Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([OH:33])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:38](Br)[CH2:39][CH2:40][CH2:41][CH3:42]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH:20]4[CH2:21][CH2:16][CH2:17][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]4)[C:10]=3[N:9]=2)=[CH:34][CH:35]=1
Reactant: CCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CCCCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCCN(C(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C

Procedure:
A solution of (RS) 2-(4-chlorophenoxymethyl)-4-hydroxy-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole (75 mg, 0.15 mmol, 1.0 eq) in dry N,N-dimethylformamide (1.0 ml) was treated with sodium hydride (60% in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting mixture was stirred at room temperature for thirty minutes, after which time 5-[1-(t-butoxycarbonyl)piperidin-3-yl)]pentyl bromide (0.18 mmol, 1.2 eq) was added. The resulting mixture was stirred for three hours at 70° C. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with diethyl ether (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to give a crude product. The title product was further purified by flash chromatography to provide a crystalline product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([NH2:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22].C(N(CC)C(C)C)(C)C>C(Cl)Cl.Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([NH:15][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=2)=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ncc(N)cc1Br
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ncc(NC(=O)c2cccc(F)c2)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
(5-Amino-3-bromo-pyridin-2-yl)-carbamic acid tert-butyl ester (50 mg, 0.17 mmol), 3-fluoro-benzoyl chloride (28 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.03 mL, 0.19 mmol) were dissolved in CH2Cl2 (2 mL), and stirred or 1 h at 0° C. The reaction solution was diluted with 1 M HCl/CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 20 to 70% EtOAc/hexanes to provide of [3-bromo-5-(3-fluoro-benzoylamino)-pyridin-2-yl]-carbamic acid tert-butyl ester (47 mg, 66% yield) as a solid.
Reaction SMILES: [C:1]1([C:7]2[C:12](B(O)O)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24](C3C(C)=CC=C4C=3C=CC=N4)[C:25]3[O:29][C:28](=[O:30])[NH:27][C:26]=3[CH:31]=2)=[C:20]([CH3:43])[O:19][N:18]=1>>[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:12]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:8][CH:9]=[CH:10][CH:11]=3)[C:25]3[O:29][C:28](=[O:30])[NH:27][C:26]=3[CH:31]=2)=[C:20]([CH3:43])[O:19][N:18]=1
Reactant: Cc1ccc2ncccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)oc12
Reactant: OB(O)c1cccnc1-c1ccccc1
Product: Cc1noc(C)c1-c1cc(-c2cccnc2-c2ccccc2)c2oc(=O)[nH]c2c1

Procedure:
The title compound was synthesized using 2-phenylpyridin-3-ylboronic acid in a similar fashion with 5-(3,5-dimethylisoxazol-4-yl)-7-(6-methylquinolin-5-yl)benzo[d]oxazol-2(3H)-one (Example 11).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19](OC)=[O:20])=[N:4][N:5]2[CH:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][N:8]([CH3:17])[C:7](=[O:18])[C:6]=12.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CO>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:19]([C:3]2[C:2]([OH:1])=[C:6]3[C:7](=[O:18])[N:8]([CH3:17])[CH2:9][CH:10]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)[N:5]3[N:4]=2)=[O:20])=[CH:26][CH:25]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nn2c(c1O)C(=O)N(C)CC2c1cccnc1
Solvent: CO
Product: CN1CC(c2cccnc2)n2nc(C(=O)NCc3ccc(F)cc3)c(O)c2C1=O

