Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:15](=[O:24])[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:11]N(C)C)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[OH-:26].[K+]>>[OH:17][C:16]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:24])[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[CH:11][O:26]1
Reactant: CN(C)C=C(C(=O)C(=O)c1ccccc1)c1ccc(C(=O)O)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: O=C(O)c1ccc(C2=COC(O)(c3ccccc3)C2=O)cc1
Temperature: 0 °C
Yield: 71 %

Procedure:
A solution of 3.23 g of 2-(4-carboxyphenyl)-1-dimethylamino-4-phenyl-1-butene-3,4-dione in 100 ml of 2% potassium hydroxide solution was stirred at room temperature for 5 hrs. The reaction mixture was poured onto 300 ml of ice-water and acidified with 100 ml of 1N hydrochloric acid. The precipitate was collected, washed with water and then dissolved in 300 ml of ether. The solution was dried over anhydrous sodium sulfate. The drying agent was collected and the filtrate was evaporated. Recrystallization from ether gave 2.12 g (71%) of 2-hydroxy-2-phenyl-4-(4-carboxyphenyl)-3(2H)-furanone, m.p. 294°-299° C. dec.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([Br:3])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CN
Solvent: Cc1ccccc1
Product: CNCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
800 ml of an 8% solution of methylamine in toluene are added, whilst cooling with ice, to 100 g of 4-bromobenzaldehyde and 300 g of molecular sieve (3 Angstroms). The mixture is stirred overnight at ambient temperature, suction filtered to remove the molecular sieve and the solvent is evaporated off. The residue is dissolved in 1.4 litres of ice cold methanol and 48 g of sodium borohydride are added in batches whilst cooling with ice. Then the mixture is stirred for 30 minutes at 0° C., for one hour at 10° C. and for two hours at ambient temperature, then evaporated to dryness, the residue is taken up in ice water, acidified with half concentrated hydrochloric acid and extracted twice with ether. The ether is discarded, the aqueous phase is made alkaline with concentrated sodium hydroxide solution whilst cooling and then extracted three times with ether. The organic phase is washed with water and saturated saline solution, dried and evaporated down. 96.8 g of N-methyl-4-bromobenzylamine are obtained in the form of a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[O:12])=[N:7][N:8]2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=2)=[CH:4][CH:3]=1
Reactant: Nc1nccc(Cl)n1
Reactant: O=C(c1n[nH]c2cc(Br)ccc12)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nccc(-n2nc(C(=O)N3CCOCC3)c3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-bromo-3-[(morpholin-4-yl)carbonyl]-1H-indazole (78%, 458 mg, 1.15 mmol) in DMF (8 mL) was added NaH (60% oil suspension, 73.71 mg, 1.84 mmol) at 0° C. Mixture was stirred at RT for 10 minutes before addition of 4-chloropyrimidin-2-amine (298.44 mg, 2.3 mmol). The mixture was stirred at RT for 10 minutes and then at 65° C. for 5 hr. Reaction mixture was quenched by addition of water (5 mL) and a little EtOAc (2 mL) was added. Precipitate formed was collected and dried under vacuum to give the title compound: 1H NMR (500 MHz, DMSO) delta 3.58-3.80 (6H, m), 3.87-4.13 (2H, m), 7.07 (1H, d, J=5.52 Hz), 7.59 (1H, dd, J=8.51, 1.42 Hz), 7.94 (1H, d, J=8.83 Hz), 8.35 (1H, d, J=5.52 Hz), 9.19 (1H, d, J=1.26 Hz); LC-MS: m/z=+404.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]([NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:3]1=[O:30].[C:32]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O>[CH3:31][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]([N:11]([CH3:32])[C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:3]1=[O:30]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCCN1C(=O)C(C)(C)c2cc(N(C)C(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of N-(3,3-dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionamide (142 mg) in dry N,N-dimethylformamide (6 ml) is added K2CO3 (163 mg; 1.18 mmol) and methyl iodide (45 μl; 0.72 mmol). The mixture is stirred at 75° C. for 2 days. After an aqueous work-up the compound is obtained.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17](Cl)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>O.ClCCl>[C:17]([C:10]1[C:6]([CH3:5])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][C:9]=1[CH3:11])(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCC(=O)c1c(C)[nH]c(C(=O)OCC)c1C

