Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:12])[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.I[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O.CS(C)=O>[OH:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:1](=[O:12])[N:2]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:3]=[CH:4]2
Reactant: COc1ccc(I)cc1
Reactant: Oc1ccc2c(O)nccc2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-n2ccc3cc(O)ccc3c2=O)cc1
Temperature: 130 °C

Procedure:
6-Methoxyisoquinoline-1-ol was prepared as described above, followed by deprotection of the methoxy group using chlorobenzene and boron tribromide (6 equivalents, neat) added dropwise under argon atmosphere at room temperature, to obtain isoquinoline-1,6-diol (14v). Compound 14v (11.5 mmol) reacted with 4-iodoanisole (4.01 g, 17.13 mmol), copper (I) iodide (0.44 g, 2.28 mmol). L-proline (0.53 g, 4.57 mmol) and anhydrous potassium carbonate (3.16 g, 22.84 mmol) were placed in a dry 250 mL three-necked round-bottomed flask fitted with a stirring bar and reflux condenser. The reaction flask was vacuumed and refilled with dry argon. 50 mL of anhydrous methyl sulfoxide was added via syringe. The reaction mixture was stirred and heated to 130° C. for 20 hours. 50 mL of water was added to quench the reaction, and solid precipitated out. The solid was filtered, washed with water (2×20 mL) and dried in air. This solid was purified by flash column chromatography (silica gel, ethyl acetate) to give 6-hydroxy-2-(4-methoxyphenyl)isoquinolin-1(2H)-one (14w) a brown solid product. Compound 14w (1.8 mmol) was placed in a dry 250 mL single-necked round-bottomed flask fitted with a stirring bar and septa. Acetonitrile (10 mL) was added via a syringe under argon atmosphere at room temperature. N-Bromosuccinimide or NBS (0.33 g, 1.87 mmol) was added portionwise under argon atmosphere at room temperature. The reaction mixture was allowed to stir at room temperature for 2 hours. 20 mL of saturated sodium bicarbonate solution was then added. The mixture was extracted with ethyl acetate (3×10 mL). Organic layers were separated, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, hexanes/EtOAc=2/3 v/v) to give white solid of 4-bromo-6-hydroxy-2-(4-methoxyphenyl)isoquinolin-1(2H)-one (14xME)
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:16]=2[C:15](=[O:23])[N:14]([C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH3:25])[C@@H:13]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[OH:40])[C:12]1=[O:41])(C)(C)C.ClC1C=CC([C@@H]2N([C@@H](C3C=CC(Cl)=CC=3)C)C(=O)C3C=CC=CC=3N(CCCCC(O)=O)C2=O)=C(O)C=1>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@H:13]2[N:14]([C@@H:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH3:25])[C:15](=[O:23])[C:16]3[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:17]=3[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:42])=[O:5])[C:12]2=[O:41])=[C:34]([OH:40])[CH:35]=1
Reactant: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2N(CCCCC(=O)OC(C)(C)C)C(=O)[C@@H]1c1ccc(Cl)cc1O
Agent: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2ccccc2N(CCCCC(=O)O)C(=O)[C@@H]1c1ccc(Cl)cc1O
Product: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2N(CCCCC(=O)O)C(=O)[C@@H]1c1ccc(Cl)cc1O

