Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31].C(O)C.C(=O)([O-])[O-].[NH4+:39].[NH4+]>ClCCl.C(O)C>[ClH:31].[CH2:1]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:26](=[NH:39])[NH2:27])=[CH:24][CH:25]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)NCc3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)NCc3ccccc3)ccc21
Yield: 63 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-benzylamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 63% of theory, C24H24N6O (412.5) Rf value: 0.76 (silica gel; dichloromethane/ethanol=4:1) EKA mass spectrum: (M+H)+ =413
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:18])C(=O)C1.O>CN(C=O)C>[Br:18][C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][CH2:1]2)=[CH:5][C:6]=1[OH:10]
Reactant: Oc1ccc2c(c1)CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc2c(cc1Br)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-indanol (6.32 g, 47 mmol) in DMF (20 mL) is added NBS (8.38 g, 47 mmol) and the mixture is stirred at ambient temperature for 1 h. Water is added and the mixture is then extracted with EtOAc. The organic layer is washed with 1N HCl solution and brine, dried with NaSO4 and concentrated to give the title compound and it is used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[C:19](Cl)(Cl)=[O:20].C1(C)C=CC=CC=1>C(Cl)Cl>[N:16]([C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:18][CH:17]=1)=[C:19]=[O:20]
Reactant: O=C(Cl)Cl
Reactant: COCCOCCOCCOc1ccc(N)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COCCOCCOCCOc1ccc(N=C=O)cc1
Reaction time: 3 h

Procedure:
To a stirred 0° C. solution of 18 (0.59 g, 2.29 mmol) in DCM (23 mL) was added a 20% phosgene/toluene solution (2.42 mL). After stirring for 3 h the reaction mixture was concentrated under reduced pressure and carried on without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[O:7]1[CH2:9][CH:8]1[C:10]([O:12][CH3:13])=[O:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[OH:7][CH:8]([CH2:9][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: Ic1cn[nH]c1
Reactant: COC(=O)C1CO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C(O)Cn1cc(I)cn1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 4-iodo-1H-pyrazole (10 g, 51 mmol), methyl oxirane-2-carboxylate (6.8 g, 67 mmol) and tripotassium phosphate (12 g, 57 mmol) in dioxane (80 mL) was stirred at 90° C. for 4 hours. After cooling to room temperature, the mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc) to afford methyl 2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)propanoate. MS ESI calc'd. for C7H10IN2O3 [M+H]+ 297. found 297. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=3.2 Hz, 2H), 4.51-4.46 (m, 3H), 4.27-4.25 (m, 1H), 1.31-1.28 (m, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][C:20]1[C:28]2[CH:27]=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[N:22]2[CH2:30][CH2:31][N:32]3[C:40]4[C:35](=[CH:36][CH:37]=[C:38]([F:41])[CH:39]=4)[C:34]([CH2:42][CH:43]4[CH2:47][CH2:46][CH2:45][N:44]4[C:48](=[O:61])[CH:49]([NH:53]C(OC(C)(C)C)=O)[CH:50]([CH3:52])[CH3:51])=[C:33]3[C:21]=12)=[O:13])[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH:9]([CH3:11])[CH3:10])[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][C:20]1[C:28]2[CH:27]=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[N:22]2[CH2:30][CH2:31][N:32]3[C:40]4[C:35](=[CH:36][CH:37]=[C:38]([F:41])[CH:39]=4)[C:34]([CH2:42][CH:43]4[CH2:47][CH2:46][CH2:45][N:44]4[C:48](=[O:61])[CH:49]([NH2:53])[CH:50]([CH3:52])[CH3:51])=[C:33]3[C:21]=12)=[O:13]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCCC1Cc1c2n(c3cc(F)ccc13)CCn1c-2c(CC2CCCN2C(=O)C(NC(=O)OC(C)(C)C)C(C)C)c2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(N)C(=O)N1CCCC1Cc1c2n(c3cc(F)ccc13)CCn1c-2c(CC2CCCN2C(=O)C(N)C(C)C)c2ccc(F)cc21
Temperature: 0 °C

