Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[C:15]([N:20]=2)=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:8]([O:21]C)[CH:7]=1)([OH:3])=[O:2].Cl>>[C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[C:15]([N:20]=2)=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:8]([OH:21])[CH:7]=1)([OH:3])=[O:2]
Reactant: COc1cc(OCC(=O)O)ccc1-c1nc2ncccc2[nH]1
Agent: Cl
Product: O=C(O)COc1ccc(-c2nc3ncccc3[nH]2)c(O)c1

Procedure:
2-(4-Carboxymethoxy-2-methoxyphenyl)imidazo(4,5-b)-pyridine, m.p. 235°, hydrochloride, m.p. 262°.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:41])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:30][CH2:29]2)[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:8][C:9]1([CH3:41])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:29][CH2:30][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:32][CH2:33]2)[CH:23]=1
Reactant: Cc1ccccc1N1CCN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(c2cccc(C3Nc4ccc(C(=O)NS(C)(=O)=O)cc4CC3(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
To a suspension of 60% sodium hydride (172 mg, 4.3 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (418 mg, 4.4 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.44 mmol), and 1,1′-carbonyldiimidazole (170 mg, 1.04 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}methanesulfonamide (46 mg, 20%) as a white solid: LC/MS m/e calcd for C30H36N4O3S (M+H)+: 533.71, observed: 533.2.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: BrCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCCCBr)cccc21

Procedure:
Potassium phthalimide (5.4 mmoles) was added to a solution of 1,7-dibromoheptane (4.18 g; 16.2 mmoles) in dimethylformamide (8 ml) and heated to 80° C. approx. under stirring. Reaction times and process as per Example 4.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:11]2([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:23]([F:29])[CH:24]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 79 %

Procedure:
In a manner similar to the method described in Example 1d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 64b (1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.88 g, 79%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1.[NH3:20]>O1CCCC1.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([NH2:20])=[O:19])=[CH:11][CH:10]=1
Reactant: N
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C=CC(N)=O)cc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
44.5 ml (351 mmol) oxalyl chloride was added dropwise at 0° C. within 45 min. to a suspension of 50.0 g (281 mmol) 3-(4-Methoxyphenyl)-acrylic acid in 300 ml tetrahydrofuran and 3.0 ml N,N-dimethyl formamide. Stirring was continued at 0–5° C. for 30 min. and thereafter for 2 h at room temperature. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 750 ml of a 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 48.8 g (98%) 3-(4-Methoxyphenyl)-acrylamide were obtained.
Reaction SMILES: C([C@@H:3]([NH:15][S@](C1C=CC(C)=CC=1)=O)[C@@H:4]([CH3:14])[C@@H:5]([O:7][CH:8]1CCCC[O:9]1)[CH3:6])#N.[ClH:25]>>[ClH:25].[NH2:15][C@H:3]1[C@@H:4]([CH3:14])[C@H:5]([CH3:6])[O:7][C:8]1=[O:9]
Reactant: Cc1ccc([S@](=O)N[C@H](C#N)[C@@H](C)[C@H](C)OC2CCCCO2)cc1
Agent: Cl
Product: C[C@H]1[C@H](C)OC(=O)[C@H]1N
Yield: 100 %

Procedure:
A solution of (S)-N-[(1S,2R,3S)-1-cyano-2-methyl-3-tetrahydropyranyloxybutyl]-p-toluenesulfinamide (8) (200 mg, 0.57 mmol) in 6N HCl (14 ml) was refluxed for 6 hours. The reaction mixture was washed with dichloromethane, and it was evaporated in order to obtain (3S,4R,5S)-3-amino-4-methyl-5-methyl-2-oxotetrahydrofuran hydrochloride (9) (94 mg, 100%). [α]D=−18° (c 1.4; MeOH); IR (nujol) 3526, 2924, 2854, 1771, 1581, 1504, 1462, 1385, 1355, 1315, 1260, 1209 cm−1; 1H NMR (250 MHz, D2O) δ 4.61 to 4.54 (m, 2H); 2.72 (broad quintuplet, J=7.5 Hz, 1H); 1.40 (d, J=6.6 Hz, 3H); 1.11 (d, J=7.3 Hz, 3H); 13C NMR (50 MHz, D2O) δ 174.3; 85.2; 52.3; 38.1; 19.5; 13.0; MS (CI) m/z 130 [M+H]+. HRMS: calculated for C6H12NO2 (M+H), 130.08680; found, 130.08604.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2.I[CH3:16].[OH-].[Na+]>CS(C)=O>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:16])[CH:10]=2)[CH:5]=1
Reactant: CI
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 4.5 g, 112 mmol) was added in small portions to a mixture of 6-bromo-2-naphthol (25.0 g, 112 mmol), iodomethane (11.8 g, 168 mmol) and dimethylsulfoxide (150 ml). The mixture was stirred at room temperature overnight. Sodium hydroxide (200 ml, 1 M) was added, and the mixture was filtered. Yield 25.1 g, 95%. Mp 76-82° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH2:8]([O:10][C:11](OCC)(OCC)[O:12][CH2:13][CH3:14])[CH3:9].C(OC(=O)C)(=O)C>>[CH3:1][O:2][C:3](=[O:7])[C:4]([C:5]#[N:6])=[C:11]([O:12][CH2:13][CH3:14])[O:10][CH2:8][CH3:9]
Reactant: CCOC(OCC)(OCC)OCC
Reactant: COC(=O)CC#N
Solvent: CC(=O)OC(C)=O
Product: CCOC(OCC)=C(C#N)C(=O)OC
Temperature: 130 °C

