Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([C@H:12]1[CH2:17][CH2:16][C@H:15]([O:18][C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[C:24]([CH:29]=O)[N:25]=[CH:26]3)=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)([CH3:11])([CH3:10])[CH3:9].[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:40]([O:39][C:37]([CH:34]1[CH2:35][CH2:36][N:31]([CH2:29][C:24]2[N:25]=[CH:26][C:21]3[C:22]([CH:23]=2)=[CH:27][CH:28]=[C:19]([O:18][C@H:15]2[CH2:14][CH2:13][C@H:12]([C:8]([CH3:11])([CH3:9])[CH3:10])[CH2:17][CH2:16]2)[CH:20]=3)[CH2:32][CH2:33]1)=[O:38])[CH3:41]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ncc3c2)CC1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)C1CCN(Cc2cc3ccc(O[C@H]4CC[C@H](C(C)(C)C)CC4)cc3cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (65 μL, 0.47 mmol) was added to a solution of 7-(trans-4-tert-Butyl-cyclohexyloxy)-isoquinoline-3-carbaldehyde (0.106 g, 0.340 mmol) and Ethyl piperidine-4-carboxylate (79 mg, 0.50 mmol) in 1,2-Dichloroethane (5.00 mL) and the mixture was stirred for 1 hour at room temperature. Sodium triacetoxyborohydride (0.101 g, 0.476 mmol) was then added and stirring was continued for 2 hours. The reaction was diluted in methylene chloride and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, evaporated. The residue was taken up in methylene chloride and silica gel was added. The solvent was removed by evaporation and the residue purified by silica gel chromatography. 101 mg (66%) isolated. ESI-MS (M+H+): 453.10.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][S:11][C:12]2[NH:13][C:14]3[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].Cl>[OH-].[Na+]>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][S:11][C:12]2[NH:13][C:14]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCSc2nc3ccc(C(=O)OCC)cc3[nH]2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCc1c(OCCSc2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 77.6 %

Procedure:
The above ester (2.20 g) was added to 1 N sodium hydroxide solution (20 ml), and the mixture was refluxed for 30 minutes, then poured into ice-water, made acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane-methanol (10:1), and recrystallized from n-hexane-ethyl acetate to give the title compound (1.60 g, 77.1 %) as colorless crystals, mp 108-110° C.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:31])[C@H:7]([CH3:30])[CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:10]1[CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][OH:27])[CH2:2][CH2:3][CH3:4].C(Cl)(Cl)(Cl)Cl.I([O-])(=O)(=O)=[O:38].[Na+].C(Cl)Cl>C(#N)C.O.C(OCC)C.O.[Ru](Cl)(Cl)Cl>[CH2:1]([NH:5][C:6](=[O:31])[C@H:7]([CH3:30])[CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:10]1[CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][C:26]([OH:38])=[O:27])[CH2:2][CH2:3][CH3:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CC(=O)O
Reaction time: 5 h

Procedure:
2.9 g of 3-[3-tert-butoxycarbonyl-4(S)-(4-hydroxy-2,2-dimethylbutyl)-2,2-dimethyloxazolidin-5(S)-yl]-2(R)-methyl-propionic acid (N-butyl)amide are dissolved in 45 ml of acetonitrile and 45 ml of carbon tetrachloride and the solution is added to a solution of 8.56 g of sodium periodate and 150 mg of ruthenium(III) chloride hydrate in 85 ml of water. After 5 h, the crude product is isolated by extraction with methylene chloride. The crude product is then dissolved in 200 ml of diethyl ether and the solution is stirred with 10 g of Hyflo® and, after 30 min, filtered over Hyflo®. The filtrate is concentrated and the residue is purified by FC (100 g of silica gel, mobile phase S). The title compound is obtained: Rf (S)=0.35; Rt (II)=11.4 min; FABMS: (M+H)+ =457.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[C:22]([F:29])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.[H][H]>CN(C)C=O.C(N(CC)CC)C.[OH-].[Pd+2].[OH-]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:30][CH3:31])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)=[CH:21][C:22]=1[F:29]
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])c(F)c3)ccnc2cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Yield: 55.3 %

