Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][C:5]1[C:26](=[O:27])[N:25]([CH3:28])[C:8]2[N:9]=[C:10]([NH:13][CH:14]3[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]3)[N:11]=[CH:12][C:7]=2[CH:6]=1.I[Si](C)(C)C>ClCCl.CO>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][C:5]1[C:26](=[O:27])[N:25]([CH3:28])[C:8]2[N:9]=[C:10]([NH:13][CH:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: CCOC(=O)N1CCC(Nc2ncc3cc(Oc4ccccc4F)c(=O)n(C)c3n2)CC1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClCCl
Product: Cn1c(=O)c(Oc2ccccc2F)cc2cnc(NC3CCNCC3)nc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the free base of ethyl 4-{[6-(2-fluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}piperidine-1-carboxylate (0.500 g, 1.13 mmol) and iodotrimethylsilane (0.32 mL, 2.27 mmol) in 5 mL dichloromethane was refluxed. After 4 hours, additional iodotrimethylsilane (0.32 mL, 2.27 mmol) was added and the reaction stirred at room temperature for 3 days. The reaction was diluted with methanol and evaporated, with the residue taken up in a methanolic solution of sodium methoxide (0.5 M, 9.1 mL) and re-evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH:12]1[CH2:11][CH2:10][CH:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc(N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(SC2CCNCC2)cc1
Yield: 72 %

Procedure:
tert-Butyl 4-(4-aminophenylthio)piperidine-1-carboxylate (9.27 mmol, 2.859 g) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (10 mL) and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was purified via SCX column chromatography to afford the title compound (1.39 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]1[C:24]([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[CH:23][N:22]=[CH:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([C:24]2[O:20][CH:21]=[N:22][CH:23]=2)=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(-c2cnco2)cc1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-oxazol-5-yl-benzoyl chloride. MS: 431.3 (M+H).
Reaction SMILES: C([NH:8][CH:9]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[C:10]1[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]2[NH:20][C:16]([CH:9]([NH2:8])[C:10]3[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=3)=[N:17][C:18]=2[CH:24]=1
Reactant: Cn1ccc(C(NC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ccc(C(N)c2nc3cc(Cl)ccc3[nH]2)n1

Procedure:
Prepared analogously to Example 1g from N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methylamine and trifluoroacetic acid in dichloromethane.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[CH:5]=1.Cl>CO>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:16])=[O:17])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)cc1N(C)S(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(c1cc(Cl)ccc1C(=O)O)S(C)(=O)=O
Yield: 93.8 %

Procedure:
2N Sodium hydroxide solution (20 ml) was added to a stirred solution of methyl 4-chloro-2-(N-methyl-N-methylsulphonylamino)benzoate (2.75 g) in methanol. The mixture was stirred at reflux for 0.5 hours. After cooling, the mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic extracts were combined, dried and evaporated to yield 4-chloro-2-(N-methyl-N-methylsulphonylamino)benzoic acid as a white solid (2.45 g), m.p. 161-164° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]([NH2:16])[CH2:13][CH:14]=[CH2:15].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH2:12]([NH:16][C:2](=[O:3])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CCCNC(=O)OCc1ccccc1

