Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)[CH3:2].[O:5]1[C:9]2([CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:8][CH2:7][CH2:6]1.[CH3:16][NH:17][CH3:18].[C-]#N.[K+]>CO>[CH3:16][N:17]([CH3:18])[C:12]1([C:2]2[CH:1]=[CH:11][CH:10]=[CH:9][CH:14]=2)[CH2:13][CH2:14][C:9]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:10][CH2:11]1
Reactant: CNC
Reactant: CC(=O)O
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
Acetic acid (30 ml) was added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (128 mmol) in methanol (50 ml). The reaction mixture was cooled to 0° C. and dimethylamine solution (200 ml, 40% eq) was added dropwise. Potassium cyanide (2 eq) was added at the same temperature, then the cooling bath was removed and the reaction mixture stirred for 15 h at room temperature. It was hydrolysed with ammonium hydroxide solution (50% eq, 800 ml) and stirred for 1 h, then diluted with ethyl acetate. After phase separation the organic phase was washed with water, saturated sodium chloride solution and saturated iron sulfate solution and concentrated to small volume under vacuum. The crude dimethylaminonitrile intermediate (16 g) was dissolved in tetrahydrofuran (200 ml), cooled, and phenyl magnesium chloride solution (760 ml, 1 mol/l in hexane) was added dropwise. The cooling bath was removed and the reaction mixture stirred overnight at room temperature. It was hydrolysed with saturated ammonium chloride solution and diluted with ethyl acetate. After phase separation the organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated to small volume under vacuum. The crude product was purified by column chromatography (silica gel) with methanol/DCM. Yield: 59%
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:3]1.[N+:23](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-:24].CC(C)([O-])C.[K+].O>COCCOC>[C:24]([CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:3]1)#[N:23]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)N1CCC(=O)CC1Cc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)N1CCC(C#N)CC1Cc1ccc(C(F)(F)F)cc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of methyl 4-oxo-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (8.75 g, 27.75 mmol) (Syngene) in DME (100 mL) under nitrogen was added simultaneously 1-(isocyanomethylsulfonyl)-4-methylbenzene (8.13 g, 41.63 mmol) in 100 mL DME and potassium tert-butoxide (83 mL, 83.26 mmol) (1 M) over 30 min at −20 to −10° C. The solution was stirred at −20° C. for 2 h and then allowed to warm to room temperature overnight. To the orange reaction mixture was added water (200 mL), the solution was stirred for 20 min and then extracted with diethyl ether (3×) and EtOAc (3×). The combined organic phases were washed once with brine and then dried over Na2SO4 and evaporated to yield a brown oil. The oil was purified by flash chromatography on silica gel using a gradient of 20-60% EtOAc in heptane as eluent. Methyl 4-cyano-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (7.96 g, 87.9%) was isolated as a yellow oil.
Reaction SMILES: C1C([OH:7])=CC=CC=1C.[CH:9]1[C:14]([N:15]=[C:16]=O)=[CH:13][CH:12]=[C:11]([O:18]C2C=CC(N=C=O)=CC=2)[CH:10]=1.ClCl>>[CH3:9][C:10]1[N:15]([CH3:16])[CH:14]=[CH:13][C:12](=[O:7])[C:11]=1[OH:18]
Reactant: Cc1cccc(O)c1
Reactant: O=C=Nc1ccc(Oc2ccc(N=C=O)cc2)cc1
Agent: ClCl
Product: Cc1c(O)c(=O)ccn1C

Procedure:
Using the method described in Example 8, 240 g of m-cresol are mixed with 50.4 g of 4,4'-diisocyanatodiphenyl ether followed by 70.6 g of 4,4'-bis-α-chloroacetamidodiphenylether at 120°C and the mixture is then reacted at 185°C for 14 hours. 346 g of an approximately 30% polyhydantoin solution which has a chlorine content below 0.2% and a viscosity of 12460 cP20°C are obtained. Precipitation of this solution in methanol yields 210 g of a polyhydantoin with a nitrogen content of 10.4% and a chlorine content below 0.2%. The hydantoin structure is in both cases confirmed by the IR absorption bands at 1700 and 1755 cm-1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][C:11]([OH:13])=[O:12].S(Cl)([Cl:18])=O.[CH3:20]O>>[ClH:18].[CH3:20][O:12][C:11](=[O:13])[CH2:10][NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:15])[F:1]
Reactant: CO
Reactant: O=C(O)CNc1ccccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: COC(=O)CNc1ccccc1C(F)(F)F
Product: Cl
Temperature: 25 °C

