Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[N:9]=[C:8]([C:10]3[C:11](=[O:17])[NH:12][CH:13]=[CH:14][C:15]=3Cl)[NH:7][C:6]=2[CH:18]=1.[NH2:20][C@@H:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][OH:23].CN1CCOCC1>CN(C=O)C>[CH2:24]([C@H:21]([NH:20][C:15]1[CH:14]=[CH:13][NH:12][C:11](=[O:17])[C:10]=1[C:8]1[NH:7][C:6]2[CH:18]=[C:2]([Br:1])[CH:3]=[C:4]([CH3:19])[C:5]=2[N:9]=1)[CH2:22][OH:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(Br)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(Br)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 80 °C
Yield: 73.5 %

Procedure:
To a solution of 3-(6-bromo-4-methyl-1H-benzimidazol-2-yl)-4-chloro-1H-pyridin-2-one (1.42 g, 3.78 mmol) in DMF (15 mL) were added (S)-(−)-2-amino-3-phenyl-1-propanol (1.43 g, 9.45 mmol) and N-methyl morpholine (1.5 mL). The reaction mixture was heated to 80° C. for 6 h and cooled to room temperature. The solvent was removed with high vacuum and the residue was purified by flash chromatography (5% MeOH/CH2Cl2) to yield the title compound (1.26 g, 74%) as a yellow foam. 1H NMR (300 MHz, CDCl3) δ 6.9–7.2 (8H, m), 5.86 (1H, d, J=7.1 Hz), 3.7–3.9 (3H, m), 2.9–3.1(2H, m), 2.57 (3H, s). LCMS (M+H)+ m/z 453 (t=2.03 min.).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:2].[N:9]1[C:16]([Cl:17])=[N:15][C:13](Cl)=[N:12][C:10]=1[Cl:11].C(=O)(O)[O-].[Na+]>CC(C)=O>[Cl:11][C:10]1[N:9]=[C:16]([Cl:17])[N:15]=[C:13]([N:6]2[CH2:7][CH2:8][N:3]([CH:1]=[O:2])[CH2:4][CH2:5]2)[N:12]=1
Reactant: O=CN1CCNCC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=CN1CCN(c2nc(Cl)nc(Cl)n2)CC1
Reaction time: 4 h
Yield: 35.2 %

Procedure:
1-Formylpiperazine (5.0 g) in dry acetone (28 ml) was added dropwise to a stirred suspension of cyanuric chloride (6.2 g) and sodium bicarbonate (2.58 g) in dry acetone (153 ml) at -35°. The reaction mixture was stirred at -30° for 13/4 hours. Insoluble material was removed by filtration and washed with acetone. The combined filtrate and washings were evaporated in vacuo and the residue taken up in methylene chloride, filtered and the filtrate evaporated in vacuo. The resulting solid was re-crystallized twice from ethyl acetate to give in two fractions 4,6-dichloro-2-(4-formylpiperazino)1,3,5-triazine (3.1 g) m.p. 163°-165°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[O:22])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: C1COCCN1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCOCC3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and morpholine (9.9 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(morpholin-4-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (43.6 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5].[OH:29]O>CO>[NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[O:29])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5]
Reactant: OO
Reactant: COc1ccccc1NC(=O)c1c(N)cccc1Sc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: COc1ccccc1NC(=O)c1c(N)cccc1S(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 66 °C
Yield: 44.3 %

Procedure:
Compound 25 (1.0 equiv.) was dissolved in CH3OH (30 mL) with a magnetic stirrer at RT, and 35% H2O2 (3.0 equiv.) was added slowly to this solution. This reaction mixture was heated in an oil bath at 66° C. and monitored using TLC. The reaction was quenched with MnO2 at RT. The mixture was filtered and the residue was washed with ethyl acetate (3×5 mL). The liquid layer was concentrated under reduced pressure and the oily residue was purified by silica gel column chromatography (1:4 v/v ethyl acetate/petroleum ether) to provide a yellow solid; 44.3% yield;
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:12]([OH:14])=[O:13]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:4]2[C:5]([O:14][C:12](=[O:13])[C:3]=12)=[O:7]
Reactant: Cc1ccc(C(=O)O)c(C(=O)O)c1Cl
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2c(c1Cl)C(=O)OC2=O
Temperature: 25 °C

Procedure:
A stirred solution of 21.5 g (0.10 mol) of 3-chloro-4-methylphthalic acid in 300 mL acetic anhydride is heated under reflux for six hours, allowed to cool to room temperature and concentrated in vacuo several times with anhydrous toluene. A viscous, dark, amber syrup is obtained, characterized by an infrared spectrum and used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:10][N:11]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]1=[O:17]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:13]2[CH2:14][C:15](=[O:16])[N:11]([CH3:10])[C:12]2=[O:17])=[CH:2]1
Reactant: CN1C(=O)C=CC1=O
Reactant: c1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Product: CN1C(=O)CC(c2c[nH]c3ccccc23)C1=O
Temperature: 105 °C
Reaction time: 16 h

