Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1.[CH3:16][N:17]([CH3:30])[C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]>CO>[CH3:30][N:17]([CH3:16])[C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:15][N:14]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=3)[N:1]=2)=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Reactant: CN(C)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N(C)C)c([N+](=O)[O-])c3)n2)cc1F

Procedure:
The title compound was obtained following procedure described for example 4, step 1, but starting from Intermediate 1 (300 mg; 1.41 mmol) and Intermediate 35 (326.90 mg; 1.56 mmol). Title compound was isolated after trituration with MeOH as a brown powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.50 (d, J=2.1 Hz, 1H), 8.16 (dd, J=9.1, 2.2 Hz, 1H), 8.09 (d, J=7.2 Hz, 1H), 8.03 (dd, J=8.2, 1.5 Hz, 1H), 7.98-7.94 (m, 1H), 7.38 (d, J=9 Hz, 1H), 3.90 (s, 3H), 2.99 (s, 6H). LC/MS (Method B): 387.2 (M+H)+. HPLC (Method A) Rt. 5.07 min (purity: 98%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([CH3:19])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>>[CH3:19][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[O:20][CH2:21][CH2:22][CH3:23])[CH:26]=[CH:25][C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:17][C:16]2=[O:18]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Product: CCCOc1ccc(C=CC(=O)OC(C)(C)C)cc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
The title compound was prepared from 2-(5-bromo-2-n-propoxyphenyl)-8 -methylquinazolin-4(3H)-one (Preparation 11) and t-butyl acrylate following the procedure of Example 9 and was obtained as colorless crystals (18%), m.p. 196°-197° C. Found: C,71.54; H,6.90; N,6.69. C25H28N2O4 requires C,71.41; H,6.71; N,6.66%.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[N:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=[C:26]([C:33](O)=[O:34])[CH:25]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[CH:25]=[N:24][N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=23)=[O:34])=[O:10])[N:12]=1
Reactant: O=C(O)c1cnn2ccccc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnn3ccccc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Pyrazolo[1,5-a]pyridine-3-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=472.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[S:25])[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2C(OCC)=O)=[C:4]([F:26])[CH:3]=1>[OH-].[K+]>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([NH:12][C:13](=[S:25])[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]2)=[C:4]([F:26])[CH:3]=1
Reactant: CCOC(=O)N1CCCCN1C(=S)Nc1cc(OC(C)C)c(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Product: CC(C)Oc1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A solution of ethyl 2-(4-chloro-2-fluoro-5-(1-methylethoxy)phenylaminothioxomethyl)-3,4,5,6-tetrahydro-1(2H)pyridazinecarboxylate (0.8 g) in a 5% ethanolic potassium hydroxide solution (10 ml) was heated under reflux for 3 hours. After being allowed to cool to room temperature, ethanol was removed under reduced pressure. The residue was dissolved in ether, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 0.3 g of 2-(4-chloro-2-fluoro-5-(1-methylethoxy)phenylaminothioxomethyl)-3,4,5,6-tetrahydro-(1H,2H)-pyridazine. M.P., 113°-114.5° C. NMR δ (ppm): 1.35 (6H, d), 1.7 (4H, m), 2.95 (2H, m), 3.45 (1H, t), 4.2 (2H, m), 4.4 (1H, m), 6.95 (1H, d), 8.25 (1H, d), 9.85 (1H, m).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])C.[CH3:16]I.[H-].[Na+]>C1COCC1.C(OCC)C>[C:12]([O:11][C:9]([N:1]([CH3:16])[C@H:2]([CH2:3][CH3:5])[C:6]([OH:8])=[O:7])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.6 %

Procedure:
To a solution of N-Boc-D-Val-OH (0.678 g, 3.34 mmol) in THF (11.1 mL) at 0° C. was added MeI (2.09 mL, 33.4 mmol, 10.0 equiv). NaH (60%, 1.33 g, 33.4 mmol, 10.0 equiv) was added as a solid to the suspension over a period of 2 hours. After stirring for 12 hours at room temperature, the reaction mixture was diluted with diethyl ether and quenched with water slowly. Aqueous layer was extracted with diethyl ether followed by acidified to pH 3 with 10% citric acid and extraction with ethyl acetate. Combined organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford compound 3.1a (0.73 g) which was used for the next step without further purification. MS m/z (M+Na) 240.2. 1H NMR (400 MHz, CDCl3) 4.56 and 4.37 (br-s, 1H), 2.83 (br-s, 3H), 2.08-1.92 (m, 1H), 1.85-1.68 (m, 1H), 1.48 (br-s, 9H), 0.96 (t, J=7.38 Hz, 3H).