Procedure:
A solution containing 30 (1.09 g, 1.27 mmol) in DCM (20 mL) was cooled to 0° C. TFA (4 mL) was added via pipette and the reaction was monitored until TLC analysis revealed complete consumption of 30 (˜2 h). TLC analysis, 10% MeOH/DCM, Rf(30)=0.5; Rf(31)=0.4. The solvent was removed on a rotary evaporator and the residue was dissolved in EtOAc. The EtOAc solution was washed twice with saturated aqueous NaHCO3 and once with brine. The combined aqueous washes were back-extracted with EtOAc and the organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford 0.83 g (quant.) of 31 as a yellow solid which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ8.09 (dd, J=5.1, 8.7 Hz, 1H), 6.97 (m, 2H), 4.52 (m, 1H), 4.50 (d, J=8.7 Hz, 1H), 4.11 (m, 1H), 3.71 (br d, J=11.1 Hz, 1H), 3.51-3.32 (m, 2H), 2.74 (app t, J=12.6 Hz, 1H), 2.30 (br s, 4H), 1.92 (m, 1H), 1.68 (m, 2H), 1.41 (m, 1H), 1.03 (m, 6H) ppm. 13C NMR (CDCl3, 75 MHz) δ174.3, 171.4, 160.6 (d, JC—F=232.5 Hz), 136.8 (d, JC—F=7.5 Hz), 127.4 (d, JC—F=3.7 Hz), 125.0, 122.4 (d, JC—F=7.5 Hz), 109.6, 108.7 (d, JC—F=22.5 Hz), 95.2 (d, JC—F=22.5 Hz), 58.0, 47.3,41.9, 30.0, 28.5, 28.5, 24.1, 19.9, 17.6 ppm.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@@H:3]1[C:23]([O:25][CH3:26])=[O:24].[O:27]1[C:36]2[CH:35]=[C:34]([CH:37]=O)[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:37][C:34]2[N:33]=[CH:32][C:31]3[O:30][CH2:29][CH2:28][O:27][C:36]=3[CH:35]=2)[C@@H:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NCc1cc2c(cn1)OCCO2
Yield: 77 %

Procedure:
Methyl (3S,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 34) (120 mg, 0.328 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (54 mg, 0.328 mmol) and sodium triacetoxy borohydride (209 mg, 0.98 mmol) were reacted as described for Example 6. Chromatography on silica gel with dichloromethane/methanol (20:1) gave 130 mg (77%) of product as a colorless hard foam.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[N:4]=1)#[N:2].C(O)(C(F)(F)F)=[O:22]>>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]([CH2:13][C:14]([OH:16])=[O:15])[N:4]=1)(=[O:22])[NH2:2]
Reactant: Cc1cc2c(C#N)nn(CC(=O)OC(C)(C)C)c2cn1
Reactant: O=C(O)C(F)(F)F
Product: Cc1cc2c(C(N)=O)nn(CC(=O)O)c2cn1

Procedure:
A solution of tert-butyl 2-(3-cyano-5-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (250 mg, 0.92 mmol) in TFA (4 mL) was subjected to microwave irradiation at 140° C. for 90 min. The reaction mixture was concentrated in vacuo, the residual solid was suspended in methanol and concentrated again in vacuo. MS: 235.0 [M+H]+; tR (HPLC conditions k): 0.24 min.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[N:10][C:11]([CH3:20])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13](Cl)=[C:8]2[N:7]=[CH:6]1)CCC.ClC1[C:27]([C:28](OCC)=[O:29])=[C:26]([CH3:33])N=C2N(C)C=NC=12>>[CH2:28]([O:29][C:13]1[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([CH3:20])[N:10]=[C:9]2[N:5]([CH3:1])[CH:6]=[N:7][C:8]=12)[CH2:27][CH2:26][CH3:33]
Reactant: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl
Reactant: CCCCn1cnc2c(Cl)c(C(=O)OCC)c(C)nc21
Product: CCCCOc1c(C(=O)OCC)c(C)nc2c1ncn2C
Yield: 61 %

