Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[OH:15][C:16]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:22]([C:16]1([OH:15])[CH2:21][CH2:20][N:19]([CH2:2][C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)=[O:4])[CH2:18][CH2:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1Cc2cc(C(=O)CN3CCC(O)(Cc4ccccc4)CC3)ccc2N1

Procedure:
A mixture of 5-(chloroacetyl)-2(1H,3H)-indolone (2.05 g, 9.78 mmol), 4-hydroxy-4-benzylpiperidine (1.87 g, 9.78 mmol), potassium carbonate (2.97 g, 21.49 mmol), and potassium iodide (0.08 g, 0.48 mmol) in acetonitrile (200 ml) was refluxed overnight. The reaction was cooled and filtered through a celite™ pad. The filtrate was concentrated to give an orange foam which was flash chromatographed on silica gel with ethyl acetate elution. This afforded 0.79 g of oily yellow solid product. NMR 9.41 (br s, 1H), 7.91 (d, J=8 Hz, 1H), 7.86 (s, 1H), 7.28-7.14 (m, 5H), 6.90 (d, J=8 Hz, 1H), 3.76 (s, 2H), 3.52 (s, 2H), 2.78-2.73 (m, 4H), 2.43 (t, J=10.5 Hz, 2H), 1.86-1.76 (m, 2H), 1.50 (br d, J=12 Hz, 2H), 1.36 (br s, 1H). IR(KBr) 2920, 2815, 1710, 1685, 1615, 1240, 1115. FAB HRMS calcd for C22H25N2O3 (MH+): 365.1867. Observed m/e: 365.1883.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.[C:28]([O:32][C:33]([N:35]1[CH2:41][CH2:40][C:39]2[C:42]([NH:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([C:55](O)=[O:56])=[C:51]([F:58])[CH:50]=3)=[C:43]([Cl:46])[CH:44]=[CH:45][C:38]=2[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[C:28]([O:32][C:33]([N:35]1[CH2:41][CH2:40][C:39]2[C:42]([NH:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([C:55](=[O:56])[NH:4][CH:1]([CH3:3])[CH3:2])=[C:51]([F:58])[CH:50]=3)=[C:43]([Cl:46])[CH:44]=[CH:45][C:38]=2[CH2:37][CH2:36]1)=[O:34])([CH3:30])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(NCc3ccc(C(=O)O)c(F)c3)c2CC1
Reactant: CC(C)N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Add isopropylamine (0.15 mL, 1.8 mmol), HOBT (0.24 g, 1.8 mmol), diisopropylethylamine (0.63 mL, 3.6 mmol) and EDC (0.34 g, 1.8 mmol) to a mixture of 3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.403 g, 0.9 mmol) in anhydrous THF (11.8 mL) at room temperature. Stir overnight at room temperature and partition the mixture between EtOAc (250 mL) and saturated aqueous NaHCO3 (100 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g RediSep® column) eluting with hexane/EtOAc (19:1 to 1:1 gradient over 30 min; 50 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a thick colorless oil (0.439 g, 100%). MS (ES+) m/z: 490.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH:25]([OH:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>CO.C(Cl)Cl.C(#N)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[CH3:34][O:27][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[N:17]1[CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CCN(c2ccc(Cl)cc2)CC1
Agent: N
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: COC1c2ccccc2C(=O)N1CCCN1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 5 h
Yield: 169.2 %

