Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:29]=1[F:36])=[O:25])[C:21](O)=[O:22]>>[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:29]=1[F:36])=[O:25])[C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1F
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CC(C(=O)NCc1cc(F)cc(F)c1F)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=482.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(2,3,5-trifluoro-benzyl)-malonamic acid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9](C3C4C(C=C5C=3C=CC=C5)=CC=CC=4)[CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N(Br)C(=O)C1.C1([C:47]2[CH:48]=[C:49]([C:59]3[C:60]4[C:65]([C:66]([Br:73])=C5C=3C=CC=C5)=[CH:64][CH:63]=[CH:62][CH:61]=4)[CH:50]=[CH:51][C:52]=2C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.O>[C:13]1([C:12]2[CH:11]=[C:10]([C:61]3[C:60]4[C:65](=[C:66]([Br:73])[C:48]5[C:49]([CH:59]=4)=[CH:50][CH:51]=[CH:52][CH:47]=5)[CH:64]=[CH:63][CH:62]=3)[CH:9]=[CH:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(-c2ccc(-c3c4ccccc4cc4ccccc34)cc2-c2ccccc2)cc1
Reactant: Brc1c2ccccc2c(-c2ccc(-c3ccccc3)c(-c3ccccc3)c2)c2ccccc12
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c2ccccc2cc2c(-c3ccc(-c4ccccc4)c(-c4ccccc4)c3)cccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
9-(3,4-Diphenylphenyl)anthracene (3.7 g, 9.1 mmole) was suspended in anhydrous DMF (50 ml). After an anhydrous DMF solution (10 ml) of NBS (1.8 g, 10 mmole, 1.1 eq) was added, the resultant mixture was heated at 55° C. for 5 minutes so that the reaction mixture became a homogeneous solution. The obtained solution was stirred at the room temperature for 4 hours and then left standing for one night. The reaction mixture was diluted with water (50 ml). The formed solid substance was separated by filtration and washed with methanol, and a light yellow solid substance (4.2 g, the yield: 95%) was obtained. The obtained product was identified to be 9-(3,4-diphenylphenyl)-10-bromoanthracene in accordance with 1H-NMR.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([N:21]5[CH2:25][CH2:24][C:23](=O)[CH2:22]5)=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.FC1(F)CC[NH:30][CH2:29]1>O1CCCC1.CO.CC(N(C)C)=O>[CH3:29][NH:30][C@@H:23]1[CH2:24][CH2:25][N:21]([C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[N:20][CH:19]=2)[CH2:22]1
Reactant: O=C1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Reactant: FC1(F)CCNC1
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CN[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 80 °C
Yield: 46.2 %

Procedure:
A suspension of 1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidin-3-one (50 mg, 0.15 mmol) and 3,3-difluoropyrrolidine (42 mg, 0.29 mmol) in tetrahydrofuran/methanol/dimethylacetamide (1.0 mL each) was heated to 80° C. for 2 hours then NaBCNH3 (18 mg, 0.29 mmol) was added. After 2 hours the solution was cooled to room temperature and concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 25S column eluting with chloroform/acetone (5-50%) followed by a second column on a 12M cartridge eluting with chloroform/ethyl acetate (25-100%) to afford the title compound (25 mg, 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=[O:13])[N:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5]2.[Cl:19]N[C:21](=O)[CH2:22]CC(N)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([NH+:8]([CH2:7][CH3:15])[CH2:9][CH3:10])[CH3:22].[NH2:1][C:2]1[C:3]([Cl:19])=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([O-:14])=[O:13])[N:8]=[C:7]([C:15]([F:18])([F:16])[F:17])[CH:6]=[CH:5]2
Reactant: Nc1cc2ccc(C(F)(F)F)nc2cc1C(=O)O
Reactant: NC(=O)CCC(=O)NCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[NH+](CC)CC
Product: Nc1c(C(=O)[O-])cc2nc(C(F)(F)F)ccc2c1Cl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-Amino-2-trifluoromethyl-quinoline-7-carboxylic acid (0.50 g, 1.952 mmol is dissolved in dimethyl formamide (10 ml) and treated with N-chlorosuccinamide (0.26 g, 1.952 mmol) and the mixture warmed to 80° C. After 1 hr the reaction is complete as shown by LC/MS analysis. The reaction mixture is cooled, diluted with ethyl acetate, and then washed successively with water and brine. The organic phase is dried over sodium sulphate, filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography eluting with eluting with a mixture of toluene, ethyl alcohol, dioxane, triethylamine and water (100:40:20:20:5 parts by volume) to give the title compound as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][C:13]([OH:15])=[O:14].[C:16]1([C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N+]=[N-])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(Cl)Cl>[C:16]1([CH:22]([O:14][C:13](=[O:15])[CH2:12][C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: COc1ccc([N+](=O)[O-])cc1CC(=O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])cc1CC(=O)OC(c1ccccc1)c1ccccc1
Yield: 21 %

