Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=2[C:12]1=[O:21].[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=2[C:12]1=[O:21]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])ccc1F
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Yield: 99.9 %

Procedure:
N-(2-Fluoro-5-nitrophenyl)-3,4,5,6-tetrahydrophthalimide (VII) (5 g) and platinum dioxide (0.2 g) were suspended in ethyl acetate (50 ml), and the resultant suspension was allowed to catalytic reduction at room temperature under atmospheric pressure until 1.3 liters of hydrogen was taken up. The reaction mixture was filtered and concentrated to give 4.48 g of N-(2-fluoro-5-aminophenyl)-3,4,5,6-tetrahydrophthalimide (VIII). M.P., 117°-119° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)[C:3]=1[F:21].[OH-].[Na+].[ClH:24]>O1CCOCC1>[Cl:24][C:7]1[CH:2]=[C:3]([F:21])[C:4]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[N:5][CH:6]=1
Reactant: Cl
Reactant: CC(Oc1ccc(Oc2nccc(Cl)c2F)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 13.0 g (0.04 mol) of (R) (+)-2-[4-(5-chloro-3-fluoropyridin-2-yloxy)]-methyl ester in 65 ml of dioxane are added 42 ml of 1N sodium hydroxide and the mixture is stirred for 21/2 hours at a temperature of 35°. Then it is poured onto an ice/water mixture and acidified with 22 ml of 2N hydrochloric acid. The organic material is extracted therefrom twice with ethyl acetate. The organic layers are washed with a saturated salt solution and dried over magnesium sulfate, filtered and concentrated. The residue is cristallized from ethyl acetate/hexane and yields 10.2 g (81.8% of the theory) of the above (2R) (+)-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid as white cristals, which melt at 95°-96° ([α]D20 =+37.5°±0.5°2% in acetone).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[C:24]=1[N+:31]([O-:33])=[O:32]>CN(C=O)C>[CH3:30][NH:29][C:25]1[C:24]([N+:31]([O-:33])=[O:32])=[C:23]([O:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:14][CH:13]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: CNc1nccc(Cl)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1nccc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.83 h
Yield: 59.5 %

Procedure:
N-Boc-4-hydroxyaniline (334 mg, 1.6 mmol) was dissolved in dry DMF (5 mL) and the solution was degassed by argon bubbling for 10 minutes. Potassium tert-butoxide (179 mg, 1.6 mmol) was added, and the stirring and argon bubbling continued for 50 minutes. 4-Chloro-N-methyl-3-nitropyridin-2-amine (260 mg, 1.4 mmol) was added to the reaction mixture. The reaction mixture was heated and stirred at 80° C. for 9 hours, under argon. The solvent was evaporated and the residue was extracted between DCM and aqueous NaOH 1M. The extraction was repeated twice, the organic layer was dried over MgSO4, and evaporated. The residue was purified by column chromatography (eluent gradient DCM to DCM:AcOEt 15:1) to afford the title compound (300 mg, 60%). 1H-NMR (δ, ppm, DMSO-d6): 1.48 (s, 9H, t-Bu), 2.91 (d, 3H, Me, J=4.60 Hz), 5.94 (d, 1H, HPy,5, J=5.70 Hz), 7.09 (d, 2H, Harom,Ph,3+5, J=9.00 Hz), 7.45 (m, 1H, NHPy), 7.53 (d, 2H, Harom,Ph,2+6), 8.07 (d, 1H, HPy,6), 9.46 (s, 1H, NH).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18]([C:26]5[S:27][C:28]([CH3:31])=[CH:29][CH:30]=5)=[CH:19][C:20]([CH3:25])([CH3:24])[O:21]4)=[CH:16][C:15]=3[CH:32]=2)=[CH:7][CH:6]=1)C.[Li+].[OH-]>CO.C1COCC1.O>[CH3:24][C:20]1([CH3:25])[CH:19]=[C:18]([C:26]2[S:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:17]2[C:22](=[CH:23][C:14]3[CH:13]=[CH:12][C:11]([C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:33])=[O:3])=[CH:6][CH:7]=4)=[CH:32][C:15]=3[CH:16]=2)[O:21]1
Reactant: CCOC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(c2ccc(C)s2)=CC(C)(C)O4)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2=CC(C)(C)Oc3cc4ccc(-c5ccc(C(=O)O)cc5)cc4cc32)s1
Reaction time: 20 h