Procedure:
7-(Benzyloxy)-4-(3-fluoro-4-nitrophenoxy)-6-methoxyquinoline (190 mg) was dissolved in N,N-dimethylformamide (5 ml) and triethylamine (1 ml). Palladium hydroxide (40 mg) was added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with chloroform/methanol (20/1) to give 75 mg (yield 56%) of the title compound.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O>>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ccncc2)c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccncc4)c3F)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 2,4-difluoro-3-(pyridin-4-yl)benzeneboronic acid as described in Example 65 to give 2-[3-(2,4-difluoro-3-(pyridin-4-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as an off-white solid. Bis-hydrochloride (from ethanol/ethyl acetate): δH (360 MHz, DMSO) 1.56 (6H, s), 7.62-7.67 (1H, m), 7.85 (1H, d, J 7), 7.88-7.94 (1H, m), 7.99 (2H, d, J 6), 8.50 (1H, s), 8.94 (2H, d, J 6), 9.26 (1H, dd, J 7 and 3); m/z (ES+) 367 (M++H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.C([Li])CCC.[C:18](OCC)(=[O:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[O:27]=[C:18]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCOC(=O)CCc1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCc1ccccc1)OC
Reaction time: 2 h

Procedure:
A solution of dimethyl methylphosphonate (115.5 g.) in 2.1 l. of tetrahydrofuran is treated, while stirring at -65° C., with a solution of butyl lithium (660 ml. 1.6 M. in hexane). A solution of ethyl hydrocinnamate (93.5 g.) in 225 ml. of tetrahydrofuran is added at -65° C. Stirring is continued at -65° C. for 2 hrs. and then at about 25° C. for 16 hrs. Acetic acid (70 ml.) is added and the mixture concentrated under reduced pressure. The residue is partitioned between dichloromethane and water. The organic phase is dried and concentrated. Distillation yields the title compound, b. 188°-191° C./2 mm., having a mass spectral peak at 256.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.Cl.Cl.[CH3:31][O:32][C@@H:33]1[CH2:37][NH:36][CH2:35][C@H:34]1[NH2:38]>>[NH2:38][C@H:34]1[C@H:33]([O:32][CH3:31])[CH2:37][N:36]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=3)=[O:16])=[CH:4][N:3]=2)[CH2:35]1
Reactant: CO[C@@H]1CNC[C@H]1N
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Agent: Cl
Product: CO[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncc(F)c2)C[C@H]1N

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 284 using 2-chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Stage 236.1) and trans-4-methoxypyrrolidin-3-amine dihydrochloride (Stage 284.1, 20 h at 80° C. then 24 h at 100° C.). HPLC (Condition 10) tR=5.97 min, UPLC-MS (Condition 3) tR=0.83 min, m/z=492.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.62 (br. s, 2H) 2.82-2.90 (m, 1H) 3.02-3.11 (m, 1H) 3.21 (s, 3H) 3.26-3.34 (m, 2H) 3.47-3.57 (m, 2H) 7.35 (d, J=8.99 Hz, 2H) 7.85 (m, J=9.00 Hz, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.51 (s, 1H) 8.60 (d, J=2.74 Hz, 1H) 8.77 (d, J=1.95 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]1([O:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:14]2[CH:15]=[CH:16][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc(Br)c2)cc1
Yield: 79.6 %

Procedure:
To a cooled (0° C.) mixture of 3-bromobenzoyl chloride (5-a, 178 g, 0.82 mol) and anisole (110 g, 1.03 mol) in DCM (2.0 L) was added AlCl3 (138 g, 1.03 mol) portion wise with stirring under N2. The resulting reaction mixture was allowed to stir at r.t overnight. The reaction mixture was poured into 20% HCl (1500 ml), stirred for 1 h, and layers were separated. The aqueous layer was further extracted with DCM (2×750 ml). The combined organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was washed with hexane to afford the product, 5-b, (190 g, 84%).
Reaction SMILES: C([O:8][C:9]1[C:10]([F:22])=[C:11]([CH2:18][C:19](=[O:21])[CH3:20])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)C1C=CC=CC=1.Br>C(OC(=O)C)(=O)C.C(O)(=O)C>[F:22][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[C:11]=1[CH2:18][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Agent: Br
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Temperature: 100 °C
Yield: 79.8 %