Procedure:
Using 2-methoxyphenylacetic acid (5.00 g) as a starting material, the same procedure of Example 188 gave 2-methoxy-5-nitrophenylacetic acid. To a solution of the resulting nitro compound in methylene chloride (140 ml), a solution of diphenyldiazomethane in methylene chloride was added at room temperature until the reaction mixture turned purple and then acetic acid was added until the purple color of the reaction mixture disappeared. The reaction mixture was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 2.34 g of the titled compound (yield, 21%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:13][CH2:12]1.C1C[O:31]CC1>>[OH:31][CH:17]([CH:14]1[CH2:13][CH2:12][O:11][CH2:16][CH2:15]1)[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19]
Reactant: C1CCOC1
Reactant: O=C(CC1CCOCC1)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(OCc1ccccc1)C(O)C1CCOCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A 1.0 M sodium bistrimethylsilylamide solution in THF (13.0 ml, 12.82 mmol) was added to anhydrous THF (15 ml), and the mixture was cooled to −78° C. A solution of benzyl 2-(tetrahydro-2H-pyran-4-yl)acetate (2.5 g, 10.68 mmol) in anhydrous THF (20 ml) was added dropwise to the mixture over 30 min. The mixture was stirred at −78° C. for one hr, and a solution of n-benzyl-benzenesulfonyloxaziridine (3.35 g, 12.82 mmol) in anhydrous THF (30 ml) was added dropwise thereto over one hr. The mixture was stirred at −78° C. for one hr, was quenched with saturated ammonium chloride, and was extracted with ether. The organic layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=8:2) to give the title compound as an oil (2.1 g, yield 78%).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:13]=3)[CH2:8]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[C:40]([O:39][C:37]([N:34]1[CH2:33][CH:32]=[C:31]([C:2]2[CH:22]=[CH:21][C:5]([CH2:6][N:7]3[CH2:16][CH2:15][C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:13]=4)[CH2:8]3)=[CH:4][CH:3]=2)[CH2:36][CH2:35]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1ccc2c(c1)CCN(Cc1ccc(Br)cc1)C2
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: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(c1)CCN(Cc1ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc1)C2
Temperature: 80 °C
Yield: 82.1 %