Procedure:
Methyl 3-hydroxy-5-methyl-4-oxo-7-pyridin-3-yl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (40 mg, 0.13 mmol) and 4-fluorobenzylamine (130 mg, 1.06 mmol) were combined in MeOH (0.5 mL) and the mixture was heated to reflux, allowing the solvent to slowly evaporate over 18 hours. The residue was purified by preparative HPLC (Waters Nova Pak column (100×40 mm I.D. cartridge, C18, 6 μM pore size) eluting with 95-5% water (0.1% TFA)/acetonitrile (0.1% TFA) at 35 mL/minute.). The appropriate fractions were combined and the solvent was removed to give the title compound as a gum. 1H NMR (400 MHz, d6-DMSO) δ 8.77 (t, J=6 Hz, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 7.6-7.7 (m, 2H), 7.33 (dd, J=5.7, 8.6 Hz, 2H), 7.13 (t, J=9.0 Hz, 2H), 5.90 (t, J=4.6 Hz, 1H), 4.39 (ABX, J=15, 6.1 Hz, 2H), 4.19 (dd, J=13, 4.6 Hz, 1H), 3.91 (dd, J=13, 4.5 Hz, 1H), 2.91 (s, 3H); ES MS (M+1)=396.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:30])[N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[C:13]([C:15]2[NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[N:23]=2)[CH:14]=1)#[N:2].[CH3:31]I>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:30])[N:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:12]=[C:13]([C:15]2[N:16]=[C:19]3[N:20]([CH3:31])[CH:21]=[CH:22][CH:17]=[C:18]3[N:23]=2)[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(-c2nc3cnccc3[nH]2)cn(-c2ccccc2)c1=O
Reactant: CI
Solvent: CC(C)=O
Product: Cn1cccc2nc(-c3cc(-c4ccccc4C#N)c(=O)n(-c4ccccc4)c3)nc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3 mg of 3-(2-cyanophenyl)-5-(1H-imidazo[4,5-c]pyridin-2-yl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 3 ml of acetone. To the mixture was added 2 ml of methyl iodide, followed by stirring at room temperature overnight. The mixture was evaporated, and the residue was diluted with 1 ml of water. To the mixture was added 20 mg of sodium hydroxide, followed by stirring at room temperature for 4 hours. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated, and the residue was purified by silica gel chromatography (NH silica) (hexane/ethyl acetate system), to give 2 mg of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[C:4](O)=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccncc12
Product: Clc1ccnc2ccncc12

Procedure:
1,6-naphthyridin-4-ol (0.530 g, 3.63 mmol) was dissolved in phosphorus oxychloride (4.06 ml, 43.5 mmol) and heated at reflux for 14 h. Excess POCl3 was removed under reduced pressure and the mixture was azeotroped with toluene. The resultant gum was treated with sat. NaHCO3 until no gas was generated. The mixture was extracted with EtOAc, the combined extracts were washed with sodium bicarbonate and the solvent was removed under reduced pressure. The crude product was purified via column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-90% EtOAc/DCM) to afford 4-chloro-1,6-naphthyridine as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O.O.[C:13](O)(=[O:17])[C:14](O)=[O:15]>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Br:8])[NH:9][C:14](=[O:15])[C:13](=[O:17])[NH:10]2
Reactant: Nc1cc(Br)c(Br)cc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cc(Br)c(Br)cc2[nH]c1=O
Temperature: 125 °C
Yield: 91.7 %