Procedure:
A mixture of indole (3.14 g) and N-methylmaleimide (6.2 g, 3 equiv.) in acetic acid is heated at 105° C. for 16 hr, cooled to room temperature, held for 16 hr and filtered. The filtercake is washed with acetic acid and dried to afford the title product, 5.5 g, identified by HPLC and mass spectral analyses.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9]([C:11]1[C:20](=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[CH:22]1[CH2:24][CH2:23]1)=[O:10])[CH3:7].C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:6]([O:8][C:9]([C:11]1[C:12]([CH:22]2[CH2:24][CH2:23]2)=[N:13][C:14]2[C:19]([C:20]=1[Cl:3])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C2CC2)[nH]c2ccccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1c(C2CC2)nc2ccccc2c1Cl
Temperature: 75 °C
Yield: 10.2 %

Procedure:
Phosphorus oxychloride (0.77 ml, 0.082 mols) was added in one portion to a suspension of 2-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (1.0 g, 0.041 mols) in acetonitrile and the mixture was heated at 75° C. for 90 minutes (becomes a clear solution above 65° C.). The resulting light brown solution was poured into saturated sodium bicarbonate (100 ml); the suspension was extracted with ethyl acetate and the combined organic extracts were dried and concentrated in vacuo to leave 4-Chloro-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester (1.15 g, 106%) as an off-white solid. Rf (AcOEt)=0.73. Step 3 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl>C(Cl)(Cl)(Cl)Cl>[CH:15]1([C:9]2[CH:10]=[CH:11][C:12]([C:5](=[O:7])[CH3:6])=[CH:13][CH:14]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: c1ccc(C2CCCCC2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(C2CCCCC2)cc1

Procedure:
To a suspension of anhydrous aluminum chloride (467 g,; 3.5 moles) in carbon tetrachloride (2 l.) is added acetyl chloride (275 g.; 249 cc., 3.5 moles) during fifteen minutes with vigorous stirring and cooling in an ice-bath. Cyclohexylbenzene (481 g,; 3.0 moles) is added dropwise over a period of three hours, keeping the temperature below 5°. After addition is complete, the product is stirred for another hour before hydrolyzing by pouring into ice and hydrochloric acid with stirring. The organic phase is washed with successive portions of dilute hydrochloric acid, sodium carbonate, and water, and distilled to give p-cyclohexylacetophenone, (b.p. 88°-95.5°/0.05 mm.)
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([SH:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH2:30][CH2:31]I)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([CH2:30][CH2:31][S:14][C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][CH2:13][N:4]([C:1](=[O:3])[CH3:2])[CH2:5]3)=[CH:10][CH:9]=2)([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)C1(CCI)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)N1CCc2ccc(S)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCSc2ccc3c(c2)CN(C(C)=O)CC3)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Crude crystals (1.26 g) of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-thiol were dissolved in dimethylformamide (15 ml) and thereto were added 60% sodium hydride (243 mg) and 4-ethoxycarbonyl-4-(2-iodoethyl)piperidine-1-carboxylic acid tert-butyl ester (1 g), and the mixture was stirred at 70° C. for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7) and dried under reduced pressure to give the title compound (535 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C:6]1([CH2:8][CH2:7]1)[C:5]2=O.[CH3:15][C:16]([S:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>C1COCC1.C([O-])C.C([O-])C.C([O-])C.C([O-])C.[Ti+4]>[Br:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C:6]1([CH2:8][CH2:7]1)[C:5]2=[N:21][S:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20]
Reactant: O=C1c2cc(Br)ccc2OCC12CC2
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2OCC12CC2
Temperature: 80 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
The mixture of 6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-one (8.0 g, 32 mmol), 2-methylpropane-2-sulfinamide (12 g, 99 mmol), and titanium(IV) tetraethanolate (22 g, 95 mmol) in THF (160 ml) was stirred for 48 hours at 80° C. To the mixture was added H2O (20 ml), filtered through Celite and washed by EtOAc (50 ml). The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (hexane:EtOAc=100:0-0:100) to give N-(6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-ylidene)-2-methylpropane-2-sulfinamide (6.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[O:30][CH2:31][CH2:32][CH3:33])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:40][N:39]=[N:38][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH2:32][CH3:33]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCOc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCCOc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-propoxybenzimidazole-7-carboxylate (0.69 g) and trimethyltin azide (0.7 ) in toluene (15 ml) was heated for 4 days under reflux. The reaction mixture was concentrated to dryness and to the mixture was added methanol (20 ml) and 1N-HCl (10 ml). After stirring at room temperature for 30 minutes, he mixture was adjusted to pH 3-4 with 1N NaOH. After removal of the solvent, the residue was extracted with chloroform-water. The organic layer was washed with water and dried, and the solvent was evaporated to dryness to give a syrup. The syrup was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals (0.31g, 43%), m.p. 157°-159° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][C:14]2[CH:15]=[C:16]([CH2:20]O)[CH:17]=[CH:18][CH:19]=2)=[C:8]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:7]=1>C(Cl)Cl>[Cl:3][CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][C:9]1[C:8]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:7][C:6]([NH2:5])=[N:11][C:10]=1[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CO)c1
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CCl)c1
Reaction time: 1 h

