Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1O[C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[N:3]=1.O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.CCOCC>[NH2:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=1[C:6]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:8]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COc1ccc2nc(C)oc(=O)c2c1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(N)c(C(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-6-(methyloxy)-4H-3,1-benzoxazin-4-one (for a preparation see Reference compound A) (40.0 g, 0.21 mol) in a toluene/ether (2/1) mixture (760 ml) at 0° C. was added dropwise a solution of 4-chlorophenylmagnesium bromide (170 ml, 1M in diethyl ether, 0.17 mol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h before being quenched with 1N HCl (200 ml). The aqueous layer was extracted with EtOAc (3×150 ml) and the combined organics were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was then dissolved in ethanol (400 ml) and 6N HCl (160 ml) was added. The reaction mixture was refluxed for 2 h before being concentrated to one-third in volume. The resulting solid was filtered and washed twice with ether before being suspended in EtOAc and neutralised with 1N sodium hydroxide. The aqueous layer was extracted with EtOAc (3×150 ml) and the combined organics were washed with brine (150 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound was obtained as a yellow solid (39 g, 88% yield); LC/MS (Method D): m/z 262 [M+H]+, Rt 2.57 min.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[CH3:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([CH2:15][CH:16]([C:21]([CH3:23])=O)[C:17](OC)=[O:18])=[CH:13][CH:12]=1.O>CO>[CH3:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([CH2:15][C:16]2[C:17](=[O:18])[NH:4][C:2]([CH3:3])=[N:5][C:21]=2[CH3:23])=[CH:13][CH:12]=1
Reactant: COC(=O)C(Cc1ccc(OC)cc1)C(C)=O
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(Cc2c(C)nc(C)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of methyl acetoacetate (3.2 mL) 4-methoxy-benzyl chloride (4.1 mL), lithium bromide (2.6 g) and diisopropylethylamine (5.2 mL) in tetrahydrofuran (60 mL) was heated under reflux for 15 hours. After the reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give methyl 2-(4-methoxybenzyl)acetoacetate. To a suspension of acetoamidine hydrochloride (2.0 g) in methanol (60 mL) was added sodium methoxide (28% solution in methanol, 2.6 mL), and the mixture was stirred for 5 minutes at room temperature. To the reaction mixture was added a solution of methyl 2-(4-methoxy-benzyl)acetoacetate in methanol (6 mL), and the mixture was stirred for 48 hours at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue was added ethyl acetate, and the resulting precipitated crystals were collected by filtration and dried to give 5-(4-methoxybenzyl)-2,6-dimethyl-3H-pyrimidin-4-one (0.54 g).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([OH:36])=O)=[O:30])[CH:11]=1)=[O:9].CCN=C=NCCCN(C)C.Cl.[CH2:57]([N:59]([CH2:64][CH3:65])[CH2:60][CH2:61][NH:62][CH3:63])[CH3:58]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:57]([N:59]([CH2:64][CH3:65])[CH2:60][CH2:61][N:62]([CH3:63])[C:34](=[O:36])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:43])([F:1])[F:44])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)=[O:30])[CH:32]=1)[CH3:58]
Reactant: CCN(CC)CCNC
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
Into a 10-mL round bottom flask, was placed a solution of 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid (100 mg, 0.17 mmol, 1.00 equiv) in dichloromethane (5 mL), EDC.HCl (63.75 mg, 0.33 mmol, 2.00 equiv), 4-dimethylaminopyridine (40.5 mg, 0.33 mmol, 2.00 equiv), N1,N1-diethyl-N2-methylethane-1,2-diamine (64.8 mg, 0.56 mmol, 3.00 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 3×70 mL of NH4Cl (aq). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (150 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 47.8 mg (34%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.36 (s, 1H), 9.57 (t, 1H), 9.28 (s, 1H), 8.90 (d, J=5.1 Hz, 1H), 8.30 (m, 2H), 7.98 (d, J=7.2 Hz, 2H), 7.84 (d, J=4.8 Hz, 1H), 7.65 (m, 7H), 7.28 (d, J=8.4 Hz, 1H), 4.66 (d, J=6.0 Hz, 2H), 3.82 (m, 2H), 3.31 (m, 9H), 2.97 (s, 4H), 1.71 (m, 6H), 1.24 (m, 6H). MS (ES, m/z): 715 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[OH-].[Na+].[CH2:27]([CH2:30][O:31]C)[O:28]C>>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:27](=[O:28])[CH2:30][OH:31])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Reactant: COCCOC
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNC(=O)CO)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (171 mg) in dimethoxyethane (3 mL) was added 1 N aqueous sodium hydroxide solution (0.72 ml), and the mixture was stirred overnight. The solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexane) to give the title compound (157 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH3:14])([CH3:13])[C:5]2=[O:15].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=1)[C:7](=[O:12])[C:6]([CH3:13])([CH3:14])[C:5]2=[O:15]
Reactant: CC1(C)C(=O)Nc2ccc(Br)cc2C1=O
Reactant: OB(O)c1ccc(F)cc1
Product: CC1(C)C(=O)c2cc(Br)ccc2N(c2ccc(F)cc2)C1=O
Yield: 75.5 %