Procedure:
A mixture of 4,5-dibromo-1,2-phenylenediamine (1.862 g, 7.0 mmol) and oxalic acid dihydrate (1.06 g, 8.4 mmol) in 2N HCl (100 mL) was heated at 125° C. for 2 h then allowed to cool to 25° C. The solid was collected by vacuum filtration, washed with water and dried at 40° C. under 1 mmHg for 10 h affording 2.053 g (92%) of the title compound as a light brown powder. 1H NMR (DMSO-d6) 11.995 (s, 2H), 7.361 (s, 2H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:38](=[O:39])[N:6]2[C:7]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)=[O:26])=[C:8](P(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@@H:5]12)[CH3:3].[OH:40][CH:41]([CH2:72][NH:73][C:74]([O:76][CH2:77][C:78]1[CH:83]=[CH:82][C:81]([N+:84]([O-:86])=[O:85])=[CH:80][CH:79]=1)=[O:75])[CH2:42][C:43]([NH:45][C@H:46]1[CH2:50][CH2:49][N:48]([C:51]([C@@H:53]2[CH2:57][C@H:56]([SH:58])[CH2:55][N:54]2[C:59]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][C:66]([N+:69]([O-:71])=[O:70])=[CH:65][CH:64]=2)=[O:60])=[O:52])[CH2:47]1)=[O:44]>>[OH:1][C@@H:2]([C@H:4]1[C:38](=[O:39])[N:6]2[C:7]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=3)=[O:26])=[C:8]([S:58][C@@H:56]3[CH2:55][N:54]([C:59]([O:61][CH2:62][C:63]4[CH:64]=[CH:65][C:66]([N+:69]([O-:71])=[O:70])=[CH:67][CH:68]=4)=[O:60])[C@H:53]([C:51]([N:48]4[CH2:49][CH2:50][C@H:46]([NH:45][C:43](=[O:44])[CH2:42][CH:41]([OH:40])[CH2:72][NH:73][C:74]([O:76][CH2:77][C:78]5[CH:79]=[CH:80][C:81]([N+:84]([O-:86])=[O:85])=[CH:82][CH:83]=5)=[O:75])[CH2:47]4)=[O:52])[CH2:57]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(P(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: O=C(CC(O)CNC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)CC(O)CNC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 83.4 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-diphenylphosphoryl-1-carbapen-2-em-3-carboxylate (1.78 g) and (2S,4S)-2-[(3S)-3-[3-hydroxy-4-(4-nitrobenzyloxycarbonyl)aminobutanoylamino]pyrrolidin-1-ylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.0 g), reaction and purification were carried out in a similar manner to that described in Example 1-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[(3S)-3-[3-hydroxy-4-(4-nitrobenzyloxycarbonyl)aminobutanoylamino]pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (2.52 g) was obtained as an amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[CH2:11][CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH2:11][CH:12]=[O:13]
Reactant: Cc1cccc(C)c1N
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cccc(C)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Dimethylaniline (60 grams), the dimethyl acetal of 2-chloroacetaldehyde (25 grams) and sodium carbonate (21.2 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at 150° C. for a period of about 30 hours. After this time the mixture was filtered and the filtrate was distilled to yield the desired product the dimethyl acetal of 2-(2,6-dimethylanilino)acetaldehyde having a boiling point of 105° C. at 1 mm of Hg pressure.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[C:32]([F:42])[CH:31]=3)[O:27][N:26]=2)=[CH:21][CH:20]=1>CN(C)C=O>[F:42][C:32]1[CH:31]=[C:30]([C:28]2[O:27][N:26]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH2:18][N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13])=[CH:20][CH:21]=3)[N:29]=2)[CH:35]=[CH:34][C:33]=1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Fc1cc(-c2nc(-c3ccc(CCl)cc3)no2)ccc1-c1ccccc1
Reactant: OCCNCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCCN(CCO)Cc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(F)c3)n2)cc1
Temperature: 90 °C

Procedure:
Diisopropylethylamine (23.5 mL, 0.136 mol) and diethanolamine (14.2 g, 0.135 mol) are added to a stirred solution of 3-(4-chloromethylphenyl)-5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole (33 g, 0.090 mol) in N,N-dimethyl-formamide (200 mL). The reaction mixture is heated at 90° C. for 2.5 hrs, the solvent is removed under reduced pressure and the residue is treated with demineralized water (200 mL) to get a solid which is filtered and washed with n-hexane (150 mL) and diethyl ether (100 mL) to furnish 2-[{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]benzyl}(2-hydroxyethyl)amino]ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:17])[NH:5][C:6](=NC2C=CC=CC=2)[C:7]=1[O:8][CH3:9].Cl.[OH2:19]>>[CH3:1][O:2][C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:19])[C:7]=1[O:8][CH3:9]
Reactant: COC1=C(OC)C(=Nc2ccccc2)NC1=O
Reactant: O
Agent: Cl
Product: COC1=C(OC)C(=O)NC1=O