Procedure:
By replacing 3-butyl-7-chloro-5-methyl-3H-imidazo[4,5-b]-pyridine-6-carboxylic acid, ethyl ester in Example 5 with 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester of Example 2 c, 7-butoxy-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester is formed. Yield 61%, b.p. 180°-190°/0.01.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].C([Li])CCC.CN(C)[CH:23]=[O:24].O>O1CCCC1>[F:1][C:2]1[C:7]([CH:23]=[O:24])=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11]
Reactant: CN(C)C=O
Reactant: CC(C)S(=O)(=O)Nc1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccc(F)c(C=O)c1F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To propane-2-sulfonic acid (2,4-difluoro-phenyl)-amide (48, 2.35 g, 9.95 mmol) in tetrahydrofuran (70 mL) under an atmosphere of nitrogen cooled with a dry ice/acetone bath was added 1.60 M of n-butyllithium (1.60 M in hexane, 6.53 mL, 10.45 mmol). The reaction was stirred for 40 minutes, and then another portion of n-butyllithium (1.60 M in hexane, 6.84 mL, 10.94 mmol). The reaction was stirred for 1 hour and N,N-dimethylformamide (0.92 mL, 11.9 mmol) was added. The reaction was allowed to warm to room temperature overnight. The reaction was poured into water extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol 5%) to give the compound (49, 1.4 g, 53.4%). MS (ESI) [M−H+]−=263.4.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1.[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][N:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Reactant: O=Cc1ccc(F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(Cc4ccc(F)cc4F)C3)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A mixture of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.18 g, 0.49 mmol), 2,4-difluorobenzaldehyde (64 μL, 0.59 mmol) and 4 Å molecular sieves in chloroform (7 mL) was heated to reflux for 3.5 hours. After cooling sodium triacetoxyborohydride (0.50 g, 2.36 mmol) was added and the mixture was stirred at RT overnight. Aqueous saturated sodium bicarbonate solution was added and the phases were separated. The aqueous phase was extracted with 10% MeOH/DCM (×4) and the combined organic phase was dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 50-100% EtOAc in cyclohexane) to give 372 (122 mg, 50%). LCMS: RT=8.65 min, [M+H]+=494. 1H NMR δ (ppm) (CDCl3): 8.31 (1H, d, J=2.33 Hz), 7.90 (1H, s), 7.33 (1H, q, J=7.71 Hz), 7.14 (1H, dd, J=8.27, 2.33 Hz), 7.01 (1H, d, J=8.26 Hz), 6.86-6.74 (2H, m), 5.94-5.84 (1H, m), 4.37 (2H, t, J=5.06 Hz), 3.83-3.73 (3H, m), 3.68 (2H, s), 3.39 (2H, t, J=5.07 Hz), 3.29-3.23 (2H, m), 1.61 (6H, d, J=6.65 Hz)
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)[CH:2]=[CH2:3].[CH:13]([C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1)=[CH2:14].C(N(CC)CC)C>CO>[CH2:1]([O:4][C:5]1[C:6](=[O:12])[C:7]2[C:8](=[CH:14][CH:13]=[C:15]3[C:16]=2[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:9](=[O:11])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CC1=CCCCC1
Reactant: C=CCOC1=CC(=O)C=CC1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: C=CCOC1=CC(=O)c2ccc3c(c2C1=O)CCCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
2-Allyloxy-1,4-benzoquinone (10.0 g, 60.9 mM) and 1-Vinylcyclohexene (19.8 g, 183 mM) were dissolved in 100 ml of MeOH, and refluxed for 3 hours. The reaction solution was cooled to room temperature, and then Triethylamine (5 ml) and NaIO4 (13.0 g, 61.0 mM) were added thereto, and stirred vigorously for another 1 hours. Reaction solution therein was filtered and the filtrate was concentrated by distillation under reduced pressure and was then purified by chromatography on silica gel to give 7.6 g (28.4 mM) of 3-Allyloxy-5,6,7,8-tetrahydro-1,4-phenanthrenequinone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4]/[CH:5]=[CH:6]/[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([NH:17][CH2:18][C:19]1[O:20][C:21]([CH3:24])=[CH:22][CH:23]=1)=[N:12]2.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([NH:17][CH2:18][C:19]1[O:20][C:21]([CH3:24])=[CH:22][CH:23]=1)=[N:12]2
Reactant: [H][H]
Reactant: COC(=O)C/C=C/c1cccc2nc(NCc3ccc(C)o3)ccc12
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCCc1cccc2nc(NCc3ccc(C)o3)ccc12