Procedure:
Method R-1: To a solution of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (3.03 g, 10 mmol) in acetic anhydride (5 mL) and acetic acid (5 mL) at room temperature was added hydrobromic acid (48% aqueous solution, 3 mL). After addition, the reaction was heated at 100° C. for 30 min and then cooled to room temperature. To this mixture was added 10 mL of hexanes with stirring. The solution was decanted and concentrated. The residue was diluted with ethyl acetate (50 mL) and washed with brine (3×20 mL). The organic layer was dried and concentrated in vacuo to provide 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1.70 g, 80%) as a brown solid, which was used in the next step without further purification. LC/MS; (M+H)+=213.2
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:6]=1[C:19]([O:21]CC)=[O:20])([CH3:3])[CH3:2].[OH-].[K+]>CO>[CH:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:6]=1[C:19]([OH:21])=[O:20])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(OC(C)C)cc(OC(C)C)nc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1cc(OC(C)C)c(C(=O)O)c(C(F)(F)F)n1
Yield: 73.6 %

Procedure:
A mixture of 9.5 g (0.0283 mol) of product of Example 6, 10 g of KOH and 150 ml of methanol was held at reflux for 16 hours. Methanol was removed under reduced pressure. The residue was treated with 300 ml of water and extracted with ether. The aqueous layer was poured into 50 ml of concentrated HCl and extracted with ether. The ether extract was concentrated. The residual solid (7.7 g) was recrystallized from hexane-ether to give 6.4 g (73.6%) of acid product: mp 147°-150° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12]C)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1>CO>[C:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(-c2ccccc2)c1

Procedure:
0.90 g of methyl 3-phenylbenzoate was fed into 20 ml of a solvent mixture of aqueous solution of 2 M of sodium hydroxide, tetrahydrofuran and methanol (4/2/1) to conduct the reaction at 70° C. for 2 hours. The solvent was evaporated, and the residue was fed into 3 M of hydrochloric acid. The precipitate thus formed was taken by the filtration and dried to obtain the title compound in the form of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=O)[CH2:10][C:11]#[N:12].[NH2:14][NH2:15]>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([NH2:12])[NH:14][N:15]=1
Reactant: NN
Reactant: COc1ccccc1C(=O)CC#N
Solvent: CCO
Product: COc1ccccc1-c1cc(N)[nH]n1

Procedure:
3-(2-Methoxy-phenyl)-3-oxo-propionitrile (2.4954 gms.) is then suspended in 55 mL of anhydrous EtOH. This suspension is treated with 0.90 mL of anhydrous hydrazine and subsequently heated to refluxing temperature for 1 day. The reaction mixture is concentrated in vacuo. The residue is then triturated with isopropanol to precipitate out the 5-(2-methoxy-phenyl)-2H-pyrazol-3-ylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C@@H:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].Cl[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C@@H:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:9])[C:7]=1[O:8][CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)[C@H](O)Cc1cc(Br)c(O)c(Br)c1
Solvent: CC#N
Product: COC(=O)[C@H](O)Cc1cc(Br)c(OCOCC[Si](C)(C)C)c(Br)c1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere 11.1 g (76.6 mmol) 40% KF/Al2O3 were added to a solution of 6.78 g (19.2 mmol) methyl(R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-hydroxy-propionate in 100 mL acetonitrile and the resulting suspension was stirred for a few minutes at RT. Subsequently a solution of 4.07 mL (23.0 mmol) (2-chloromethoxy-ethyl)-trimethyl-silane in 20 mL acetonitrile was added and the reaction mixture was stirred for 20 h at RT. The mixture was filtered through Celite, the solvent was evaporated down i.vac. and the residue was purified by chromatography (silica gel, n-hexane/EtOAc 7:3).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1.O[C@@H]1CCNC1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:31]5[CH2:32][CH2:33][CH:29]([OH:28])[CH2:30]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: OC1CCNC1
Agent: O[C@@H]1CCNC1
Product: OC1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)C1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with (R)-3-hydroxypyrrolidine. A yellow solid 116 was obtained (0.0353 g, 75%). 1H-NMR (CDCl3, 400 MHz) δ 2.15-2.23 (m, 1H), 2.25-2.31 (m, 1H), 3.78-3.84 (m, 2H), 3.87-3.95 (m, 2H), 4.28-4.34 (m, 4H), 4.72-4.76 (m, 1H), 6.77 (s, 1H), 6.91 (dd, J=1.1 Hz, 6.6 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 7.05 (dd, J=2.1 Hz, 8.1 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.54 (dd, J=1.4 Hz, 8.5 Hz, 1H), 7.83 (d, J=1.1 Hz, 1H), 8.15 (d, J=6.6 Hz, 1H); MS (APCI) m/z 475 (M+H)+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(CCCO[C:20]1[CH:29]=[C:28]2[C:23]([C:24](NC3C=CC(Cl)=CC=3F)=[N:25][CH:26]=[N:27]2)=[CH:22][C:21]=1OC)(O)=O.CN1CCNCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[CH:20][CH:29]=2)[CH:24]=[N:25][CH:26]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: CN1CCNCC1
Solvent: CN(C)C=O
Product: c1ccc2ncncc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 164.8 %