Procedure:
A solution of methyl 2-(4-bromobenzyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (200.0 mg, 0.600 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (188.8 mg, 0.6107 mmol) in DME (5.15 mL) was treated with Na2CO3 (2.00 M in water, 0.83 mL, 1.66 mmol). The mixture was degassed and Pd(Ph3P)4 (13 mg, 0.011 mmol) was added. The reaction mixture was heated under argon at 80° C. overnight. The mixture was then cooled to room temperature and diluted with water. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, 10-50% EtOAc in hexanes) to give methyl 2-{4-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]benzyl}-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (228 mg, 89%). LC-MS: (FA) ES+ 263.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([C:15]2[N:20]=[C:19]3[N:21]([CH3:30])[C:22](=[O:29])[N:23]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]3=[CH:17][CH:16]=2)[CH:8]=1)(=O)=O.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.CO>[CH3:26][C:25]([CH3:27])([CH3:28])[CH2:24][N:23]1[C:18]2[C:19](=[N:20][C:15]([C:9]3[CH:8]=[C:7]([CH2:6][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:12]=[CH:11][C:10]=3[C:13]#[N:14])=[CH:16][CH:17]=2)[N:21]([CH3:30])[C:22]1=[O:29]
Reactant: C1CCNC1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(COS(C)(=O)=O)ccc3C#N)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(CN4CCCC4)ccc3C#N)nc21
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a microwave vial, 4-cyano-3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]benzyl methanesulfonate (21-1) (20 mg, 0.05 mmol) and pyrrolidine (5 mg, 0.07 mmol) were added and dissolved in NMP (0.25 ml). Diisopropyl ethyl amine (18 mg, 0.14 mmol) was then added and the reaction was heated at 65° C. allowed to stir for 4 hours. The mixture was diluted with methanol and purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile); the desired fractions were collected and concentrated to produce 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-(pyrrolidin-1-ylmethyl)benzonitrile (13-2). HRMS (M+H)+: observed=404.2456, calculated=404.2445. 1H NMR (400 MHz, CD3 OD): δ 7.91 (s, 1H); 7.83 (d, J=7.9 Hz, 1H); 7.60 (q, J=8.3 Hz, 2H); 7.54 (d, J=8.0 Hz, 1H); 3.82 (s, 2H); 3.77 (s, 2H); 3.55 (s, 3H); 2.64 (m, 4H); 1.85 (m, 4H); 1.06 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[CH:14]=[C:13]([OH:18])[N:12]=1.[CH3:19][C:20]1[N:21]([CH2:27][CH2:28][O:29][CH2:30][C:31](=O)[CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:22]([CH3:26])=[C:23]([CH3:25])[N:24]=1>>[NH2:10][C:11]1[NH:16][C:15]2[NH:17][C:31]([CH2:30][O:29][CH2:28][CH2:27][N:21]3[C:22]([CH3:26])=[C:23]([CH3:25])[N:24]=[C:20]3[CH3:19])=[C:32]([C:33]([O:35][CH3:36])=[O:34])[CH:4]([C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[Cl:1])[C:14]=2[C:13](=[O:18])[N:12]=1
Reactant: COC(=O)CC(=O)COCCn1c(C)nc(C)c1C
Reactant: O=Cc1ccccc1Cl
Reactant: Nc1cc(O)nc(N)n1
Product: COC(=O)C1=C(COCCn2c(C)nc(C)c2C)Nc2[nH]c(N)nc(=O)c2C1c1ccccc1Cl
Yield: 3 %

Procedure:
The title compound (110 mg) was prepared from 2-chlorobenzaldehyde (1.05 g), 2,4-diamino-6-hydroxypyrimidine (1.07 g) and methyl 4-[2-(2,4,5-trimethylimidazol-1-yl)ethoxy]-3-oxobutanoate (2.0 g) by the method of Example 1. M.p. 225°-227° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[N:26]1([C:30]([C:32]2[CH:37]=[CH:36][C:35](F)=[C:34]([Cl:39])[CH:33]=2)=[O:31])[CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[N:26]1([C:30]([C:32]2[CH:37]=[CH:36][C:35]([O:1][C:2]3[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]4[CH2:23][CH2:22][N:21]([CH3:24])[C:20]4=[O:25])[CH:17]=3)[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:34]([Cl:39])[CH:33]=2)=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3Cl)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Yield: 56 %

