Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]4[O:26][CH2:25][O:24][C:19]=4[CH:20]=3)[C:15]=2[CH:27]=O)[C:6]([N+:11]([O-])=O)=[CH:7][C:8]=1[O:9][CH3:10].C(C1C2C(=CC(OC)=C(OC)C=2)C=CC=1B(O)O)=O.C(C1C2C(=CC3OCOC=3C=2)C=CC=1B(O)O)=O>>[CH2:25]1[O:26][C:18]2[C:19](=[CH:20][C:21]3[CH:22]=[CH:23][C:14]4[C:5]5[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=5[N:11]=[CH:27][C:15]=4[C:16]=3[CH:17]=2)[O:24]1
Reactant: COc1cc(-c2ccc3cc4c(cc3c2C=O)OCO4)c([N+](=O)[O-])cc1OC
Agent: COc1cc2ccc(B(O)O)c(C=O)c2cc1OC
Agent: O=Cc1c(B(O)O)ccc2cc3c(cc12)OCO3
Product: COc1cc2ncc3c4cc5c(cc4ccc3c2cc1OC)OCO5
Yield: 25 %

Procedure:
2-(3,4-Dimethoxy-6-nitrophenyl)-6,7-methylenedioxy-1-naphthaldehyde (18). Using a procedure similar to that described in Example 1, sub-part d, except replacing the compound 14 used therein with compound 15, compound 18 was prepared in 25% yield; mp=225° C.; IR (Nujol) 1670, 1515, 1309; 1H NMR δ 3.92 (3H, s), 4.04 (3H, s), 6.13 (2H, s), 6.74 (1H, s), 7.13 (1H, d, J=8.3), 7.18 (1H, s), 7.77 (1H, s), 7.87 (1H, d, J=8.3), 8.76 (1H, s), 10.14 (1H, s); 13C NMR δ 57.0, 57.1, 102.1, 103.1, 104.7, 108.2, 114.9, 125.7, 127.9, 128.8, 129.5, 131.5, 133.6, 141.2, 144.1, 148.6, 149.2, 151.6, 152.9, 193.6.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[C:6](OC)(=[O:9])[CH:7]=[CH2:8].COC1C=CC(O)=CC=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C(N(CC)O)C>CO>[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:9])[CH:7]=[CH2:8]
Reactant: C=CC(=O)OC
Reactant: CCCCO
Agent: CCN(O)CC
Agent: COc1ccc(O)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CO
Product: C=CC(=O)OCCCC
Reaction time: 2 h