Procedure:
6-bromo-3,3-dimethylquinolin-2,4-(1H,3H)-dione (1.0 g) and 4-fluorophenyl-boronic acid (1.04 g) were treated in the same manner as described in Reference Example 1(2) to obtain 6-bromo-1-(4-fluorophenyl)-3,3-dimethylquinolin-2,4-(1H,3H)-dione (1.02 g) as a colorless solid.
Reaction SMILES: [CH2:1]([C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20](=[O:26])[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(BC(C(C)C)C)(C(C)C)C.C1C[O:48]CC1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C@:4]2([CH2:1][CH2:2][CH2:3][OH:48])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[C:20](=[O:26])[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)[CH3:12])[CH2:6][CH2:5]2)=[CH:28][CH:29]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3cccn(C)c3=O)cc2)C(=O)O1
Agent: CC(C)C(C)BC(C)C(C)C
Product: C[C@@H](c1ccc(-c2cccn(C)c2=O)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (13.3 mg, 0.030 mmol) in dry THF (1.5 mL) was cooled to 0° C. Disiamyl borane (0.5M in THF, 500 μL, excess) was added. After 10 min, the mixture was warmed to it and stirred for 1 h. The mixture was cooled to 0° C. again, quenched with water (1 mL) and NaBO3 (10 mg). The mixture was concentrated and purified by prep HPLC to afford (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (4.2 mg, 30% yield). LC-MS Method 1 tR=1.33 min, m/z=487 (M+1); 1H NMR (CD3Cl) δ 7.47 (dd, 1H), 7.38 (m, 3H), 7.24 (m, 2H), 7.07 (t, 2H), 6.96 (d, 2H), 6.39 (t, 1H), 5.65 (m, 1H), 4.26 (t, 1H), 3.66 (s, 3H), 2.91 (m, 1H), 2.40-2.14 (m, 3H), 1.54 (d, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=[CH:9][C:8]([Cl:20])=[CH:7][CH:6]=2.[C:21](#[N:24])[CH:22]=[CH2:23]>>[ClH:18].[Cl:20][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([CH2:2][NH:1][CH2:23][CH2:22][C:21]#[N:24])=[C:11]2[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19]
Reactant: C=CC#N
Reactant: NCc1[nH]c2ccc(Cl)cc2c1-c1ccc(Cl)cc1Cl
Product: Cl
Product: N#CCCNCc1[nH]c2ccc(Cl)cc2c1-c1ccc(Cl)cc1Cl

Procedure:
Treat 2-aminomethyl-5-chloro-3-(2,4-dichlorophenyl)indole with acrylonitrile in the same manner as in Example 1 to obtain the title compound which melts at 209°-210°C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH2:10])(C)(C)C.CCN(C(C)C)C(C)C.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[NH2:10][CH2:9][CH2:8][NH:7][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[Br:21])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NCCNS(=O)(=O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
To solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (208 mg, 1.3 mmol) in CH2Cl2 (20 mL) was added DIEA (300 μL, 1.72 mmol) at 0° C., followed by the addition of 2-bromo-benzenesulfonyl chloride (383 mg, 1.5 mmol). After it was stirred at 0° C. for 1 h and at the room temperature for another 16 h, the reaction mixture was evaporated thoroughly. The residue was diluted with 20% TFA in CH2Cl2 (10 mL), stirred for 3 h at the room temperature, and evaporated. Chromatography of the residual crude with CH2Cl2/MeOH/28% aqueous NH4OH (90:10:1) afforded the title compound (313 mg, 86%). 1H NMR (DMSO-d6) δ 2.86 (t, J=8 Hz, 2H), 3.04 (t, J=8 Hz, 2H), 7.55-7.65 (2H), 7.89 (d, J=8 Hz, 1H), 8.01 (d, J=8 Hz, 1H); ESI-MS m/z 279.1 (MH+).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[C:15]([NH2:17])[C:14]([Cl:18])=[C:13]([Cl:19])[N:12]=1)=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1COCC1>[NH2:17][C:15]1[CH:16]=[C:11]([C:9]2[O:10][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)[N:12]=[C:13]([Cl:19])[C:14]=1[Cl:18]
Reactant: Nc1cc(C(=O)Nc2ccccc2O)nc(Cl)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1cc(-c2nc3ccccc3o2)nc(Cl)c1Cl
Yield: 80.7 %