Procedure:
To a solution of ethyl-4-[2,2-dimethyl-4-(5-methyl-thien-2-yl)-benzo[1,2-g]-chrom-3-en-7-yl]benzoate (Compound 11, 18 mg, 0.03 mmol) in methanol (0.5 mL) and THF (1 mL), was added LiOH in water (1M solution, 0.3 mL). The reaction mixture was stirred for 20 hours, the solvent was removed under reduced pressure, the residue dissolved in water (5 mL), washed with ether (10 mL) and the aqueous layer was acidified to PH 5. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried, and the solvent was removed under reduced pressure to afford the title compound as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH2:8][CH2:7]1)C.[OH-].[Li+]>O1CCCC1CO>[F:30][C:27]([F:28])([F:29])[C:24]1[CH:25]=[CH:26][C:21]([C:16]2[C:15]([C:13]([NH:12][CH:9]3[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:31])=[O:3])[CH2:11][CH2:10]3)=[O:14])=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)CN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: O=C(O)CN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
To a solution of [4-(4′-trifluoromethylbiphenyl-2-carbonylamino)piperidin-1-yl]acetic acid ethyl ester (595 mg) obtained in Example 8c) in tetrahydrofuran-methanol (1:2; 10.2 mL) was added 1M aqueous lithium hydroxide (6.8 mL), and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated in vacuo and 2N hydrochloric acid was added to the residue to adjust the pH to about 3, thereby crystals were precipitated. The crystals were collected by filtration, washed with cold water and dried in vacuo to give the title compound (411 mg).
Reaction SMILES: [Si]([O:8][C@H:9]([C:17]#[C:18]/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C@H:23]([O:40][Si](C(C)(C)C)(C)C)[CH2:24][C:25]#[C:26]/[CH:27]=[CH:28]/[C@H:29]([O:32][Si](C(C)(C)C)(C)C)[CH2:30][CH3:31])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:8][C@H:9]([C:17]#[C:18]/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C@H:23]([OH:40])[CH2:24][C:25]#[C:26]/[CH:27]=[CH:28]/[C@H:29]([OH:32])[CH2:30][CH3:31])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CC[C@H](/C=C/C#CC[C@H](/C=C/C=C/C#C[C@H](CCCC(=O)OC)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H](O)/C=C/C#CC[C@@H](O)/C=C/C=C/C#C[C@@H](O)CCCC(=O)OC
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution of the product of Example 4 (40 mg, 0.065 mmol) in THF (1 ml) was treated with 1.0 M TBAF (0.32 ml, 0.32 mmol) at 0° C. The reaction was stirred for 3 h and then poured into water and extracted with ether. The ether extracts were washed with brine, dried and concentrated. The ethereal solution was then treated with an excess of freshly prepared diazomethane in ether to convert the free acid to the product. Flash column chromatography (silica gel, 4% MeOH/CH2Cl2) afforded the pure product in 90% yield. 1H NMR (500 MHz, C6D6): δ 6.55 (dd, J=15.5 Hz and 10.9 Hz, 1H), 6.16 (dd, J=15.2 Hz and 11.0 Hz, 1H), 6.05 (dd, J=15.5 Hz and 5.3 Hz, 1H), 5.70 (d, J=16.2 Hz, 1H), 5.61 (dd, J=14.6 Hz and 5.5 Hz, 1H), 5.58 (d, J=14.7 Hz, 1H), 4.28 (t, J=5.8 Hz, 1H), 4.06 (dd, J=11.2 Hz and 5.3 Hz, 1H), 3.65 (dd, J=1.0 Hz and 6.7 Hz, 1H), 3.30 (s, 3H), 2.36 (m, 2H), 2.06 (t, J=6.9 Hz, 2H), 1.72 (m, 2H), 1.59 (m, 2H), 1.27 (m, 2H), 0.74 (t, J=7.4 Hz, 3H). 13C NMR (125 MHz, C6D6): δ 173.819, 145.219, 141.143, 136.647, 130.007, 111.340, 109.915, 92.672, 85.857, 84.082, 81.330, 73.505, 70.225, 62.533, 51.488, 37.097, 33.599, 29.912, 28.658, 20.615, 9.451. HPLC: Beckman Ultrasphere reverse phase column (30% water in MeOH, 3.8 ml/min, 252 bar): elution time=5.41 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[CH2:31][NH2:32])[CH:20]=[N:19][N:18]=[N:17]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:32][CH2:31][C:22]1[CH:23]=[C:24]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:26][C:21]=1[N:16]1[CH:20]=[N:19][N:18]=[N:17]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCc1cc(C(F)(F)F)ccc1-n1cnnn1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1cc(C(F)(F)F)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-L-proline (39 mg, 0.18 mmol), 1-[2-(1H-tetraazol-1-yl)-5-(trifluoromethyl)phenyl]methanamine (42 mg, 0.17 mmol), EDC (49 mg, 0.26 mmol) and HOAt (12 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature for 2 h. The crude product was purified by reverse phase HPLC followed by neutralization of an aqueous slurry of the compound with saturated aqueous K2CO3 and repeated extraction of the resulting aqueous mixture with EtOAc (the aqueous layer was saturated with NaCl before each extraction). The combined organic extracts were dried (anhydrous Na2SO4) and concentrated to afford the title compound as an oil which was carried on directly to the deprotection step (Step D below). LCMS (M+H): 441.2.
Reaction SMILES: [C:1]1([C:8]2[CH:14]=[CH:13][C:11](N)=[CH:10][CH:9]=2)[CH:7]=[CH:6][C:4]([NH2:5])=CC=1.[NH2:15]C1C(C)=CC=CC=1.C(C1C=CC(N)=CC=1)C1C=CC(N)=CC=1.COC1(OC)C(N)=CC=C(C2C=CC(N)=CC=2)C1.ClC1C=C(C2C=CC(N)=C(Cl)C=2)C=CC=1N>>[C:4]1([NH2:5])[C:9]2[C:8](=[CH:14][CH:13]=[CH:11][C:10]=2[NH2:15])[CH:1]=[CH:7][CH:6]=1
Reactant: Nc1ccc(-c2ccc(N)cc2)cc1
Reactant: Cc1ccccc1N
Agent: COC1(OC)CC(c2ccc(N)cc2)=CC=C1N
Agent: Nc1ccc(-c2ccc(N)c(Cl)c2)cc1Cl
Agent: Nc1ccc(Cc2ccc(N)cc2)cc1
Product: Nc1cccc2cccc(N)c12