Procedure:
One hundred forty eight grams (2.0 moles) of n-butanol, 516 g (6.0 moles) methyl acrylate, 1.15 g hafnium acetylacetonate, 0.10 g of MEHQ inhibitor, 0.1 g phenothiazine, and 0.10 g diethylhydroxylamine were added to a 2 liter flask equipped as described in Example 3. The solution was heated at reflux (atmospheric pressure) while an azeotropic mixture of methyl acrylate and methanol was removed from the top of the column. The reaction was continued in this manner for 2 hours while the temperature at the top of the column was 62°-64° C. and the temperature in the reaction vessel was 82°-97° C. GLC analysis of the reaction mixture showed >99% conversion of the n-butanol to butyl acrylate.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccncc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccncc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with pyridine-4-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Br.[Br:46][C:47]1[N:48]=[C:49]2[C:54]([NH:55][C@H:56]3[C@@H:60]([CH3:61])[CH2:59][NH:58][CH2:57]3)=[C:53]([C:62]([NH2:64])=[O:63])[CH:52]=[N:51][N:50]2[CH:65]=1>C(Cl)Cl>[Br:46][C:47]1[N:48]=[C:49]2[C:54]([NH:55][C@H:56]3[C@@H:60]([CH3:61])[CH2:59][N:58]([C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)=[O:8])[CH2:57]3)=[C:53]([C:62]([NH2:64])=[O:63])[CH:52]=[N:51][N:50]2[CH:65]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of 1-cyanocyclopropanecarboxylic acid (0.264 g, 2.380 mmol) in DCM (15.9 ml) were added DIEA (2.079 ml, 11.90 mmol), and BOP (1.263 g, 2.86 mmol). The solution was stirred at room temperature for 10 minutes, and 2-bromo-8-(((3S,4S)-4-methylpyrrolidin-3-yl)amino) imidazo[1,2-b]pyridazine-7-carboxamide, hydrobromide (from Step 2 of Example 1, 1.00 g, 2.380 mmol) was added. The reaction was stirred for 1 hr. After removal of the solvent, the crude product was purified by flash chromatography (ISCO, prepacked silica gel column eluting with 0-5% EtOAc/MeOH over 15 column volumes) to afford 2-bromo-8-(((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide as a white solid, 1.01 g, 2.336 mmol, 98% yield. ESI-MS (Method B): m/z 434.1 ([M+H]+). HPLC (Method B) Rt: 2.505 min.
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([F:18])=[CH:13][C:12]=3[Cl:19])[N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1.[CH3:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:12]1[CH:13]=[C:14]([F:18])[CH:15]=[C:16]([Cl:17])[C:11]=1[N:9]1[CH:8]=[C:7]2[C:2]([NH:27][C:23]3[CH:22]=[C:21]([CH3:20])[N:26]=[CH:25][N:24]=3)=[N:3][CH:4]=[CH:5][C:6]2=[N:10]1
Reactant: Cc1cc(N)ncn1
Reactant: Fc1cc(Cl)c(-n2cc3c(Cl)nccc3n2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc3nn(-c4c(Cl)cc(F)cc4Cl)cc23)ncn1
Yield: 61.9 %

Procedure:
A suspension of 4-chloro-2-(2,6-dichloro-4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine (70 mg, 0.22 mmol), 6-methylpyrimidin-4-ylamine (26 mg, 0.24 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), Xantphos (12.8 mg, 0.022 mmol) and cesium carbonate (144 mg, 0.44 mmol) in dioxane (3 ml) was sealed in a microwave vial, purged with nitrogen and irradiated at 150° C. for 25 minutes in the microwave. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (50-100% ethyl acetate in cyclohexane), then further triturated with diethyl ether:pentane (1:1) to afford the title compound as a yellow solid (53 mg, 62% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.65 (br s, 1H), 9.15 (s, 1H), 8.70 (s, 1H), 8.51 (s, 1H), 8.00 (d, J=6.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.23 (d, J=6.4 Hz, 1H), 2.46 (s, 3H). LCMS (Method B): RT=2.94 min, m/z: 389 [M+H+].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][C:28]([CH3:38])([CH2:31][N:32]3[CH2:37][CH2:36][S:35][CH2:34][CH2:33]3)[CH2:29][N:30]=1)=[CH:9]2.[O:39]1CCCC1.OOS([O-])=O.[K+].S([O-])([O-])=O.[Na+].[Na+]>O.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][C:28]([CH3:38])([CH2:31][N:32]3[CH2:37][CH2:36][S:35](=[O:39])[CH2:34][CH2:33]3)[CH2:29][N:30]=1)=[CH:9]2
Reactant: C1CCOC1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(C)(CN4CCSCC4)S3)cc2c1
Agent: O=S([O-])OO
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(C)(CN4CCS(=O)CC4)S3)cc2c1
Yield: 99 %