Procedure:
The title compound was synthesized from 5-[(3S)-3-(4-chloro-2-hydroxyphenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-iodo-2,5-dioxo-1,4-benzodiazepin-1-yl]valeric acid tert-butyl ester following the procedure for example 1, step b: 1H NMR (400 MHz, Cl3CD) δ 7.99 (d, J=2.1 Hz, 1H), 7.42 (m, 3H), 7.22 (d, J=8.5 Hz, 2H), 6.62 (d, J=8.6 Hz, 1H), 6.50 (d, J=1.9 Hz, 1H), 6.34 (m, 2H), 6.09 (m, 1H), 5.26 (s, 1H), 3.87 (m, 1H), 3.74 (m, 1H), 2.39 (m, 2H), 1.75 (m, 7H). Mass spectrum (LCMS, ESI pos.): Calcd for C28H25Cl2IN2O5: 666.02; found 666.6 (M+H); together with 21 mg 5-[(3S)-3-(4-chloro-2-hydroxyphenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-1,4-benzodiazepin-1-yl]valeric acid:
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.[N-:7]=[N+:8]=[N-:9].[Na+].[NH4+].[Cl-]>CO.O>[N:7]([C@@H:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[OH:6])=[N+:8]=[N-:9]
Reactant: [N-]=[N+]=[N-]
Reactant: C1CC2OC2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1CCC[C@H]1O
Yield: 92.5 %

Procedure:
To a soln of cyclopenteneoxide (2.0 g, 23.8 mmol) in CH3OH and H2O (40 mL) (4/1, v/v), were added NaN3 (7.73 g, 119 mmol) and NH4Cl (3.17 g, 59.2 mmol). The resulting mixture was heated to solvent reflux for 18 h then cooled to 23°. The mixture was concentrated and the residue was diluted with EtOAc, washed with H2O, the organic layer was dried over Na2SO4, concentrated to give the desired product (2.8 g, 93%). 1H NMR (CDCl3): δ 4.10 (m, 1H), 3.72 (m, 1H), 2.10 (m, 2H), 1.72-1.60 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.O>[N:16]([CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1)=[N+:17]=[N-:18]
Reactant: O=C1OC(CCl)CN1c1ccc(Cl)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CN(c2ccc(Cl)cn2)C(=O)O1
Yield: 66.4 %

Procedure:
A mixture of 5-(chloromethyl)-3-(5-chloropyridin-2-yl)-1,3-oxazolidin-2-one (204 mg, INTERMEDIATE 1) and sodium azide (107 mg) was heated to 100° C. in 10 ml of dimethylformamide for 15 h. The sample was then diluted with 100 ml of water and extracted with 100 ml of ethyl acetate (3×). The combined organic layers were washed with water (100 ml) and brine (100 ml). They were then dried over sodium sulfate and concentrated in vacuo to provide 139 mg (67%) of the title compound in >95% purity via LC/MS. Mass spectrum (ESI) 254.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:18])[N:11]([CH2:13][C:14]([O:16]C)=[O:15])[CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[C:10](=[O:18])[N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: OC(CBr)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C

Procedure:
A quantity of 1.0 g (3.75 mmol) of methyl [4-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]acetate (prepared according to WO 2007/134862 Example 323A) was dissolved with 796 mg (4.13 mmol) of 3-bromo-1,1,1-trifluoropropan-2-ol in 50 ml of acetone, 1.47 g (4.50 mmol) of caesium carbonate were added at RT, and the mixture was heated under reflux for 16 h. For work-up, it was cooled to RT and admixed with 50 ml of water. It was neutralised by addition of 1M hydrochloric acid and extracted with three times 50 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC [Method 19]. This gave 171 mg (13% of theory) of the target compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].CCN(CC)CC.[CH2:19]([O:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH3:31])[CH2:20][CH3:21].C(Cl)Cl>CN(C=O)C>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:25]([CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:23][O:22][CH2:19][CH2:20][CH3:21]
Reactant: CCCOCCNCCOCCC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCOCCN(CCOCCC)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 72.8 %