Procedure:
benzidine; toluidine; 4,4'-methylenedianiline; 3,3-dimethoxy-4,4'-biphenyldiamine; 3,3'-dichloro-4,4'-biphenyldiamine;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.C([O:21][B:22](OC(C)C)[O:23]C(C)C)(C)C>>[F:8][C:6]1[CH:7]=[C:2]([B:22]([OH:23])[OH:21])[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Product: OB(O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
3-Bromo-5-fluorobenzotrifluoride was lithiated with n-butyllithium and treated with tri-isopropylborate to give 3-fluoro-5-trifluoromethylphenyl boronic acid. This was coupled to 5-bromopyrimidine, using Suzuki methodology to afford 3-fluoro-5-(pyrimidin-5-yl)benzotrifluoride. Hydrolysis with conc. sulphuric acid and chlorosulphonic acid afforded 3-fluoro-5-(pyrimidin-5-yl)benzoic acid. This was converted to the methyl ester by treatment with methanol and conc. sulphuric acid, and to the hydrazide by treatment with hydrazine hydrate. Diazotisation and treatment with potassium carbonate afforded the title compound.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)#[N:36]>>[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)=[CH:39][CH:38]=1)#[N:36]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C#N)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-cyano-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.88 (dd, J=6.60, 3.18 Hz, 6H) 1.47 (dt, J=13.45, 6.72 Hz, 1H) 1.66 (ddd, J=13.63, 7.09, 6.91 Hz, 1H) 1.91-2.00 (m, 1H) 3.77 (t, J=7.83 Hz, 1H) 7.61 (dd, J=4.16, 1.71 Hz, 2H) 7.68 (d, J=8.31 Hz, 2H) 7.73-7.81 (m, 7H).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)=[N:14][CH:15]=[C:10]3[CH2:9][NH:8][C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>C1COCC1>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:21][CH:22]=4)=[N:14][CH:15]=[C:10]3[CH:9]=[N:8][C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(c2ccc(Nc3ncc4c(n3)N(C3CCCC3)C(=O)NC4)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3ncc4cnc(=O)n(C5CCCC5)c4n3)cc2)CC1
Yield: 66.7 %

