Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:17][OH:18])=[O:11])=[CH:6][CH:5]=1.[CH2:19](I)[CH:20]=[CH2:21].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:21]([O:18][CH2:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:10]([C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)=[O:11])[CH:20]=[CH2:19]
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CO
Reactant: C=CCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Sodium hydride (61.5 mg, 1.41 mmol) (55% in paraffin liquid) was added to a solution of 200 mg (0.704 mmol) of (S)-(4-bromophenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone in N,N-dimethylformamide (2 ml) synthesized in the same manner as in step (i) of Reference Example 8, and the mixture was stirred at room temperature for 30 min. Thereafter, allyl iodide was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 155 mg (yield 68%) of the title compound.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][NH:10][CH:11]([CH3:37])[CH:12]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[CH2:13][C:14]2[O:15][C:16]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C@@H](C)[C@@H](C1C=CC([N+]([O-])=O)=CC=1)CC1OC(C(OCC)=O)=CC=1>>[C:1]1(/[CH:7]=[CH:8]/[CH2:9][NH:10][C@H:11]([CH3:37])[C@@H:12]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[CH2:13][C:14]2[O:15][C:16]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(NC/C=C/c1ccccc1)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)c1ccc(C[C@H](c2ccc([N+](=O)[O-])cc2)[C@H](C)O)o1
Product: C[C@@H](NC/C=C/c1ccccc1)[C@H](Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared in the same manners as in Reference Example 4(3) to (5) by using ethyl 5-{(2R,3S)-3-hydroxy-2-(4-nitrophenyl)butyl}-2-furancarboxylate as the starting material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](O)=[O:28].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:27](=[O:28])[C:26]5[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:25]=5[F:24])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cc(C(F)(F)F)ccc1F
Yield: 39.6 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (309 mg, 1.00 mmol), 2-fluoro-5-(trifluoromethyl)benzoic acid (312 mg, 1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg, 1.50 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (198 mg, 40%) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[C:41]=1[OH:55].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[Cl:39][C:40]1[C:41]([OH:55])=[C:42]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:43]=[CH:44][CH:45]=1
Reactant: CC1(C)OB(c2cccc(Cl)c2O)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc(Cl)c3O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 55 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.30 mmol), sodium carbonate (32 mg, 0.30 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 0.01 mmol) in 1,2-dimethoxyethane (900 μl) and water (225 μl) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 35%, hexane-ethyl acetate) to give 58 mg (55% yield, 77% purity) of the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]3[C:24]([F:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O.O1CCOCC1>[F:25][C:24]1[CH:23]=[N:22][C:21]2[NH:3][C:4]3[N:5]=[CH:6][CH:7]=[C:8]([CH:9]=3)[CH2:10][CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]=1[N:20]=2)[CH:15]=[CH:16][CH:17]=3
Reactant: Nc1cc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Fc1cnc2nc1Nc1cccc(c1)CCc1ccnc(c1)N2
Yield: 30.2 %

Procedure:
To a mixture of N-{3-[2-(2-aminopyridin-4-yl)ethyl]phenyl}-2-chloro-5-fluoropyrimidin-4-amine dihydrochloride (35.0 mg, 0.084 mmol) and triethylamine (0.035 mL, 0.25 mmol) in a mixed solvent of 1,4-dioxane (0.70 mL) and N,N-dimethylformamide (0.70 mL) were added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.8 mg, 0.01 mmol), palladium acetate (2.3 mg, 0.01 mmol) and cesium carbonate (54.7 mg, 0.17 mmol). The mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 160° C. for 30 min. The reaction mixture was diluted with THF/MeOH, filtered and concentrated to give the residue, which was purified by silica gel column chromatography to provide the desired product as a white powder (7.8 mg, 30%). LCMS for C17H15FN5 (M+H)+: m/z=308.1. 1H NMR (400 MHz, CD3OD): δ 8.09 (d, J=5.2 Hz, 1H), 8.00 (s, 1H), 7.96 (d, J=4.0 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.31 (m, 1H), 7.04 (m, 2H), 6.91 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8](=[O:15])[CH2:9][C:10](OCC)=O)[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].Cl>C1(C)C=CC=CC=1>[O:15]=[C:8]1[C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[O:16][CH:10]=[CH:9]1
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=c1ccoc2ccccc12
Temperature: 25 °C
Reaction time: 36 h
Yield: 122.6 %