Reaction SMILES: [ClH:1].[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[N:11](=[C:13]([CH3:17])[C:14](=O)[CH3:15])[OH:12]>C(OCC)(=O)C>[ClH:1].[CH3:17][C:13]1[N+:11]([O-:12])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=2)[O:9][C:14]=1[CH3:15]
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)C(C)=NO
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1

Procedure:
At 0°-5° C., dry HCl was bubble through a solution of p-tolualdehyde (125 g, 1.04 mol) and 3-oximino-2-butanone (95.6 g, 0.946 mol) in 350 ml of ethyl acetate. Title product was precipitated by dilution with ether and recovered by filtration with ether wash, 207 g; mp 198°-200° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][C:4]=1[C:14](=[O:16])[CH3:15].[C:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([OH:19])=[O:18]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][C:4]=1[C:14](=[O:16])/[CH:15]=[CH:24]/[C:23]1[CH:26]=[CH:27][C:20]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COc1cc(-c2cccs2)ccc1C(C)=O
Product: COc1cc(-c2cccs2)ccc1C(=O)/C=C/c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared by condensing 1-(2-methoxy-4-thiophen-2-yl-phenyl)-ethanone (Ex-19A) and 4-carboxybenzaldehyde in a similar manner as described in Ex-17 except an acidic workup. Yellow solid, mp 193–195° C. 1H-NMR (CDCl3) □ 7.70 (d, J=8 Hz, 2H), 7.38 (d, J=8 Hz, 1H), 7.07–7.16 (m, 4H), 6.75–6.80 (m, 4H), 6.42 (d, J=16 Hz, 1H), 3.67 (s, 3H), MS m/z=364 ([M]+, 100%). Anal. Calculated for C21H16O4S: C, 69.21; H, 4.43; S, 8.80; found: C, 69.02; H, 4.56; S, 8.75.
Reaction SMILES: [Br:1][C:2]1[C:6](Br)=[CH:5][S:4][CH:3]=1.C([Li])CCC.[CH2:13]([S:15]SCC)[CH3:14].[OH-].[Na+]>O.C(OCC)C>[Br:1][C:2]1[C:6]([S:15][CH2:13][CH3:14])=[CH:5][S:4][CH:3]=1
Reactant: CCSSCC
Reactant: Brc1cscc1Br
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCSc1cscc1Br
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A mixture of 9.68 g of 3,4-dibromothiophene and 80 mL of diethylether was cooled to −70° C., 27 mL of n-butyl lithium (1.63 M hexane solvent) was added over 30 minutes, and the mixture was stirred at −70° C. for 30 minutes. To the mixture was added 5.86 g of diethyl disulfide at such a rate that the internal temperature is maintained at −60° C. or less, and the mixture was stirred at −70° C. for 2 hours. The reaction mixture was heated to −35° C. and then 100 mL of water was added. After heating to room temperature, a 2 N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 3.27 g of 3-bromo-4-ethylthiothiophene.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.CC(C)([O-])C.[K+].C1COCC1.C[O:27][C:28](=O)[C:29]([C:31]1[C:39]2[C:34](=[CH:35][C:36]([Br:40])=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=O>CN(C=O)C>[Br:40][C:36]1[CH:35]=[C:34]2[C:39]([C:31]([C:29]3[C:28](=[O:27])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:32][NH:33]2)=[CH:38][CH:37]=1
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2cc(Br)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5cc(Br)ccc45)C(=O)NC3=O)c21
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 73.4 %

Procedure:
To solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.300 g, 1.59 mmol) in DMF (15 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.59 mL, 1.59 mmol), followed after 5 minutes by (6-bromo-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.235 g, 0.83 mmol) in DMF (1.25 mL). After another 5 minutes additional potassium tert-butoxide (1.59 mL) was introduced followed by the additional (6-bromo-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.235 g, 0.83 mmol) in DMF (1.25 mL). The reaction was stirred for 5 minutes and an additional potassium tert-butoxide (1.59 mL) was introduced. After heating at 50° C. over night, then deep red solution and was cooled to room temperature, quenched with 1N HCl and poured in EtOAc. The two layers were separated and the organic layer was washed with H2O, saturated aq NaHCO3, and brine (×3), dried (MgSO4), filtered, and concentrated. Flash chromatography (80% EtOAc/hexane) gave the title compound (0.256 g, 38%) as a red solid. 