Procedure:
1.46 g (11 mmol) of AlCl3 were added to a solution of 1.67 g (10 mmol) of ethyl 3,5-dimethylpyrrole-2-carboxylate a 2.63 g (12 mmol) of dodecanoyl chloride in 30 ml of absol. Dichloromethane and then stirred for 24 h. Addition of water and dilute HCl is followed by extraction twice with CH2Cl2. The organic phases are washed with dilute NaOH, dried over Na2SO4 and concentrated. The product is recrystallized from isopropanol.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C[Li].[CH2:14](OCC)C.Cl[Si](C)(C)C>C1COCC1>[F:11][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8](=[O:10])[CH3:14])[CH2:6][CH2:7]1
Reactant: CCOCC
Reactant: O=C(O)C1CCC(F)(F)CC1
Agent: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C1CCC(F)(F)CC1
Reaction time: 2 h

Procedure:
To a clear solution of 4,4-difluorocyclohexanecarboxylic acid (2.00 g, 12.18 mmol) in 100 mL THF at 0° C. was added slowly dropwise methyllithium, 1.6M solution in diethyl ether (30.5 mL, 48.7 mmol) from an addition funnel. The resulting cloudy mixture was allowed to stir 2 h, then was treated with chlorotrimethyl silane (24.74 mL, 195 mmol) dropwise over 10 min. The bath was removed and the clear solution allowed to stir 1 h. 5 mL 1M HCl aq. Was added and the reaction mixture stirred an additional hour. The reaction mixture was then concentrated in vacuo to a small volume, diluted with Et2O, and the organic layer was washed with water, sat'd aq. NaHCO3, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give impure 1-(4,4-difluorocyclohexyl)-ethanone as a clear/colorless oil, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([C:11]=1C(O)=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:16]([O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][CH:28]=[C:27]2Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH2:16]([O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][CH:28]=[C:27]2[O:1][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OCc1ccccc1
Reactant: Cc1nc2ccccc2c(C(=O)O)c1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCc1ccccc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
3-Hydroxy-2-methyl-4-quinoline carboxylic acid (549 mg), 6-benzyloxy-4-chloro-7-methoxyquinoline (810 mg), and 4-(N,N-dimethylamino)-pyridine (990 mg) were dissolved in 1,2-dichlorobenzene (40 ml) to prepare a solution. The mixture was stirred at 150° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give the title compound (718 mg, yield 63%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.[Br:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.[CH2:32]=[O:33]>C1COCC1>[Br:21][C:22]1[C:31]([CH2:32][OH:33])=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: C=O
Reactant: Brc1ccc2ccccc2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OCc1cc2ccccc2nc1Br
Reaction time: 1 h

Procedure:
To a solution of LDA, freshly prepared from diisopropylamine (0.42 mL, 2.97 mmol) and n-BuLi (2.97 mmol), in THF (10 mL) at -78° C. was added 2-bromoquinoline (T. Young and E. Amstutz, J. Am. Chem. Soc. 73, 4773 (1951)) (570 rag, 2.7 mmol) and stirring was continued for 1 h. This mixture was cannulated into a solution of formaldehyde in THF at -78° C., which was prepared by cracking paraformaldehyde (1.24 g, 14.8 mmol) under 140°-180° C. and releasing the gas into THF (25 mL) at -23 ° C. Stirring was continued for 6.5 h at -78° C. The reaction was quenched with water (5 mL) and extracted with EtOAc (3×25 mL). After drying (MgSO4), concentration gave a light yellow solid (660 mg) which was purified by recrystallization and chromatography (silica gel, 15% EtOAc/hexanes) to give 373 mg (58%) of the product as a white solid: mp 173°-4° C. 1H NMR (300 MHz, CDCl3) δ8.24 (s, 1H), 8.05 (d, 1 H, J=8 Hz), 7.84 (d, 1 H, J=8 Hz), 7.75 (m, 1 H), 7.59 (m, 1 H). 4.90 (d, 2 H, J=6 Hz), 2.36 (rt, 1 H, J=6 Hz). Analysis calculated for C10H8BrNO was as follows: C, 50.45; H, 3.39; N, 5.88. Found: C, 50.72; H, 3.35; N, 5.94 .