Procedure:
500 g of 2,5-dihydro-3,4-dimethoxy-5-phenyliminopyrrol-2-one were stirred with 500 ml of concentrated hydrochloric acid in 2 l of water for 2 days at room temperature. Thereafter, the mixture was cooled and filtered under suction. 325 g of dimethoxymaleimide of melting point 126°-127° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=2)=[O:9])[C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-c2cncn2C)c(C(=O)O)c1
Product: Cc1ccc(-c2cncn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(1-methyl-1H-imidazol-5-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 472 [M+1]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:21]>>[ClH:21].[NH2:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To methyl (S)-4-(1-tert-butoxycarbonylaminoethyl)benzoate (1.00 g, 3.58 mmol), add hydrogen chloride (4 M in dioxane, 5 mL, 20 mmol) and stir the resulting mixture at room temperature for one hour. Concentrate the mixture under reduced pressure to furnish the title compound as a white solid (750 mg, 97% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.57 (br s, 3H), 7.99 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 4.47 (q, J=6.7 Hz, 1H), 3.84 (s, 3H), 1.50 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][C:4]=1[OH:16])#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][C:4]=1[O:16][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])#[N:2]
Reactant: N#Cc1ccc(Nc2ccccn2)cc1O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2ccccn2)ccc1C#N
Yield: 38 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-cyano-5-(pyridin-2-ylamino)phenol (2 mg, 0.01 mmol) and Cs2CO3 (3 mg, 0.01 mmol) in acetone (1.5 mL) was treated with 4-bromo-2-methyl-2-butene (1.1 μL, 0.01 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 38% yield (1 mg).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2B(O)O)[CH2:18][CH2:17]1>>[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[CH2:17][CH2:18]1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(F)cc1OCC1CC1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)cc1OCC1CC1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 2-(cyclopropylmethoxy)-4-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H17FN4O, 349. Found, 349.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18](=[O:22])[C:19](Cl)=[O:20])=[C:10]1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1>O1CCCC1>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18](=[O:22])[C:19]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[O:20])=[C:10]1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1
Reactant: CC1CCNCC1
Reactant: Cn1c(COc2ccc(Cl)cc2)c(C(=O)C(=O)Cl)c2ccccc21
Solvent: C1CCOC1
Product: CC1CCN(C(=O)C(=O)c2c(COc3ccc(Cl)cc3)n(C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 4-methylpiperidine (0.490 ml, 0.411 g, 4.14 mmol) was dissolved in 3.0 ml of dry tetrahydrofuran in a round bottom flask over an ice bath. To this reaction mixture was added 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-chloro-1,2-ethanedionyl]-1H-indole (0.500 g, 1.39 mmol) and the resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]2=[O:24])[CH:7]=1.[C:26](Cl)([Cl:28])=[O:27]>C1(C)C=CC=CC=1>[Cl:28][C:26]([O:25][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[CH2:8][N:9]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[O:11][C:10]1=[O:24])=[O:27]
Reactant: O=C(Cl)Cl
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1O
Solvent: Cc1ccccc1
Product: O=C(Cl)Oc1ccc(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Temperature: 120 °C

Procedure:
A stirred suspension of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (1 g, 2.69 mmol) and BnPh3PCI (25 mg) in 1.9 molar toluene solution of phosgene (15 mL) was heated at 120° C. overnight in a sealed tube. After removal of excess phosgene, the toluene solution was rotary evaporated to dryness to afford the chlorotormate product as a white semi-solid (1.18 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=[O:11])[C:7]([NH:13][C:14]([C:16]([O:18]CC)=O)=[O:15])=[CH:6][C:3]=1[C:4]#[N:5].CN(C)C=O.N>O1CCCC1.[Pd]>[Cl:1][C:2]1[CH:9]=[C:8]2[C:7]([NH:13][C:14](=[O:15])[C:16](=[O:18])[N:10]2[OH:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCOC(=O)C(=O)Nc1cc(C#N)c(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1cc2[nH]c(=O)c(=O)n(O)c2cc1Cl
Yield: 52.6 %

Procedure:
To a solution of 0.6 g (2.0 mmol) 2-chloro-5-ethoxalylamino-4-nitrobenzonitril in 50 ml tetrahydrofuran was added 15 ml dimethylformamide and 0.7 ml 25% aqueous ammonia. The mixture was hydrogenated at atm. pressure by using 0.1 g Pd-C as a catalyst. The catalyst was filtered off, and the filter cake was washed with tetrahydrofuran. The precipitated product was dissolved in 1N aqueous potassium hydroxide. Addition of concentrated hydrochloric acid to pH 1 gave 0.25 g (50%) 7-chloro-6-cyano-1-hydroxyquinoxaline-2,3(1H,4H)-dione. M.p. 320° C. decomp. 1H-NMR (DMSO-d6): 7.6 (1H, s), 7.5 (1H, s).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:17][CH:14]1[CH2:15][CH2:16][C:7]2([CH2:6][C:5]3[C:9](=[CH:10][C:2]([C:25]4[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=4)[C:19]#[N:20])=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH2:12][CH2:13]1
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC1CCC2(CC1)Cc1ccc(-c3cccc(C#N)c3)cc1C2=O
Temperature: 100 °C
Reaction time: 0.1 h
Yield: 46.4 %