Procedure:
A solution of N-(2-hydroxyphenyl)-4-amino-5,6-dichloropyridine-2-carboxamide (1.80 g, 5.7 mmol) (obtained from N-(2-hydroxyphenyl)-2-(4,5,6-trichloro)pyridinecarboxamide via azide formation followed by sodium borohydride reduction) and p-toluenesulfonic acid (0.2 g) in toluene (50 mL) was refluxed overnight under nitrogen with a Dean-Stark trap. After cooling, the reaction mixture was diluted with ethyl acetate and THF, and the organic mixture washed with saturated aqueous sodium bicarbonate. The organic layer was dried, concentrated, and the residue triturated with petroleum ether/diethyl ether to provide 4-amino-2,3-dichloro-6-(2-benzoxazolyl)pyridine (1.30 g, 4.6 mmol). 1H NMR (DMSO-d6): δ 7.82 (d, 2H), 7.66 (s, 1H), 7.55-7.38 (m, 2H), 7.18 (br.s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][CH:26]([CH2:35][CH2:36][CH3:37])[CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1.C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>O.CN(C)C=O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:14](=[O:16])[NH:34][CH:31]2[CH2:32][CH2:33][N:28]([CH2:27][CH:26]([F:25])[CH2:35][CH2:36][CH3:37])[CH2:29][CH2:30]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(F)CN1CCC(N)CC1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(F)CN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(Cc3ccccc3)C[C@H]2C)CC1
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
A mixture of (3R*,4S*)-1-benzyl-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Example 1j (300 mg, 0.9 mmol), the chiral form of 1-(2-fluoropentyl)piperidin-4-amine obtained in Example 1d (182 mg, 0.967 mmol), triethylamine (0.376 ml, 2.7 mmol), PyBOP (656 mg, 1.26 mmol) and N,N-dimethylformamide (4.5 ml) was stirred at room temperature for 61 hours and 30 minutes. Triethylamine (0.207 ml, 1.49 mmol) and PyBOP (360 mg, 0.69 mmol) were further added, followed by stirring for four hours and 30 minutes. Water was added to the reaction mixture, which was extracted with ethyl acetate twice. The organic layer was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (161 mg, yield 35.5%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1

Procedure:
Prepared from the product of Example 15 and morpholine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([N:7]1[C:6]2[CH:11]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][CH2:8]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)NCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)N(S(C)(=O)=O)CCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
6-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine (1.49 g, 10 mmol) was dissolved in dichloromethane (50 mL) and treated with triethylamine (1.14 g, 11 mmol) followed by the dropwise addition of methanesulfonyl chloride (1.26 g, 11 mmol). The mixture was stirred at ambient temperature for 18 h then evaporated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The phases were separated and the organic phase washed with water, saturated brine, dried (MgSO4) and evaporated to dryness under reduced pressure to give the title compound (2.09 g, 93%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22](Cl)=[O:23]>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)=[O:23]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Product: O=C1N=C(NC(=O)c2ccc3ccccc3c2)N=C2N=CC=C12

Procedure:
Using 2-aminopyrrolo(2,3-d)pyrimidin-4-one and 2-naphthoyl chloride, the above-identified compound is produced by the same procedure as Reference Example 2.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[Na+].C(O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:30](=[S:32])=[S:31]>>[CH2:22]([S:32][C:30]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: BrCc1ccccc1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a mixture of (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (5.4 g), 2N NaOH (25 ml) and 50% ethanol (70 ml) is added dropwise carbon disulfide (1.5 ml) at room temperature. The mixture is stirred at room temperature for 30 minutes, and thereto is added dropwise benzyl bromide (3.5 ml), and the mixture is further stirred at the same temperature for 3 hours and then distilled to remover the solvent. To the residue is added water, and the mixture is extracted with ether. The aqueous layer is acidicied with 10% HCl, and extracted with ethyl acetate. The extract is washed with water, dried and distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent, chloroform:methanol=20:1) to give the title compound (4.8 g, 50%) as pale yellow powder.
Reaction SMILES: [I:1][C:2]1[CH:7]=C(N)C=[CH:4][C:3]=1[C:9]1[CH:15]=[CH:14][C:12](N)=[CH:11][C:10]=1[I:16].F[B-](F)(F)F.[H+].N([O-])=[O:24].[Na+].[C:27]([OH:30])(=O)[CH3:28]>>[OH:24][C:12]1[CH:14]=[CH:15][C:9]([C:3]2[CH:4]=[CH:28][C:27]([OH:30])=[CH:7][C:2]=2[I:1])=[C:10]([I:16])[CH:11]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(-c2ccc(N)cc2I)c(I)c1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Product: Oc1ccc(-c2ccc(O)cc2I)c(I)c1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Glacial acetic acid (200 ml) and 2,2'-diiodobenzidine (20.0 g, 49 mmol) were stirred at room temperature for 20 minutes, and then 100 ml 48% tetrafluoroboric acid was added to the solution. After 30 minutes, the acidic solution was cooled to -5° C., and a sodium nitrite solution (7.2 g NaNO2 in 80 ml water) was slowly added to maintain the temperature below 0° C. The reaction was stirred for 1 hour at 0° C., and the precipitate which formed was filtered and dried for 18 hours under vacuum. The dried product was added over a period of 1 hour to a solution of 2 L water containing 30 ml 85% phosphoric acid at 75° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=2[N:7]=1.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[S:10][C:9]([CH2:11][OH:12])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (3.2 g, 11.31 mmol) in anhydrous THF (100 mL) and IMS (70 mL) was added sodium borohydride (0.47 g, 12.42 mmol) and the resulting mixture stirred at RT for 2 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was isolated, dried (MgSO4) and concentrated in vacuo. The resultant residue was triturated with water to give the title compound as a white solid (2.9 g, 91%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 835.7 %

