Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][N:9]([CH3:13])[CH2:10]2)=[CH:5][CH:4]=1.OC1C=C2C(C(C3C=CC=CC=3)[CH2:26][N:27]([CH3:31])[CH2:28]2)=CC=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>O>[CH3:26][N:27]([CH2:31][CH2:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][N:9]([CH3:13])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:28]
Reactant: COc1ccc2c(c1)CN(C)CC2c1ccccc1
Reactant: CN1Cc2cc(O)ccc2C(c2ccccc2)C1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Product: CN(C)CCOc1ccc2c(c1)CN(C)CC2c1ccccc1

Procedure:
The title compound was prepared from (+)- 7 -methoxy- 2 -methyl- 4 -phenyl- 1,2,3,4 -terahydro isoquinoline via (+)- 7 -hydroxy- 2 -methyl- 4 -phenyl- 1,2,3,4 -tetrahydro isoquinoline which was characterised as its hydrochloride salt m.p. 222°-3° C. (methanol-ether) [α]D25 + 24.1° (water) by the method of Example 1. The title compound was characterised as its dihydrochloride salt m.p. 160°-4° (hydroscopic) (ethanol ethyl acetate), [α]D5 + 13° (water). -tetrahydro
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1)[CH:2]=[CH2:3].[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CS(C)=O>[CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:30]3[CH2:31][CH2:32][N:27]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:28][CH2:29]3)[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: C=CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: CS(C)=O
Product: C=CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(Cc4ccccc4)CC3)cc21
Temperature: 110 °C
Yield: 35.6 %

Procedure:
2.8 g (0.01 mol) of 1-allyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 7.2 g (0.04 mol) of 4-benzylpiperzine and 15 cm3 of DMSO were stirred and heated at 110° C. for 6 hours. The solvent was removed by distillation in vacuo. The residue was taken up in 40 cm3 of water. The suspension was adjusted to pH 7.3 by adding acetic acid. The precipitate was extracted with chloroform (4×20 cm3). The combined organic extracts were washed with water and then evaporated to dryness to give a viscous residue which crystallized on mixing with 10 cm3 of isopropanol. The solid was separated and recrystallised from methylcellosolve (30 cm3). 1.5 g of the acid, m.p. 209° C., were obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1>C1COCC1.O>[CH2:3]([O:10][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cc(OCc2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) slurry of washed (hexanes) sodium hydride (14.07 g, 352 mmol) in THF (650 mL) was added dropwise a solution of benzyl alcohol (35.2 mL, 337 mmol) in THF (200 mL). After stirring for 15 minutes, a solution of 2-chloro-4-nitropyridine (50 g, 306 mmol) in THF (200 mL) was added dropwise. After heating to reflux for 16 hours, the black slurry was diluted with water (200 mL) and concentrated to remove the THF. The resulting mixture was diluted with more water and filtered. The filtrate was extracted with ether and ethyl acetate. The combine organics were dried and concentrated. The residue was chromatographed (10% ethyl acetate in hexanes) to provide the product as orange solid.
Reaction SMILES: [C:1]([C:3]1[N:4](C(OC(C)(C)C)=O)[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15](=[S:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=3[CH:20]=2)=[CH:6][CH:7]=1)#[N:2].CC[O-].[Na+]>C1COCC1.CCO>[CH3:18][C:13]1([CH3:19])[C:12]2[CH:20]=[C:8]([C:5]3[NH:4][C:3]([C:1]#[N:2])=[CH:7][CH:6]=3)[CH:9]=[CH:10][C:11]=2[NH:16][C:15](=[S:17])[O:14]1
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=S)N2
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)OC(=S)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Temperature: 80 °C
Yield: 73.3 %