1H NMR (400 MHz, DMSO-d6) 3.64 (s, 3H), 6.26 (d, J=4.4 Hz, 1H), 6.47 (d, J=2.8 Hz, 1H), 6.60 (dd, J=2, 8.8 Hz, 1H), 6.88 (d, J=7.2 Hz, 1H), 6.98 (dd, J=7.2, 7.2 Hz, 1H), 7.24 (d, J=3.6 Hz, 1H), 7.61 (dd, J=1.2, 8 Hz, 1H), 7.87 (d, J=2.8 Hz, 1H), 11.18 (s, 1H), 11.91 (s, 1H). MS (electrospray, m/z) 420/418 (M−−1).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].[H-].[Na+].I[CH3:22].O>O1CCCC1>[CH3:18][N:2]([CH3:1])[C:3]([CH2:5][CH2:6][N:7]([CH3:22])[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: CN(C)C(=O)CCNC(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)CCN(C)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Benzyl [2-(dimethylcarbamoyl)ethyl]carbamate (I-139) (0.69 g, 2.76 mmol) was dissolved in tetrahydrofuran (10 ml), and with cooling with ice, sodium hydride (oily, about 55%, 0.15 g, 3.44 mmol) was added, followed by stirring for 10 minutes. Iodomethane (0.26 ml, 4.18 mmol) was added, followed by stirring at room temperature for 18 hours, and water was added. After extraction with ethyl acetate and drying over anhydrous sodium sulfate, the solvent was evaporated away, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1) to obtain a colorless oil (0.63 g, 86%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]=12)#[N:13]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)c(F)c2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(Cc3ccc(F)c(F)c3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(3,4-difluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 387 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[O:14])=[N:7][CH:8]=1.[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23].C[Si](Cl)(C)C>>[OH:14][CH:13]([P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:8][N:7]=2)[CH:11]=1
Reactant: CCOP(OCC)OCC
Reactant: O=Cc1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Agent: C[Si](C)(C)Cl
Product: CCOP(=O)(OCC)C(O)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
To an ethereal solution of 3-(5-(trifluoromethyl)pyridin-2-yloxy)benzaldehyde (1.6 g, 5.98 mmol) and LiClO4 (5 mL, 5 M solution in diethylether) was added triethyl phosphite (1.24 g, 7.48 mmol) and TMSCl (0.813 g, 7.48 mmol) at 0° C. The reaction mixture was allowed to reach RT and stirred for 10 min. The reaction was quenched by adding distilled water (10 mL), extracted with CH2Cl2, dried and concentrated to dryness. The residue was purified by column chromatography (1:1 EtOAc:Hexane) to afford pure title compound (1.3 g). 1H NMR (500 MHz, CDCl3): δ 1.2 (m, 6H), 2.9 (m, 1H), 4.0 (m, 4H), 5.0 (d, 1H, J=11 Hz), 7.0 (d, 1H, J=8.5 Hz), 7.1 (d, 1H, J=7.5 Hz), 7.3 (s, 1H), 7.4 (m, 1H), 7.8 (m, 1H), 8.4 (s, 1H).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6]Br.[CH3:8][Si:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([O:14]CC)=O.[Cl-].[NH4+]>C1COCC1>[CH3:18][Si:9]([CH3:8])([CH3:17])[CH2:10][CH2:11][C:12]1([OH:14])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrCCCCBr
Reactant: CCOC(=O)CC[Si](C)(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCC1(O)CCCC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A flask was charged with 9.82 g of magnesium and 150 ml of THF, to which a solution of 43.5 g of 1,4-dibromobutane diluted with 50 ml of THF was added dropwise at 50° C. The solution was stirred for one hour at 65° C., after which 23.5 g of ethyl 3-trimethylsilylpropionate was added dropwise below 50° C. The solution was stirred for one hour at room temperature, after which an aqueous solution of ammonium chloride was added for hydrolysis. This was followed by ordinary post-treatments. Upon vacuum distillation, there was obtained 23.6 g (yield 94%) of 1-(2-trimethylsilylethyl)cyclopentanol.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[O:25])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6].C(OCC)(=O)C.[Na]>FC(F)(F)C(O)=O>[F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)=[O:25])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(ccn4C(=O)NCCF)c3)ccn2)CC1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NCCF)c2)ccn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
After dissolving 160 mg of N1-(2-fluoroethyl)-5-[(2-{[(1-tert-butyloxycarbonyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide in 10 ml of trifluoroacetic acid, the solution was stirred at room temperature for 10 minutes. Ethyl acetate and sodium bicarnobate water were added to alkalinity for liquid separation. The ethyl acetate layer was washed once with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 86 mg of a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.Cl>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(c1)CC(=O)N2
Temperature: 140 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 5-methoxyisatin (10.62 g, 60 mmol) in DMSO (30 mL) was added N2H4.×H2O (hydrazine hydrate, 6 mL, 120 mmol) dropwise over 5 min (exothermic). After addition, the resulting mixture was heated at 140° C. (oil temp.) for 2 h and then cooled to rt. After diluting with H2O (30 mL), 6 M HCl (12 mL, 72 mmol) was added and the resulting mixture was stirred for 1 h at rt. Ice (30 mL) was added and the reaction mixture was stirred O/N at rt. The precipitate formed was collected by suction filtration, rinsed with H2O, then dried to give the 5-methoxyoxindole (6.523 g) as a brown solid. (about 10% impurity being the oxime from starting material 5-methoxyisatin) 1H NMR (400 MHz, d6-DMSO) 6.78 (s, 1H), 6.85 (s, 1H), 6.72-6.79 (m, 2H), 3.39 (s, 3H); ESI 164.0 [M+H]+, calcd for [C9H9NO2+H]+ 164.1.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[Cl-].[CH2:14]([O:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH2+:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:12][C:8]1[C:9]([CH3:11])=[CH:10][C:4]2[O:3][C:2]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]3[C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:23])=[N:6][C:5]=2[CH:7]=1
Reactant: Cc1cc2nc(Cl)oc2cc1C
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCC[NH2+]1
Agent: [Cl-]
Product: Cc1cc2nc(N3CCCC[C@H]3C(=O)OCc3ccccc3)oc2cc1C

Procedure:
The title compound was prepared by a similar method to Preparation 2 from 2-chloro-5,6-dimethyl-1,3-benzoxazole [see J.Med. Chem. (1972), 15, 523-9] and (2S)-2-[(benzyloxy)carbonyl]piperidine [see EP 530167 A1 930303]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100 : 0 changing to 80:20, by volume, hexane:ethyl acetate to afford benzyl (2S)-1-[5,6-dimethyl-1,3-benzoxazol-2-yl]-2-piperidinecarboxylate as a yellow coloured solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([N:23]3C(=O)C4C(=CC=CC=4)C3=O)[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][N:4]=[CH:3]1.O.NN>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][N:4]=[CH:3]1
Reactant: Cn1cncc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(=NOCc1cccc(N)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 29 h
Yield: 81.5 %

Procedure:
