Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([CH3:17])[CH:19]=2)[NH:23][C:22]1=[O:27])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(c1)CC(=O)N2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(C)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-methyl-2-oxindole to give 0.3 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-5-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1]([C:6]1[NH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])([O:3][CH2:4][CH3:5])=[O:2].[C:17]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[C:1]([C:6]1[N:7]([CH3:17])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1c[nH]c(C(=O)OCC)c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c(C(=O)OCC)c1C
Yield: 91 %

Procedure:
A solution of 2, 4-dicarbethoxy-3 methylpyrrole (25) (2.44 g, 10.9 mmol), K2CO3 (9.9 g), and iodomethane (55 ml) in 750 ml acetone was refluxed at 50° C. for 15 hours. The solution was concentrated in vacuo, partitioned between 450 ml of dichloromethane and 600 ml of water. The aqueous layer was extracted with CH2Cl2 (2×500 ml), dried (sodium sulfate), and concentrated in vacuo to yield a brown oil that solidified upon standing at room temperature for several minutes and was used without further purification. (2.37 g, 91% yield). TLC (benzene) Rf 0.3; 1H NMR (CD2Cl2) δ 7.31 (s, 1H), 4.23 (m, 4H), 3.84 (s, 3H). 2.54 (2, 3H), 1.33 (m, 6H).
Reaction SMILES: F[B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+]([F:21])(CC1)CC2.[C:22]([O:26][C:27](=[O:44])[C:28]1[C:33]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:36]=2[Cl:42])=[CH:32][C:31]([NH2:43])=[N:30][CH:29]=1)([CH3:25])([CH3:24])[CH3:23].CO>CCOC(C)=O.O>[C:22]([O:26][C:27](=[O:44])[C:28]1[C:33]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:36]=2[Cl:42])=[C:32]([F:21])[C:31]([NH2:43])=[N:30][CH:29]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: CC(C)(C)OC(=O)c1cnc(N)cc1Nc1ccc(Br)cc1Cl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cnc(N)c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 2 h
Yield: 7.2 %

Procedure:
1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (889 mg, 2.508 mmol) was added to a mixture of 6-amino-4-(4-bromo-2-chlorophenylamino)nicotinic acid tert-butyl ester (42) (1.00 g, 2.51 mmol) in 1:1 MeOH:water (25 mL). After about 2 hours, the reaction mixture was diluted with EtOAc and water. The layers were separated and the organic layer washed with 0.5 N HCl and brine. The aqueous washes were back extracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated. Purification by flash column chromatography using the Biotage system (20:1 hexanes:EtOAc to 15:1 hexanes:EtOAc) provided the desired product (45) as a yellow solid (75 mg, 7%).
Reaction SMILES: [NH2:1][C:2]1(C(OC)=O)[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].O.O.O.[I-].[Li+]>N1C=CC=CC=1>[NH2:1][C@H:2]1[C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19]
Reactant: COC(=O)C1(N)C(=O)Nc2ccccc2CC1c1ccccc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Product: N[C@@H]1C(=O)Nc2ccccc2C[C@@H]1c1ccccc1
Product: N[C@@H]1C(=O)Nc2ccccc2C[C@H]1c1ccccc1