Procedure:
To a solution of 1,2-difluoro-4-nitrobenzene (2.94 g, 18.45 mmol) in DMF (30 mL) were added Et3N (3.11 g, 30.75 mmol) and bis(2-propoxyethyl)amine (1.16 g, 6.15 mmol) with stirring. The reaction mixture was heated at 90° C. overnight, then cooled to rt and poured into CH2Cl2 (100 mL). The organic phase was washed with water (100 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as yellow oil (1.47 g, 73%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:25])=[CH:4][CH2:5][CH2:6][C:7]([CH3:24])=[CH:8][CH2:9][CH2:10][C:11]([CH3:23])=[CH:12][CH:13]=[C:14]([CH:20]([CH3:22])[CH3:21])[C:15](OCC)=[O:16].[H-].C([Al+]C(C)C)(C)C.O.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([CH3:25])=[CH:4][CH2:5][CH2:6][C:7]([CH3:24])=[CH:8][CH2:9][CH2:10][C:11]([CH3:23])=[CH:12][CH:13]=[C:14]([CH:20]([CH3:21])[CH3:22])[CH2:15][OH:16]
Reactant: CCOC(=O)C(=CC=C(C)CCC=C(C)CCC=C(C)CCl)C(C)C
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=CCCC(C)=CCCC(C)=CC=C(CO)C(C)C)CCl
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
Ethyl 14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenoate (670 mg, 1.81 mmol) was dissolved in dry toluene (20 ml) under argon atmosphere. To the solution cooled on an ethanol-dry ice bath was added with stirring 1M diisopropyl aluminium hydride in toluene (4 ml). After 30 minutes, disappearance of the starting material was confirmed. Water (1.5 ml) was added to the reaction mixture, the cooling bath was removed, and the stirring was continued. After further stirring with addition of MgSO4 as a drying agent, the mixture was filtered and condensed. The resulting residue was subjected to silica gel column chromatography (solvent: n-hexane/ethyl acetate (12:1)), and relevant fractions gave 14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraen-1-ol (492 mg, 79%).
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)S([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])(=O)=O.[Br:23][C:24]1[C:25]([CH3:36])=[C:26]([CH3:35])[C:27]2[O:31][CH2:30][C:29](=O)[C:28]=2[C:33]=1[CH3:34].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:23][C:24]1[C:25]([CH3:36])=[C:26]([CH3:35])[C:27]2[O:31][CH:30]=[C:29]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:28]=2[C:33]=1[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cc1c(C)c2c(c(C)c1Br)C(=O)CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(Br)c(C)c2c(O[Si](C)(C)C(C)(C)C)coc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Triethylamine (2.15 g, 21.2 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (4.68 g, 17.7 mmol) were sequentially added to a solution of toluene (100 mL) containing 5-bromo-4,6,7-trimethyl-1-benzofuran-3(2H)-one (3.00 g, 11.8 mmol) synthesized in Reference Example 45, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was poured into saturated sodium bicarbonate water, and extraction was performed using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 99:1 to 94/6) to give 4.14 g of the title compound (yield: 95%).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.[CH3:18][NH:19][C:20]([NH:22][C:23]1[S:24][C:25]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[CH:28][C:26]=2[N:27]=1)=[O:21].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[C:10]2[C:2]([C:30]3[CH:29]=[CH:28][C:26]4[N:27]=[C:23]([NH:22][C:20]([NH:19][CH3:18])=[O:21])[S:24][C:25]=4[CH:31]=3)=[CH:3][N:4]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CNC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: Nc1ncnc2c1c(I)cn2C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNC(=O)Nc1nc2ccc(-c3cn(C4CCOCC4)c4ncnc(N)c34)cc2s1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A mixture of 5-iodo-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (402) (100 mg, 0.29 mmol), 1-methyl-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)urea (J-2) (127 mg, 1.3 eq, 0.38 mmol), Pd(PPh3)4 (38 mg, 0.1 eq, 0.03 mmol) and Na2CO3 (2 N, 2 mL) in DME (10 mL) was stirred at reflux for 30 min. under argon. The mixture was cooled to room temperature, and then concentrated in vacuo. Brine (10 mL) was added to the residue and then extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine (10 mL), dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography eluting with MeOH/DCM (1/30) to afford the desired product, 1-(6-(4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-methylurea (403) (60 mg 58% yield) as a white solid. ESI-MS m/z: 424.05 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:21]([O:22][CH3:23])=[CH:20][C:6]2[NH:7][C:8]([S:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=3N)=[N:9][C:5]=2[CH:4]=1.Cl.N([O-])=O.[Na+].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH3:1][O:2][C:3]1[C:21]([O:22][CH3:23])=[CH:20][C:6]2[NH:7][C:8]([S:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=3)=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(N)c(Sc2nc3cc(OC)c(OC)cc3[nH]2)c1
Reactant: c1ccncc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2ccccn2)c(Sc2nc3cc(OC)c(OC)cc3[nH]2)c1