Procedure:
2 g (7 mmol) of 4-(4-fluoro-phenoxy)-piperidine 1-carboxylic acid tert-butyl ester was solvated in dichloromethane (12 mL) and trifluoroacetic acid was added at 0° C. (6.17 mL, 54 mmol). The mixture was stirred at room temperature overnight. NaHCO3 was slowly added until pH 9 and the mixture extracted 3 times with dichloromethane and ethyl acetate. The solvent was evaporated to yield 1.81 g (58.5 mmol, 85%) of a white solid that was used without purification on the next steps. MS (m/e): 196.3 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[C:8]3[CH:9]=[C:10]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11](=O)[NH:12][C:13]=3[CH:14]=[CH:15][C:6]2=[N:5][N:4]=1)[CH3:2].O=P(Cl)(Cl)[Cl:25]>C(#N)C>[Cl:25][C:11]1[N:12]=[C:13]2[C:8](=[CH:9][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:7]1[C:3]([CH2:1][CH3:2])=[N:4][N:5]=[C:6]1[CH:15]=[CH:14]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nnc2ccc3[nH]c(=O)c(-c4ccccc4)cc3n12
Solvent: CC#N
Product: CCc1nnc2ccc3nc(Cl)c(-c4ccccc4)cc3n12
Temperature: 150 °C

Procedure:
A mixture of 1-ethyl-8-phenyl[1,2,4]triazolo[4,3-a]-1,5-naphthyridin-7(6H)-one (7-4) (70 mg, 0.241 mmol) and POCl3 (3.0 mL, 32.2 mmol) in acetonitrile (2 mL) was heated under microwave irradiation at 150° C. for 1.5 hours. The solvent was removed under reduced pressure, and the residue was diluted with CHCl3, washed with sat. NaHCO3 solution, dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 7-chloro-1-ethyl-8-phenyl[1,2,4]triazolo[4,3-a]-1,5-naphthyridine (7-5) as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:10])=[CH:4][C:3]=1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C.[C:26]([O:29][CH2:30][C:31](Cl)=[O:32])(=[O:28])[CH3:27]>CN(C=O)C>[C:26]([O:29][CH2:30][C:31]([N:14]1[CH2:13][CH2:12][CH:11]([C:3]2[CH:4]=[C:5]([I:10])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[CH2:16][CH2:15]1)=[O:32])(=[O:28])[CH3:27]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(F)c(C2CCNCC2)cc1I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1I

Procedure:
A stirred solution of 4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidine (50 mg; 0.149 mmol) in DMF (1.2 mL) under N2 was treated with N,N-diisopropylethylamine (26 μL; 0.149 mmol), followed by acetoxyacetyl chloride (16 μL, 0.149 mmol). The resultant solution was stirred at room temperature for 5 h. The reaction was partitioned between EtOAc (25 mL) and saturated NaHCO3 (25 mL). The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic fractions were washed with water and brine (25 mL each), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography, eluting with EtOAC/hexanes, to afford 2-[4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidin-1-yl]-2-oxoethyl acetate as a colorless oil. LCMS=435.8 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.52 (d, J=8.2 Hz, 1H), 6.56 (d, J=12.2 Hz, 1H), 4.76 (s, 2H), 4.76-4.70 (m, 1H), 3.85 (s, 3H), 3.76 (br d, J=13 Hz, 1H), 3.17 (t, J=12.6 Hz, 1H), 2.98 (tt, J=12.1, 3.4 Hz, 1H), 2.68 (t, J=12.4 Hz, 1H), 2.20 (s, 3H), 1.90-1.82 (m, 2H), 1.70-1.62 (m, 2H).