Procedure:
The keto-ester (Step 1) (19.2 g, 79.1 mmol), was added to trifluoroacetic anhydride (67.2 mL, 49.9 g, 475.8 mmol), potassium carbonate (44 g, 318 mmol) and toluene (400 mL). This suspension was stirred at room temperature for 36 hours, then heated to reflux for 4 hours. After cooling to room temperature, the suspension was poured over rapidly stirred (mechanical stirrer) ice (300 mL) and aqueous HCl (12 N, 50 mL). The resulting organic phase was separated from the clear mixture, was washed with water (5×500 mL), brine (1×500 mL), dried over MgSO4, filtered and concentrated in vacuo yielding tan solid which was dried under high vacuum. This sample was partially dissolved in heptane (100 mL) and ethyl acetate (12 mL) with heating on a steam bath, was filtered to remove insoluble material. The filtrate was allowed to cool to room temperature yielding the desired 4-oxo-4H-1-benzopyran as a fluffy tan solid (14.17 g, 56%): mp 106.7-108.6° C. This material was of suitable purity to use in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1F.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC>CCOC(C)=O>[F:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.5 %

Procedure:
A mixture of 1,2,3-trifluoro-5-nitrobenzene (3.54 g, 20.0 mmol), morpholine (2.0 mL, 23.0 mmol) and Et3N (8.5 mL, 61.0 mmol) in EtOAc (30 mL) was stirred at rt for 5 h. The mixture was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=8:1) to give the title compound as a yellow solid (4.76 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH3:18])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: O=C(O)c1ccc(Br)c(O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Br)c(O)c1

Procedure:
4-Bromo-3-hydroxybenzoic acid (100 mg) was dissolved in absolute ethanol (10 ml) and concentrated sulfuric acid (60 μl) added. The reaction was heated at reflux under nitrogen for 22 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate/chloroform (1:1) and water. The organic layers were combined, dried using a hydrophobic filter and the solvent evaporated leaving ethyl 4-bromo-3-hydroxybenzoate as a white solid (109 mg).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:16](\[CH2:22]CO)/[C:17]([O:19][CH2:20]C)=[O:18])=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[Cl:31][C:28]1[CH:27]=[CH:26][C:25](/[C:15](=[C:16]2\[C:17](=[O:18])[O:19][CH2:20][CH2:22]\2)/[C:12]2[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)/C(CCO)=C(\c1ccc(Cl)cc1)c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2ccc(Cl)cc2)cc1
Yield: 50 %

Procedure:
A solution of 10 g of ethyl (Z)-3-(4-t-butylaminosulphonylphenyl)-3-(4-chlorophenyl)-2-(2-hydroxyethyl)-2-propenoate prepared in Example 124, in 80 ml of trifluoroacetic acid is heated under reflux for 15 hours. After evaporation of the solvent under vacuum, the residue is taken up in dichloromethane. The organic phase is washed with water and then dried over magnesium sulphate and evaporated under vacuum to give an oil which crystallises in an acetone/diisopropyl ether mixture giving 3.9 g of (Z)-4-[(4-chlorophenyl)-(2-oxo-dihydro-furan-3-ylidene)-methyl]benzenesulphonamide in the form of crystals melting at 187-189° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](/[CH:13]=[CH:14]/[CH2:15][O:16][CH3:17])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CC=CCCC=C1.C1C=CN=CC=1.F[P-](F)(F)(F)(F)F.[Ir].ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC/C=C/c1cc(C(=O)OC)cc(Br)c1C
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: c1ccncc1
Solvent: C1=CCCC=CCC1
Solvent: ClCCl
Product: COCCCc1cc(C(=O)OC)cc(Br)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a dichloromethane (0.2 M) solution of methyl 3-bromo-5-[(1E)-3-methoxy-1-propen-1-yl]-4-methylbenzoate (1 eq.) from the previous step was added Crabtree's catalyst (0.01 eq.). The resulting orange red solution was bubbled with hydrogen for 10 min to activate the catalyst and then stirred at RT under a static balloon atmosphere of hydrogen for 3 h. Finally, removal of the volatiles in vacuo afforded the crude title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([F:14])([F:13])[F:12])[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].Cl.C(=O)(O)[O-].[Na+].[CH2:28]([O:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C.[C].[Pd]>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([F:14])([F:12])[F:13])[CH2:9][N:8]([C:36]([O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(F)(F)F
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(F)(F)F
Temperature: 40 °C
Reaction time: 11 h
Yield: 92.3 %