Procedure:
To a mixture of N-{5-(2-methoxyethoxy)-2-[5-methyl-5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylpyridine-2-sulfonamide (253 mg), tetrahydrofuran (5 mL), ethanol (5 mL) and water (5 mL) was added OXONE (registered trade mark, 160 mg) at room temperature, and the mixture was added at room temperature for 2 hr. 10% Aqueous sodium sulfite solution was added, and the mixture was concentrated to dryness. The residue was diluted with ethyl acetate, tetrahydrofuran and water, and the organic layer was washed with saturated brine, dried over sodium sulfate, and filtrated. The filtrate was concentrated, and the residue was purified by preparative HPLC to give the title compound (605 mg, yield 99%) as a colorless amorphous solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:6]=[CH:7][CH:8]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:43])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:43])[NH:13]3)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: FC(F)(F)c1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To the suspension of 4-(3-trifluoromethyl-phenyl)-1H-indole (3.37 g, 12.90 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (155 mL) was added pyridinium tribromide (12.38 g, 38.70 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (63 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (2.07 g, 58%) as a tan solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[OH-].[K+].[Br:15][CH2:16][CH2:17][CH2:18]Br>CN(C=O)C.O>[Br:15][CH2:16][CH2:17][CH2:18][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: BrCCCBr
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1ccn2CCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.2 %

Procedure:
To a solution of 4-nitroindole (5 g, 31 mmol) in anhydrous N,N′-dimethylformamide (200 mL) was added grounded potassium hydroxide (1.74 g, 31 mmol) in portions. Then a solution of 1,3-dibromopropane (18 g, 89 mmol) in N,N′-dimethylformamide was added dropwise. The mixture was stirred at room temperature for 12 hours, diluted with water and extracted with ethyl acetate. The organic phases were combined, washed by brine, dried over anhydrous sodium sulfate, filtrated and evaporated. The residue was purified by silica gel chromatography to afford the product 1-(3-bromopropyl)-4-nitro-1H-indole as brown-red oil (8.18 g, yield 94%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].[NH2:44][CH2:45][C:46]1[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=1[NH2:48].C(Cl)CCl.ON1C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[NH2:48][C:47]1[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=1[CH2:45][NH:44][C:10](=[O:11])[C:9]1[CH:13]=[C:14]([CH:15]=[CH:16][C:8]=1[N:5]1[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4]1)[C:17]([NH:18][S:19]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)(=[O:21])=[O:20])=[O:32]
Reactant: NCc1ccccc1N
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)NCc2ccccc2N)c(C)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 50 mg, 0.080 mmol) in CH2Cl2 (1.1 mL) and DMF (0.2 mL) was added 2-(aminomethyl)aniline (20 mg, 0.16 mmol) followed by EDC (34 mg, 0.18 mmol) and 1-hydroxy-7-azabenzo-triazole (290 μL, 0.18 mmol, 0.6M solution in DMF). The resulting reaction mixture was stirred at room temperature overnight, then quenched with sat. aq. NH4Cl solution and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (gradient from 0% to 10% MeOH/CH2Cl2) provided the title compound (35 mg, 60%) as a pale yellow, oily solid. MS(ESI+) m/z 729.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](N)[C:5]([C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20].C(O)(=O)C.S(=O)(=O)(O)O.N([O-])=O.[Na+].[ClH:34]>O.[Cu]Cl>[F:1][C:2]1[CH:7]=[C:6]([Cl:34])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20]
Reactant: CC1=C(C)C(=O)N(c2cc(C(=O)O)c(N)cc2F)C1=O
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC1=C(C)C(=O)N(c2cc(C(=O)O)c(Cl)cc2F)C1=O
Reaction time: 1 h

Procedure:
11.4 g of N-(2-fluoro-5-carboxy-4-aminophenyl)-2,3-dimethylmaleic acid imide are introduced in portions, at a temperature of 25°-30°, into 60 ml of glacial acetic acid and 60 ml of 96% sulphuric acid and the whole is stirred at that temperature for 1 hour. The solution is then stirred at 5° and an aqueous solution of 2.9 g of sodium nitrite in 17 ml of water is added dropwise thereto. The resulting diazo solution is added in portions, while stirring vigorously at 30°, to a solution of 4.5 g of copper(I) chloride in 32 ml of concentrated hydrochloric acid. When the evolution of nitrogen has ceased, the reaction mixture is heated at 60° for a further 30 minutes, while stirring, and then poured onto ice. The product which precipitates is filtered with suction, washed with water and recrystallised from methanol/water. 9.8 g of N-(2-fluoro-5-carboxy-4-chlorophenyl)-2,3-dimethylmaleic acid imide having a melting point of 230°-231° are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH2:20][CH2:21][S:22][CH3:23])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:24]([O:26]CC)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH2:20][CH2:21][S:22][CH3:23])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:24]([OH:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2CCSC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSCCC1OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Yield: 108.9 %

