to give 3-bromo-6-chloropicolinonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH:10]([CH3:17])[C:11]([O:15]C)=[CH:12][CH2:13]O)=[CH:7][CH:6]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH:10]([CH3:17])[C:11](=[O:15])[CH:12]=[CH2:13])=[CH:7][CH:6]=1
Reactant: COC(=CCO)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Solvent: ClCCl
Product: C=CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
The foregoing alcohol (380 mg) is reacted with 35% HClO4 (4 ml) in CH2Cl2 (4 ml) at RT for 24 hours. The mixture is then extracted with CH2Cl2 and the combined extracts washed, dried and concentrated to dryness. The product is purified by prep. thin layer chromatography to give 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-oxo-1-pentene, MS m/e 396 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1.[H-].[Na+].Cl.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>CN(C)C=O>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][N:10]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:9]1[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=2[S:7][CH:8]=1
Reactant: CN(C)CCCCl
Reactant: Fc1ccc2c(Nc3ccncc3)csc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN(c1ccncc1)c1csc2cc(F)ccc12
Temperature: 0 °C
Yield: 74.2 %

Procedure:
6-Fluoro-3-(4-pyridinylamino)benzo[b]thiophene (3.30 g, 13.5 mmol) was added portionwise as a powder to a suspension of sodium hydride (60% oil dispersion, 1.35 g, 33.8 mmol, washed with hexanes) in 50 mL dimethylformamide. After the anion formation was completed, 3-dimethylaminopropyl chloride hydrochloride (2.56 g, 16.2 mmol) was added as a powder and the resultant mixture was stirred at 70°-75° C. for two hours. After cooling, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution and dried (anhydrous magnesium sulfate), filtered and concentrated to 4.6 g of a brown oil. Elution through silica with 10% methanol in dichloromethane via flash column chromatography yielded 3.3 g of a yellow oil. Kugelrohr distillation (210°-220°/0.1 mm Hg) yielded 2.8 g of a clear colorless oil which eventually solidified to a white solid, mp 82°-84°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:9][C:10]1[C:11]([C:19]2[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=2)=[N:12][O:13][C:14]=1[C:15]([F:18])([F:17])[F:16]>C1COCC1>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:24]([C:22]1[S:23][C:19]([C:11]2[C:10]([CH3:9])=[C:14]([C:15]([F:17])([F:18])[F:16])[O:13][N:12]=2)=[CH:20][CH:21]=1)=[O:25]
Reactant: Cc1c(-c2ccc(C(=O)Cl)s2)noc1C(F)(F)F
Reactant: Nc1cnccc1Cl
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)Nc3cnccc3Cl)s2)noc1C(F)(F)F
Reaction time: 1 h
Yield: 16 %

Procedure:
A solution of 3-amino-4-chloropyridine (129 mg, 1.0 mmol) in THF (2 mL) was treated with solid 5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (148 mg, 0.5 mmol, as prepared in Example 2 Method B) and allowed to stir for 1 hr. The reaction was then evaporated and the residue chromatographed on silica gel with EtOAc/hexanes (70%) as eluant to afford product as a colorless solid (31 mg, 16%). 1H NMR (CDCl3) 2.39 (d, J=1.5, 3H), 7.39 (d, J=5.3, 1H), 7.56 (d, J=7.56, 4.1, 1H), 7.72 (d, J=4.1, 1H), 8.22 (s, 1H), 8.33 (d, J=4.7, 1H), 9.61 (s, 1H). 13C NMR 8.0, 114.8, 118.7 (q, J=271), 129.0, 129, 7, 132.9, 134.6, 140.5, 143.8, 146.1, 157.7, 159.0, 19F NMR −63.1. LC/MS 6.34 min, [M+1]+ 388.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1.[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(Cc2ccc(Cl)c(Cl)c2)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(Cc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.7 %