Procedure:
A reaction mixture consisting of methylcyanoacetate (5.0 ml, 57 mmol) and tetraethylorthocarbonate (17.99 ml, 86 mmol) in acetic anhydride (8.11 ml, 86 mmol) was heated at 130° C. for 5 hours, and then heated at 110° C. for 18 hours. The cooled reaction residue was extracted twice with 125 ml portions of hexane. A hexane-insoluble orange oil containing approximately 40% by weight of the desired compound (as established by NMR inspection) remained. This crude product was used in the next step without further purification. TLC Rf (silica gel plates, u.v. detection, ethyl acetate/hexane=15:85 in volume): 0.13.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH:11]=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[CH3:37][Li]>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH:11]([OH:12])[CH3:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C=O
Reactant: [Li]C
Solvent: C1CCOC1
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C(C)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.1 %

Procedure:
To a solution of Intermediate AW (N-{4-[4-amino-7-formyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea (25 mg, 0.05 mmol)) in THF (1 ml) at −78 C under N2 was added methyllithium (0.18 ml, 0.25 mmol) and stirred for 10 min. The reaction was quenched by the addition of H2O and after warming to rt, the reaction mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), concentrated and purified via column chromatography (5:95 v/v MeOH—CH2Cl2) to afford 13 mg of the title compound (yield 50%). 1H-NMR (DMSO-d6) 9.32 (s, 1H), 8.97 (d, J=2 Hz, 1H), 8.63 (dd, J=8, 2 Hz, 1H), 7.87 (s, 1H), 7.55 (d, J=8 Hz, 2H), 7.53 to 7.31 (m, 4H), 5.49 to 5.45 (m, 1H), 5.19 (d, J=6 Hz, 1H), 4.52 (d, J=10 Hz, 1H), 4.19 (d, J=10 Hz, 1H), 3.16 (s, 3H), 1.50 (d, J=6 Hz, 3H) ppm; MS [M+H]+=519.1; LCMS RT=2.74 min.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]([C:30](=[O:36])[CH2:31][CH2:32][CH:33]([OH:35])[CH3:34])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]([C:30](=[O:36])[CH2:31][CH2:32][CH:33]([OH:35])[CH3:34])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCC(C)O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCC(C)O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
A solution of 0.150 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(4(RS)-hydroxyvaleryl)-2′-isobutyl-4-methylvalerohydrazide in 5 ml of methanol was treated with 0.015 g of p-toluenesulphonic acid monohydrate. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.027 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-(4(RS)-hydroxyvaleryl)-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:33]([NH:32][C:24]2[C:23]([CH:20]([CH3:21])[CH3:22])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:29]([CH3:31])[CH3:30])=[O:34])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)c1ccc(NCc2ccc(Cl)c(Cl)c2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(Cl)c(Cl)c2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 28.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(3,4-dichlorophenyl)methyl](4-isopropylphenyl)amine (2.5 g) and 2,6-diisopropylphenyl isocyanate (2.7 g) as starting materials, N-(3,4-dichlorophenylmethyl)-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (1.2 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: Oc1ccccc1Cl
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: COc1ccccc1Cl