Procedure:
Thionyl chloride (0.17 mL) was added to a stirred solution of the product from step (iv) (0.60 g) in DCM (10 mL) at rt. The mixture was stirred for 1 h and the solvent evaporated under reduced pressure to give the subtitle compound as a yellow oil 0.62 g that was used without further purification.
Reaction SMILES: [Na].Cl.[CH2:3]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[NH:18])=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O:24][C:25](=O)[CH:26]([CH2:32][CH2:33][C@@H:34]([F:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:27](OCC)=[O:28])C.Cl>CO>[OH:24][C:25]1[C:26]([CH2:32][CH2:33][C@@H:34]([F:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:27]([OH:28])[N:19]=[C:17]([C:16]2[CH:15]=[CH:14][C:13]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:21][CH:20]=2)[N:18]=1
Reactant: CCCCCCCCCCc1ccc(C(=N)N)cc1
Reactant: CCCCCC[C@H](F)CCC(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCCCCCCCCCc1ccc(-c2nc(O)c(CC[C@@H](F)CCCCCC)c(O)n2)cc1
Reaction time: 0.33 h
Yield: 55.1 %

Procedure:
Under nitrogen atmosphere, 3 ml of dry methanol was placed in a two-necked round-bottomed flask. To the methanol, 113 mg (4.92 mM) of metal sodium was added and dissolved therein. To the solution, 584 mg (1.97 mM) of 4-decylbenzamidine hydrochloride was added and stirred for 20 minutes. To the mixture, a solution of 500 mg (1.64 mM) of (S)-2-(3-fluorononyl)malonic diethyl ester in 1 ml of dry methanol was added, followed by stirring for 16 hours at room temperature and distilling-off of methanol under reduced pressure. To the resultant reaction mixture, 4 ml of 6M-HCl was added to precipitate a crystal. The crystal was recovered by filtration and washed with ethanol and Et2O and further dried. The resultant crystal was recrystallized from 2.5 ml of N,N-dimethylformamide (DMF) to obtain 428 mg (0.91 mM) of (S)-4,6-dihydroxy-5-(3-fluorononyl)-2-(4-decylphenyl)pyrimidine (Yield: 55.3%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][N:23]1[C:27]([CH3:28])=[N:26][N:25]=[N:24]1.OP([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[CH3:28][C:27]1[N:23]([CH2:22][C@@H:7]2[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9](=[O:10])[NH:6]2)[N:24]=[N:25][N:26]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nnnc2C)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1nnnn1C[C@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
Prepared in an analogous manner to example 4, step 2 using benzyl ((2R,3S)-1-(2,4-dimethoxybenzyl)-2-((5-methyl-1H-tetrazol-1-yl)methyl)-4-oxoazetidin-3-yl)carbamate (221 mg, 0.474 mmol), K2S2O8 (179 mg, 0.663 mmol) and K2HPO4 (107 mg, 0.616 mmol) in ACN:water (2:1, 7.9 mL) at 90° C. for 1.5 h. More K2S2O8 (38.4 mg, 0.142 mmol) and K2HPO4 (21.5 mg, 0.123 mmol) were added and it was heated for an additional 30 min then cooled to rt then concentrated in vacuo. The mixture was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-10%), to afford the title compound (97 mg, 65%). LCMS: Rt=1.00 min, m/z=317.3 (M+1) Method 2m_acidic.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH:13]1[CH2:14][O:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCNC(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NCCC1CO1)OCc1ccccc1
Reaction time: 20 h
Yield: 93 %

Procedure:
To a solution of but-3-enyl-carbamic acid benzyl ester (prepared according to Heterocycles (2006), 67(2), 549-554; 21.5 g, 105 mmol) in chloroform (380 mL) was added, dropwise over a period of 1 h, a solution of MCPBA (28.3 g, 1.1 eq.) in chloroform (270 mL) at 10° C. Stirring was continued for 20 h at rt. The reaction mixture was filtered and 10% sodium sulfite solution was added to the filtrate (until starch-iodide paper test was negative). The mixture was washed with 5% Na2CO3 and brine. The org. layer was dried over MgSO4 and concentrated to afford the title intermediate as a colourless liquid (21.6 g, 93% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:10][C:9](=[O:11])[CH:8]([C:6]1[CH:7]=[C:2]([F:1])[C:3]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)=[CH:4][CH:5]=1)[CH3:12]
Reactant: CC(C(=O)O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc(-c2ccc(C(F)(F)F)cc2)c(F)c1
Yield: 95 %