Procedure:
1-(3-Dimethylaminopropyl)3ethylcarbodiimide hydrochloride (145 mg, 0.75 mmol) was added to a mixture of 7-(3-carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (250 mg, 0.62 mmol), (prepared as described for the starting material in Example 42), 1-methylpiperazine (0.21 ml, 2.32 mmol) and 4-dimethylaminopyridine (300 mg, 2.46 mol) in DMF (7.5 ml). The reaction mixture; was stirred at ambient temperature for 24 hours and the volatiles were removed by evaporation. Water was added to the residue and the aqueous mixture was extracted with methylene chloride (3×30 ml). The combined organic extracts were washed with brine and the solvent was removed by evaporation. The residue was triturated with ether and the precipitate was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product was triturated with ether collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-73-(4-methylpiperazin-1-ylcarbonyl)propoxy)quinazoline (133 mg, 44%).
Reaction SMILES: [CH3:1][NH2:2].[O:3]1[CH2:23][CH:4]1[CH2:5][O:6][C:7]1[C:20]2[CH:19]3[CH2:21][CH2:22][CH:12]([C:13]4[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[ClH:24]>C(O)(C)C>[ClH:24].[OH:3][CH:4]([CH2:23][NH:2][CH3:1])[CH2:5][O:6][C:7]1[C:20]2[CH:19]3[CH2:21][CH2:22][CH:12]([C:13]4[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CN
Reactant: c1ccc2c(c1)C1CCC2c2c(OCC3CO3)cccc21
Agent: Cl
Solvent: CC(C)O
Product: CNCC(O)COc1cccc2c1C1CCC2c2ccccc21