Procedure:
To a solution of 6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (40 mg, 0.130 mmol) and 3-cyanophenylboronic acid (30.5 mg, 0.208 mmol) in Cs2CO3 (2 M, 0.247 mL) and 1,4-dioxane (1.2 mL) under N2 was added Pd(PPh3)2Cl2 (7.5 mg). The mixture was stirred at 100° C. for 6 minutes. After cooled to room temperature, the organic layer was dried and concentrated to give the residue, which was purified by TLC to give 3-(4-methoxy-1′-oxo-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-6′-yl)benzonitrile (20 mg, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11]3[CH2:12][CH2:13][N:14]4[C:19]([C:10]=3[NH:9][C:6]2=[CH:7][CH:8]=1)=[CH:18][CH2:17][CH2:16][C:15]4=[O:20]>C1COCC1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11]3[CH:12]=[CH:13][N:14]4[C:19]([C:10]=3[NH:9][C:6]2=[CH:7][CH:8]=1)=[CH:18][CH:17]=[CH:16][C:15]4=[O:20]
Reactant: COc1ccc2[nH]c3c(c2c1)CCN1C(=O)CCC=C31
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1ccc2[nH]c3c(ccn4c(=O)cccc34)c2c1

Procedure:
Activated manganese dioxide (400 mg) is added to a solution of 9-methoxy-2,3,4,6,7,12-hexahydroindolo[2,3-a]quinolizin-4-one (150 mg) in THF (5 ml). After refluxing for 2 h 30, the mixture is cooled and activated manganese dioxide (400 mg) is again added. The medium is refluxed for 24 h. After filtration ard washing of the dioxide with an ethyl acetate/methanol mixture (98/2), and after recrystallization from ethyl acetate, 9-methoxy4,12-dihydroindolo[2,3-a]quinolizin-4-one is obtained.
Reaction SMILES: [C:1]([N:5]1[CH2:22][CH:21]([CH2:23][O:24][CH3:25])[O:20][C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>ClCCl>[C:1]([N:5]1[CH2:22][CH:21]([CH2:23][O:24][CH3:25])[O:20][C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1CN(C(C)(C)C)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCC1CN(C(C)(C)C)CC2(CCNCC2)O1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Tert-butyl 8-tert-butyl-10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (732 mg, 2.05 mmol) was dissolved in dichloromethane (10 mL) and treated dropwise with a solution of HCl in dioxane (12.8 mL of 4 M, 51.3 mmol). The reaction was stirred for 1.5 h and then diluted with dichloromethane. The organic phase was washed with 1:1 saturated NaHCO3/1 M NaOH, dried over Na2SO4 and concentrated to provide 8-tert-butyl-10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane (526 mg, 2.05 mmol, 99%) as a viscous amber colored oil. ESI-MS m/z calc. 256.2. Found 257.3 (M+1)+; Retention time: 0.2 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 3.88-3.71 (m, 1H), 3.43-3.38 (m, 1H), 3.37 (d, J=2.5 Hz, 3H), 3.35-3.30 (m, 1H), 3.24 (td, J=12.2, 3.4 Hz, 1H), 3.15-3.07 (m, 1H), 3.02 (td, J=12.2, 3.0 Hz, 1H), 2.93-2.84 (m, 1H), 2.78-2.68 (m, 1H), 2.58 (d, J=8.9 Hz, 2H), 2.48-2.19 (m, 1H), 1.97 (d, J=11.4 Hz, 1H), 1.92 (ddd, J=16.6, 12.2, 9.6 Hz, 2H), 1.84-1.74 (m, 1H), 1.70-1.55 (m, 2H), 1.00 (s, 9H).