Procedure:
To a solution of tert-butyl 2-cyano-5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate (0.5 g, 1.3 mmol, 1 eq) in THF (5 mL) was added NaOEt (0.27 g, 3.9 mmol, 3 eq) in EtOH (5 mL) and the reaction was heated to 80° C. for 2 h. The solvents were removed in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (10% ethyl acetate/hexane) gave the title compound (0.27 g, 73%) as a brown powder, mp 261-262° C. 1H NMR (DMSO-d6) δ 1.68 (s, 6H), 6.72-6.73 (m, 1H), 6.99-7.01 (m, 1H), 7.06 (d, 1H, J=7.9 Hz), 7.66-7.70 (m, 2H), 12.26 (s, 1H), 12.62 (s, 1H); MS (ESI) [M−H]−=282; Anal. Calcd. For C15H13N3OS: C, 63.58; H, 4.62; N, 14.83. Found: C, 63.25; H, 4.78; N, 15.11.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31](C(OC(C)(C)C)=O)[C:30]([CH3:40])([CH3:39])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[NH:31][C:30]([CH3:40])([CH3:39])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and tert-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].C(N(CC)CC)C.Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31]>CC(C)=O>[N+:27]([C:24]1[CH:23]=[C:22]([N+:30]([O-:32])=[O:31])[CH:21]=[CH:26][C:25]=1[O:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])([O-:29])=[O:28]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1 L four-necked flask equipped with an overhead stirrer, thermocouple and a condenser was charged with 2-hydroxyisoindoline-1,3-dione (25 g, 153 mmol) and acetone (500 mL). To this stirred suspension was added triethylamine (15.7 g, 154 mmol). The reaction mixture turned dark red and 2-hydroxyisoindoline-1,3-dione slowly dissolved and became a homogeneous solution after 10 minutes. 1-Chloro-2,4-dinitrobenzene (31 g, 153 mmol) was added and the reaction was stirred at room temperature for 2 hours. After this time, a bright yellow suspension formed, and the reaction mixture was poured into 500 mL of ice-water. The precipitate was filtered and washed three times with cold MeOH (100 mL). The solid was compressed and washed with heptanes (3×100 mL) and dried under vacuum to give 2-(2,4-dinitrophenoxy)isoindoline-1,3-dione (I-33). 1H NMR (400 MHz, CDCl3) δ 8.99 (d, 1 H), 8.44 (dd, 1 H), 8.03-7.97 (m, 2 H), 7.95-7.90 (m, 2 H), 7.46 (d, 1 H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=1[CH3:13]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]([Cl:3])=[O:18])[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C=CC(=O)O)ccc1C
Solvent: Cc1ccccc1
Product: COc1cc(C=CC(=O)Cl)ccc1C