Procedure:
To a solution of 4-(3,4-dichlorobenzyl)benzoic acid (Preparation 148,150 mg, 0.54 mmol) in dichloromethane (25 mL) was added methanesulphonamide (153 mg, 1.61 mmol), 4-dimethylaminopyridine (196 mg, 1.61 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (307 mg, 1.61 mmol) and the mixture was stirred at room temperature for 5 hours. The mixture was diluted with dichloromethane, washed with water and 1M hydrochloric acid solution, dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was purified by silica gel column chromatography eluting with 95:5 dichloromethane:methanol to afford the title compound (102 mg, 53%).
Reaction SMILES: [OH-].[OH:2][CH2:3][CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[F:9][C:10]1[C:28]([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH2:31][CH2:30]2)=[CH:27][C:13]2=[N:14][C:15]3[N:16]([CH3:26])[CH:17]=[C:18]([C:23]([OH:25])=[O:24])[C:19](=[O:22])[C:20]=3[CH:21]=[C:12]2[CH:11]=1>CO>[OH:2][CH2:3][CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[F:9][C:10]1[C:28]([N:29]2[CH2:30][CH2:31][N:32]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH2:33][CH2:34]2)=[CH:27][C:13]2=[N:14][C:15]3[N:16]([CH3:26])[CH:17]=[C:18]([C:23]([O-:25])=[O:24])[C:19](=[O:22])[C:20]=3[CH:21]=[C:12]2[CH:11]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C(=O)[O-])c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.6 cm3 of a 45% solution of choline hydroxide in methanol were added to a suspension of 7.6 g of 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid in 75 cm3 of methanol. The reaction mixture was stirred for approximately 2 hours at approximately 25° C. The solution was filtered in order to remove a slight insoluble material and was concentrated at approximately 50° C. on a rotary evaporator at approximately 20 kPa. The residual solid was recrystallized from 70 cm3 of 2-propanol and 30 cm3 of methanol. The crystals were filtered off with 10 cm3 of 2-propanol on each occasion and dried in an oven at 100° C. at 10 kPa. 7.4 g of choline 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate were obtained in the form of a yellow solid melting at about 285-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[NH:9][CH:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:9][CH:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH3:11])[C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CC(NC(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1)c1cc(F)cc(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(NC(c1ccc(Cl)cc1)c1cccc(N)c1)c1cc(F)cc(F)c1

Procedure:
Following a reaction and purification procedure similar to those described in Example (59b), 2.79 g of N-[(4-chlorophenyl)-(3-nitrophenyl)methyl]-N-[1-(3,5-difluorophenyl)ethyl]amine [prepared as described in step (a) above], 3.79, of nickel chloride hexahydrate and 1.10 g of sodium borohydride were reacted, to obtain 808 mg of isomer A and 572 mg of isomer B of the title compound as colorless oils, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:8]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([Cl:39])=[CH:24][N:23]=1.Cl.O1CCOCC1>CC(O)C>[Cl:39][C:25]1[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:27][C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:10](=[CH:11][CH:12]=2)[CH:9]2[CH2:13][CH2:14][CH:5]3[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:8]2)=[N:23][CH:24]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)C1CCC2CN(C(=O)C(F)(F)F)C1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(=O)C(F)(F)F)C2)ncc1Cl
Temperature: 120 °C
Yield: 77.9 %

Procedure:
1-(4-Amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone (30 mg, 0.106 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (34.5 mg, 0.116 mmol, 1.1 eq) were dissolved in IPA (1.5 mL). 4.0 M HCl in dioxane (29 μL, 0.116 mmol, 1.1 eq) was added and the reaction was heated at 120° C. in a microwave for 20 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (10 mL) and washed with sat. NaHCO3 (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-75% EtOAc/hex as the eluting solvent to obtain 2-{5-chloro-2-[10-(2,2,2-trifluoro-acetyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide as a yellow foam (45 mg, 78%). LCMS (m/e) 545 (M+1); 1H-NMR (CDCl3, 400 MHz) major rotomer δ 11.01 (s, 1H), 8.61 (d, 1H, J=8.4 Hz), 8.10 (s, 1H), 7.53-7.40 (m, 3H), 7.36-7.26 (m, 1H), 7.13-6.95 (m, 3H), 6.22 (bs, 1H), 4.31-4.17 (m, 1H), 3.92-3.82 (m, 1H), 3.40-3.28 (m, 1H), 3.22-3.08 (m, 2H), 3.04 (d, 3H, J=4.5 Hz), 2.10-1.98 (m, 2H), 1.88-1.72 (m, 2H), 1.30-1.20 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:11])[CH:3]=1.Cl.[CH:13]([O:16][NH2:17])([CH3:15])[CH3:14]>CO>[CH:13]([O:16][N:17]=[CH:6][C:5]1[C:4]([CH3:11])=[CH:3][C:2]([NH2:1])=[C:9]([CH3:10])[CH:8]=1)([CH3:15])[CH3:14]
Reactant: Cc1cc(C=O)c(C)cc1N
Reactant: CC(C)ON
Agent: Cl
Solvent: CO
Product: Cc1cc(C=NOC(C)C)c(C)cc1N
Yield: 80.8 %