Procedure:
To a stirred solution of intermediate 21, ethyl 3-(benzyloxy)-9-(2-(methylthio)ethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate (97 mg, 0.2 mmol) in 3 mL tetrahydrofuran was added lithium hydroxide (15 mg, 0.6 mmol) in 3 mL water. After 20 min the reaction mixture was acidified with 1N HCl and extracted with CH2Cl2. The extract was dried over MgSO4, filtered and concentrated to give 82 mg of the title compound (88% yield). LC/MS m/e 377.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([NH:4][C:5]3=[O:12])[CH2:2]1)[CH2:9]2.O(C)S([C:17](F)(F)F)(=O)=O>C(Cl)Cl>[CH3:17][O:12][C:5]1[CH:6]2[CH2:11][CH:1]3[CH2:9][CH:8]([CH2:10][CH:3]([CH2:2]3)[N:4]=1)[CH2:7]2
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: O=C1NC2CC3CC(C2)CC1C3
Solvent: ClCCl
Product: COC1=NC2CC3CC(C2)CC1C3

Procedure:
To a solution of 4-azatricyclo[4.3.1.13,8]undecan-5-one 3-A (1.00 g, 6.05 mmol) in 10 mL methylene chloride was added methyl triflate (2.98 g, 3 eq) and the reaction was heated at reflux for 20 min, after which time all volatiles were removed under reduced pressure to afford crude 5-methoxy-4-azatricyclo[4.3.1.13,8]undec-4-ene 3-B which was used in the next step without further purification.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.C(OC(=O)[N:16]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][N:27]=1)[CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)(C)(C)C>>[CH3:25][O:24][C:21]1[N:20]=[CH:19][C:18]([CH2:17][NH:16][C:26]2[N:27]=[CH:28][C:29]([C:32]([C:9]3[C:5]4[CH:4]=[N:3][CH:2]=[N:1][C:6]=4[NH:7][CH:8]=3)=[O:33])=[CH:30][CH:31]=2)=[CH:23][CH:22]=1
Reactant: c1ncc2cc[nH]c2n1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)cn1
Product: COc1ccc(CNc2ccc(C(=O)c3c[nH]c4ncncc34)cn2)cn1

Procedure:
{6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-yl}-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone P-0008 was prepared in three steps from 7H-pyrrolo[2,3-d]pyrimidine 6 and (5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester 71 as shown in Scheme 13.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](OCC)=O)[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]=2[CH:8]=1.O.[OH-].[Na+]>O1CCCC1>[Br:6][C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH3:18])[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]=2[CH:8]=1
Reactant: CCOC(=O)N1c2ccccc2C=C(Br)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1c2ccccc2C=C(Br)c2ccccc21