Procedure:
Toluene (750 ml) and thionyl chloride (11 ml) were subsequently added to 3-(3-methoxy-4-methylphenyl)acrylic acid (20 g, 0.104 mol) at room temperature. The suspension was refluxed for 2 h while vigorously stirring to give a clear slightly yellow solution. The reaction mixture was concentrated in vacuo, then toluene added and the mixture re-concentrated in vacuo to give 3-(3-methoxy-4-methylphenyl)acryloyl chloride for use in the next step.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:40]2[CH:45]=[CH:44][C:43]([O:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[CH:42][CH:41]=2)=[N:6][N:7]2[C@H:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:39])/[CH:20]=[CH:21]/[CH2:22][N:23]4[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)[CH2:25][CH2:24]4)[CH2:15][CH2:14]3)[CH2:11][CH2:10][NH:9][C:8]=12)(=[O:3])[NH2:2].[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>C(Cl)Cl>[F:56][C:55]([F:58])([F:57])[C:53]([OH:59])=[O:54].[NH2:31][CH2:30][CH2:29][N:26]1[CH2:25][CH2:24][N:23]([CH2:22]/[CH:21]=[CH:20]/[C:19]([N:16]2[CH2:15][CH2:14][CH:13]([C@H:12]3[N:7]4[N:6]=[C:5]([C:40]5[CH:45]=[CH:44][C:43]([O:46][C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)=[CH:42][CH:41]=5)[C:4]([C:1]([NH2:2])=[O:3])=[C:8]4[NH:9][CH2:10][CH2:11]3)[CH2:18][CH2:17]2)=[O:39])[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)NCCN1CCN(C/C=C/C(=O)N2CCC([C@@H]3CCNc4c(C(N)=O)c(-c5ccc(Oc6ccccc6)cc5)nn43)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCN1CCN(C/C=C/C(=O)N2CCC([C@@H]3CCNc4c(C(N)=O)c(-c5ccc(Oc6ccccc6)cc5)nn43)CC2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S,E)-tert-butyl (2-(4-(4-(4-(3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)carbamate (150 mg, 0.21 mmol) in 10 mL of DCM was added 2 mL of TFA. The reaction mixture was stirred at RT for 15 hr and concentrated to remove the solvent. The residue was used in the next step without further purification. MS (ESI) m/e [M+1]+ 613.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[O:3]1.[H-].[Na+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>C1COCC1.O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[N:10]=2)[O:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(c2ccn(COCC[Si](C)(C)C)n2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (388 mg, 2 mmoL) was added to NaH (160 mg, 60%, 4 mmoL) in THF (12 mL). After stirring at room temperature for 30 min, the mixture was cooled to 0° C. and SEMCl (705.7 μL, 4 mmoL) was added. The mixture was stirred at room temperature overnight, diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation afforded crude 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole.
Reaction SMILES: [Na+].[C:2]([CH2:4][C@@H:5]([OH:10])[CH2:6][C:7]([O-:9])=[O:8])#[N:3].S(=O)(=O)(O)O>C(O)C>[C:2]([CH2:4][C@@H:5]([OH:10])[CH2:6][C:7]([OH:9])=[O:8])#[N:3]
Reactant: N#CC[C@@H](O)CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: N#CC[C@@H](O)CC(=O)O

Procedure:
The reaction mixture containing (R)-4-cyano-3-hydroxy butyric acid sodium salt was acidified to pH 1 with concentrated sulfuric acid. The reaction mixture was condensed, dissolved in ethanol and filtered. The filtrate was concentrated to give (R)-4-cyano-3-hydroxybutyric acid which was used for esterification without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CN1C(=O)CCC1>[CH2:1]([NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cnc(Cl)cc1NCc1ccccc1
Reactant: Cc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cccc(Nc2cc(NCc3ccccc3)c(C#N)cn2)c1
Temperature: 120 °C

Procedure:
To ˜10 ml of NMP was added 15.1 (150 mg) and DIEA (˜0.1 mL). To this stirring solution was added benzylamine (1.1 eq in ˜5 mL NMP) dropwise. After stirring for 1 hour, H2O was added to the reaction mixture, followed by EtOAc. HPLC analysis indicated substantial amounts of product in each layer. Both layers were concentrated and the resulting oil was dissolved in a H2O/TFA/ACN mixture. This solution was purified via preparative rpHPLC utilizing a mobile phase with 0.1% TFA in water as solvent A and 0.1% TFA in acetonitrile as solvent B and eluting with a 20% to 60% B mixture over 10 minutes to give 205 mg of 4-(benzylamino)-6-chloronicotinonitrile (11). To 100 mg of 4-(benzylamino)-6-chloronicotinonitrile (11) in ˜3 mL NMP was added 1 ml of 60 mg/ml m-toluidine and 45 mg pTSA.H2O. Reaction heated at 120° C. for 72 hours. Due to inadequate conversion to product, the reaction mixture was transferred to a microwave tube and subsequently heated via microwave irradiation at 220° C. for 20 minutes. Water was added to the crude reaction mixture and a preparative rpHPLC was run in order to isolate pure 4-(benzylamino)-6-(m-tolylamino)nicotinonitrile (12). To 12 in ˜3 mL DMSO was added K2CO3 (˜100 mg) and 1.5 mL H2O2 (50% by wt.). The reaction was heated to 70° C. at which point the reaction mixture bubbled rigorously. Heat was removed until bubbling ceased and then the reaction mixture was again heated at 70° C. for an additional hour. The reaction mixture was cooled and a H2O/TFA mixture was added. The resulting solution was purified via preparative rpHPLC utilizing a mobile phase with 0.1% TFA in water as solvent A and 0.1% TFA in acetonitrile as solvent B and eluting with a 15% to 55% B mixture over 10 minutes. UV: 257 nm. M+H found for C20H20N4O: 333.3. NMR (CD3OD): 8.12 (1H, s), 7.37-7.24 (6H, m), 7.14-7.09 (1H, m), 6.99 (1H, br), 6.92-6.87 (1H, m), 5.88 (1H, s), 4.45 (2H, s), 2.38 (3H, s) ppm.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[CH:11]([CH:20]([CH3:31])[C:21]([O:23]CC2C=CC=CC=2)=[O:22])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[CH:11]([CH:20]([CH3:31])[C:21]([OH:23])=[O:22])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(C(C)C(=O)OCc1ccccc1)CN2C(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)C(C(C)C(=O)O)CN2C(=O)c1ccccc1