Procedure:
The same procedure is followed as in Example 2, but starting from an agitated solution of 2-[3-(4-(4-chlorophenyl)-1-piperazinyl)propyl-3-hydroxy-1-isoindolinone (4.8 g) in methanol (115 cc) to which 22.6 cc of concentrated sulphuric acid is added at a temperature close to 20° C. and in the course of 10 minutes. Agitation is continued for 5 hours at a temperature close to 65° C. After cooling the solution to a temperature close to 0° C., 55 cc of a 33% aqueous solution of ammonia is added in the course of 1 hour. The precipitate formed is filtered and washed with methanol (50 cc). The filtrate is diluted with distilled water (200 cc) and 33% aqueous solution of ammonia (50cc), and extracted with methylene chloride (3×200 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (20 cc) and the solution is poured onto silica (500 g) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (98.5-1.5 by volume). The first 100 cc are eliminated and the next 630 cc are evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in acetonitrile (30 cc). A solution of oxalic acid (0.63 g) in acetonitrile (15 cc) is added and agitation is continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 2.9 g of 3-methoxy-2-[3-(4-(4-chlorophenyl)-1-piperazinyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 200° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12]Br.[NH3:15]>CO.[NH4+].[OH-]>[CH3:11][O:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:2])[NH:15][CH2:12]2
Reactant: N
Reactant: COC(=O)c1ccc(OC)cc1CBr
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)CNC2=O

Procedure:
2-Bromomethyl-4-methoxy-benzoic acid methyl ester, 2% ammonia in MeOH (4 mL) and NH4OH (1.5 mL) were stirred for at 18 hours at room temperature. The reaction was partitioned between CH2Cl2 and water and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford a white solid (151 mg). 1H NMR (300 MHz, CDCl3): δ 7.80 (d, 2H), 7.02 (dd, 1H), 6.97 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:21]#[N:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([Cl:23])[CH:11]=1.O1C2C=CC=CC=2N=[C:25]1C1C=CC(CC#N)=C(Cl)C=1.BrCCCCCBr>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:21]#[N:22])[CH2:25][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([Cl:23])[CH:11]=1
Reactant: N#CC1(c2ccc(-c3nc4ccccc4o3)cc2Cl)CCCC1
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)cc1Cl
Agent: BrCCCCCBr
Product: N#CC1(c2ccc(-c3nc4ccccc4o3)cc2Cl)CCCCC1

Procedure:
Utilizing the general procedure outlined for 1-[4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]cyclopentanecarbonitrile, [4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]acetonitrile (400 mg, 1.5 mmol) and 1,5-dibromopentane (250 μL, 1.8 mmol) reacted to afford the desired 1-[4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]cyclohexanecarbonitrile as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.22 (d, 1H), 8.06 (d, 1H), 7.68–7.73 (m, 1H), 7.51–7.55 (m, 2H), 7.28–7.35 (m, 2H), 2.49 (d, 2H), 1.73–2.00 (m, 8H). MS (ESI) 337 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[C:1]([C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7]([O:9][CH3:17])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 2-tert-butyl-5-nitrobenzoic acid (120 mg, 0.53 mmol) and K2CO3 (147 mg, 1.1 mmol) in DMF (5.0 mL) was added CH3I (40 μL, 0.64 mmol). The reaction mixture was stirred at room temperature for 10 min, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After filtration, the filtrate was concentrated to give methyl 2-tert-butyl-5-nitrobenzoate, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=2.6 Hz, 1H), 8.17 (t, J=1.8 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 4.11 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: C1C=CC(O[C:8](OC2C=CC=CC=2)=[N:9][C:10]#[N:11])=CC=1.[CH:19]1([CH2:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[NH:27]1[CH:31]=[C:30]([CH2:32][CH2:33][CH2:34][NH2:35])[N:29]=[CH:28]1>C(#N)C>[C:10]([NH:9][C:8]([NH:35][CH2:34][CH2:33][CH2:32][C:30]1[N:29]=[CH:28][NH:27][CH:31]=1)=[N:26][CH2:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)#[N:11]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: NCCCc1c[nH]cn1
Reactant: NCC1CCCCC1
Solvent: CC#N
Product: N#CNC(=NCC1CCCCC1)NCCCc1c[nH]cn1