Procedure:
The product of step (b) above (500 mg) was treated with concentrated hydrochloric acid (0.8 ml) and water (0.8 ml) to form a paste. The paste was stirred at 0°-10° and a solution of sodium nitrite (105 mg) in water (0.5 ml) added dropwise. After stirring for 40 minutes the resultant solution was added slowly to pyridine (5 ml) stirred at 80°. The mixture was stirred for a further 40 minutes then concentrated in vacuo. The residue was slurried with 0.880 ammonia and the mixture again concentrated in vacuo. The residue was slurried with water and extracted with ethyl acetate. The ethyl acetate was washed with water and brine, then dried and evaporated to leave a brown gum. Flash chromatography produced the required product as a pale brown solid, MS MW 393 bp 216.
Reaction SMILES: [NH2:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][CH2:6][CH2:7][O:8][N+:9]([O-:11])=[O:10])=[O:4].[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>C(OCC)(=O)C>[CH:14]([NH:17][C:18]([NH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][CH2:6][CH2:7][O:8][N+:9]([O-:11])=[O:10])=[O:4])=[O:19])([CH3:16])[CH3:15]
Reactant: CC(C)(N)C(=O)NCCO[N+](=O)[O-]
Reactant: CC(C)N=C=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)NC(C)(C)C(=O)NCCO[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
1.9 g. 2-Amino-2-methyl-N-(2-nitroxyethyl)-propionic acid amide is dissolved in 10 ml. ethyl acetate and mixed with 1.1 ml. isopropyl isocyanate while cooling with ice-water to 5° to 10° C. The reaction mixture is stirred for 2 hours at 10° C., filtered off with suction and washed with diethyl ether. There is obtained 1.4 g. of the title compound, i.e. 50% of theory; m.p. 120°-122° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].N12CCCN=C1CCCCC2>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=[C:2]([Cl:1])[N:11]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc2nc(Cl)nc(NC3CCN(C(=O)OC(C)(C)C)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (5.12 g, 19.8 mmol, 1.0 equiv) in THF (50 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.34 g, 21.7 mmol, 1.1 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.31 g, 3.25 mL, 21.7 mmol, 1.1 equiv) and the reaction mixture stirred at rt for 16 h. Additional 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 4.3 mmol, 0.2 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.66 g, 0.65 mL, 4.3 mmol, 0.2 equiv) were added and the mixture was stirred for 2 h. The solvent was evaporated under reduced pressure and the mixture dissolved in dichloromethane (100 mL). The solution washed with water (2×20 mL) and a sat. solution of NaCl (20 mL), the aqueous layers were combined and extracted with dichloromethane (20 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure to give an amber solid. The solid was crystallized from MeOH (500 mL) to afford 4-(2-chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.67 g, 22%) as a white solid. The mother liquours were evaporated and purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (1:1)→ethyl acetate and the fractions combined to afford additional 4-(2-chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 12%). 1H NMR (250 MHz, CDCl3): δ 1.49-1.51 (m, 2H), 1.61 (s, 9H), 2.30-2.48 (m, 2H), 2.89-3.10 (m, 2H), 4.04 (s, 3H), 4.09 (s, 3H), 4.29-4.48 (m, 2H), 4.75-4.50 (m, 1H), 5.61 (d, J=8.0 Hz, 1H), 6.87 (s, 1H), 7.18 (s, 1H). MS (ESP): 423.5 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([NH:19][C:20](=[O:30])[C:21]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=1[CH3:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[C:15]([CH:17]=O)[CH:16]=2)=[CH:8][CH:7]=1.[CH3:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[CH:34]=1.[Li+].[OH-].Cl>ClC(Cl)C.C(OCC)(=O)C>[CH3:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH2:17][C:15]2[CH:16]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([NH:19][C:20](=[O:30])[C:21]4[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])[C:3]([OH:2])=[O:31])=[CH:7][CH:8]=3)[S:13][CH:14]=2)[CH:34]=1
Reactant: Cc1ccnc(N)c1
Reactant: COC(=O)C(Cc1ccc(-c2cc(C=O)cs2)cc1)NC(=O)c1c(C)cc(C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccnc(NCc2csc(-c3ccc(CC(NC(=O)c4c(C)cc(C)cc4C)C(=O)O)cc3)c2)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 33.5 %

