Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH2:10]O.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([O-:24])(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][C:15]1[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([CH3:12])[C:14]=1[S:21]([O-:24])(=[O:23])=[O:22].[NH2:10][N:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[N:5][C:4]1=[NH2+:9]
Reactant: NO
Reactant: Cc1cc(C)nc(N)n1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)n(N)c(=[NH2+])n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4,6-Dimethyl-pyrimidin-2-ylamine (25 g, 200 mmol) in 400 mL of CH2Cl2 was added dropwise a solution of hydroxylamine-2,4,6-Trimethyl-benzenesulfonate (105 g, 488 mmol) in 300 mL of CH2Cl2 at 0° C., and the mixture was stirred at 0° C. for 1 hour and filtered. The solid collected was washed with CH2Cl2 (100 mL) to give 1-Amino-4,6-dimethyl-1H-pyrimidin-2-ylidene-ammonium 2,4,6-Trimethyl-benzenesulfonate (40 g, yield: 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)[CH:5]=[CH:6][CH:7]=1.[C:23]([N:31]=[C:32]=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[C:23]([NH:31][C:32]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)[CH:3]=1)=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCn1c(-c2cccc(N)c2)c(C#N)c2ccc(OC)cc21
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: CCn1c(-c2cccc(NC(=S)NC(=O)c3ccccc3)c2)c(C#N)c2ccc(OC)cc21
Reaction time: 17 h
Yield: 90.5 %

Procedure:
The starting material 2-(3-amino-phenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (187 mg, 0.642 mmol) is dissolved in anhydrous acetone (3.0 mL). Benzoyl isothiocyanate (107 mg, 0.656 mmol) is added to the solution at room temperature and the mixture is stirred for 17 h during which time a precipitate forms. The precipitate is filtered, washed with acetone and dried to give 264 mg of 1-benzoyl-3-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (90% yield) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=O)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.ClC(OC)=O>O1CCCC1>[CH2:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)c2ccccc2O)cc1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOc1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
To a solution of 4-allyloxy-2′-hydoxybenzophenone (0.87 g) in tetrahydrofuran (14 mL) were added triethylamine (0.53 mL) and methyl chloroformate (0.29 mL) at 0° C., and the mixture was stirred at room temperature for 1.5 hours. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (18 mL) and water (9 mL) was added sodium borohydride (0.52 g) at 0° C., and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added 0.5 mol/L aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=8/1) to give 2-(4-allyloxybenzyl)phenol (0.72 g).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([CH3:24])=[CH:18]2)([O-])=O>C(Cl)CCl>[C:24]1([C:19]2[NH:20][C:21]3[C:17]([C:18]=2[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:16][CH:15]=[CH:23][CH:22]=3)[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12

Procedure:
Proceeding in a manner similar to that described in part A of Example 10, 29.6 g (0.20 mole) of phthalic anhydride and 35.2 g (0.20 mole) of 5-nitro-2-methylindole were interacted in 100 ml of ethylene dichloride to obtain 2-[(2-methyl-5-nitro-3-indolyl)-carbonyl]benzoic acid (Formula VIII: R°=R1 =R2 =R3 =R6 =H; R5 =CH3 ; Y1 =5-NO2), a red brown solid melting at 144°-148° C. and showing a strong carbonyl absorption maximum at 1700 cm-1 in the infrared spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])#[CH:16]>>[C:15]([C:17]1[CH:18]=[C:19]([NH:20][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])[CH:21]=[CH:22][CH:23]=1)#[CH:16]
Reactant: C#Cc1cccc(N)c1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: C#Cc1cccc(NC(=O)c2cc(C(N)=O)ccc2OC)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 3-ethynylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Br:19][C:20]1[CH:46]=[CH:45][C:23]2[N:24]([C:32]([C:34]3[CH:35]=[CH:36][C:37]4[O:42][CH2:41][C:40](=[O:43])[NH:39][C:38]=4[CH:44]=3)=[O:33])[CH:25]([CH2:28][C:29](O)=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1.[CH3:47][NH2:48].C1COCC1>CCOC(C)=O>[Br:19][C:20]1[CH:46]=[CH:45][C:23]2[N:24]([C:32]([C:34]3[CH:35]=[CH:36][C:37]4[O:42][CH2:41][C:40](=[O:43])[NH:39][C:38]=4[CH:44]=3)=[O:33])[CH:25]([CH2:28][C:29]([NH:48][CH3:47])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1
Reactant: O=C(O)CC1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)CC1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Reaction time: 0.08 h
Yield: 56 %