Procedure:
Prepared from 150 mg (0.37 mmol) of 1-cyclopentyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 165 mg (1.47 mmol) of potassium tert-butoxide in 6 mL of THF. The dark orange semi-solid is triturated in diethyl ether, and the yellow powder is collected and dried to give 100 mg (67%) of the title compound: mp 220-225° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Clc1cc(-c2ccccc2)ncn1
Yield: 34 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 3.35 g of 4,6-dichloropyrimidine, 3.02 g of phenylboronic acid, 1.7 mL of tricyclohexylphosphine (abbreviation: Cy3P), 14.7 g of cesium carbonate, 0.31 g of tris(dibenzylideneacetone)palladium(0) (abbreviation: Pd2(dba)3), and 30 mL of dioxane, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 120 W) for 60 minutes for reaction. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using a mixed solvent of dichloromethane and hexane as a developing solvent in a volume ratio of 1:1, to give 4-chloro-6-phenylpyrimidine (light yellow powder, 34% in yield). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme of Step 1 is shown in (b-1) given below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:11])=[C:6]([NH2:12])[CH:5]=1.[CH:14]([N:17](CC)C(C)C)(C)[CH3:15].BrCC#N.O>C1COCC1>[C:14]([CH2:15][NH:12][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[CH3:11])[C:3]([O:2][CH3:1])=[O:13])#[N:17]
Reactant: COC(=O)c1cc(N)c(C)c(F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(F)c(C)c(NCC#N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 3-amino-5-fluoro-4-methyl-benzoic acid methyl ester (Example 252e, 34.7 g) in THF (300 mL) at room temperature was added N,N-diisopropylethylamine (61.2 mL) followed by bromoacetonitrile (24.41 mL). The mixture was heated at reflux for 16 h, further bromoacetonitrile (4.8 mL) and N,N-diisopropylethylamine (12.5 mL) were added and heating was continued for 6 h. The reaction was cooled to room temperature and concentrated. 1N HCl (600 mL) and dichloromethane (800 mL) were added. This gave some solid precipitate which did not dissolve. Water (300 mL) was added to help identify layers. The lower organic layer containing solid and a bit of water was separated and this organic fraction was washed with 1M HCl/brine (400 mL of 1:1 mixture) before being dried (MgSO4). A second drying (Na2SO4) was needed. After the drying agent was filtered off (washed through with 400 ml dichloromethane) the filtrate was concentrated (˜60 g). This was azeotroped with toluene (400 mL) and final solvent removal gave subtitle compound (39.4 g).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[H-].[Na+].I[CH3:20]>CN(C)C=O>[CH3:20][N:8]1[C:2](=[O:1])[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]1=2
Reactant: CI
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccccc2Nc2ccccc21
Reaction time: 1.5 h
Yield: 62.2 %

Procedure:
To a solution of 11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine (10 g, 0.048 mol, Synthesis, (1985), 550) in dry dimethylformamide (100 ml) kept under an atmosphere of nitrogen, sodium hydride (2.1 g, 0.052 mol, 60% dispersion in oil) was added, and the reaction mixture was stirred for 1.5 h. Iodomethane (3.27 ml, 0.052 mol) was slowly added keeping the temperature below 30° C. and the mixture was stirred overnight. The reaction mixture was quenched with saturated ammonium chloride (20 ml) and poured onto ice water (300 ml). The solid was filtered off and washed with plenty of water and dried. This yielded 10.4 g of crude 10-methyl-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine which was recrystallised from methanol (200 ml), to give 6.7 g (63%) of 10-methyl-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine. M.p. 210°-211° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].N12CCCN=C1CCC[CH2:16][CH2:15]2.ICC>CN(C)C=O.O>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:15][CH3:16])[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2s1
Solvent: CN(C)C=O
Solvent: CCI
Solvent: O
Product: CCn1c(=O)sc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 6-nitro-2-benzothiazolinone (2.5 g, 12.7 mmol) in anhydrous N,N-dimethylformamide (25 mL) under N2 is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (2.48 mL, 16.6 mmol) dropwise followed by iodoethane (1.22 mL, 15.3 mmol). Following a slight exotherm, the reaction mixture is stirred at ambient temperature for 21 h, diluted with water (20 mL) and filtered to give the title compound, mp 200-203° C.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:10][CH2:11][C:12](Cl)=[O:13]>C1(C)C=CC=CC=1>[CH2:1]([NH:7][C:12](=[O:13])[CH2:11][Cl:10])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CCl)NCc1ccco1
Yield: 85 %