Procedure:
300 mg (1.37 mmol) of DL-[2-(trifluoromethyl)phenyl]-glycine are placed in 9 ml methanol and slowly treated at RT with 130 μl thionyl chloride. The solution is heated overnight under reflux, then cooled to RT and freed of the volatile components on the rotary evaporator. Since by LC/MS the residue still contains ca. 44% educt, it is reacted again under the conditions described above. After this, the conversion is complete. 371 mg (93% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-piperidinecarboxylic acid ethyl ester (25.0 g) and 3-nitrophenylboronic acid (31.9 g) in dichloromethane (1.0 L) are added pyridine (64.8 ml), anhydrous copper (II) acetate (28.9 g) and Molecular Sieves 4 Å (500 g), and the mixture was stirred at 25° C. for 3 days. The reaction solution is poured into 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with aqueous sodium hydrogen carbonate solution and saturated brine, and the solvent is evaporated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:31]2[CH:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[CH:34]=[CH:33][C:32]=2[O:40][CH3:41])[C:12]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[Si]([N:52]=[N+:53]=[N-:54])(C)(C)C>ClCCl>[CH2:16]([O:15][C:14]1[CH:13]=[C:12]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([C:31]2[CH:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[CH:34]=[CH:33][C:32]=2[O:40][CH3:41])=[CH:10][C:9]=1[C:7]1[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[N:54]=[N:53][N:52]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCCCNC(=O)c1cc(-c2cc(C(C)C)ccc2OC)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCCCn1nnnc1-c1cc(-c2cc(C(C)C)ccc2OC)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
4,6-Bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid-(3-methoxypropyl)-amide (183 mg, 0.33 mmole) was dissolved in anhydrous dichloromethane (5 ml), then PCl5 (0.5 mmol) was added and the resulting solution was stirred at r.t. for 3 hr. TMSN3 (0.3 ml, neat, excess) was added and the resulting mixture was stirred at r.t. for 3 hr. After quenching the reaction with NaHCO3 solution, and extracting with dichloromethane (20 ml×3), the combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography on silica gel to give product 5-(4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-yl)-1-(3-methoxy-propyl)-1H-tetrazole (166 mg, 87%). M.p.: 102-104° C.; 400 MHz 1H NMR (CDCl3) δ: 7.43 (s, 1H), 7.35-7.13 (m, 12H), 6.87 (d, J=8.0 Hz, 1H), 6.70 (s, 1H), 5.07 (s, 2H), 5.03 (s, 2H), 4.34 (t, J=7.2 Hz, 2H), 3.72 (s, 3H), 3.24 (t, J=6.0 Hz, 2H), 3.16 (s, 3H), 2.93-2.81 (m, 1H), 2.06 (pent, J=6.4 Hz, 2H), 1.23 (d, J=6.9 Hz, 6H); LCMS: 579 [M+H].
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH:45]([CH3:47])[CH3:46])[C:11]([N:13]([CH2:38][C:39]1C=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:14][C:15]([NH:17][C@H](C(C1OC=C(C2C(Cl)=CC=CC=2Cl)N=1)=O)CC(O)=O)=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48](N[C@@H](C(C)C)C(N(CC(O)=O)CC1C=CC=CC=1)=O)(=O)[C:49]1C=CC=C[CH:50]=1.C(OC(=O)C(N)[C@H](C(OCC=C)=O)C(C1OC=C(C2C(Cl)=CC=CC=2Cl)N=1)O)(C)(C)C.C([O:110][C:111](=[O:134])[CH:112](N)[C@H:113](C(OCC=C)=O)[CH:114]([C:116]1[O:117][C:118]2[CH:124]=[C:123]([Cl:125])[CH:122]=[C:121]([Cl:126])[C:119]=2[N:120]=1)[OH:115])(C)(C)C.C(OC(=O)C[C@H](NC(=O)CN(C(=O)[C@@H](NC(=O)C1C=CC=CC=1)C(C)C)CC1C=CC=CC=1)C(C1OC=C(C2C(Cl)=CC=CC=2Cl)N=1)O)(C)(C)C>>[C:1]([NH:9][C@@H:10]([CH:45]([CH3:46])[CH3:47])[C:11]([N:13]([CH:38]1[CH2:50][C:49]2[C:40](=[CH:41][CH:42]=[CH:43][CH:48]=2)[CH2:39]1)[CH2:14][C:15]([NH:17][C@H:113]([C:114]([C:116]1[O:117][C:118]2[CH:124]=[C:123]([Cl:125])[CH:122]=[C:121]([Cl:126])[C:119]=2[N:120]=1)=[O:115])[CH2:112][C:111]([OH:110])=[O:134])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)O)Cc1ccccc1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Reactant: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc2c(Cl)cc(Cl)cc2o1
Agent: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc(-c2c(Cl)cccc2Cl)co1
Agent: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)c1nc2c(Cl)cc(Cl)cc2o1)C1Cc2ccccc2C1