Procedure:
A mixture of 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 18) (136 mg, 0.4 mmol), azetidin-1-yl-(3-chloro-4-fluoro-phenyl)methanone (CAS no. 863454-79-9) (128 mg, 0.6 mmol) and potassium carbonate (111 mg, 0.8 mmol) in DMA (5 mL) was stirred at 120° C. for 16 hours. The solution was evaporated under reduced pressure, then the residue was dissolved in ethyl acetate (40 mL), washed with water (2×20 mL) and brine (10 mL), then dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by chromatography on silica eluting with 0-4% methanol/DCM to afford the product (120 mg, 56%). m/z 536 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N+:4]=[N-:5].[CH3:19]I>C1COCC1>[N:3]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[N+:4]=[N-:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCOCCN=[N+]=[N-])C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
Sodium hydride (60% oil dispersion, 9.1 g, 228 mmol) was placed in a round bottom flask and washed with hexanes (3×) under N2. The dried sodium hydride was treated with 800 mL of anhydrous THF. A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (41.9 g, 182 mmol) in 200 mL of THF was then added to the stirred sodium hydride solution over 40 min. After addition was complete, the reaction was stirred an additional 20 min followed by addition of methyl iodide (13.6 mL, 218 mmol). After stirring overnight, the reaction was quenched with 300 mL of saturated NaHCO3 solution. The reaction mixture was then treated with 200 mL of H2O and 1 L of Et2O. The organic phase was separated and washed with H2O and brine. The organic portion was then dried over MgSO4 and concentrated under reduced pressure to give 41.9 g of tert-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate as a yellow liquid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20].[N+]([CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([O-])=O>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:20]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1cccc(Cl)c1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Product: Clc1cccc(Cn2cc(-c3ccccc3)c3c2CCNC3)c1

Procedure:
The title compound (159.0 mg) was prepared from 0.55 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 334 μL of 3-chlorobenzylamine, and 0.40 g of (2-nitro-vinyl)-benzene and without SiO2. MS (ESI): exact mass calculated for C20H19ClN2, 322.12. found, m/z 323.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.38-7.32 (m, 5H), 7.31-7.28 (m, 1H), 7.23-7.19 (m, 1H), 7.17-7.16 (m, 1H), 7.13 (s, 1H), 7.12-7.10 (m, 1H), 5.16 (s, 2H), 4.37 (s, 2H), 3.52 (t, J=6.3 Hz, 2H), 2.86 (t, J=6.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12].ClCC(C1C=CC=CC=1)=O.[NH2:27][C:28]1[C:32]([C:33]#[N:34])=[CH:31][NH:30][N:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:29]2[N:30]=[CH:31][C:32]([C:33]#[N:34])=[C:28]2[N:27]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1Cl
Agent: O=C(CCl)c1ccccc1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccccc3Cl)nc12
Yield: 22.6 %

Procedure:
Reaction of 1-(2-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg, 1.0 mmol), prepared from commercially available 2-chloro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (73 mg, 23%). MS (ISP) 323.1 [(M+H)+]; mp 169° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH:9]([C:18]([OH:20])=[O:19])[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH2:13][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:21]O>>[CH3:1][C:2]1[C:7]2[O:8][CH:9]([C:18]([O:20][CH3:21])=[O:19])[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH2:13][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1OC(C(=O)O)Oc1ccccc1C2
Reactant: CO
Product: COC(=O)C1Oc2ccccc2Cc2cccc(C)c2O1

Procedure:
4-Methyl-12H-dibenzo-[d,g][1,3]dioxocin-6-carboxylic acid from Example 1 (1.8 g, 6.6 mmol) was mixed with 75 ml of methanol and 5 g of Dowex™ sulfonic acid resin and the mixture heated at reflux for 16 hours. The mixture was allowed to cool, the resin removed by filtration, and the volatile components removed by evaporation under reduced pressure The residue was taken up in 150 ml of ether and the solution extracted with saturated aqueous sodium bicarbonate and dried over magnesium sulfate. The volatiles were removed by evaporation under reduced pressure and the light yellow residual solid, which amounted to 1.29 g, was recrystallized from ethanol to obtain 0.77 g (41 percent of theory) of the title compound as a solid melting at 104°-105° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: CC[O-].[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16]([N:19]1[C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:28][C:23]=2[C:22](=O)[O:21]C1=O)[CH:17]=[CH2:18].Cl>CN(C=O)C>[CH2:10]([O:9][C:7]([C:6]1[C:5](=[O:13])[N:19]([CH2:16][CH:17]=[CH2:18])[C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:28][C:23]=2[C:22]=1[OH:21])=[O:8])[CH3:11]
Reactant: C=CCn1c(=O)oc(=O)c2cnc(-c3ccccc3)nc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c(C(=O)OCC)c(O)c2cnc(-c3ccccc3)nc21