Procedure:
Benzyl chloroformate (38 g, 0.22 mol) was added at 0° C. over 15 minutes to a mixture of but-3-en-1-amine (10 g, 0.14 mol) and sodium bicarbonate (35 g, 0.52 mol) in DCM (500 mL) and water (40 mL). The mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc) to afford benzyl but-3-en-1-ylcarbamate. MS ESI calc'd. for C12H16NO2 [M+H]+ 206. found 206. 1H NMR (400 MHz, CDCl3) δ 7.36-7.30 (m, 5H), 5.80-5.70 (m, 1H), 5.11-5.01 (m, 4H), 3.79-3.25 (m, 2H), 2.29-2.24 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br:32][CH2:33][CH2:34]Br>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C.CCCCCC.C(OCC)(=O)C.O>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([CH2:34][CH2:33][Br:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: BrCCBr
Reactant: CCOC(=O)CC1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCBr)C1CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
13 ml of diisopropylamine was dissolved in a solvent mixture of tetrahydrofuran (140 ml) with HMPA (15 ml) in a nitrogen atmosphere and cooled to −78° C. Into the obtained solution was dropped 42 ml of a 2.5 M solution of n-butyllithium in hexane and the resulting mixture was stirred at 0° C. for 30 minutes. After cooling to −78° C. again, 15 ml of a solution of 5.8 g of ethyl (1-benzylpiperidin-4-yl)acetate in tetrahydrofuran was dropped thereinto. The reaction mixture was stirred at 0° C. for 1 hour. Then 1,2-dibromoethane was dropped thereinto at −78° C. again. The reaction mixture was stirred at 0° C. for 30 minutes and then brought back to room temperature. Next, it was distributed into water and ethyl acetate. The organic layer was extracted, washed with water and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.40 g of ethyl 2-(1-benzyl-4-piperidyl)-4-bromobutanoate as a colorless oily substance. A solution of 1.40 g of ethyl 2-(1-benzyl-4-piperidyl)-4-bromobutanoate in tetrahydrofuran (20 ml) was stirred at room temperature and 1.0 g of t-butoxypotassium was added thereto. The reaction mixture was distributed into water and ethyl acetate. The organic layer was extracted and washed with water. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 800 mg of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[C:18]([C:19]([O-])=[O:20])=[CH:17][N:16]=[C:15]([S:22][CH3:23])[N:14]=1)[CH2:9][CH2:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[C:18]([CH2:19][OH:20])=[CH:17][N:16]=[C:15]([S:22][CH3:23])[N:14]=1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(Nc1nc(SC)ncc1C(=O)[O-])CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc2c1C(Nc1nc(SC)ncc1CO)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidine-5-carboxylate (3.25 g, 9.04 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise to a suspension of lithium aluminum hydride (0.54 g, 14.25 mmol) in anhydrous tetrahydrofuran (8 mL) at 0-5° C. The reaction mixture was allowed to slowly warm to room temperature and stirred for 18 h, then the mixture was cooled to 0-5° C. and quenched with water:tetrahydrofuran (15 mL:5 mL), followed by a 10% sodium hydroxide solution (11 mL). After stirring for 1 h, the precipitate was filtered off and washed with ethyl acetate (5×25 mL). The combined filtrates were diluted with saturated brine solution (20 mL) and water (15 mL), the two phases were separated, and the organic layer was washed with water (1×25 mL), dried over magnesium sulfate, filtered and evaporated to a light brown solid (2.43 g, 7.65 mmol, 84%). ESMS m/z 318 (M+H)+.
Reaction SMILES: C1(ON2C(=O)C3=CC=CC=C3C2=O)CCCC=C1.O.NN.Cl.[CH:23]1([O:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]1.C([NH:33][C:34]1[S:35][CH:36]=[C:37]([C:39](=O)[C:40]([OH:42])=[O:41])[N:38]=1)=O.[OH-].[Na+].NC1SC=C(C(=O)C(O)=O)N=1.Cl>C(O)C.O>[CH:23]1([O:29][N:30]=[C:39]([C:37]2[N:38]=[C:34]([NH2:33])[S:35][CH:36]=2)[C:40]([OH:42])=[O:41])[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]1
Reactant: NOC1C=CCCC1
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: NN
Agent: Nc1nc(C(=O)C(=O)O)cs1
Solvent: CCO
Solvent: O
Product: Nc1nc(C(=NOC2C=CCCC2)C(=O)O)cs1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A mixture of N-(2-cyclohexen-1-yl)oxyphthalimide (17.6 g) and hydrazine hydrate (7.2 g) in ethanol (180 ml) was stirred for 1.5 hours at 60° C. After the addition of water (100 ml) and conc.hydrochloric acid (20 ml) to the reaction mixture, the resulting mixture was filtered and the filtrate was evaporated. The remaining mixture was filtered to give the filtrate containing (2-cyclohexen-1-yl)oxyamine hydrochloride (Filtrate A). To a suspension of 2-(2-formamidothiazol-4-yl)glyoxylic acid (10.0 g) in water (50 ml) was added a solution of sodium hydroxide (4.4 g) in water (50 ml). The resulting mixture was stirred for 2.5 hours at room temperature and the mixture containing 2-(2-aminothiazol-4-yl)glyoxylic acid was adjusted to pH 7.0 with 10% hydrochloric acid and then thereto was added the above obtained Filtrate A. The mixture was stirred for 2 hours at room temperature. The reaction mixture was adjusted to pH 7.5 with 4N aqueous solution of sodium hydroxide and then evaporated. The residue was washed with ethyl acetate and then adjusted to pH 2.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water, dried over phosphorus pentoxide to give 2-(2-cyclohexen-1-yl)oxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer)(2.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]3[O:39][CH2:38]3)[C:32]([O:34]C)=[O:33])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]([OH:39])[CH2:38][S:10][C:8]3[NH:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=4[N:7]=3)[C:32]([OH:34])=[O:33])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: COc1ccc2nc(S)[nH]c2c1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc4ccc(OC)cc4[nH]3)C(=O)O)cc2)cc1