Procedure:
Compound 725 was prepared by a method similar to the method used to prepare compound 710, except compound 704 was replaced with compound 724 and compound 707 was replaced with compound 718 in the preparation of compound 708: 1H NMR (500 MHz, CD3OD) δ 8.7-8.6 (m), 8.6-8.4 (m), 8.1 (d), 8.0-7.8 (m), 7.6-7.5 (m), 7.5-7.4 (m), 7.2-7.0 (m), 7.0-6.9 (m), 5.5-5.3 (m), 5.3-5.2 (m), 4.6-4.5 (m), 4.5-4.3 (m), 4.2-4.0 (m), 3.8-3.6 (m), 3.3 (s), 3.2-3.1 (m), 3.1-3.0 (m), 3.0-2.8 (m), 2.7-2.6 (m), 2.4-2.0 (m), 1.2-0.6 (m). ##STR104##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C)[CH:3]=1.[CH3:16][Si:17]([CH2:20][CH3:21])([CH3:19])[CH3:18]>>[CH2:9]([O:8][C:4]1[CH:3]=[C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:7]=[CH:6][CH:5]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCOc1cccc(Br)c1
Reactant: CC[Si](C)(C)C
Product: CCCCCCOc1cccc(C#C[Si](C)(C)C)c1
Yield: 52.4 %

Procedure:
According to the method described in Example S117a, 1-bromo-3-(heptyloxy)benzene (1 g, 4 mmol) was reacted with trimethylsilylethane (0.43 g, 4.4 mmol) to give the title compound as a yellow oil (575 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 7.19 (t, 1H, J=7.6 Hz), 7.05 (d, 1H, J=7.2 Hz), 6.99 (s, 1H), 6.87 (d, 1H, J=7.0 Hz), 3.94 (t, 2H, J=6.8 Hz), 1.79-1.75 (m, 2H), 1.47-1.30 (m, 6H), 0.91 (t, 3H, J=6.8 Hz), 0.26 (s, 9H).
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])=[O:12])=[CH:6][CH:5]=1.[C:23]([Mg]Br)#[C:24][CH3:25]>COCCOC.C1COCC1>[F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[C:11]([C:13]2[CH:20]=[CH:19][CH:18]=[C:15]([CH:16]([OH:17])[C:23]#[C:24][CH3:25])[CH:14]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(C(=O)C(=O)c2ccc(OC(F)F)cc2)c1
Reactant: CC#C[Mg]Br
Solvent: C1CCOC1
Solvent: COCCOC
Product: CC#CC(O)c1cccc(C(=O)C(=O)c2ccc(OC(F)F)cc2)c1
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A stirred solution of 3-[2-(4-difluoromethoxyphenyl)-2-oxo-acetyl]-benzaldehyde (0.1 g, 0.33 mmol) in dry DME at 0° C. under nitrogen was treated over 10 min with 0.5 M 1-propynyl magnesium bromide in THF. The reaction was stirred for 0.5 h, quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The combined extracts were dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by flash chromatography (20% to 40% ethyl acetate/petroleum ether) gave 1-(4-difluoromethoxyphenyl)-2-[3-(1-hydroxybut-2-ynyl)phenyl]ethane-1,2-dione as a clear oil, 55 mg (49% yield). Using essentially the same procedure described as described in Example 1, step c, and employing 1-(4-difluoromethoxyphenyl)-2-[3-(1-hydroxy-but-2-ynyl)phenyl]-ethane-1,2-dione (0.055 g, 0.16 mmol), the title product was obtained as a slight yellow foam, 0.044 g (69% yield), identified by NMR and mass spectral analyses. MS (ES+): 400 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Br:15][CH2:16][C:17](Br)=[O:18].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:17](=[O:18])[CH2:16][Br:15])[CH:3]=1
Reactant: O=C(Br)CBr
Reactant: Nc1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CBr)Nc1cccnc1
Reaction time: 2 h