Procedure:
To a 50 ml. solution of NaOEt (0.3 g. Na--0.013 mole) was added 2.08 g. (0.013 mole) of diethyl malonate and this was stirred 10 minutes, then stripped to dryness. DMF was added to form a solution and then 1.85 g. (0.0065 mole) of 1-(2-propenyl)-7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione was added and heated at reflux for 1.5 hours. When cool, the reaction was poured into dilute HCl and the resulting precipitate collected on a filter and rinsed with water. Recrystallization from ethyl acetate gave 1.0 g. of product--m.p. 177°-180° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.O(C1C=CC(C[N:20]2[CH:35]=[C:23]3[C:24](=[O:34])[N:25]([CH3:33])[C:26]4[N:27]([CH2:28][C:29]([CH3:32])([CH3:31])[N:30]=4)[C:22]3=[N:21]2)=CC=1)C1C=CC=CC=1.C(S(O)(=O)=O)(F)(F)F.O>C(Cl)Cl>[CH3:33][N:25]1[C:24](=[O:34])[C:23]2=[CH:35][NH:20][N:21]=[C:22]2[N:27]2[CH2:28][C:29]([CH3:32])([CH3:31])[N:30]=[C:26]12
Reactant: CN1C(=O)c2cn(Cc3ccc(Oc4ccccc4)cc3)nc2N2CC(C)(C)N=C12
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)c2c[nH]nc2N2CC(C)(C)N=C12
Temperature: 25 °C
Yield: 79.9 %

Procedure:
TFA (600 mL) is added into a suspension of 2-(4-phenoxybenzyl)-7,8-dihydro-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (103 g, 257 mmol) in methylene chloride (210 mL) to give a tan solution, and then TFMSA (168 mL) is added. The reaction mixture is stirred at room temperature until the starting material disappears. The mixture is poured into cold water (3 L). After filtration, the filter cake is washed with water twice, and then basified with ammonium hydroxide aqueous solution, followed by adding ethyl acetate with stirring. The precipitated solids are filtered, washed successively with water three times, ethyl acetate twice and methanol once, and then dried under vacuum to give 45 g of product (yield: 80%). MS (ESI) m/z 220.2 [M+H]+.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17])(=[O:11])[CH3:10]>CCOCC.O1CCCC1>[CH3:17][C:16]1[N:15]=[CH:14][NH:13][C:12]=1[C:9]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:11])[CH3:10]
Reactant: CC(=O)c1nc[nH]c1C
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc[nH]c1C(C)(O)c1ccccc1

Procedure:
A 3.0 M solution of phenyl-magnesium bromide (1.3 ml, 4 mmol) in ether was added to a solution of 0.25 g (2.0 mmol) 4-acetyl-5-methyl-imidazole in 20 ml dry tetrahydrofuran at ambient temperature. The mixture was refluxed for 2 h. The solvents are evaporated and the organics are extracted twice with ethyl acetate. The combined organic extracts are concentrated and the residue was purified by flash chromatography (silica gel, dichloromethane/methanol 95:5) to yield a product mainly containing 1-(5-methyl-3H-imidazol-4-yl)-1-phenyl-ethanol. This product was dissolved in 20 ml ethanol/ethyl acetate (1:1) and 0.5 ml of 10M hydrochloric acid was added. The mixture was hydrogenated (5% Pd/C, 0.07 g; 4 bar H2, 50° C.) for 4 h. Then the mixture was filtered through Celite®, and the solvent was evaporated. The residue was partitioned between an aqueous solution of potassium carbonate and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated to yield a yellow oil that was purified by flash chromatography (silica gel, dichloromethane/methanol 95:5). To the amine an equimolar amount of hydrochloric acid in ethanol (5M) was added. By dilution with ether 4-methyl-5-(1-phenyl-ethyl)-1H-imidazole hydrochloride precipitated as a colourless solid that was filtered off (45 mg, 12%); MS (EI): 186.1 (M+.), 171.1 (((M-CH3)+.), 100%).