Procedure:
A mixture of 17.98 g of 3-amino-3-methoxycarbonyl-4-phenyl-1,3,4,5-tetrahydro-1-benzazepin-2(2H)-one, 21.76 g of lithium iodide trihydrate and 400 ml of dried pyridine is stirred under reflux for 2 days. To the residue obtained after the mixture is concentrated under reduced pressure, an aqueous solution of potassium carbonate, an aqueous solution of sodium thiosulfate and chloroform are added, and the organic substance is extracted. The chloroform layer is dried and concentrated. The obtained residue is subjected to silica gel chromatography (eluent: chloroform:methanol =20:1) to give 5.6 g of cis-3-amino-4-phenyl-1,3,4,5-tetrahydro-1-benzazepin-2(2H)-one and 5.44 g of trans-3-amino-4-phenyl-1,3,4,5-tetrahydro-benzazepin-2(2H)-one.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[CH:21]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:20][CH2:19]4)=[C:12]([C:31]([F:34])([F:33])[F:32])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].O1CCCC1.[Li+].[OH-].Cl>O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[CH:21]([CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:19]4)=[C:12]([C:31]([F:33])([F:32])[F:34])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)CC1CCc2cc(OCc3c(-c4ccc(CC)cc4)nsc3C(F)(F)F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc3c(c2)CCC3CC(=O)O)cc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl 2-(5-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-dihydro-1H-inden-1-yl)acetate (220 mg, 0.45 mmol, 1.00 equiv), tetrahydrofuran (5 mL), water (4 mL), LiOH (97 mg, 4.05 mmol, 9.01 equiv). The resulting solution was stirred overnight at 30° C. The pH value of the solution was adjusted to 2 with hydrogen chloride (1 mol/L). The resulting solution was extracted with 3×3 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (waters2767-16): Column, SunFire Prep C18,19*150 mm 5 umH PrepC-001(T)18600256819513816414 04; mobile phase, PhaseA:water with 0.05% NH4HCO3, PhaseB:CH3CN(50% CH3CN up to 100% in 10 min, hold 100% in 1.9 min, down to 50% in 0.1 min, hold 50% in 1.9 min); Detector, UV220&254 nm. This resulted in 18 mg (19%) of 2-(5-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-dihydro-1H-inden-1-yl)acetic acid as light yellow oil. 1H NMR: (CDCl3, 400 MHz): δ 7.65 (d, J=8.0 Hz, 2H), 7.30 (d, J=4.8 Hz, 2H), 7.17 (d, J=8.0 Hz, 1H), 6.79-6.85 (m, 2H), 5.05 (s, 2H), 3.58-3.61 (m, 1H), 2.82-2.98 (m, 3H), 2.69-2.75 (m, 2H), 2.44-2.54 (m, 2H), 1.79-1.88 (m, 1H), 1.28 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C24H22F3NO3S, 460.1 (M−H). found 460.1.
Reaction SMILES: [F:1][B-](F)(F)F.[CH2:6]([O:8][C:9]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[N:15][C:16]([O:24][CH3:25])=[C:17]([N+]#N)[CH:18]=2)[N:13]([CH2:26][CH3:27])[CH:12]=1)=[O:10])[CH3:7]>C1(C)C(C)=CC=CC=1>[CH2:26]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([F:1])=[C:16]([O:24][CH3:25])[N:15]=2)[C:20](=[O:21])[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])=[CH:12]1)[CH3:27]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1cn(CC)c2nc(OC)c([N+]#N)cc2c1=O
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cn(CC)c2nc(OC)c(F)cc2c1=O
Yield: 47.7 %

Procedure:
A suspension of 10 g of 3-ethoxycarbonyl-1-ethyl-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-6-diazonium tetrafluoroborate in 300 ml of xylene was heated under reflux for 30 minutes. After evaporation of the xylene, the residue was taken up in chloroform. The chloroform solution was washed with water and the solvent was distilled off. The crude product was chromatographed on silica gel with chloroform as an eluent to give 3.6 g of ethyl 1-ethyl-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 181°-182° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-methylphenol (10 g) in N,N-dimethylformamide (50 mL) were added potassium carbonate (8.87 g) and benzyl bromide (6.36 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-benzyloxy-1-bromo-2-methylbenzene (14.6 g). This material was dissolved in tetrahydrofuran (200 mL). To the solution was added n-butyl lithium (2.66 mol/L n-hexane solution, 21.7 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. To the reaction mixture was added N,N-dimethylformamide (10.1 mL), and the mixture was allowed to warm to 0° C. and stirred for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-benzyloxy-2-methylbenzaldehyde. This material was dissolved in ethanol (100 mL). To the solution was added sodium borohydride (1.99 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added methanol, and the resulting mixture was concentrated under reduced pressure. To the residue was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with diethylether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=6/1-3/1-1/1) to give the title compound (10.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[O:9][C:8]([CH3:13])([CH3:12])[O:7][C:6]=2[CH:14]=1.CC1C=CC(S(O[CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH3:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[O:9][C:8]([CH3:12])([CH3:13])[O:7][C:6]=2[CH:14]=1
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCOCCOc1ccc2c(c1)OC(C)(C)OC2=O
Yield: 74.2 %