Procedure:
N-Furfurylchloroacetamide was prepared by adding 20.0 g. (0.206 mole) furfuryl amine in sufficient toluene to make a 15% solution to a 500 ml. three neck round bottom flask equipped with magnetic stir bar, addition funnel, and cooling bath and then adding 36 ml. of 20% sodium hydroxide. The mixture was cooled to 0°-5° C. and chloroacetyl chloride was added dropwiseso that the reaction temperature was maintained at 5°-10° C. After the addition, a solid deposited on the walls of the flask. It was recrystallized from ether as a light tan solid. Yield was 85%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:22])=[C:7]([CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N+:15]=2[O-:21])[CH:10]=[C:11]([CH3:13])[CH3:12])[CH:8]=1)#[N:2].S(=O)(=O)(O)O>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:22][C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N+:15]=3[O-:21])[C:7]=2[CH:8]=1)#[N:2]
Reactant: CC(C)=CC(c1cc(C#N)ccc1O)c1cccc(C)[n+]1[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1cccc(C2CC(C)(C)Oc3ccc(C#N)cc32)[n+]1[O-]
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
350 mg of 2-[1-(5-cyano-2-hydroxyphenyl)-3-methyl-2-butenyl]-6-methylpyridine N-oxide in 15 ml of dichloromethane were stirred with 100 μl of concentrated sulphuric acid for 1 hour. A further 100 μl of concentrated sulphuric acid were added and stirring was continued for 30 minutes. The mixture was washed with water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using methanol/ethyl acetate (1:9) for the elution to give an oil which crystallized from diethyl ether. There was obtained 0.26 g of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-6-methylpyridine N-oxide of melting point 165°-167° C.
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[NH:12][C:11](=[O:14])[CH:10]=[CH:9][C:8]=2[CH2:7][C:6]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:5]1)[CH:2]=[CH2:3].I[CH3:20]>C(Cl)(Cl)Cl>[CH2:1]([CH:4]1[C:13]2[N:12]=[C:11]([O:14][CH3:20])[CH:10]=[CH:9][C:8]=2[CH2:7][C:6]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1CC2(Cc3ccc(=O)[nH]c31)OCCO2
Reactant: CI
Solvent: ClC(Cl)Cl
Product: C=CCC1CC2(Cc3ccc(OC)nc31)OCCO2
Yield: 89.8 %

Procedure:
A mixture of Ag2CO3 (7.17 g, 26.2 mmol), pyridone 3 (5.4 g, 21.9 mmol), and iodomethane (8.0 mL, 131 mmol) in 200 mL of CHCl3 was refluxed in the dark with stirring. After cooling, filtration, and concentration, the residue was purified by flash chromatography with 25% ethyl acetate in hexanes as the eluent to afford 5.14 g (90%) of 4a: IR (neat) 2953, 1589, 1487, 830 cm-1 ; 1H NMR δ7.22 (d, 1H, J=8.2 Hz), 6.52 (d, 1H, J=8.2 Hz), 5.80 (m, 1H), 5.03 (m, 2H), 4.01 (m, 4H), 3.89 (s, 3H), 3.11 (m, 1H), 2.96 (m, 2H), 2.80 (dd, 1H, J=16.0, 2.4 Hz), 2.50 (m, 1H), 2.06 (m, 1H), 1.80 (dd, 1H, J=13.2, 10.9 Hz); 13C NMR δ162.0, 154.5, 139.7, 137.1, 121.6, 116.3, 108.1, 107.9, 64.5, 64.4, 53.1, 39.4, 38.1, 38.0, 36.6; MS m/z 261 (M+), 246, 220, 174, 148.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1F.CC(C)([O-])C.[Na+].O>CS(C)=O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=2[Br:17])[C@@H:10]([CH2:14][CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC[C@H]1CN(Cc2ccccc2)CCN1
Reactant: Cc1ccc(Br)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Br)c(N2CCN(Cc3ccccc3)C[C@@H]2CCO)c1

Procedure:
To a solution of (S)-2-(4-benzylpiperazin-2-yl)ethanol (150 mg, 0.681 mmol) and 1-bromo-2-fluoro-4-methylbenzene (167 mg, 885 mmol) in dimethyl sulfoxide (5 mL) was added sodium tert-butoxide (164 mg, 1.70 mmol). The reaction mixture was allowed to stir for 16 hours at room temperature before addition of water and ethyl acetate. The organic layer was separated and concentrated onto silica gel. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.40 (d, J=7.80 Hz, 1H), 7.18-7.35 (m, 5H) 6.92 (d, J=1.36 Hz, 1H), 6.65-6.73 (m, 1H), 4.08 (t, J=6.44 Hz, 2H), 3.36-3.51 (m, 2H), 2.55-2.89 (m, 6H),1.87-1.99 (m, 1H), 1.68-1.77 (m, 2H); MS (APCI+) m/z 389, 391 (M+H)+.