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[C:13]4[S:18][CH:17]([CH3:19])[N:14]43)=[CH:9][C:8]=2[F:24])[CH2:3]1.II.[Cl:27]S(O)(=O)=O>>[NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([Cl:27])=[C:15]3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[C:13]4[S:18][CH:17]([CH3:19])[N:14]43)=[CH:9][C:8]=2[F:24])[CH2:3]1
Reactant: CC1Sc2c(C(=O)O)c(=O)c3cc(F)c(N4CCC(N)C4)cc3n21
Reactant: O=S(=O)(O)Cl
Agent: II
Product: CC1Sc2c(C(=O)O)c(=O)c3cc(F)c(N4CCC(N)C4)c(Cl)c3n21

Procedure:
To a solution of 1.80 g of 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid in 10 ml of chlorosulfonic acid, a trace of iodine was added, and the mixture was bubbled with chlorine gas for 3.5 hours under ice-cooling with stirring. The reaction mixture was poured into ice-water and neutralized to pH 8 with 10% aqueous sodium hydroxide. The precipitate obtained was collected by filtration and converted to the methanesulfonate. The salt was dissolved into water and filtered. The filtrate was neutralized to pH 8 with 10% aqueous sodium hydroxide. The precipitate was collected by filtration to give 1.50 g of pale yellowish-brown crystals.
Reaction SMILES: [OH:1][C:2]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C:7]2[C:3]=1[C:4]([CH3:18])([CH3:17])[C:5](=[O:16])[N:6]=2.[C:19]([O-])([O-])=O.[K+].[K+].CI>CO>[CH3:19][O:1][C:2]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C:7]2[C:3]=1[C:4]([CH3:18])([CH3:17])[C:5](=[O:16])[N:6]=2
Reactant: CC1(C)C(=O)N=C2C1=C(O)C(=O)c1ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CO
Product: COC1=C2C(=NC(=O)C2(C)C)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione (compound 1) (0.1 g, 0.415 mmol) in MeOH (5 mL) was added K2CO3 (0.132 g, 0.96 mmol) while stirring at RT. After 10 min. MeI (100 μL, 0.228 g, 1.6 mmol) was added via a syringe and the mixture was allowed to stirred over night. The solvent was removed in vacuum and the solid was dissolved in CHCl3, filtered and purified by prep. HPLC (SF/CHCl3). Yield: 0.051 mg (50%). 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 6 H), 3.68 (s, 3 H), 7.58 (t, 1 H), 7.68 (t, 1 H), 8.02 (d, 1 H), 8.23 (d, 1 H). MS (CI) m/z: 256.31 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.O[CH2:7][S:8]([CH2:11][CH2:12][Cl:13])(=[O:10])=[O:9].[Cl:14][C:15]1[C:23]([NH2:24])=[CH:22][C:21]([Br:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]>C(#N)C>[Cl:14][C:15]1[C:23]([NH:24][CH2:7][S:8]([CH2:11][CH2:12][Cl:13])(=[O:10])=[O:9])=[CH:22][C:21]([Br:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: O=S(=O)(CO)CCCl
Reactant: Nc1cc(Br)cc(C(=O)O)c1Cl
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: O=C(O)c1cc(Br)cc(NCS(=O)(=O)CCCl)c1Cl
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 63.9 %

Procedure:
1 ml of concentrated sulfuric acid, followed by 9.6 g (60 mmoles) of hydroxymethyl-(β-chloroethyl)-sulfone were added at 60° C, whilst stirring, to a filtered solution of 12.6 g (50 moles) of 2-chloro-5-bromo-3-aminobenzoic acid in 150 ml of hot acetonitrile. The mixture was stirred for a further 2.5 hours at 50° C and was then cooled to 10° C, and the product which had precipitated was filtered off. It was rinsed with water and dried in air. 15 g (77% of theory) of 2-chloro-5-bromo-[(β-chloroethyl)-sulfonylmethylamino]-benzoic acid were obtained in the form of a yellow powder of melting point 164° C (with decomposition).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:3].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:33][C:34](=[NH:53])[C:35]1[CH:52]=[CH:51][C:38]2[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43][C:37]=2[CH:36]=1>CN(C=O)C>[CH3:3][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:33]=[C:34]([C:35]3[CH:52]=[CH:51][C:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:42][CH2:43][C:37]=4[CH:36]=3)[N:53]=2)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:1]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=N)NO)cc2CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
4-[(1-Methylethyl)oxy]-3-(trifluoromethyl)benzoic acid (Preparation 39) (744 mg, 3.00 mmol), HOBT (446 mg, 3.30 mmol) and EDC (630 mg, 3.30 mmol) were stirred in DMF (28 ml) under argon for 20 minutes. 1,1-dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 41) (915 mg, 3.00 mmol) was added and the mixture stirred at room temperature for 2 hrs before it was heated to 80° C. for 20 hrs. The reaction mixture was partitioned between EtOAc and water and the organic layer washed with aqueous sodium bicarbonate before it was dried in the usual manner and evaporated. The residue was purified by Biotage Horizon, reverse phase cartridge, eluting with 5-100% acetonitrile in water to give the title compound (749 mg, 1.45 mmol). δH (d6DMSO, 400 MHz): 8.40 (1H, dd), 8.31 (1H, d), 7.89 (1H, br.s), 7.86 (1H, dd), 7.58 (1H, d), 7.37 (1H, d), 4.98 (1H, septet), 3.54-3.46 (4H, m), 3.00-2.92 (4H, m), 1.41 (9H, s), 1.36 (6H, d).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:8])[CH3:7].[H-].[Na+].[C:11](=O)([O:15]CC)[O:12][CH2:13][CH3:14]>>[O:8]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:7][C:11]([O:12][CH2:13][CH3:14])=[O:15]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cccs1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1cccs1
