Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)=[CH:9][CH:8]=1>COCOC>[CH3:18][C:16]1([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14][B:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][NH:4][CH:1]([CH3:3])[CH3:2])=[CH:12][CH:11]=2)[O:17]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: CC(C)N
Solvent: COCOC
Product: CC(C)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Isopropylamine (0.5 ml) was added dropwise to a solution of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.5 g) in dimethoxymethane (10 ml) and the resulting solution was stirred at room temperature for 18 h. The reaction mixture was evaporated under reduced pressure and used immediately. b) 2-[(Aminocarbonyl)amino]-5-{4-[(isopropylamino)methyl]phenyl}thiophene-3-carboxamide A solution of N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]propan-2-amine (0.46 g), 2-[(aminocarbonyl)amino]-5-bromothiophene-3-carboxamide (0.2 g) and sodium carbonate (0.32 g) in a DME (15 ml)/water (1.5 ml) mixture was heated to 80° C. under an argon stream. Tetrakis-(triphenylphosphine)palladium(0) (5.1 g) was then added and the reaction was stirred at 90° C. for 4 h, cooled and evaporated under reduced pressure. The residue was partitioned between DCM and saturated sodium carbonate and the solid interlayer was filtered and washed with water. The pure product was obtained by cation exchange chromatography eluting with ammonia/methanol mixtures (0.06 g). MS (ES) 333 (M+H)+. 1H NMR (DMSO-D6) 1.0 (d, 6H), 2.7 (m, 1H), 3.7 (s, 2H), 6.9 (br, 2H), 7.3 (br, 1H), 7.4 (d, 2H), 7.5 (d, 2H), 7.7 (br, 1H), 7.75 (s, 1H), 11.0 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].C[O:9][C:10]([C:12]1([CH3:33])[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Br:25])[CH:21]=3)[NH:16][C:15]=2[CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[NH:13]1)=O>>[Br:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[CH:14]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=3)[N:13]3[C:6](=[O:7])[N:5]([CH2:4][CH2:3][CH2:2][Cl:1])[C:10](=[O:9])[C:12]3([CH3:33])[CH2:24][C:23]2=1
Reactant: O=C=NCCCCl
Reactant: COC(=O)C1(C)Cc2c([nH]c3ccc(Br)cc23)C(c2cccc(O)c2)N1
Product: CC12Cc3c([nH]c4ccc(Br)cc34)C(c3cccc(O)c3)N1C(=O)N(CCCCl)C2=O

Procedure:
The title compound is prepared analogously to the procedure described for example 22, using chloro propyl isocyanate and (1RS,3SR)-6-bromo-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-betacarboline-3-carboxylic acid methyl ester. MS: m/z (MH+)=501.9/503.9
Reaction SMILES: Br[C:2]1[C:6]2[N:7]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[CH:8]=[CH:9][C:5]=2[S:4][CH:3]=1.C(Cl)Cl.CCN(CC)CC.C[CH2:32][O:33][C:34](C)=[O:35]>CS(C)=O.CO.O>[CH3:32][O:33][C:34]([C:2]1[C:6]2[N:7]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[CH:8]=[CH:9][C:5]=2[S:4][CH:3]=1)=[O:35]
Reactant: FC(F)(F)c1ccc(Cn2ccc3scc(Br)c32)cc1
Reactant: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1csc2ccn(Cc3ccc(C(F)(F)F)cc3)c12

Procedure:
A mixture of 2.0 g of the product of Step 5, 0.54 g of PdCl2dppf.CH2Cl2, and 1.8 ml of Et3N in 60 ml of 2:1 DMSO/MeOH was heated under CO (balloon pressure) at 75° C. for 24 h. The reaction mixture was poured into 400 ml of 1:1 heaxan/EtOAc and stirred with 200 ml of water for 4 h. The organic layer was washed with 100 ml of brine and dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with a gradient up to 15% EtOAc/hexane to give 1.7 g of the title compound as a light brown solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1.Br[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCN2CC=C(c3ccc(F)cc3)CC2)cc1