Procedure:
5 mmol of diphenyl N-cyanocarbonimidate are stirred with 5 mmol of cyclohexylmethylamine in 20 ml of acetonitrile for 2 h at room temperature. 5 mmol of 3-(1H-imidazol-4-yl)propanamine are then added and the mixture is brought to reflux for 8 h. The solution is concentrated under vacuum until dryness and the residue taken up in 5% acetic acid and washed with diethyl ether. After having been basified, the solution is extracted several times with dichloromethane. The combined and concentrated organic phases are purified by chromatography. The title compound is obtained, after concentration, in the form of a dry foam from diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[C:4]=1[C:14]([F:17])([F:16])[F:15].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]2[C:14]([F:16])([F:15])[F:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(C)cccc2c1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(CBr)cccc2c1C(F)(F)F
Yield: 106.5 %

Procedure:
A suspension of 2-methoxy-5-methyl-1-(trifluoromethyl)naphthalene (1.2 g, 5.0 mmol), N-bromosuccinimide (1.07 g, 6.0 mmol) and benzoyl peroxide (20-30 mg) in carbon tetrachloride (10 mL) was heated at reflux for 1.5 hr. The residual solid in the reaction mixture was removed by filration, and the collected solid on the filter was washed with methylene chloride. The combined filtrates were washed with water, dried (MgSO4) and evaporated to give 1.7 g of 5-(bromomethyl)-1-(trifluoromethyl)-2-methoxynaphthalene (IX, R=CH3 and R1 =CH2Br) which was used in the next step without purification. Crystallization of a sample from hexane furnished pure 5-(bromomethyl)-1-trifluoromethyl-2-methoxynaphthalene having mp 97°-99° C.; nmr (CDCl3) δ 3.95 (s, 3H), 4.85 (s, 2H), 7.7 (m, 5H); ir (CHCl3) 1265, 1125 cm-1 ; uvλmax (MeOH) 339 nm (ε 3,510), 326 (3,280), 300 (7,230), 288 (7,150), 229 (44,150); Anal Calcd for C13H10BrF3O: C, 48.93% H, 3.16%; Found: C, 48.88% H, 3.14%.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][C:17](=O)[CH2:18][CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:17]([C:18]1([CH3:19])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH3:16]
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 2-butanone (1.0 mL), p-toluenesulfonic acid monohydrate (0.0096 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 1 h at 70° C. The reaction mixture was poured into aqueous sodium hydrogen carbonate (200 mL). Extraction with ethyl acetate (200 mL, 100 mL), washing with aqueous sodium hydrogen carbonate, drying over magnesium sulfate, filtration and concentration at reduced pressure gave a residue, which was triturated with dichloromethane/ethyl acetate (1:1, 6 mL), and the precipitate was collected by filtration to afford the title compound (0.095 g, 69%) as a yellow solid:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[CH3:20][S:21][C:22]1[N:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[N:26][CH:27]=1>>[CH:28]([OH:30])=[O:29].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[N:23][C:22]([S:21][CH3:20])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: CSc1cnc(C(=O)O)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Product: CSc1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)COCC3(F)F)c2)cn1
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A9B) and 5-methylsulfanyl-pyrazine-2-carboxylic acid (prepared according to Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016) yielded the title compound as an off-white solid. MS (ISP): m/z=426.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)#[N:2].[OH:42]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)(=[O:42])[NH2:2]
Reactant: OO
Reactant: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide (0.34 g, 0.57 mmol) in DMSO (15 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.56 g, 16 mmol), then aqueous solution (1N) of NaOH (5.7 mL, 5.7 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50%-100% EtOAc in CH2Cl2) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as a off white solid (Yield, 0.22 g, 63%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.[O:34]1[CH2:39][CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35]1>>[O:34]1[CH2:39][CH2:38][CH:37]=[C:36]([C:12]2[N:11]=[C:10]([F:23])[C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:30]2[C:25]([F:24])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:7][CH:6]=4)[CH2:35]1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(CCO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(C2=CCCOC2)nc1F