Procedure:
0.32 g (2.10 mmol) of 4-amino-2,5-dimethylbenzaldehyde is initially charged in 10 ml of methanol, 0.31 g (2.73 mmol) of O-isopropyl hydroxylamine hydrochloride is added at room temperature and the reaction mixture is heated under reflux for 6 h. The mixture is then concentrated using a rotary evaporator, the residue is taken up in dichloromethane, extracted twice with water, dried over Na2SO4 and freed from the solvent under reduced pressure. This gives 0.35 g of product (purity 98.0%, yield 79.1%, log P (pH 2.3)=2.77).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.CC(C)([O-])C.[Li+].CCCCCC.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1F.[NH4+].[Cl-]>C1COCC1.O1CCOCC1>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][C:25]=1[N:3]1[C:2]([CH3:1])=[CH:6][N:5]=[CH:4]1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: Cc1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1cncn1-c1cc(C(F)(F)F)ccc1Br
Temperature: 180 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
A solution of 4-methyl-1H-imidazole (1.352 g, 16.46 mmol) in 20 mL THF was treated with lithium tert-butoxide 1N in hexane (16.46 ml, 16.46 mmol) and was allowed to stir for one hour. The reaction mixture was concentrated and then transferred to a microwave vial charged with 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (2.360 ml, 16.46 mmol) and 10 mL dioxane. The reaction mixture was heated to 180° C. in a microwave reactor for one hour. After cooling to room temperature, the reaction mixture was poured into saturated NH4Cl solution and was extracted with DCM. The organics were concentrated. then purified directly by silica gel column chromatography (0 to 50% EtOAc/heptane) yielding 1-(2-bromo-5-(trifluoromethyl)phenyl)-5-methyl-1H-imidazole (0.710 g, 2.327 mmol).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[CH:9]([O:11][CH2:12][CH3:13])=[CH2:10].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:9]([O:11][CH2:12][CH3:13])[CH3:10])=[CH:1][CH:2]=1
Reactant: C=COCC
Reactant: Oc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
p-Bromophenol (50 g, 0.29 mole), ethyl vinyl ether (41.7 g, 0.58 mole) and pyridinium p-toluenesulfonate (1.5 g) were dissolved in methylene chloride (300 ml), followed by reaction with stirring at room temperature for 6 hours. Then 5% aqueous sodium bicarbonate (400 ml) was added to the reaction mixture, and stirred. Then, the organic layer was separated, washed with H2O (300 ml×3), dried over anhydrous MgSO4 and evaporated. The residue (82 g) was distilled under reduced pressure to give 71.1 g of p-bromo-(1-ethoxyethoxy)benzene as a pale yellow oil having a boiling point of 112°-114° C./6 mmHg.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(OCC)(OCC)OCC>ClCCl>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COc1ccccc1CN
Solvent: CCOC(OCC)OCC
Solvent: ClCCl
Product: COc1ccccc1CNCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g (66.17 mmol) 2-nitrobenzaldehyde, 9.08 g (66.17 mmol) 2-methoxybenzylamine and 100 mL triethyl orthoformate in 100 mL dichloromethane were stirred for approx. 24 hours at room temperature. The residue obtained after evaporation was dissolved in 190 mL ethanol and mixed by portions with a total of 5.02 g NaBH4 while stirring at room temperature. After approx. 1 hour, the mixture was poured into water, extracted three times with dichloromethane; the combined organic phases were dried with MgSO4, filtered and concentrated until dry; 18.36 g yellow oil. ESI-MS [M+H+]=273.15.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].[C:16](=O)(OC(Cl)(Cl)Cl)[O:17]C(Cl)(Cl)Cl>C(Cl)Cl>[O:15]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:16]1=[O:17]
Reactant: Nc1ccccc1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2o1
Reaction time: 0.5 h
Yield: 235.1 %

Procedure:
Triethylamine (27.0 mL) was added to a mixture of 2-aminophenol (10 g, 91.74 mmol) in CH2Cl2 (200 mL) at 5° C. A solution of bis(trichloromethyl) carbonate (9.35 g, 31.48 mmol) in dichloromethane (40 mL) was then added, maintaining the temperature below 10° C. The resulting solution was then maintained below 10° C. for 6 hours. The reaction mixture was then quenched by the addition of water (50 mL) and ethanol (20 mL). After 0.5 hours, the mixture was concentrated and then poured into 400 mL of H2O. After filtration, the filter cake was washed with hydrochloric acid (10%) and water to afford 10 g (48%) of benzo[d]oxazol-2(3H)-one as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH:9](=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: Oc1ccccc1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-aminophenol (28.55 g, 261.61 mmol) in ethanol (40 mL), was added benzaldehyde (30 mL, 31.32 g, 295.14 mmol), and this reaction mixture was refluxed for two hours, and left stirring at room temperature overnight. The creamy white precipitate was filtered, washed with ethanol and dried in vacuum oven at 80° C. for 4 hours. Giving 40.27 g (78% yields).