Procedure:
A mixture of 2.15 g. of 4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride, 2.5 g. of p-(2-bromoethoxy)-nitrobenzene, 2.8 g. of potassium carbonate, 20 ml. of ethanol and 2 ml. of water is refluxed for 3 days. After filtration the crude product crystallizes from the hot reaction mixture. It is purified by chromatography on silica gel using methylene chloride for elution. The 4-(p-fluorophenyl)-1,2,3,6-tetrahydro-1-[2-(p-nitrophenoxy)ethyl]pyridine obtained melts at 104°-107° after recrystallization from ethanol.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([C:9]1[S:13][C:12]([NH2:14])=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]>C(OCC)(=O)C>[C:5]([C:9]1[S:13][C:12]([N:14]=[C:1]=[O:2])=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-t-butyl-2-amino-1,3,4-thiadiazole (10 grams) in ethyl acetate (300 ml) was added to the reaction vessel and the resulting mixture was stirred for a period of about 16 hours resulting in the formation of a precipitate. The reaction mixture was then purged with nitrogen gas to remove unreacted phosgene. The purged mixture was then filtered to recover the desired product 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer as a solid having a melting point of 261° to 263° C.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)[C:37]2=[O:48])[S:31][C:32]=1[C:33]([OH:35])=O.[CH2:49]([NH2:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH2:49]([NH:56][C:33]([C:32]1[S:31][C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)[C:37]2=[O:48])=[N:29][C:28]=1[CH3:27])=[O:35])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(N2CCN(Cc3cccnc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3cccnc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 13 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(pyridin-3-ylmethyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 13% yield: mp 110-113° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.58-8.56 (m, 2H), 7.67 (d, J=7.8 Hz, 1H), 7.33-7.28 (m, 6H), 6.02 (br s, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.49 (s, 2H), 4.11-4.06 (m, 2H), 3.51-3.45 (m, 2H), 2.61 (s, 3H); MS (ES+) m/z 408.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])O)=[C:5]([CH3:8])[NH:6][CH:7]=1>O1CCCC1.[O-2].[O-2].[Mn+4]>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]2[C:4]3[C:3](=[CH:7][NH:6][C:5]=3[CH3:8])[CH2:2][N:1]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:10]=2[CH:11]=1
Reactant: Cc1[nH]cc(CN)c1-c1ccc(Cl)cc1C(O)c1ccccc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A mixture of 150 mg (0.43 mmole) of 4-aminomethyl-3-{4-chloro-2-[(2-fluorophenyl)hydroxymethyl]phenyl}-2-methyl-1H-pyrrole and 600 mg (7.3 mmole) of manganese dioxide in 30 ml of tetrahydrofuran was refluxed for 2 hours. The mixture was cooled and filtered over celite. The filtrate was concentrated at reduced pressure to give an amber oil. Purification by column chromatography (silica gel, 10 g; eluent 5% ether in methylene chloride) gave a cream colored solid. Recrystallization from ether gave colorless needles, mp 226°-227° which was identical in every respect to an authentic sample.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:12]([C:17](=O)[CH3:18])[C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:21][C:22]([NH2:29])=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].CN1CCOCC1>C(O)(C)C>[NH2:21][C:22]1[NH:29][C:17]([CH3:18])=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[O:1][CH2:2][CH2:3][CH2:4]3)[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: COC(=O)C(=Cc1ccc2c(c1)CCCO2)C(C)=O
Reactant: CCOC(=O)C=C(N)N
Agent: Cl
Solvent: CC(C)O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1=C(N)NC(C)=C(C(=O)OC)C1c1ccc2c(c1)CCCO2
Temperature: 90 °C