Procedure:
To 275 parts of a 3 1/2% solution of lithium aluminate(1-) in tetrahydrofuran at 0°-5° is slowly added, with vigorous stirring, 15 parts of concentrated sulfuric acid. The resultant mixture is stirred at 0°-5° for 1 hour, whereupon a solution of 34 parts of ethyl 10-bromo-5H-dibenz[b,f]azepine-5-carboxylate in 225 parts of tetrahydrofuran is introduced. The mixture thus obtained is stirred for 1 hour, whereupon a solution of 20 parts of water in 40 parts of tetrahydrofuran, followed by 30 parts of aqueous 25% sodium hydroxide and then finally by 30 parts of water, is added. Insoluble solids are filtered out and washed with several portions of tetrahydrofuran. Washings and filtrate are combined, dried over magnesium sulfate, and stripped of solvent by vacuum distillation to give 10-bromo-5-methyl-5H-dibenz[b,f]azepine as the residue.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14]CC)=[O:13])[C:6]2[S:10][CH:9]=[CH:8][C:7]=2[CH:11]=1)#[N:2].[OH-].[Na+]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6]2[S:10][CH:9]=[CH:8][C:7]=2[CH:11]=1)#[N:2]
Reactant: CCOC(=O)c1cc(C#N)cc2ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cc(C(=O)O)c2sccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
Ethyl 5-cyano-1-benzothiophene-7-carboxylate (5.6 g, 24.3 mmol) was dissolved THF (96 mL) and to the resultant solution was added an aqueous solution of NaOH (1.07 g of NaOH in 14 mL of water, 26.7 mmol) at 0° C. The mixture was stirred at room temperature overnight and then most of the solvent was removed by evaporation. The residue was dissolved in an aqueous solution of NaOH (0.1 M). The solution was washed thrice with chloroform, acidified with 2M HCl and then extracted with ethyl acetate. The organic solution was separated and the solvent was evaporated. The residue was flash chromatographed on silica gel (CH2Cl2-MeOH—NH4OH, 8:2:0.5). There was obtained 4.3 g (85%) of 5-cyano-1-benzothiophene-7-carboxylic acid as a tan solid. 1H NMR (500 MHz, DMSO-d6): 7.7 (d, 1H), 8.1 (d, 2H), 8.3 (d, 1H), 8.7 (s, 1H), 14 (b, 1H); LCMS: m/z 202 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:7][C:4]=1[CH:5]=O.[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:7][C:4]=1/[CH:5]=[CH:20]/[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=[O:21]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2cncnc2)cc1C=O
Product: COc1cc(OC)c(-c2cncnc2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 26 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-pyrimidin-5-yl-benzaldehyde (Ex-31A) and 4-acetylbezoic acid in a similar manner as described in Ex-3. Yellow solid, mp>260° C., 26% yield. 1H-NMR (DMSO-d6) δ 9.11 (s, 1H), 8.96 (s, 2H), 8.13–8.16 (m, 3H), 8.01–8.09 (m, 3H), 7.90 (d, J=15 Hz, 1H), 6.85 (s, 1H), 3.99 (s, 3H), MS m/z=391 ([M+H]+, 100%). HRMS (ES+) Calcd. for C22H18N2O5: 391.1294. Found: 391.1295.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.C(OCC1C=CC=CC=1)(=O)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C.CS(C)=O.O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][C:7]1[C:6]([F:9])=[C:5]([F:10])[N:4]=[C:3]([F:11])[C:2]=1[Cl:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1c(F)c(F)nc(F)c1Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.6 %

Procedure:
3-Chloro-2,4,5,6-tetrafluoropyridine (33.1 g, 178 mmol) and dibenzyl malonate (44.5 ml, 178 mmol) were dissolved in anhydrous DMF (360 ml) under nitrogen atmosphere. The mixture (142) was then cooled in an ice bath. To a stirred mixture, was portionwise added 60% sodium hydride (15.68 g, 392 mmol) during 2.5 hr. The mixture was then stirred in a water bath for ca. 15 hr. The mixture was neutralized with aqueous saturated ammonium chloride solution and the mixture was partitioned between ether and water. Ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as an yellow oil. The crude product was then dissolved in DMSO (200 ml) and stirred with water (3.2 ml) in an oil bath (130˜140° C.) for 3 hr. After cooling to room temperature, water was added to the mixture and the product was extracted with ether. The ether layer was washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light brown oil. The crude product was purified by silica gel column chromatography (eluent, ether:hexane (1:9)) to afford 41.9 g (74% for two steps) of (3-chloro-2,5,6-trifluoro-pyridin-4-yl)-acetic acid benzyl ester as a white solid. m.p. 87-92° C.; 1H NMR (200 MHz, CDCl3) δδ 3.96 (2H, d, J=1.6 Hz), 5.19 (2H, s), 7.30-7.39 (5H, m).