Procedure:
(E)-4-{2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinolin-5-yl}-but-3-enoic acid methyl ester (290 mg, 0.86 mmol) was dissolved in 45 mL ethanol. Palladium on charcoal (10%, 92 mg, 0.086 mmol) was added and the reaction mixture war hydrogenated with a hydrogen balloon overnight. The palladium was filtered off and the solvent was evaporated. The title compound was obtained as a brown oil (256 mg, 88%), MS: m/e=339.1 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C:10](=[O:25])[CH2:9][CH2:8][C@@:7]4([OH:26])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[C:20]#[N:21])[CH2:3][CH2:2]1.C(=O)([O-])[O-:28].[K+].[K+].OO>CS(C)=O.C(Cl)Cl>[CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C:10](=[O:25])[CH2:9][CH2:8][C@@:7]4([OH:26])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[C:20]([NH2:21])=[O:28])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: OO
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: NC(=O)c1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To an ice/water cooled suspension of (5a)-17-(cyclopropylmethyl)-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-carbonitrile [P2] (6.0 g, 17.1 mmol) and potassium carbonate (7.09 g, 51.37 mmol) in DMSO (120 mL) was added hydrogen peroxide (25 mL, 35 wt. % in H2O) drop wise at a rate to ensure the temperature remained below 20° C. The mixture was stirred for 2 hours then diluted with DCM (800 mL). The solution was washed with water (3×500 mL) before the organic phase was dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave crude product that was purified by trituration with methanol giving (5a)-17-(cyclopropylmethyl)-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-carboxamide [P3] (4.50 g, 71% yield); LC/MS (r.t. 10.1 minutes [5 to 95% B]), 369 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([O-:16])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[C:4]1([CH2:3][CH2:2][CH2:10][C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(CCCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 72 %

Procedure:
The above mentioned ester (13 g) was dissolved in chloroform (200 ml). This solution was added dropwise to the solution obtained by dissolving L-phenylalanine (16.5 g) and Na2CO3 (15.9 g) in water (150 ml) while stirring at room temperature. After that, the mixture was stirred for 7 hours and the insoluble matter thus produced was removed by filtration. The filtrate was acidified to pH 1.0 with 6N HCl. The precipitated crystals were filtered, washed with water, and re-crystallized from 90% aqueous methanol to obtain N-(4-phenylbutyroyl)-L-phenylalanine (11.2 g) having melting point: 178° C.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[CH2:9]([N:16]=[C:17]=[S:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)(=O)C>[CH2:9]([NH:16][C:17]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:17](=[S:18])[NH:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:2][CH:1]=1)=[S:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: S=C=NCc1ccccc1
Reactant: Nc1ccc(N)cc1
Solvent: CCOC(C)=O
Product: S=C(NCc1ccccc1)Nc1ccc(NC(=S)NCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
p-Phenylenediamine (2.707 g, 25 mM) was dissolved in 20 ml of ethyl acetate, and 2 equivalents of benzylisothiocyanate (7.461 g, 50 mM) were added. The mixture was stirred at 80° C. for 30 minutes. After cooling, the reaction mixture was filtered, and washed with ethylacetate/n-hexane to obtain 6.26 g (61.6% yield) of a colorless crystal of compound A-25.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][C:7]3([O:18][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][N:9](C)[CH2:8]3.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].CCCCCC>ClCCl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][C:7]3([O:18][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][N:9]([C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23])[CH2:8]3
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To an ice cold solution of 6-chloro-2'-methylspiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (5.0 g) in dichloromethane (150 ml) is slowly added dropwise phenyl chloroformate (3.7 g) in dichloromethane (20 ml). The mixture is stirred at ambient temperature overnight. Removal of the solvent in vacuo yields an orange oil which solidifies upon trituration with hexane. An analytical sample is twice recrystallized from hexane to yield product as a solid (6.6 g, 99%), mp 138°-140°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].C(N(CC)CC)C>CO>[F:12][C:13]([F:20])([F:19])[C:14]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:15]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCCCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 87 %