Procedure:
A mixture of methyl 2-(chroman-6-ylmethylene)-3-oxobutanoate (8.27 g, 31.8 mmol), ethyl 3,3-diaminoacrylate, hydrochloride (5.29 g, 31.8 mmol) and 4-methylmorpholine (3.49 mL, 31.8 mmol) in Isopropanol (76.0 mL) was heated to 90° C. overnight. The mixture was concentrated, dissolved in ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated to provide crude 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate which was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.00-6.87 (m, 3 H), 6.64-6.58 (m, 1 H), 6.20 (br. s., 2 H), 4.83-4.77 (m, 1 H), 4.15-4.05 (m, 4 H), 3.71-3.63 (m, 3 H), 2.71 (t, J=6.3 Hz, 2 H), 2.27-2.16 (m, 3 H), 1.99-1.93 (m, 2 H), 1.27-1.22 (m, 3 H); LC/MS (m/z) ES+=373.3 (M+1). A solution of crude 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate in dichloromethane (DCM) (216 mL) was treated with DDQ (7.22 g, 31.8 mmol) and then stirred at ambient temperature (mixture turned dark within one minute). The mixture was filtered over Celite™. The filtrate was diluted with saturated sodium bicarbonate and the layers were separated. The aqueous phase was extracted with DCM. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-100% hexane/EA) to afford 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methylpyridine-3,5-dicarboxylate (7.64 g, 20.63 mmol, 64.9% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.86 (d, 1 H), 6.81 (s, 1 H), 6.73 (d, J=8.4 Hz, 1 H), 6.23-6.02 (m, 2 H), 4.17 (t, J=4.7 Hz, 2 H), 3.99-3.77 (m, 2 H), 3.52-3.43 (m, 3 H), 2.73 (br. s., 2H), 2.45-2.35 (m, 3 H), 1.98 (br. s., 2 H), 0.83-0.67 (m, 3 H); LC/MS (m/z) ES+=371.3 (M+1).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[O:16][CH3:17].[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CC(C)([O-])C.[Na+]>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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:28]2[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]2)=[CH:11][C:10]=1[O:16][CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(Br)ccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a 3-necked, 5-L Morton flask equipped with a mechanical stirrer, gas adapter, heating mantle and thermometer was added rac-BINAP (4.24 g, 0.005 equiv) and Pd2(dba)3 (3.20 g, 0.0025 equiv). The flask was evacuated, and back-filled with nitrogen. Toluene (100 mL) was added by cannula. The mixture was stirred at room temperature for 15 min to give a purple solution. Toluene (2.0 L) was then added. 2-Chloro-5-bromoanisole (300.3 g, 1.356 mol, 1 equiv) was added in one portion. Boc-piperazine (252.4 g, 1 equiv) was added in one portion. Sodium tert-butoxide (183.0 g, 1.4 equiv) was added in one portion. The flask was evacuated and back-filled with nitrogen. The mixture was then heated to an internal temperature of 60° C. A heterogeneous light-orange slurry was obtained. After 1 h, the mixture becomes a homogeneous brown solution. After an additional 15 h, the mixture was cooled to room temperature. EtOAc (2.0 L) was added to the stirring mixture. The solid was filtered. The filtrate was washed with EtOAc (100 mL). The combined filtrate was washed with 10% aq. K2CO3 solution (1×1 L), water (1×1 L), and dried over MgSO4. The solvent was removed in vacuo to afford the product as an orange solid (410.3 g, 93% yield).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11](Cl)=[O:12].Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:18][O:17][N:16]([CH3:15])[C:11]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:12]
Reactant: CNOC
Reactant: O=C(Cl)N1CCc2ccccc2C1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)N1CCc2ccccc2C1
Yield: 93.5 %

Procedure:
A solution of 2.73 g of 3,4-dihydro-1H-isoquinoline-2-carbonyl chloride, 55 mg of 4-dimethylamino-pyridine, 1.36 g of N,O-dimethylhydroxylamine hydrochloride and 4.85 ml of triethylamine in 30 ml of methylene chloride was heated to boiling under reflux for 22 h. The reaction mixture was treated at room temperature with 50 ml of a 5% sodium carbonate solution and extracted twice with 50 ml of methylene chloride each time. The combined organic phases were washed once with 50 ml of water and once with 50 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was triturated with 50 ml of t-butyl methyl ether, a small amount of insoluble residue was filtered off under suction and the filtrate was concentrated. The residue was dried at room temperature and about 12 mbar. 2.87 g (93%) of 3,4-dihydro-1H-isoquinoline-2-carboxylic acid methoxy-methyl-amide were obtained as an orange oil. MS (EI): 220M30 .
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[NH:4][C:3](=[O:15])[C:2]=1[C:16]([OH:18])=[O:17].S(Cl)(Cl)=O.[CH3:23]O>>[CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[NH:4][C:3](=[O:15])[C:2]=1[C:16]([O:18][CH3:23])=[O:17]
Reactant: O=C(O)c1cc2c([nH]c1=O)CCc1ccccc1-2
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2c([nH]c1=O)CCc1ccccc1-2