Procedure:
TEA (0.461 mL, 3.33 mmol) and T3P (50 wt. % in EtOAc, 0.989 mL, 1.66 mmol) were added to a solution of {7-bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetic acid (Intermediate 29, 372 mg, 0.83 mmol) in EtOAc (5 mL). The mixture was stirred for 5 min. Methanamine in THF (1.248 mL, 2.50 mmol) was added and the mixture was stirred at rt for 2 h. EtOAc (50 mL) was added and the mixture washed with Na2CO3 (40 mL), HCl (1 M, 30 mL) and brine (30 mL), dried through a phase separator and evaporated. The compound was purified by preparative HPLC (Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% ACN in H2O/ACN/FA 95/5/0.2 buffer over 20 min with a flow of 100 mL/min, UV detection at 254/280 nm) to give the title compound (215 mg, 56%) as a white solid.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[NH:43]1[CH2:46][CH:45]([NH:47][C:48](=[O:50])[CH3:49])[CH2:44]1>>[CH3:41][C@@H:39]1[CH2:40][N:35]([C:21]2[C:20]([CH2:19][OH:18])=[CH:33][C:24]3[C:25]([C:28]([N:43]4[CH2:46][CH:45]([NH:47][C:48](=[O:50])[CH3:49])[CH2:44]4)=[O:29])=[N:26][O:27][C:23]=3[C:22]=2[F:34])[CH2:36][C@H:37]([CH3:42])[O:38]1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: CC(=O)NC1CNC1
Product: CC(=O)NC1CN(C(=O)c2noc3c(F)c(N4C[C@@H](C)O[C@@H](C)C4)c(CO)cc23)C1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and N-(azetidin-3-yl)acetamide
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[N:18]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:19]3[C:24]([N:25]=2)=[CH:23][N:22]=[CH:21][N:20]=3)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][N:18]2[C:17]([NH:16][CH:13]3[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][NH:7][C:2]4[S:3][CH:4]=[CH:5][N:6]=4)[CH2:11][CH2:12]3)=[N:25][C:24]3[C:19]2=[N:20][CH:21]=[N:22][CH:23]=3)=[CH:32][CH:31]=1
Reactant: Brc1nccs1
Reactant: NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4nccs4)CC3)nc3cncnc32)cc1
Temperature: 130 °C
Yield: 26.5 %

Procedure:
A mixture of 3.3 parts of 2-bromothiazole, 5.55 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine, 2.12 parts of sodium carbonate and 18 parts of N,N-dimethylacetamide was stirred and heated for 20 hours at 130° C. After cooling, the reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol saturated with ammonia, (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried in high vacuo at 100° C., yielding 1.8 parts (26.5%) of 9-[(4-fluorophenyl)methyl]-N-[1-[2-(2-thiazolylamino)ethyl)-4-piperidinyl]-9H-purin-8-amine; mp. 165.4° C. (compound 172).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[OH:14][C:15]1[CH:19]=[C:18]([N:20]2[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:23]=3[N:22]=[CH:21]2)[S:17][C:16]=1[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:14][C:15]2[CH:19]=[C:18]([N:20]3[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][C:23]=4[N:22]=[CH:21]3)[S:17][C:16]=2[C:29]([O:31][CH3:32])=[O:30])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccc(F)cc1C(F)(F)F