Temperature: 71 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(thiophen-2-yl)ethanone (2.944 g, 23.3 mmol) and Diethyl carbonate (70 mL) at 0° C. was added sodium hydride (1.86 g, 46.6 mmol). The resulting off-white slurry solution was gradually warmed to 71° C., and stirred for 1.5 hour. The reaction mixture was poured into ice-HOAc—H2O, and extracted with ethyl acetate. The organic phase was washed (brine), dried (MgSO4) and concentrated to give a brown liquid. The crude product was purified via flash chromatography (silica gel cartridge with eluent of 0-3% ethyl acetate/hexane) to afford ethyl 3-oxo-3-(thiophen-2-yl)propanoate as an amble liquid, 4.193 g (91%). LCMS m/z 388.99, 390.09 (M+23); HPLC: Rt 2.01 min. (4.0 min. gradient, Column: YMC Combiscreen C-18, Method A).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH:23][C:24]([NH2:26])=[S:25])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:29][C:30](=O)[CH3:31].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH:23][C:24]2[S:25][CH:29]=[C:30]([CH3:31])[N:26]=2)=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CCl
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(NC(N)=S)c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(Nc3nc(C)cs3)c2c1
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
To solution of (6,8-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (50 mg, 0.127 mmol) and chloroacetone (16.1 mg, 0.166 mmol) in acetone (1.4 mL) was added MgSO4 (7.7 mg, 0.0637 mmol). The resulting suspension was stirred at 60° C. and for 4.5 h. The reaction was cooled and concentrated. The residue passed through a 5 g silica cartridge, eluting with 2% MeOH in DCM, to give [6,8-dimethoxy-4-(4-methyl-thiazol-2-ylamino)isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester as a yellow solid (21.3 mg; 39%). 1H-NMR (CDCl3): δ, 8.59 (s, 1H), 7.00 (s, 1H), 6.76 (s, 1H), 6.61 (d, 1H, J=2.2 Hz), 6.13 (s, 1H), 5.05 (d, 2H, J=4.3 Hz), 3.99 (s, 3H), 3.92 (s, 3H), 2.32 (s, 3H), 1.51 (s, 9H); MS: calculated for C21H26N4O4S+H 431.0; found: 431.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][N:16]([S:22](Cl)(=[O:24])=[O:23])[CH2:17]2.[N:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[N:28][CH:27]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][N:16]([S:22]([NH:32][C:29]1[CH:30]=[CH:31][N:26]=[CH:27][N:28]=1)(=[O:24])=[O:23])[CH2:17]2
Reactant: O=S(=O)(Cl)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Reactant: Nc1ccncn1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccncn1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A 15-mL round-bottom flask was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate D, 287.2 mg, 0.731 mmol) and triethylamine (224 μl, 1.609 mmol) in DCM (3.8 mL) to give a brown solution. The flask was cooled in an ice-bath for 10 min, then sulfuryl chloride (125 μl, 1.536 mmol) was added dropwise. Stirring was continued for 2 hours at which time the mixture was quenched with water, then extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on a 40 g silica gel column with 0 to 40% EtOAc/Heptane to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (253.01 mg, 0.556 mmol) as a clear, very viscous oil that was immediately used in the next step. A vial was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (40.045 mg, 0.088 mmol), pyrimidin-4-amine (41.9 mg, 0.440 mmol), chloroform (587 μl), and pyridine (71.2 μl, 0.881 mmol) and was placed into a 50° C. bath. The mixture was heated overnight before being allowed to cool to rt. The mixture was concentrated under a vacuum, and the residue was chromatographed on a 12 g silica gel column with 0 to 6% MeOH/DCM to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (29.77 mg, 0.058 mmol) as a yellow solid. [M+H]+=513.0. 1H NMR (400 MHz, DMSO-d6) δ ppm=9.55 (br. s., 1H), 9.07 (br. s., 1H), 8.57 (br. s., 1H), 8.13 (d, J=1.3 Hz, 1H), 7.99 (br. s., 1H), 7.83 (dd, J=1.1, 8.0 Hz, 1H), 7.55-7.44 (m, 1H), 7.35-7.21 (m, 2H), 7.02 (dd, J=2.0, 6.8 Hz, 1H), 4.71 (d, J=6.4 Hz, 1H), 4.32-4.17 (m, 2H), 3.24-3.07 (m, 2H), 2.45 (br. s., 2H).