To a solution of 2-{6-[({[(1-methyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (1.87 g, 4.27 mmol) in tetrahydrofuran (20 mL) was added dropwise hydrazine hydrate (1.04 mL, 21.4 mmol). After stirring at room temperature for 29 h, the reaction mixture was filtered, the insolubles washed with ethyl acetate, and the filtrate concentrated in vacuo. Purification on silica gel afforded 6-[({[(1-methyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine [1.07 g, yield 77%; HPLC/MS: m/z=308 (M+H); log P(HCOOH)=0.29].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[C:24]1(/[CH:30]=[CH:31]/B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2](/[CH:31]=[CH:30]/[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Reactant: OB(O)/C=C/c1ccccc1
Product: CCCCc1nc2c(N)nc3cc(/C=C/c4ccccc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and trans-2-phenylvinylboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from toluene followed by chromatography on silica gel (8% methanol in CH2Cl2) afforded 2-butyl-1-isobutyl-7-[(E)-2-phenylethenyl]-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 215–216° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.P([O-])([O-])([O-])=[O:21].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11]=1[C:12]([OH:21])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=Cc1c(Cl)nc(-c2ccccc2)c2ccccc12
Reactant: O=P([O-])([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1c(Cl)nc(-c2ccccc2)c2ccccc12
Reaction time: 2 h

Procedure:
53.5 g 3-Chloro-1-phenyl-isoquinoline-4-aldehyde are suspended in 1.5 l of acetone and 500 ml of phosphate buffer of pH 7. At 40° C., 40 g of potassium permanganate are introduced portionwise within 2 hours and stirring is continued at this temperature for 2 hours. The excess potassium permanganate is destroyed with 10 g sodium hydrogenosulfite and the solution is concentrated to 500 ml and filtered. The filtrate is brought to pH 4 with concentrated hydrochloric acid followed by thorough extraction with acetic ester. Removal of the solvent in vacuo provides 41.1 g of 3-chloro-1-phenyl-isoquinoline-4 carboxylic acid having a melting point of 208° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[F:26][C:23]1[CH:22]=[N:21][C:20]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:5][CH2:4]2)=[N:25][CH:24]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncc(F)cn2)CC1
Temperature: 100 °C

Procedure:
A stirred mixture of benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, STEP 1) (10.0 g, 0.040 mol), 2-chloro-5-fluoropyrimidine (5.3 g, 0.040 mol) and cesium carbonate (26.2 g, 0.081 mol) in DMF (100 mL) was heated at 100° C. for 2 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (400 mL), washed with aqueous saturated NaHCO3 (100 mL), water (5×100 mL), and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60 (0.5 kg), eluting with 50–100% ethyl acetate in hexane to give the title compound. M.S. (M+1): 345.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4]1.[H-].[Na+].[CH3:19]I>O1CCCC1>[CH3:19][O:1][CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4]1
Reactant: CI
Reactant: CCOC(=O)c1ccc2c(c1)CC(CO)O2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)CC(COC)O2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
A solution of 2.5 g (11.26 mmole) ethyl 2-hydroxymethyl-2,3-dihydrobenzofuran-5-carboxylate in 50 ml tetrahydrofuran was cooled under nitrogen to 0° C. and 595 mg (12.38 mmole) of a 50% by weight dispersion of sodium hydride in oil was added in portions. The mixture was stirred to 0° C. for 15 minutes, then a solution of 1.756 g (12.38 mmole) methyl iodide in 30 ml tetrahydrofuran was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated in vacuo, the residue partitioned between ethyl ether and water. The ether extracts were combined, washed with brine, dried (MgSO4) and the solvent evaporated in vacuo to yield 2.28 g of product as an oil. 1H-NMR(CDCl3) showed singlet at 3.4 ppm, consistent with the presence of a CH2OCH3 group.