Procedure:
Add 6.0 gm of 5,6-dihydrobenzo[f]quinolin-3(4H)-one-2-carboxylic acid to 100 ml of methanol. Dropwise at 0° C., add 10 ml of thionyl chloride to the system. Heat the system at reflux for 6 hours. Remove the solvent by stripping. Isolate the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Cl)nc1I
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Clc1ccc(OCc2ccccc2)c(I)n1

Procedure:
6-Chloro-2-iodo-3-pyridinol (1.28 g, 5 mmol) and silver carbonate (1.52 g, 5.5 mmol) were dissolved in toluene (25 ml) and benzyl bromide (654 μl, 5.5 mmol) added. The mixture was heated to reflux under nitrogen for 1 hour. After cooling, the mixture was filtered, washed with water (×2), dried (MgSO4) and evaporated to an orange oil which was flash chromatographed eluting with 5% ethyl acetate in isohexane to give the title compound as an oil which crystallised on standing. LC/MS t=3.70, [MH+] 346, 348.
Reaction SMILES: FC(F)(F)C(O)=O.C(=O)([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[CH:29]=[C:28]([O:31][CH3:32])[C:27]([O:33][CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)=[CH:26][C:25]=3[C:24]3[C:42]([CH3:45])=[N:43][NH:44][C:23]=3[N:22]=2)=[CH:17][CH:16]=1)OC(C)(C)C.[ClH:47]>O1CCOCC1>[ClH:47].[CH3:45][C:42]1[C:24]2[C:25]3[CH:26]=[C:27]([O:33][CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[C:28]([O:31][CH3:32])=[CH:29][C:30]=3[C:21]([C:18]3[CH:17]=[CH:16][C:15]([OH:14])=[CH:20][CH:19]=3)=[N:22][C:23]=2[NH:44][N:43]=1
Reactant: COc1cc2c(-c3ccc(OC(=O)OC(C)(C)C)cc3)nc3[nH]nc(C)c3c2cc1OCC1CCN(C)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COc1cc2c(-c3ccc(O)cc3)nc3[nH]nc(C)c3c2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-{1-methyl-7-(methyloxy)-8-{[(1-methylpiperidin-4-yl)methyl]oxy}-3H-pyrazolo[3,4-c]isoquinolin-5-yl}phenyl carbonate trifluoroacetate (32 mg, 0.049 mmol) was taken into 4 N HCl in dioxane and the mixture was stirred for 1 h at rt. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in water, frozen, and lyophilized. 4-(1-methyl-7-(methyloxy)-8-{[(1-methylpiperidin-4-yl)methyl]oxy}-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol hydrochloride was isolated as a solid (13.0 mg, 0.028 mmol, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ9.71 (br m, 2H), 7.59 (d, 2H), 7.54 (d, 2H), 6.94 (m, 2H), 4.18 (d, 2H), 3.76 (s, 3H), 3.04-2.96 (m, 2H), 2.81 (s, 3H), 2.82-2.74 (m, 2H), 2.15 (m, 1H), 2.04 (br d, 2H), 1.67-1.61 (m, 2H); MS (EI) for C25H28N4O3: 433 (MH+).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:37]=[CH:36][N:14]3[C:15](=[O:35])[C:16](/[CH:26]=[CH:27]/[C:28]([O:30]C(C)(C)C)=[O:29])=[C:17]([O:19][CH2:20][CH:21]4[CH2:25][CH2:24][O:23][CH2:22]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]>C(Cl)Cl.C(O)=O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:37]=[CH:36][N:14]3[C:15](=[O:35])[C:16](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[C:17]([O:19][CH2:20][CH:21]4[CH2:25][CH2:24][O:23][CH2:22]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(OCC4CCOC4)nc3c2)n1
Solvent: O=CO
Solvent: ClCCl
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(OCC4CCOC4)nc3c2)n1
Yield: 156.7 %