Procedure:
In 150 ml of ethanol, is dissolved 15.0 g (49.8 mmol) of trans-1-benzyl-4-trifluoromethylpyrrolidine-3-carboxylic acid ethyl ester. To the above solution, are added 6 ml of conc-hydrochloride and then 3 g of 10% palladium carbon. The mixture is stirred at 40° C. and 1 atmospheric pressure to perform a hydrogenation. Four hours later, the catalyzer is removed by filtration. The filtrate is concentrated under reduced pressure, and the residue was dissolved in 60 ml of water. To the solution, is added 11 g (131 mmol) of sodium bicarbonate. Further, 10.2 g (59.8 mmol) of benzylchloroformate is added to the above solution on cooling with ice. The mixture is stirred at 0° C. for 1 hour and then at room temperature for 11 hours. The reaction mixture is extracted with 150 ml of diethyl ether. The organic phase is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried organic phase is concentrated under reduced pressure. The residue was purified with silica gel column chromatography (elusion solvent; n-hexane/ethyl acetate (10/1→5/1)) to give 15.87 g of the objective substance as a colorless oily matter (yield 92.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]3[N:33]4[C:29]([S:30][CH:31]=[CH:32]4)=[N:28][C:27]=3[CH3:34])=[O:25])[CH2:18]2)=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: NC1C=C(OC)C=CC=1O.[C:11]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:13])[CH3:12].COC1C=CC(O)=C([N+]([O-])=O)C=1>>[C:11]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: COc1ccc(O)c(N)c1
Agent: COc1ccc(O)c([N+](=O)[O-])c1
Product: CC(=O)Oc1ccc(N)cc1

Procedure:
Compound 55 was prepared in the manner of compound 12 substituting 4-nitrophenyl acetate for compound 11 in part C-1 of Example 1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH3:24])[C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:24][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]1=[O:25]
Reactant: [H][H]
Reactant: CN1C(=O)N(C2CCN(Cc3ccccc3)CC2)Cc2ccccc21
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)N(C2CCNCC2)Cc2ccccc21
Yield: 63.7 %

Procedure:
2 g palladium charcoal was added to 7.3 g 3-(1-benzyl-piperidin-4-yl)-1-methyl-3,4-dihydro-1H-quinazolin-2-one in 150 mL methanol and stirred for 5 h under 50 psi hydrogen atmosphere. The mixture was filtered and the solvent was removed. Diethylether was added and the precipate was filtered to yield 3.4 g of the desired product.
Reaction SMILES: S(=O)(=O)(O)N.CC(CC)=C.[CH:11]([C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:12].Cl([O-])=[O:25].[Na+]>O1CCCC1.O.CS(C)=O>[OH:23][C:16]1[CH:15]=[CH:14][C:13]([C:11]([OH:25])=[O:12])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: [O-][Cl+][O-]
Reactant: COC(=O)c1cc(C=O)ccc1O
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(C(=O)O)ccc1O
Temperature: 0 °C

Procedure:
Sulfamic acid (1.83 g, 18.87 mmol) and 2-methyl-1-butene (1.20 ml, 11.10 mmol) were added to a solution of methyl 5-formyl-2-hydroxybenzoate (may be prepared as described in Description 106; 1 g, 5.55 mmol) in tetrahydrofuran (20 ml), water (20 ml) and dimethyl sulfoxide (20 ml). The solution was cooled to 0° C. and sodium chlorite (1.51 g, 16.65 mmol) in water (5 ml) was added. After 45 minutes at 0° C. the reaction the mixture was quenched with saturated Na2S2O3 solution (20 ml) and extracted with ethyl acetate (3×30 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a solid. 1.09 g (damp with DMSO/H2O).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[NH:28]1[CH2:33][CH:32]=[CH:31][CH2:30][CH2:29]1>C(Cl)Cl.C(OCC)C.CCCCCC>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([N:28]3[CH2:29][CH:30]=[CH:31][CH2:32][CH2:33]3)=[O:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: C1=CCNCC1
Reactant: O=C(O)c1ccc2nccnc2c1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(c1ccc2nccnc2c1)N1CC=CCC1
Reaction time: 0.25 h