Procedure:
To a mixture of 3-aminopyridine (11 g.) and triethylamine (13.0 g.) in dry ethyl acetate (300 ml.) was added a solution of bromoacetyl bromide (26.0 g.) in dry ethyl acetate (26 ml.) over a period of 30 minutes with stirring at 0° to 5° C. and stirring was continued for an additional 2 hours at the same temperature. To the reaction mixture was added a chilled aqueous solution of sodium bicarbonate. After shaking well, the ethyl acetate layer was separated, washed successively with water, an aqueous solution of sodium bicarbonate and water, dried and then concentrated. There was obtained concentrate (200 ml.) containing the title compound. Thus obtained concentrate was used directly in the next step reaction without further purification.
Reaction SMILES: [C:1]([C@@H:4]([C@H:6]([C:8](O)=O)O)O)(O)=O.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C1(C)C=CC(S(OCCC#C)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:1]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[CH3:11])[CH2:4][C:6]#[CH:8]
Reactant: C[C@@H]1CCCN1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCC[C@H]1C
Temperature: 85 °C

Procedure:
To a sealed flask was added 2-(R)-methylpyrrolidine L-tartrate (21.1 g, 90 mmol), 3-butynyl p-toluenesulfonate (15.7 mL, 89 mmol), potassium carbonate powder (18.5 g, 134 mmol) and CH3CN (160 mL). The resulting mixture was heated to 85° C. for 24 hours and the reaction was monitored by GC for the complete consumption of the tosylate. The reaction mixture was cooled to room temperature and filtered; the wet cake was washed with CH3CN (40 mL). The combined filtrate was used in the next step without further processing.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([N:15]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:17][C:16]2([CH3:28])[CH3:27])[N:3]=1.[CH2:29]([NH2:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O>[CH2:29]([NH:37][C:2]1[N:7]=[C:6]([N:8]([CH:9]([CH3:10])[CH3:11])[CH:12]([CH3:13])[CH3:14])[N:5]=[C:4]([N:15]2[C:16]([CH3:27])([CH3:28])[CH2:17][C:18]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:19][C:20]2([CH3:22])[CH3:21])[N:3]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CC(C)N(c1nc(Cl)nc(N2C(C)(C)CC3(CC2(C)C)OCCO3)n1)C(C)C
Reactant: CCCCCCCCN
Solvent: O
Product: CCCCCCCCNc1nc(N(C(C)C)C(C)C)nc(N2C(C)(C)CC3(CC2(C)C)OCCO3)n1

Procedure:
15 g (36.4 mmol) of the product from Example 18 are heated to 120° for 3 hours together with 30 ml of octylamine. After cooling, 40 ml of water are added and the mixture is extracted three times using 30 ml of methylene chloride. The CH2Cl2 solution is washed with water, dried over Na2SO4 and evaporated. The oily residue is dissolved in hexane/acetone and purified chromatographically on an SiO2 column. The main fraction is a viscous material.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:17](CC1C=CC=CC=1)[C@@H](C1C=CC=CC=1)C)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([F:16])[CH:8]=1)[CH3:2]>CCO.CC(O)=O.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH:6]([NH2:17])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([F:16])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(c1ccc(OCC)c(F)c1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC(N)c1ccc(OCC)c(F)c1
Reaction time: 12 h