Procedure:
A solution of 7-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one, (19.4 g, 100 mmol), 2-(2-methoxyethoxy)ethyl 4-methylbenzenesulfonate (27.4 g, 100 mmol) and K2CO3 (41 g, 300 mmol) in CH3CN (500 mL) was refluxed for 4.5 hours. The mixture was poured in H2O (1000 mL) and extracted twice with CH2Cl2 (500 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE/EtOAc=9/1) to give the title compound (22 g) as white solid. LC-MS (ES, m/z): 297 [M+H]+.
Reaction SMILES: [CH2:1](OS(C1C=CC(C)=CC=1)(=O)=O)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[CH-:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.[Na+]>C1COCC1>[CH2:1]([C:22]1[CH2:21][CH:20]=[CH:19][CH:18]=1)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCO2)cc1
Reactant: c1cc[cH-]c1
Agent: [Na+]
Solvent: C1CCOC1
Product: C1=CCC(CC2CCCO2)=C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To a solution of 26.0 g (101 mmol) tetrahydrofurfuryltosylate prepared according to step (a) above in 200 ml THF cooled to 0° C. was added 63 ml of 2.0M (126 mmol) sodium cyclopentadienylide in THF. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. 100 ml concentrated aqueous saline solution was then added to the mixture and the product extracted with diethyl ether (3×75 ml). The combined organic fractions were dried over sodium sulphate for 16 h, filtered and the solvents removed under reduced pressure using a rotary evaporator to yield a brown oil. The crude product was distilled under reduced pressure (b.p. 32°-34° C. at 0.3-0.4 mm Hg) to give 7.1 g of a colourless oil (47.3 mmol, 46.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH3:12])=[C:5]2[CH2:13][CH3:14].[C:15](Cl)([Cl:17])=[O:16].[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>>[ClH:17].[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[C:5]([CH2:13][CH3:14])=[C:6]1[CH3:12]
Reactant: Nc1ccncc1
Reactant: CCc1c(C)n(C)c2ccc(N)cc12
Reactant: O=C(Cl)Cl
Product: CCc1c(C)n(C)c2ccc(NC(=O)Nc3ccncc3)cc12
Product: Cl
Yield: 47 %