Procedure:
A solution of 2-(2-fluoro-4′-trifluoromethylbiphenyl-4-yl)propionic acid (0.2 g, 0.64 mmoles) in methanol (3 ml) is added with 98% sulfuric acid (0.5 g) and refluxed for 2.5 hours. The solvent is removed under vacuum, the residue is taken up with ethyl acetate (5 ml) and washed with a 5% NaHCO3 solution (5 ml), then with water. The solution is dried over Na2SO4 and concentrated under vacuum to afford an oil (0.2 g, 95%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH:19]=O>>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:19][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=Cc1cc(F)cc(F)c1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2cc(F)cc(F)c2)CC1

Procedure:
The title compound was prepared (3.3 g, 100%) from tert-butyl piperidin-4-ylcarbamate (2 g, 10 m. mol) and 3,5-difluorobenzaldehyde (1.42 g, 10 mmol) by following the general procedure described for Preparation 3. 1H NMR (400 MHz, CDCl3): δ 6.85 (m, 2H), 6.65 (m, 1H), 4.45 (bs, 1H), 3.50 (m, 1H), 3.05 (s, 2H), 2.75 (m, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.45 (m, 11H). MS (ESI) m/z: Calculated: 326.38; Observed: 327.0 (M++1).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].C1CCC(N=C=NC2CCCCC2)CC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[N:29]=[CH:28][C:27]([C:40]#[N:41])=[C:26]2[NH:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[C:45]([Cl:50])[CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Cl:50][C:45]1[CH:44]=[C:43]([CH:48]=[CH:47][C:46]=1[F:49])[NH:42][C:26]1[C:25]2[C:30](=[CH:31][C:32]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:24]=2)[N:29]=[CH:28][C:27]=1[C:40]#[N:41]
Reactant: CN1CCN(c2cc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c3cc2N)CC1
Reactant: CC#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC#CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cc1N1CCN(C)CC1
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a stirred solution of 2-butynoic acid (0.25 g, 3.0 mmol) in 1.5 ml of DCM at 0° was added DCC (0.21 g, 1.0 mmol). After 15 m the mixture was warmed to 25°, recooled to 0°, and treated with 6-amino-4-(3-chloro-4-fluroanilino)-7-(4-methyl-1-piperazinyl)-3-quinolinecarbonitrile (0.21 g, 0.50 mmol) followed by 0.5 ml DCM rinse. The resulting mixture was stirred at 25° for 18 h and filtered to remove dicyclohexyl urea. The filtrate was partitioned with water which contained potassium carbonate (0.4 g, 3 mmol). The organic layer was washed with water, dried, and concentrated. The residue was passed as a solution in DCM onto a pad of silica gel. The product was eluted with 50:2:1 acetone-MeOH-TEA and concentrated to give 0.165 g amorphous solid; ms 477.2 (M+H)+, 239.1 (M+2H)+2.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:13][C:12]2=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:13][C:12]2=1
Reactant: Fc1ccc(CCNC2CCc3[nH]c4ccc(OCc5ccccc5)cc4c3C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Oc1ccc2[nH]c3c(c2c1)CC(NCCc1ccc(F)cc1)CC3
Yield: 44.7 %

Procedure:
To a solution of 0.700 gin (1.69 mMol) 6-benzyloxy-3-(2-(4-fluorophenyl)eth-1-yl)amino-1,2,3,4-tetrahydro-9H-carbazole in 50 mL methanol were added 1.07 gm (16.90 mMol) ammonium formate followed by 0.190 gm 5% palladium on carbon. The resulting mixture was stirred at reflux for 15 minutes. The reaction mixture was then filtered through a bed of celite and the filter cake washed well with methanol. The combined filtrates were concentrated under reduced pressure and the residue partitioned between water and dichloromethane. The phases were separated and the aqueous was extracted again with 4:1 isopropanol:dichloromethane. The combined extracts were dried over magnesium sulfate, concentrated under reduced pressure, and the residue subjected to silica gel chromatography, eluting with 91:8:1 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.245 gm (52%) of 6-hydroxy-3-(2-(4-fluorophenyl)eth-1-yl)amino-1,2,3,4-tetrahydro-9H-carbazole. The hydrochloride salt was prepared and crystallized from ethanol/diethyl ether to give the title compound.