Procedure:
In a similar manner as described for example B11, 110.5 mg of 4-fluoro-2-(trifluoromethyl)benzyl bromide, 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[S:13][C:12]([CH2:14]O)=[N:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:30]1([CH2:33][NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[O:45])=[CH:40][CH:39]=2)=[O:36])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:30]1([CH2:33][NH:34][C:35]([NH:37][C:38]2[CH:39]=[CH:40][C:41]([C:44]([N:46]3[CH2:51][CH2:50][N:49]([CH2:14][C:12]4[S:13][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:17])([F:16])[F:1])=[CH:10][N:11]=4)[CH2:48][CH2:47]3)=[O:45])=[CH:42][CH:43]=2)=[O:36])[CH2:31][CH2:32]1
Reactant: OCc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCNCC2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(Cc3ncc(C(O)(C(F)(F)F)C(F)(F)F)s3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 0.5 %

Procedure:
To a stirring solution of 1,1,1,3,3,3-hexafluoro-2-(2-(hydroxymethyl)thiazol-5-yl)propan-2-ol (0.533 mmol, 150 mg) and triethylamine (1.600 mmol, 162 mg) in dichloromethane (4 mL) at 0° C. was added methanesulfonyl chloride (0.533 mmol, 61.1 mg). The mixture was stirred at 0° C. for 1 hour before warming to room temperature and stirring for 1 hour. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2×20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (4 mL) and 1-(cyclopropylmethyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea (0.635 mmol, 192 mg) was added followed by potassium carbonate (1.905 mmol, 263 mg). The mixture was heated to reflux for 6 hours then was cooled, diluted with dichloromethane (75 mL) and washed with water (2×20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC, strong cation exchange column chromatography and silica gel column chromatography (10% methanol/90% dichloromethane) to afford the title compound (1.5 mg).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[N:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[N:27]1[CH:26]=[C:25]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[O:14][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:11][N:12]=3)=[CH:16][CH:17]=2)[CH:30]=[N:29][CH:28]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)o2)cc1
Reactant: Brc1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)o2)c1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
4-(5-{[3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (160.6 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilysilyl)amide (149.6 mg, 0.75 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 5-bromopyrimidine (119.2 mg, 0.75 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 200° C. for 20 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca, 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (87.0 mg). Yield 43.5%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[OH:11][C@H:12]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[NH:20][CH:21]=[C:22]([CH3:23])[C:16]=2[C:15]1=[O:24]>ClCCl>[OH:11][C@H:12]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[NH:20][C:21]([CH:8]=[O:9])=[C:22]([CH3:23])[C:16]=2[C:15]1=[O:24]
Reactant: Cc1c[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 74.9 %

Procedure:
Phosphorus oxychloride (674 μL, 4.04 mmol) and N,N-dimethylformamide (963 μL, 12.32 mmol) were dissolved in 21.18 mL of dichloromethane under stirring at room temperature, and the reaction solution was stirred for 15 minutes while maintaining the temperature at −10° C. in an ice-water bath. (R)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 1e (790 mg, 2.7 mmol) was dissolved in 10 mL of dichloromethane under stirring, and the solution was then added dropwise to the above reaction system. Upon completion of the addition, the ice-water bath was removed, and the reaction system was allowed to warm up to room temperature and stirred for another 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the reaction system was quenched with iced water and stirred for 15 minutes. The mixture was adjusted to pH about 12 with 10N sodium hydroxide solution and extracted with the solvent mixture of dichloromethane and methanol (V:V=20:1, 100 mL ×8). The combined organic extracts were washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to give the crude product (800 mg). The crude product was purified by silica gel column chromatography to give the title compound (R)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 1f (650 mg, yield 75%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[CH3:1][N:2]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: BrCCc1ccccc1
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(CCc1ccccc1)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 21.1 %