Procedure:
Thirty grams of benzyl 2-(1-benzoyl-5-methoxy-3-indolinyl)propionate were hydrogenated over palladium-on-carbon in ethanol to remove the benzyl ester group. 2-(1-Benzoyl-5-methoxy-3-indolinyl)propionic acid thus formed crystallized on cooling in the hydrogenation bomb and separated with the catalyst on filtration. The desired product was dissolved away from the catalyst by washing with hot ethanol. Ethanol was removed from the combined filtrate and washings by evaporation. The resulting residue was dissolved in tetrahydrofuran (THF). The THF solution was filtered and the THF removed from the filtrate in vacuo. The resulting residue was crystallized from about 500 ml. of ethanol; yield=21.2 g. of 2-(1-benzoyl-5-methoxy-3-indolinyl)propionic acid melting at 169°-70° C.
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[S:18][C:19]([CH2:22]C)=[CH:20][CH:21]=2)O)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:17]1[S:18][C:19]([CH3:22])=[CH:20][CH:21]=1
Reactant: CCc1ccc(C(O)c2cccc(Br)c2)s1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(Cc2cccc(Br)c2)s1
Reaction time: 2 h

Procedure:
1,3-Dibromobenzene (25 g) and a solution of a Grignard reagent prepared using metal magnesium in ether (50 ml) were added to a solution of 5-ethylthiophene-2-carboxyaldehyde (5.0 g) in tetrahydrofuran (50 ml) at 0° C., and the mixture was stirred for one hour. The reaction mixture was poured into ice-cooled water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (3-bromophenyl) (5-ethyl-2-thienyl) methanol (5.57 g). Borontrifluoride diethyl ether complex (1.57 ml) and triethylsilane (3.83 ml) were added to a solution of (3-bromophenyl) (5-ethyl-2-thienyl) methanol in acetonitrile (20 ml) at −40° C., and the mixture was stirred for two hours. Aqueous solution of saturated potassium carbonate was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 2-(3-bromobenzyl)-5-methylthiophene (3.77 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:39][CH2:40][CH2:41][CH3:42]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH:33]([CH2:39][CH2:40][CH2:41][CH3:42])[C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCI
Reactant: O=C1CCCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Product: CCCCC1CCN([C@H]2CC[C@@]3(O)[C@H]4Cc5ccc(OCc6ccccc6)c6c5[C@@]3(CCN4CC3CC3)[C@H]2O6)C1=O
Yield: 62 %