Procedure:
The title compound was prepared in 47% yield from the aminoindole (D1), phosgene and 4-aminopyridine using a procedure similar to that described for Example 1, the product being isolated as the hydrochloride salt, m.p. 237°-243° C.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)CCl.[CH:12]1[CH:13]=[CH:14][C:15]2[N:20](O)N=[N:18][C:16]=2[CH:17]=1.NCC1C=CC=CN=1>C1COCC1>[N:18]1[CH:14]=[CH:13][CH:12]=[CH:17][C:16]=1[CH2:15][NH:20][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)O
Reactant: On1nnc2ccccc21
Agent: NCc1ccccn1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCCCC(=O)NCc1ccccn1
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a solution of pentanoic acid (5.3 mL, 48.7 mmol) in THF (50 mL) was added EDC (11.2 g, 58.4 mmol) and HOBt (7.88 g, 58.4 mmol). The mixture was stirred for 10 min. then 2-(aminomethyl)pyridine (4.7 mL, 46.3 mmol) was added. The solution was allowed to stir for 3 h then quenched with water (100 mL). The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield pentanoic acid (pyridin-2-ylmethyl)-amide (8.60, 92%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19](=[O:22])[NH:20][CH:21]=2)[CH2:12][CH2:11]1.[CH3:23]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>C(Cl)(Cl)Cl.O>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19](=[O:22])[N:20]([CH3:23])[CH:21]=2)[CH2:12][CH2:11]1
Reactant: CN(C)C=O
Reactant: O=c1ccc(N2CCN(c3cccc(CO)c3F)CC2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CI
Product: Cn1cc(N2CCN(c3cccc(CO)c3F)CC2)ccc1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
5-{4-[2-Fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one (352 mg) and DMF (10 ml) were mixed, and potassium carbonate (240 mg) and methyl iodide (200 mg) were added thereto, followed by stirring at 60° C. overnight. Methyl iodide (49 mg) and potassium carbonate (48.1 mg) were added thereto, followed by stirring at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, and water and CHCl3 were added thereto at 0° C. The organic layer was washed with water and saturated brine, and then dried over Na2SO4, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-{4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}-1-methylpyridin-2(1H)-one (256 mg).
Reaction SMILES: Br.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[SH:13][C:14]1[NH:15][C:16]2[C:17](=[CH:19][S:20][CH:21]=2)[N:18]=1.CC(C)=O>CC(N(C)C)=O>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:13][C:14]1[NH:18][C:17]2=[CH:19][S:20][CH:21]=[C:16]2[N:15]=1
Reactant: CN(C)c1ccccc1CBr
Reactant: Sc1nc2cscc2[nH]1
Agent: Br
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: CN(C)c1ccccc1CSc1nc2cscc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.9 g of 2-dimethylaminobenzyl bromide hydrobromide are added to a solution of 1.56 g of 2-mercaptothieno[3,4-d]imidazole in 20 ml of anhydrous dimethylacetamide. A crystalline precipitate separates out in a weakly exothermic reaction. The mixture is stirred at room temperature for one hour, acetone is added, and the crystals are filtered off and dried in a stream of air. The crystalline solid is then introduced into saturated aqueous NaHCO3 solution, the mixture is heated briefly on a steam bath and, after stirring at room temperature, the crystals are filtered off. Treatment with active charcoal in ethanol and concentration is followed by solution being induced to crystallize with a little acetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:4]=1.[Cl:17][C:18]([Cl:24])([Cl:23])[C:19](=N)OC>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]2[N:7]=[C:19]([C:18]([Cl:24])([Cl:23])[Cl:17])[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]=2[CH:4]=1
Reactant: COCCCCNc1cc(OC)ccc1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COCCCCn1c(C(Cl)(Cl)Cl)nc2ccc(OC)cc21
Reaction time: 1.5 h

Procedure:
4-Methoxy-2-(4-methoxybutylamino)aniline (2.50 g) was dissolved in acetic acid (30 ml), methyl 2,2,2-trichloroethanimidate (1.62 ml) was added, and the mixture was stirred for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with diisopropyl ether, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object product (1.75 g). MS (ESI+, m/e) 351 (M+1)
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]=[CH:6][S:5][CH:4]1[C:8]#[N:9].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]#[N:9]
Reactant: COC1C=CSC1C#N
Solvent: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: COc1ccsc1C#N
Yield: 91 %

Procedure:
14.1 parts of 3-methoxy-2-cyanodihydrothiophene in 80 parts by volume of chloroform are reacted with 6.75 parts of sulfuryl chloride in 20 parts by volume of chloroform for 0.5 hour at 0° C. The end product is isolated from the reaction mixture by the method described in Example 14c). 12.6 parts (91% of theory) of 3-methoxy-2-cyanothiophene of boiling point 73° C./0.16 mbar are obtained.
Reaction SMILES: [Br-:1].[C:2]([O:5][C:6]1[C:15]2[N+:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Br:16])(=O)[CH3:3].CCOC1C=CC(N)=CC=1>C(O)(C)C>[CH3:3][CH2:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH3+:10])=[CH:14][CH:15]=1.[Br-:16].[Br:16][C:7]1[CH:8]=[CH:9][N+:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]=1[OH:5].[Br-:1]
Reactant: CC(=O)Oc1c(Br)cc[n+]2ccccc12
Agent: CCOc1ccc(N)cc1
Agent: [Br-]
Solvent: CC(C)O
Product: CCOc1ccc([NH3+])cc1
Product: Oc1c(Br)cc[n+]2ccccc12