Procedure:
Methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (150 mg, 0.45 mmol) was treated with (2-bromoethyl)benzene (100 mg, 0.54 mmol) and potassium carbonate (187 mg, 1.35 mmol) in a sealed tube under microwave (Smith Personal Synthesiser) (55° C.) for 80 min. The reaction mixture was taken in DCM (10 mL) and water (5 mL). The organic layer was separated and washed twice with water and brine. The combined organic extracts were dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel eluting with DCM:MeOH (90:10) with 10% NH3 to give the title compound as a colorless oil (41.4 mg, 20%). 1H NMR (400 MHz, CDCl3) δ7.23 (m, 7H), 6.87 (d, 2H), 4.00 (t, 2H), 3.66 (m, 2H), 3.51 (m, 2H), 3.29 (t, 2H), 3.20 (t, 2H), 2.62 (t, 2H), 2.51 (m, 6H), 2.10 (m, 2H), 1.99 (m, 2H), 1.90 (m, 2H), 1.86 (s, 3H), 1.78 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH3:33][C:34]([CH3:45])([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[C:34]([CH3:33])([CH3:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)C(C)(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.23 mmol) in pyridine (2.5 mL) was treated with 2,2-dimethyl-3-phenylpropanoyl chloride (0.120 g, 0.61 mmol). The reaction mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. Saturated sodium bicarbonate solution (10 mL) was added, and the reaction mixture was stirred for 20 min. Solvent was removed under reduced pressure. Dichloromethane and saturated sodium bicarbonate solution was added to the residue. The layers were separated using an Empore extraction cartridge. The organic solvent was removed under reduced pressure. The crude compound was purified by flash chromatography on silica gel, using 10% methanol in dichloromethane as eluent to give 0.085 g (62%) cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide. 1H NMR (CDCl3, 400 MHz) δ 8.595-8.574 (m, 1H), 8.372 (s, 1H), 7.985 (s, 1H), 7.292-7.158 (m, 7H), 4.923 (m, 1H), 3.891 (s, 3H), 3.050-3.013 (m, 1H), 2.965 (s, 2H), 2.65-2.55 (m, 5H), 2.440-2.346 (m, 4H), 2.244-2.166 (m, 4H), 1.854-1.823 (m, 3H), 1.688 (m, 3H), 1.334 (s, 6H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.517 min (100%).
Reaction SMILES: [CH3:1][N:2]1[CH:11]2[C:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: COc1cccc2sc(Cl)nc12
Reactant: CN1C(=O)CCC2(C)c3ccc(S)cc3CCC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 66.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-methoxybenzothiazole (92 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 107 mg (66%) of the title compound as an off white solid. mp 200°-205°. FDMS: m/e=424. α[D]589 =+60.56 (c=0.96, chloroform).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]4[O:22][CH2:23][C:24]5[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=5[CH:26](O)[C:20]=4[CH:19]=3)=[N:13]2)=[CH:8][CH:7]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[C:1]([S:3][CH:26]1[C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[CH2:23][O:22][C:21]2[CH:32]=[CH:33][C:18]([O:17][CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([Cl:5])=[CH:7][CH:8]=4)[N:13]=3)=[CH:19][C:20]1=2)(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Temperature: 0 °C

Procedure:
Under ice cooling and stirring, 1.25 ml of thioacetic acid was added to 7.03 g of 2-(7-chloroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 36 dissolved in a mixed solution of 58 ml of trifluoroacetic acid and 30 ml of methylene chloride and the mixture was stirred at the same temperature for 3 hours. 300 ml of ice water was added to the reaction mixture, crystals precipitated by neutralization with a 1N-sodium hydroxide aqueous solution were collected by filtration and these crystals were dissolved in methylene chloride. Then, this organic layer was washed with water and dried over anhydrous sodium sulfate and then the solvent was removed. The resulting residue was applied to silica gel column chromatography to obtain 4.6 g of the title compound as white powder.