Reaction SMILES: [F:1][C:2]1[C:21]([I:22])=[CH:20][C:5]2[C:6]3[N:10]=[C:9]([C:11]([O:13]CC)=O)[NH:8][C:7]=3[CH:16]3[CH2:19][CH:18]([C:4]=2[CH:3]=1)[CH2:17]3.[NH3:23]>CO>[F:1][C:2]1[C:21]([I:22])=[CH:20][C:5]2[C:6]3[N:10]=[C:9]([C:11]([NH2:23])=[O:13])[NH:8][C:7]=3[CH:16]3[CH2:17][CH:18]([C:4]=2[CH:3]=1)[CH2:19]3
Reactant: CCOC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(I)cc1-2
Reactant: N
Solvent: CO
Product: NC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(I)cc1-2
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of ethyl 8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (302 mg at 69% purity) in methanolic ammonia (7 mL of a 7.0M solution of ammonia in methanol, 49.0 mmol) was warmed to 44° C. for 72 hr in a pressure tube. After cooling to room temperature, the precipitous solution was evaporated to dryness in vacuo. The residue was re-suspended in methanol (1 mL) and the solid collected by filtration to furnish the title compound (155 mg, 0.40 mmol, 78%) as an off-white powder: 1H NMR (500 MHz, d6-DMSO) δ 1.47-1.49 (m, 2H), 2.83-2.91 (m, 2H), 3.40-3.44 (m, 1H), 3.60-3.68 (m, 1H), 7.10 (d, J=9.2 Hz, 1H), 7.42 (br. s, 1H), 7.82 (br, s, 1H), 8.64 (d, J=6.9 Hz, 1H), 13.08 (br. s, 1H); M+H=384
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][N:15]=2)=[N:6]1.[CH:26]1([N:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[CH2:28][CH2:27]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH:26]1([N:29]2[CH2:34][CH2:33][CH:32]([NH:21][C:17]3[C:18]([NH2:20])=[N:19][C:14]([C:7]4[C:8]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[N:5]([CH2:4][C:3]5[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=5[F:1])[N:6]=4)=[N:15][CH:16]=3)[CH2:31][CH2:30]2)[CH2:28][CH2:27]1
Reactant: O=C1CCN(C2CC2)CC1
Reactant: Nc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1NC1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
200 mg (0.596 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamine (synthesis described in US2004/67937; Example V) were initially charged in methanol (16 ml) and admixed with 75 μl (1.312 mmol) of acetic acid, and then 182 mg (1.312 mmol) of 1-cyclopropyl-4-piperidinone were added. After stirring at RT for 15 min, 104 mg (1.67 mmol) of sodium cyanoborohydride were added and the mixture was stirred at RT for 2.5 h. Subsequently, within 2 days, the above-stated amounts of reagents (1-cyclopropyl-4-piperidinone, acetic acid, sodium cyanoborohydride) were added three times, in order to achieve substantially full conversion. Thereafter, saturated aqueous sodium hydrogencarbonate solution (5 ml) was added and the mixture was stirred vigorously for 10 min. Subsequently, the mixture was extracted with water and ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated and then purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 165 mg of the title compound were obtained (60% of theory).