Procedure:
A solution of 20 g of methylamine in 150 ml of 95% strength alcohol is added all at once to a solution of 12.4 g of 1-[2,3epoxy-propoxy]-9,10-dihydro-9,10-ethano-anthracene. The reaction mixture is subsequently heated to the boil for 12 hours and is then evaporated to dryness. The evaporation residue is recrystallised three times from methylcyclohexane. The base thus obtained, which melts at 128°-129° C, is dissolved in 100 ml of isopropanol by warming, and 35 ml of 2.2 N alcoholic hydrochloric acid are added to the solution. The hydrochloride which precipitates is filtered off, washed with isopropanol and dried at 70°-80° C and 12 mm Hg. 1-[2-Hydroxy-3-methylamino-propoxy]-9,10-dihydro-9,10-ethano-anthracene hydrochloride, thus obtained, melts at 213° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+].Cl.Cl.[NH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:46][CH2:45][C:44]3([O:51][C:50](=[O:52])[NH:49][C:48]4[CH:53]=[CH:54][CH:55]=[CH:56][C:47]3=4)[CH2:43][CH2:42]2)[CH2:37][CH2:36]1.I[C:58]1[CH:63]=[N:62][CH:61]=[CH:60][N:59]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl.O1CCOCC1>[N:59]1[CH:60]=[CH:61][N:62]=[CH:63][C:58]=1[N:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:46][CH2:45][C:44]3([O:51][C:50](=[O:52])[NH:49][C:48]4[CH:53]=[CH:54][CH:55]=[CH:56][C:47]3=4)[CH2:43][CH2:42]2)[CH2:37][CH2:36]1
Reactant: Ic1cnccn1
Reactant: O=C1Nc2ccccc2C2(CCN(C3CCNCC3)CC2)O1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2C2(CCN(C3CCN(c4cnccn4)CC3)CC2)O1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Pd2(dba)3-CHCl3 (5 mg, 0.5 mol %), 2′-(dicyclohexylphosphino)biphenyl-2-amine (8 mg, 2 mol %) and sodium tert-butoxide (13 mg, 0.14 mmol) were weighed in air and transferred into flask, followed by dioxane (750 μL), 1′-(piperidin-4-yl)spiro[benzo[d][1,3]oxazine-4,4′piperidin]-2(1H)-one bis-hydrochloride (compound no. 49) (37 mg, 0.10 mmol) and iodopyrazine (viia) (20.6 mg, 0.10 mmol). The flask was flushed with nitrogen and stirred at 80° C. for 16 hours. The reaction mixture was diluted with methanol (500 μL), filtered (Whatman 0.45 μm PTFE) and subjected to reverse-phase HPLC purification (2-25% CH3CN gradient [w/0.1% TFA (aq)] over 10 minutes, 1.0 mL injected, 35 mL/min) to provide 1′-(1-(pyrazin-2-yl)piperidin-4-yl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (compound no. 74). LC/MS m/z 380.2 [M+H]+, retention time 1.35 min (RP-C18, 10-99% CH3CN/0.05% TFA).
Reaction SMILES: C1COCC1.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]#[CH:19])[C:10](Cl)=[O:11].[CH:20]1([CH2:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:20]1([CH2:26][NH:27][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]#[CH:19])=[C:7]([F:6])[CH:8]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1F
Reactant: NCC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCOc1ccc(C(=O)NCC2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a mixture of 10 ml of THF and 0.40 g of 3-fluoro-4-(2-propynyloxy)benzoyl chloride were added 0.45 g of cyclohexylmethylamine and 0.50 g of triethylamine in order at room temperature. The mixture obtained was stirred at room temperature for 1 hour. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.35 g of N-cyclohexylmethyl-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 22 of the present invention) represented by the formula:
Reaction SMILES: Cl[CH2:2][CH:3]([OH:13])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[N+:10]([O-:12])=[O:11].[OH-].[Na+]>>[N+:10]([C:6]1[N:5]([CH2:4][C@H:3]2[CH2:2][O:13]2)[CH:9]=[CH:8][N:7]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1nccn1CC(O)CCl
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1nccn1C[C@H]1CO1

Procedure:
Alternatively, reaction of 0.56 g of (S)-(+)-(α-(chloromethyl)-2-nitro-1H-imidazole-1-ethanol with 3 mL of 10% aqueous sodium hydroxide at 25° C. for 30 minutes followed by further processing as above gives 0.3 g of the product.
Reaction SMILES: [NH2:1][CH:2]([CH2:15][CH2:16][CH3:17])[CH2:3][O:4][C:5]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[O:7][N:6]=1.[CH:18](OC(=O)C)=[O:19].[OH-].[Na+]>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[O:7][N:6]=[C:5]([O:4][CH2:3][CH:2]([NH:1][CH:18]=[O:19])[CH2:15][CH2:16][CH3:17])[C:9]=2[CH:10]=1
Reactant: CCCC(N)COc1noc2ccc(Cl)cc12
Reactant: CC(=O)OC=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCC(COc1noc2ccc(Cl)cc12)NC=O

Procedure:
To a solution of 1 g of 3-(2-aminopentyloxy)-5-chloro-1,2-benzoisoxazole in 10 ml of methylene chloride is added 0.42 g of acetic formic anhydride with ice-cooling, and they are subjected to reaction at room temperature for one hour. The solvent is removed by distillation under reduced pressure, and water and ethyl acetate are added to the residue obtained, and the pH is adjusted to 8 with a 20% (w/w) aqueous sodium hydroxide solution. After shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure, to obtain 1.1 g of colorless, crystalline 5-chloro-3-(2-formylaminopentyloxy)-1,2-benzoisoxazole having a melting point of 107.2°-108.3° C.