Procedure:
The title compound was synthesized by steps analogous to those described in method A1 above, but using intermediate 15B, 2-fluoropyridin-3-ylboronic acid and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[O:15]1[CH2:16][CH2:17][O:18][C:19]2[CH:24]=[C:23]([C:25]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=4)[N:1]=3)[CH:22]=[CH:21][C:20]1=2
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc2nc(-c3ccc4c(c3)OCCO4)[nH]c(=O)c2cc1OC
Yield: 69 %

Procedure:
2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,5-dimethoxybenzamide and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxy-quinazolin-4(3H)-one (180 mg, 69%) was isolated as a light yellow solid. Selected data: MS (m/z): 341.03; MP 316.4-318.2° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:39]=[CH:38][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=3)[S:16][CH2:15][C:14]2([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH3:27])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49].[Cl-].[NH4+]>C(Cl)Cl>[CH3:47][S:48]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:39]=[CH:38][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=3)[S:16][CH2:15][C:14]2([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH3:27])=[CH:7][CH:6]=1)(=[O:50])=[O:49]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2CCCOc2ccc(OCCO)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2CCCOc2ccc(OCCOS(C)(=O)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
4-{3-[4-(2-Hydroxyethoxy)phenoxy]propyl}-7-methoxymethoxy-3-[4-(methoxymethoxy)phenyl]-3-methylthiochroman (7) prepared in Step 5 (45.6 mg, 0.082 mmol) was dissolved in CH2Cl2 (0.4 ml), which was then cooled down to 0° C. Triethylamine (23 μl, 0.17 mmol) and methanesulfonylchloride (16 μl, 0.21 mmol) were added thereto, and the mixture was stirred for 30 minutes. Saturated aqueous ammonium chloride solution was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and subjected to silica gel column chromatography to give 4-{3-[4-(2-methanesulfonyloxyethoxy)phenoxy]propyl}-7-methoxymethoxy-3-[4-(methoxymethoxy)phenyl]-3-methylthiochroman (8) (49.2 mg, yield 95%) as a colorless oily substance.
Reaction SMILES: C(=O)([O-])O.[Na+].CS(C)=O.Cl.[OH:11][NH2:12].[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]#[N:33])=[N:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C.O>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32](=[N:12][OH:11])[NH2:33])=[N:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)nc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C(N)=NO)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Process 2: Sodium hydrogen carbonate (2.02 mg, 24.0 mmol) was added to a dimethyl sulfoxide (20 mL) solution of hydroxyl amine hydrochloride (1.42 g, 20.4 mmol), and the reaction solution was stirred at 40° C. for 1 hour. The reaction solution was added a dimethyl sulfoxide (3 mL) solution of 2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}benzonitrile (430 mg, 0.987 mmol), and stirred at 90° C. for 19 hours. The reaction solution was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residues obtained were subjected to silica gel column chromatography (ethyl acetate), to obtain 2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}-N′-hydroxybenzimidamide (430 mg, 93%) as a white solid.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:34])([F:33])[C:17]1[C:27]2[S:26][C:25]3[CH:28]=[CH:29][CH2:30][CH2:31][C:24]=3[NH:23][C:22](=O)[C:21]=2[CH:20]=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[F:15][C:16]([F:34])([F:33])[C:17]1[C:27]2[S:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[NH:23][C:22](=[S:2])[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1NC2=C(C=CCC2)Sc2c1cccc2C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1cccc2c1Sc1ccccc1NC2=S
Yield: 80.8 %

Procedure:
Phosphorus pentasulphide (0.6 g, 2.5 mmol) was added to a stirred solution of 4-trifluoromethyl-9,10-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.59 g, 2 mmol) in pyridine (20 ml). The mixture was heated under reflux for 6.5 hr and then at room temperature overnight before hot water (40 ml) added. Filtration and recrystallisation from ethanol gave the title compound as fine yellow needles (0.503 g, m.p. 265°-267° C., Rf 0.65, petrol/EtOAc 1:1).