Procedure:
A 2 mM solution of 2-chlorophenol containing 1.23 mM chloromethane and buffered at pH 4.0 with 20 mM citrate buffer was incubated with 0.035 g of fungal mycelium (Phellinus pomaceus, NCWRF. FPRL 33A or CBS 137.42) at 25° C. for 12 h. 2-chloroanisole was formed at a rate of 16 nanomoles/g fungal mycelium/hour.
Reaction SMILES: [C:1]1([P:7]2(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]=[O:14].C1(C)C=CC=CC=1>C1COCC1>[C:1]1([P:7]2(=[O:12])[CH2:8][CH2:9][CH2:10][CH:11]2[CH2:13][OH:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=P1(c2ccccc2)CCCC1
Reactant: C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=P1(c2ccccc2)CCCC1CO
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
In a 1 l round bottom 2-neck flask charged a with a magnetic stirring bar, 23.4 g 1-phenylphospholane-1-oxide (0.11 mol) was dissolved in 300 ml freshly distilled THF, and 10.4 g dry paraformaldehyde was added. The reaction flask was flushed with argon and cooled to −20° C. Subsequently 100 ml phenyllithium solution in cyclohexane/diethylether 7:3 (1.8M) was added in one portion. The resulting mixture was stirred until the temperature reached +10° C. and additionally 5 minutes at that temperature. Then 10 g NH4Cl was added. The mixture was filtered, concentrated, and the residue purified by flash chromatography (EtOAc, followed by EtOAc/methanol 10:1). Yields: 2.5 g substrate (1-phenylphospholane-1-oxide) (11%), 11.7 g (43%) trans-1-phenyl-2-phospholanemethanol-1-oxide as white crystals, m.p. 109-110° C. (toluene); 1H NMR (500 MHz) δ: 1.70-1.85 (m, 1H), 1.95-2.30 (m, 6H), 3.90-4.00 (m, 2H), 4.19 (t, 1H, J=6.1), 7.45-7.55 (m, 3H), 7.70-7.76 (m, 2H); 31P NMR (200 MHz) δ: 63.3; and 2.2 g (8%) cis-1-phenyl-2-phospholanemethanol-1-oxide, white crystals, m.p. 149-151° C. (toluene); 1H NMR (500 MHz) δ: 1.46-1.57 (m, 1H), 2.02-2.22 (m, 4H), 2.28-2.42 (m, 1H), 2.44-2.58 (m, 1H), 3.32-3.49 (m, 2H), 3.76 (t, 1H, J=5.7), 7.46-7.51 (m, 2H.), 7.52-7.57 (m, 1H), 7.67-7.73 (m, 2H); 31P NMR (200 MHz) δ: 62.7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:22][C:23]1[C:28]2[CH2:29][O:30][C:31](=O)[C:27]=2[CH:26]=[CH:25][N:24]=1.Cl>C1COCC1>[Cl:22][C:23]1[C:28]2[CH2:29][O:30][C:31](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:27]=2[CH:26]=[CH:25][N:24]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C1OCc2c1ccnc2Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2c1ccnc2Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (825 mg, 5.46 mmol.) in THF (5 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (11 mL of a 1 M solution in THF, 11 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 4-chloro-3H-furo[3,4-c]pyridin-1-one (620 mg, 3.67 mmol) in THF (7 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (160 mL). The resulting mixture is heated to 90° C. for 2 h and then stirred at room temperature for 36 h. The precipitate which formed is collected by filtration, washed with small volumes of ethyl acetate (10×3 mL) and dried under vacuum to give the title compound as a yellow solid (810 mg, 73%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[CH3:18])([O-])=O.CO.[H][H]>[Pt].ClCCl>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[CH3:18]
Reactant: Cc1cc(Br)ccc1Nc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Br)ccc1Nc1ccccc1N

Procedure:
A suspension of 5.34 g (17.4 mmol) of N-(2-nitrophenyl)-4-bromo-2-methyl-aniline and 1.7 g of platinum on charcoal is stirred in 100 ml of dichloromethane and 100 ml of methanol at a hydrogen pressure of 3 bar for 1 hour. Then the catalyst is filtered off and the filtrate is evaporated down.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>O1CCCC1>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[NH:1][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cnccn1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 3.4 %

Procedure:
To a solution of aminopyrazine (2.00 g, 21.0 mmol) and pyridine (5.10 ml, 63.1 mmol) in tetrahydrofuran was added 2,2,2-trichloroethyl chloroformate (4.34 ml, 31.5 mmol) with ice-cooling, the mixture was stirred for 2 hours with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (193 mg, 3.4%) as a solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].[CH3:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15].C(OC(=O)C)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[CH3:8])=[O:7]
Reactant: Cc1ccncc1N
Reactant: O=C=NCCCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccncc1NC(=O)NCCCCl
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.7 %