Procedure:
To a 2 liter round bottom flask, charged with 100.2 g (0.552 mol) of amine hydrochloride 2 and 1 liter of methanol was added 100 g (0.703 mol) of ethyl trifluoroacetate followed by 120 mL (0.861 mol) of triethylamine. The mixture was stirred at 20-30° C. for 19 h and then concentrated via rotary evaporation. The residue was diluted with 500 mL of diethyl ether and then filtered. The filtrate was washed with 3×300 mL aliquots of iN aqueous HCl, 200 mL of de-ionized water, 2×200 mL aliquots of saturated aqueous sodium bicarbonate and finally with 200 mL of de-ionized water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was distilled under vacuum to afford 115.8 g of the product (3) as a colorless oil: b.p.=113-116° C. at 120 mm Hg: 1H NMR (d6 -DMSO) d 3.57 (3H, s), 2.75 (2H, m), 2.29 (2H, t), 1.60-1.40 (4H, m) and 1.37-1.19 (2H, m) ppm.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14](Cl)[CH3:15].[OH-].[Na+].C(N(CCCC)CCCC)CCC>ClC1C=CC=CC=1Cl>[CH2:14]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:15]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: CCCCN(CCCC)CCCC
Product: CCn1c2ccccc2c2ccccc21
Temperature: 100 °C
Reaction time: 9 h

Procedure:
A 0.5-liter autoclave equipped with a stirrer was charged with carbazole (82.4 g), o-dichlorobenzene (100 g), ethyl chloride (40.2 g), 48% sodium hydroxide (55.8 g) and tributylamine (9.2 g). After the atmosphere in the autoclave was replaced with nitrogen gas, the autoclave was heated to the reaction temperature of 100° C. and the reaction mixture was stirred at the same temperature for 9 hours, while keeping the temperature. After completion of the reaction, the mixture was cooled to 50° C. The same procedures as those described in Example 1 gave 275.9 g of an o-dichlorobenzene solution of N-ethylcarbazole. The analysis of this solution by chromatography revealed that the content of N-ethylcarbazole was 32.9% and the yield thereof was 94.3%.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1C=CC=CC=1.[OH-].[Na+]>CCOCC>[CH3:1][CH:2]([CH3:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:15][C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1
Reactant: CC(C)COc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)COc1ccc(C=CC(=O)O)cc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
A 500 mL, 1 neck, round-bottomed flask equipped with a magnetic stirrer and reflux condenser is charged with 4-(2-methylpropoxy)benzaldehyde (17.84 g, 0.100 mol, as from Example 2a), malonic acid (10.42 g, 0.100 mol), and 19 mL of pyridine. The mixture is heated with stirring in a 130° C. oil bath for 24 hours, then stirred at room temperature for 16 hours. The reaction mixture is then poured into a separatory funnel containing 300 mL of pH 12 aqueous sodium hydroxide and 300 mL of ether. The layers are separated and the aqueous phase washed with 150 mL of ether. The aqueous phase is then acidified with concentrated hydrochloric acid to bring the pH to 1 whereupon the powdery white acid precipitates out. The mixture is chilled in an ice/salt bath and the solid collected giving 5.89 g (0.027 mol, 27%) of product, m.p. 161°-164° C.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[S:2].[CH:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([P:1]([Cl:5])([Cl:3])=[S:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccccc1
Reactant: S=P(Cl)(Cl)Cl
Product: S=P(Cl)(Cl)c1ccccc1
Temperature: 200 °C
Reaction time: 4 h

Procedure:
In a 100 cc autoclave, 42.35 g (0.25 mole) of thiophosphoryl trichloride, 19.53 g (0.25 mole) of benzene were charged, and the mixture was heated with stirring at 200° C for 4 hours. The reaction mixture was treated in accordance with the process of Example 1. No phenylphosphonothioic dichloride was produced.