Procedure:
In a manner similar to the method described in Example 36-2, using 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl)-pyrrolidin-2-one obtained in Example 36-1, and using iodobutane in place of iodoethane, 203 mg (yield: 62%) of the captioned compound was obtained as a diastereomer mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][CH:36]([O:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH3:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:42][CH2:41][CH2:40][CH2:39][O:38][CH:36]([CH3:37])[CH3:35])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: CC(C)OCCCN
Product: CC(C)OCCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-[(1-methylethyl)oxy]-1-propanamine using methods similar to Example 563 to provide a white solid: ES+ MS: 539 (M+H+).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].C=O.[CH3:20]COCC>CO>[ClH:1].[CH2:20]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]=2[CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][NH:2]1
Reactant: CCOCC
Reactant: COC(=O)C(CN)c1c[nH]c2ccccc12
Agent: C=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CNCc2[nH]c3ccccc3c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
2.04 g of methyl 3-amino-2-(indol-3-yl)propionate hydrochloride are dissolved in 60 ml of methanol. 0.83 g of 35% formalin is added thereto, and the mixture is stirred at room temperature for 18 hours. After the reaction, ether is added to the mixture and crystalline precipitates are collected by filtration and dried, whereby 2.04 g of methyl (4RS)-1,2,3,4-tetrahydro-β-carboline-4-carboxylate hydrochloride are obtained as colorless needles. Yield: 95%
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1C
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)cc1C

Procedure:
A solution of 11.5 g. (0.07 mol.) of 3-methyl-4-methoxybenzoic acid and 10.7 g. (0.09 mol.) of thionyl chloride in 60 ml. of methylene chloride is refluxed on a steam bath for two hours. Concentration under reduced pressure and distillation of the residue gives 3-methyl-4-methoxybenzoic acid chloride, m.p. 37°-39°.
Reaction SMILES: [F:1][C:2]1[C:19]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])=[CH:18][CH:17]=[C:16]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5].[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:28][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:16]([F:27])=[CH:17][CH:18]=[C:19]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[C:2]=3[F:1])[CH:8]=2)[NH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Solvent: ClC(Cl)Cl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(Br)c3c2)c1F
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
2,6-Difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.500 g, 1.268 mmol) was charged to a 100 mL round-bottom flask. CHCl3 (25 mL) was added to form a slurry. N-Bromosuccinimide (0.271 g, 1.52 mmol) was added and stirred for 20 minutes. The reaction mixture was filtered, washed with DCM, and dried under vacuum providing N-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.427 g, 71.2%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 12.12 (br s, 1H), 11.04 (s, 1H), 9.81 (br s, 1H), 8.41-8.43 (m, 1H), 8.34-8.35 (m, 1H), 7.74-7.76 (m, 1H), 7.53-7.59 (m, 1H), 7.25-7.30 (m, 1H), 3.11-3.15 (m, 2H), 1.75-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-pos) M+1=473.0, 475.0.
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:25]3[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][C:26]=3[CH3:36])[C:20]=1[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:15])[CH2:10]2>CO>[CH:3]12[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:6][CH:5]([CH2:11]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:25]3[CH:35]=[CH:34][C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]=3[CH3:36])[C:20]=1[C:21]([CH3:23])([CH3:24])[CH3:22])=[O:15])[CH2:12]2
Reactant: CCOC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C(C)(C)C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1-n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1C(C)(C)C
Temperature: 20 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
A solution of Sodium hydroxide (1.904 mL, 3.81 mmol) was added in one portion to a stirred solution of ethyl 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-3-methyl-benzoate (Intermediate #113) (353 mg, 0.76 mmol) in methanol (6 mL). The resulting suspension was stirred at 20° C. for 16 hours. The resulting mixture was evaporated to remove the methanol and washed with ether (20 mL). The reaction mixture was acidified with 2M HCl. The precipitate was collected by filtration, washed with water (10 mL) and dried under vacuum to afford 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-3-methyl-benzoic acid (266 mg, 80%) as a white solid.