Procedure:
The tert-butyl (E)-3-{8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-2-(tetrahydro-3-furanylmethoxy)-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (10 mg) obtained in (A) was dissolved in methylene chloride (1 ml) and formic acid (1 ml), and then the mixture was stirred for 5 hours. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (14 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([CH3:29])=[CH:24][C:23]=1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([CH3:29])=[CH:24][C:23]=1[S:30]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:32])=[O:31]
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Reactant: Nc1cc(Cl)c(Cc2ccc3ccccc3n2)c(Cl)c1
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2cc(Cl)c(Cc3ccc4ccccc4n3)c(Cl)c2)c(Cl)cc1Cl

Procedure:
2,4-Dichloro-N-(3,5-dichloro-4-quinolin-2-ylmethyl-phenyl)-5-methyl-benzenesulfonamide was synthesized (76%) from 3,5-dichloro-4-quinolin-2-ylmethyl-phenylamine (223), 2,4-dichloro-5-methylbenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.22 (br s, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.15 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.88 (s, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.69 (t, J=7.1 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.21 (s, 2H), 4.48 (s, 2H), 2.39 (s, 3H). MS (EI): m/z 523 (M−H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[N:6]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:5]([CH2:25][CH3:26])[C:4]1=[O:27])[CH3:2].C([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[N:6]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:5]([CH2:25][CH3:26])[C:4]1=[O:27])[CH3:2]
Reactant: CC[C@H]1C(=O)N(CC)c2cc(F)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: CC[C@H]1C(=O)N(C)c2cc(F)ccc2N1S(=O)(=O)c1ccc(O)cc1
Product: CC[C@H]1C(=O)N(CC)c2cc(F)ccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
(3S)-1,3-Diethyl-7-fluoro-4-[(4-methoxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3S)-3-ethyl-7-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 29) to yield (3S)-1,3-Diethyl-7-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1 h)-one. MS (ESI) m/z 379 ([M+H]+); MS (ESI) m/z 377 ([M−H]−).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([CH3:26])([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:28]1([C:34]2[O:35][C:36]([CH3:52])=[C:37]([CH2:39][CH2:40]OS(C3C=CC(C)=CC=3)(=O)=O)[N:38]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:26][C:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:40][CH2:39][C:37]2[N:38]=[C:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:35][C:36]=2[CH3:52])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:27]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C)(Oc2ccc(OC(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The representative procedure (B) was utilized to prepare the title compound from 3-(4-hydroxy-phenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.79-7.94 (m, 2H), 7.43-7.41 (m, 3H), 7.18 (d, 2H, J=8.8 Hz), 7.07 (d, 2H, J=8.4 Hz), 6.89 (d, 2H, J=8.8 Hz), 6.82 (d, 2H, J=8.4 Hz), 4.19 (t, 2H, J=6.4 Hz), 3.24 and 3.14 (d of Abq, 2H, J=14.0 Hz), 3.01 (t, 2H, J=6.4 Hz), 3.00 (bs, 1H), 2.39 (s, 3H), 1.42 (s, 3H). IR (KBr) 3600, 2980, 1725, 1611, 1504, 1265 cm−1. HRMS (ES+) m/z exact mass calcd for C29H27NO6F3 542.1790, found 542.1802.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=O)[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([F:25])[CH:3]=1.[ClH:26].Cl.Cl.[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1>>[ClH:26].[ClH:26].[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH:46][C:22]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[C:13]([O:12][CH2:11][C:8]3[C:7]5[C:2]([F:1])=[CH:3][C:4]([F:25])=[CH:5][C:6]=5[O:10][CH:9]=3)[CH:21]=[CH:20][CH:19]=4)=[O:24])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (115) (preparation see below) and amine 61 analogously to the method described in example 1.