Procedure:
To a solution of 1-acetoxy-2-bromoquinolizinium bromide (30.0 g., 0.09 mole) in isopropanol (600 ml.) was added p-phenetidin (24.0 g., 0.18 mole). The stirred mixture was boiled under reflux for 4 hours, during which time solid had precipitated from solution. The cooled mixture was filtered and washed with ether. The product as yellow needles weighed 37.0 g. (97%). Recrystallization from alcohol-ether provided yellow needles which melted at 161°-162°.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([N:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)(=[O:18])=[O:17])COC)=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].I[C:32]1[C:33]2[CH:40]=[CH:39][N:38](COCC[Si](C)(C)C)[C:34]=2[N:35]=[CH:36][N:37]=1.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:12][C:11]2[C:6]([C:4]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)=[O:5])=[N:7][CH:8]=[CH:9][CH:10]=2)(=[O:18])=[O:17])=[CH:20][C:21]=1[C:26]([F:28])([F:27])[F:29]
Reactant: COCN(c1cccnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ncnc2[nH]ccc12

Procedure:
Prepared from 248 mg (0.53 mmol) of 3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid methoxy-methyl-amide, 239 mg (0.58 mmol) of 90% 4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with 0.32 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 4 mL methanol and 4 mL 6N hydrochloric acid mixture to give after purification 29 mg of the final product as a yellow solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=2)[C:7]1=[O:19])[CH3:4].[C:20]1([N:26]2[C:30]3([CH2:35]CNC[CH2:31]3)[C:29](=[O:36])[NH:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH3:16][O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:17][CH3:18])[C:7](=[O:19])[CH:6]([CH2:5][N:3]1[CH2:4][CH2:35][C:30]3([N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][NH:28][C:29]3=[O:36])[CH2:31][CH2:2]1)[CH2:14]2
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: COc1cc2c(cc1OC)C(=O)C(CN(C)C)C2
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=O)C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)C2
Yield: 90.2 %

Procedure:
2-[(Dimethylamino)methyl]-5,6-dimethoxy-1-indanone, hydrochloride (1:1) (2.0 g) and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (1.94 g) are stirred for 20 hours in 20 ml of absolute ethanol while a slow stream of nitrogen is bubbled through. The resultant precipitate is filtered off and dried to yield 2.75 g of the title compound, melting point 174°-177° C.
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([NH:41][C:42]([C:44]2[C:49](=[O:50])[N:48]([C:51]3[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=3)[CH:47]=[CH:46][N:45]=2)=[O:43])[CH:38]=[CH:37][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[N:11]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:12]=[C:13]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[C:6]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:40]=[C:39]([NH:41][C:42]([C:44]2[C:49](=[O:50])[N:48]([C:51]3[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=3)[CH:47]=[CH:46][N:45]=2)=[O:43])[CH:38]=[CH:37][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[N:11]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[N:12]=[C:13]([CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:6]=12
Reactant: COc1ccc(Cn2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2nc(CC3CCNCC3)c3c(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolved tert-butyl 4-((4-(2-fluoro-4-(4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)piperidine-1-carboxylate (43 mg, 0.055 mmol) in DCM (1 mL) and added excess TFA (d 1.48) (0.100 ml). The mixture was stirred at room temperature for 18 hours. The solvent was removed, and the crude was partitioned between DCM (15 mL) and aqueous 10% Na2CO3 (20 mL). The organic layer was washed with brine, dried over sodium sulfate and evaporated to afford title compound as free-base. Yield 41 mg, 89% purity by HPLC, 97%. LRMS (APCI pos) m/e 678.3 (M+H).