Procedure:
6-Quinoxalinecarboxylic acid (320 mg; 1.8 mmol) is suspended in 10 ml methylene chloride. As the suspension is stirred, 2 equivalents of triethylamine are added, followed by 0.22 ml (1.8 mmol) of trimethylacetyl chloride. After 15 min, 164 ul (1.8 mmol) of 1,2,3,6-tetrahydropyridine is added and the solution is stirred overnight. The solution is diluted with 20 ml of diethyl ether and washed with 10 ml water followed by 10 ml 10% NaCO3. The organic solution is dried over Na2SO4 /K2 CO3 and concentrated to a red-brown oil. Purification by chromatography on silica gel (eluted with CC14 /CHC13 1:1) gives a pale yellow oil that eventually solidifies. The solid is layered with hexane and finely dispersed by mechanical crushing to yield pale yellow XIII. EMIS m/z=239 (parent), 157 (base), and 129. 1H NMR δ 2.22 and 2.34 (br, 2), 3.54, 3.94, 3.97, and 4.29 (br, 4), 5.5-6.0 (br, 2), 7.85 (dd, 1, J=8.7, 1.3 Hz), 8.15 (d, 1, J=1.6 Hz), 8.18 (br d, 1, J=8.5 Hz), and 8.90 ppm (s, 1).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([C:10]1[CH:14]=[C:13]([NH2:15])[O:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:6]([C:10]1[CH:14]=[C:13]([NH:15][C:3](=[O:4])[CH2:2][Cl:1])[O:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)CCl)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
Chloroacetic acid chloride (0.25 ml; 3.14 mmol) is dropped slowly into a stirred solution of 3-t-Butyl-5-amino isoxazole (400 mg; 2.85 mmol) in pyridine (0.3 ml; 3.71 mmol) and dichloromethane (2 ml), cooled to 0° C. Stirring is continued for 2 h at room temperature. The reaction mixture is diluted with dichloromethane, washed twice with 1 N aqueous hydrochloric acid, twice with an aqueous solution of NaHCO3 and with water. The reaction mixture is then dried over Na2SO4, filtered and evaporated to yield 600 mg (97%) brownish solid of 11.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[NH2:20]>C(O)(C)C>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1OC
Yield: 85.1 %

Procedure:
4-chloro-6,7-dimethoxy-quinazoline (1.50 g) and 3-choro-4-(m-fluoro-benzyloxy)-aniline (1.70 g) were dissolved into 150 mL of isopropanol. The mixture was reacted under reflux for 3 h, and a lot of yellow solid was deposited. The precipitated solid was filtered, and the filter cake was washed with cold ethanol and dried at 60° C. under vacuum overnight to obtain the title compound (2.50 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([C:21]([CH3:27])([CH3:26])[C:22](OC)=[O:23])=[C:18](O)[N:19]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:37]>C(#N)C>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]3[C:21]([CH3:26])([CH3:27])[C:22](=[O:23])[NH:37][C:18]=3[N:19]=2)=[N:6]1
Reactant: N
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncncc23)nc1O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncncc34)nnc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
186 mg (0.438 mmol) of methyl 2-{3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-hydroxy-1,2,4-triazin-6-yl}-2-methylpropanoate were admixed with 4 ml (42.913 mmol) of phosphoryl chloride and the mixture was stirred at RT for 2.5 h. The reaction solution was diluted with 20 ml of dry acetonitrile and gradually added dropwise while cooling with ice to 30 ml of a 25% aqueous ammonia solution, and the mixture was stirred at RT overnight. The reaction mixture was concentrated on a rotary evaporator and the precipitate was filtered off. 127 mg of the target compound were obtained (74% of theory).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][Cl:30]>O.C(#N)C>[Cl:30][CH2:29][CH2:28][CH2:27][O:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCCl)ccc21
Temperature: 70 °C
Yield: 90.6 %

Procedure:
1-Ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.85 g, 7.1 mmol) and potassium carbonate (1.2 g, 8.5 mmol) were added to 50% water-containing acetonitrile (40 ml), and dissolved by heating to 70° C. 1-Bromo-3-chloropropane (2.1 ml, 21 mmol) was added thereto, and heating was conducted under reflux for 6 hours. The reaction mixture was cooled to room temperature. Water was added, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 2.18 g (yield: 91%) of 7-(3-chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a colorless oil.