Procedure:
99 mg of (18) were dissolved in/ml of dichloroethane and 37 mg (1.5 eq.) of 4-methylpyridin-2-ylamine and 240 mg (5 eq.) of NaHB(OAc)3 were added. The solution was stirred for 2.5 h. After pouring in ethyl acetate the organic layer was washed with saturated NaHCO3, brine and dried over Na2SO4. The crude product was redissolved in 6 ml of 1,4-dioxane and 1 ml of water. The solution was cooled to 0° C. and 3 eq. of LiOH*H2O were added. The solution was neutralized after 6 h with 1 M HCl and concentrated in vacuo. The product was purified by HPLC to give 39.1 mg of (19) as TFA salt.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[Cl:27][CH2:28][CH2:29][CH2:30]/[C:31](=[CH:35]\[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)/[C:32]([OH:34])=O.[NH:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]([CH:59]([NH2:61])[CH3:60])=[CH:51]1>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)CCl>[NH:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]([CH:59]([NH:61][C:32](=[O:34])/[C:31](=[CH:35]/[C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]3)=[C:38]([O:48][CH3:49])[CH:37]=2)/[CH2:30][CH2:29][CH2:28][Cl:27])[CH3:60])=[CH:51]1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Reactant: CC(N)c1c[nH]c2ccccc12
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc(/C=C(\CCCCl)C(=O)NC(C)c2c[nH]c3ccccc23)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 104.1 %

Procedure:
EDC (384 mg), HOBT (271 mg) and IPEA (0.582 mL) were sequentially added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 1-(1H-indol-3-yl)ethylamine (130 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 12 hours. After confirming that the raw materials disappeared, ethyl acetate and water were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was sequentially washed with a saturated aqueous solution of ammonium chloride and brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: chloroform:methanol system) to obtain (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(1H-indol-3-yl)ethyl)amide (332 mg). Sodium hydride (containing mineral oil at 40%, 19.3 mg) was added to a solution of the resulting (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(1H-indol-3-yl)ethyl)amide (92 mg) in THF (3 mL) at 0° C., and the reaction solution was stirred at room temperature for 90 minutes. The reaction solution was cooled to 0° C., water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: chloroform:methanol system) to obtain (E)-1-[1-(1H-indol-3-yl)ethyl]-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidin-2-one as a racemate (37.3 mg). The compound (37 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 10 minutes (15 mg; >99% ee) and the title optically active substance with a retention time of 14 minutes (14.2 mg; >99% ee).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH2:33][CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH2:33][CH2:34][C:35]3[N:39]=[CH:38][NH:37][CH:36]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCCc1c[nH]cn1
Product: Cc1cc(F)ccc1-c1nc(NCCc2c[nH]cn2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 30.9 %

Procedure:
Following the general procedure outlined in Example 217, the product of Example 48 (150 mg, 0.34 mmol) and histamine (187 mg, 1.68 mmol) were reacted to give the desired product 50 mg (31%). LC-MS: 477.0 (MH+, m/z), 1.59 (Rt, min).