Procedure:
A solution of the dibenzylamine 14-4 (30.0 gm, 66.8 mmol) in EtOH/HOAc (340/30 mL) was purged with argon and treated with Pd(OH)2 (6 g) and placed under 1 atm of H2 for 12 h. Additional portions (2.5 g) of Pd(OH)2 were added after 24 h and 48 h. The reaction mixture was purged with argon, filtered through Celite, and the filtrate collected. The filtrate was concentrated to yield the desired amine 14-5.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17](I)[CH:16]=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].[Cl-].[CH3:30][Zn+]>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([CH3:30])[CH:16]=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5]
Reactant: O=C(Nc1ccn(Cc2cc(I)ccc2C(F)(F)F)n1)c1c(F)cccc1F
Reactant: C[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(C(F)(F)F)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[5-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Example 102)(80 mg, 0.158 mmol) in THF (1 ml) was added tetrakis(triphenyl-phosphine)palladium(0) (25 mg, 0.022 mmol, Aldrich). To the solution was added 2.0 M methylzinc chloride in THF (0.5 mL, 1.0 mmol, Aldrich) and the mixture stirred at 80° C. under nitrogen for 4 h. The solvent was removed in vacuo and the residue diluted with methanol:DMSO (1:1, 2 ml). The suspension was filtered and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a white solid (26.3 mg); LCMS: (System 4) MH+=396, tRET=3.00 min.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[CH:12]=[C:13]([C:17]([O:19]C(C)C)=[O:18])[CH:14]=[CH:15][C:16]=3[C:8]=2[N:7]=[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:5]=1)(=[O:3])[NH2:2].CO.[OH-].[Na+]>C1COCC1>[C:1]([C:4]1[C:9]2[NH:10][C:11]3[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][C:16]=3[C:8]=2[N:7]=[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CC(C)OC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccccc3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A solution of isopropyl 4-carbamoyl-2-phenyl-5H-pyrido[3,2-b]indole-7-carboxylate (2 g, 5.36 mmol) in a mixture of THF (36 ml), MeOH (15 ml) and 1 N aqueous NaOH (12 ml, 120 mmol) was stirred at 25° C. overnight. The organic solvents were removed and the residue was dissolved in water, washed with DCM (20 mL), and acidified to about pH 3 with 1 N aqueous HCl to give a yellow gel-like precipitate. This was chilled in an ice bath and the precipitate was collected by filtration, washed with water, and dried to leave 4-carbamoyl-2-phenyl-5H-pyrido[3,2-b]indole-7-carboxylic acid (2.1 g, 5.1 mmol, 95% yield). MS (ESI) m/z 332.00 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.67 (1H, d, J=8.55 Hz), 8.58-8.64 (1H, m), 8.54 (1H, s), 8.03-8.17 (3H, m), 7.67-7.79 (3H, m).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=4[F:44])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:44][C:37]1[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:36]=1[O:35][CH:32]1[CH2:31][CH2:30][N:29]([C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[NH:25][CH:26]([CH3:28])[CH3:27])[CH2:34][CH2:33]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCN(Cc3ccccc3)C4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCNC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (122 mg, 0.197 mmol) and Pd(OH)2 on carbon (20 wt %, 12 mg, 0.017 mmol) in THF (2.0 mL) was stirred under an atmosphere of hydrogen gas (balloon) at rt. After 2 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (83.2 mg, 80%) as a yellow oil. 1H NMR (400 MHz, methanol-d4) δ ppm 1.25 (d, J=6.6 Hz, 6H), 1.88-1.98 (m, 2H), 2.04-2.13 (m, 2H), 2.93-3.03 (m, 4H), 3.35-3.41 (m, 3H), 3.54 (t, J=6.3 Hz, 2H), 3.76 (s, 3H), 4.14-4.18 (m, 2H), 4.18-4.23 (m, 1H), 4.32-4.40 (m, 1H), 6.67 (ddd, J=9.0, 3.0, 1.4 Hz, 1H), 6.74 (dd, J=12.9, 3.0 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 416.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:7]=1[C:8]#[N:9].[NH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.O>C(O)CCC>[ClH:1].[ClH:1].[O:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][NH:16][C:2]2[N:3]=[N:4][C:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][C:7]=2[C:8]#[N:9])[CH2:20][CH2:21]1
Reactant: NCCN1CCOCC1
Reactant: N#Cc1cc(-c2ccccc2)nnc1Cl
Solvent: CCCCO
Solvent: O
Product: Cl
Product: N#Cc1cc(-c2ccccc2)nnc1NCCN1CCOCC1
Yield: 81.3 %

Procedure:
7.3 g of the chlorine compound of Example 18 are dissolved in 60 ml of normal butanol, and 8 g of N-(2-aminoethyl)-morpholine are added. The mixture is heated under reflux for 3 hours and then poured into 1000 ml of water. The organic phase is extracted with ether and the ether solution is then extracted with a 1N solution of sulphuric acid. The aqueous phase is separated off, rendered alkaline with sodium hydroxide and extracted with ether. The ether phase is dried over magnesium sulphate and the solvent is then evaporated off to dryness in vacuo. This gives a yellow solid. Yield 81.3%; melting point 138° C.
Reaction SMILES: I[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.Br[C:29]1[C:37]2C(=O)N(COCC[Si](C)(C)C)N=C[C:32]=2N(COCC[Si](C)(C)C)C=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH:29]1([C:2]2[C:10]3[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=3[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=2)[CH2:37][CH2:32]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(I)cn2COCC[Si](C)(C)C)c1=O
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(Br)cn2COCC[Si](C)(C)C)c1=O
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Product: C[Si](C)(C)CCOCn1ncc2c(c(C3CC3)cn2COCC[Si](C)(C)C)c1=O
Yield: 79 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 20-(b) except for using 7.00 g (purity: 78.4%, 10.5 mmol) of 3-iodo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 18-(b) in place of 3-bromo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, and using 589 mg (2.10 mmol) of tricyclohexylphosphine in place of butyl-di-1-adamantylphosphine, respectively, whereby 3.60 g of the title compound was obtained as a white solid. (Yield: 79%)