Procedure:
1-Chloro-3-isocyanato-propane (1.6 g, 13.87 mmol) was added dropwise to a stirred solution of 4-methyl-pyridin-3-ylamine (1 g, 9.25 mmol) in toluene (15 mL) at 0° C. The reaction mixture was stirred at room temperature for 18 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was filtered, washed with toluene and dried under reduced pressure to afford 2.12 g (99.5% yield) of 1-(3-chloro-propyl)-3-(4-methyl-pyridin-3-yl)-urea.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](OCC)(=[O:25])[C:22]#[C:23][CH3:24]>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]4=[N:18][C:21](=[O:25])[CH:22]=[C:23]([CH3:24])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC#CC(=O)OCC
Reactant: NC1=NCC(COc2ccc(C3CCCCC3)cc2)O1
Solvent: CCO
Product: Cc1cc(=O)nc2n1CC(COc1ccc(C3CCCCC3)cc1)O2
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 51 %

Procedure:
To a solution of 5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (300 mg, 1.095 mmol) in ethanol (6 mL) was added ethyl 2-butynoate (246 mg, 2.19 mmol). The reaction mixture was heated in a microwave oven at 150° C. for 30 min, then at 160° C. for 20 min, and at 170° C. for 30 min. Solvent was removed under vacuum, and the residue purified via flash column chromatography (silica gel, 1-18% EtOH/CH2Cl2) to afford 190 mg of 2-(4-cyclohexyl-phenoxymethyl)-5-methyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:17]2[C:5]([CH2:6][C:7]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH2:16]2)=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[C:22]([O:24][CH3:25])=[O:23].[H-].[Na+].I[CH2:29][CH3:30]>>[CH2:29]([N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:7]2[CH2:6][C:5]3[N:17]([CH2:16][C:8]1=2)[C:2]([CH3:1])=[C:3]([C:22]([O:24][CH3:25])=[O:23])[C:4]=3[C:18]([O:20][CH3:21])=[O:19])[CH3:30]
Reactant: COC(=O)c1c(C(=O)OC)c2n(c1C)Cc1[nH]c3ccccc3c1C2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCn1c2c(c3ccccc31)Cc1c(C(=O)OC)c(C(=O)OC)c(C)n1C2

Procedure:
This compound was prepared from dimethyl 3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate (5.1 g, 15 mmol), NaH (0.54 g, 22.5 mmol) and iodoethane (2.3 g, 15 mmol). Yield 5.1 g (92%); mp 202-203° C. 1H NMR (DMSO-d6) δ 1.29 (3H, t, J=6.9 Hz, Me), 2.46 (3H, s, Me), 3.73 (3H, s, COOMe), 3.74 (3H, s, COOMe), 4.17 (2H, s, CH2), 4.20 (2H, q, J=6.9 Hz, CH2), 5.29 (2H, s, CH2), 7.05-7.09 (1H, m, ArH), 7.16-7.20 (1H, m, ArH), 7.49-7.51 (1H, m, ArH), 7.53-7.55 (1H, m, ArH). Anal. Calcd for (C21H22N2O4): C, 68.84; H, 6.05; N, 7.65. Found: C, 68.46; H, 6.06; N, 7.59.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([O:33][CH3:34])[CH:27]=3)[S:25][C:18]=12.[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49]O)[CH2:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:13][C:14]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:49][CH2:48][N:45]4[CH2:46][CH2:47][O:42][CH2:43][CH2:44]4)=[C:28]([O:33][CH3:34])[CH:27]=3)[S:25][C:18]=12
Reactant: OCCN1CCOCC1
Reactant: COc1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)ccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)ccc1OCCN1CCOCC1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
DEAD (0.96 mL, 6.07 mmol) was added to a solution of the compound 137 (1.78 g, 4.33 mmol), 2-morpholinoethanol (0.74 mL, 6.07 mmol) and triphenylphosphine (1.59 g, 6.07 mmol) in THF (43 mL). The reaction mixture was stirred at room temperature until completion of the reaction. The mixture was quenched with a saturated aqueous solution of ammonium chloride then extracted three times with ethyl acetate and 3 times with dichloromethane (with a bit of methanol inside). The combined organic layers were washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The residue was triturated with diethyl ether, filtered and dried on a vacuum pump to afford title compound 138 as a yellow-brown solid (1.80 g, 79% yield). MS (m/z): 526.2 (M+H).