Procedure:
Example 41 is prepared from 5-methoxy-2-benzimidazolethiol and 1d using the procedure described for compound 20.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:18]([Cl:19])=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][N:29]=1)[C:25]#[N:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:12]1[CH:13]=[C:14]([C:15]#[N:16])[CH:17]=[C:18]([Cl:19])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:21][C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][N:29]=3)[C:25]#[N:26])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: N#Cc1ccnc(N)c1
Reactant: N#Cc1cc(Cl)c(-c2nc3ccnc(Br)c3s2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1ccnc(Nc2nccc3nc(-c4c(Cl)cc(C#N)cc4Cl)sc23)c1
Temperature: 70 °C
Yield: 68.7 %

Procedure:
Argon was bubbled through a suspension of 4-(4-bromo-thiazolo[5,4-c]pyridine-2-yl)-3,5-dichloro-benzonitrile (92 mg, 0.24 mmol), 2-amino-isonicotinonitrile (26 mg, 0.22 mmol), XantPhos (14 mg, 0.024 mmol) and cesium carbonate (195 mg, 0.6 mmol) in dioxane (2.5 ml) for 5 minutes then Pd2(dba)3 (11 mg, 0.012 mmol) was added. The reaction was heated at 70° C. for 8 hours and then cooled to room temperature. The reaction was partitioned between water (10 mL) and DCM (20 mL). The organic layer was separated, dried over Na2SO4 and concentrated to dryness under reduced pressure. The resultant residue was purified by silica gel flash chromatography eluting with 0-60% EtOAc in DCM. The resultant solid was triturated with diethyl ether, filtered, and left to air dry to give the desired compound as a yellow solid (64 mg, 63% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.74 (br s, 1H), 8.50 (dd, J=5.1, 0.9 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H), 8.39 (s, 2H), 8.23 (s, 1H), 7.79 (d, J=5.6 Hz, 1H), 7.38 (dd, J=5.1, 1.4 Hz, 1H). LCMS (Method C): RT=4.70 min, m/z: 423 [M+H+].
Reaction SMILES: C(OC(=O)[NH:7][C@:8]([CH2:31][OH:32])([CH3:30])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[C:13]([O:28][CH3:29])[CH:12]=1)(C)(C)C.[ClH:34]>C(O)(=O)C.OO>[ClH:34].[NH2:7][C@:8]([CH3:30])([CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([O:28][CH3:29])[C:14]([O:17][CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[C:15]([Cl:34])[CH:16]=1)[CH2:31][OH:32]
Reactant: COc1cc(CC[C@](C)(CO)NC(=O)OC(C)(C)C)ccc1OCCCC(F)(F)C(F)(F)F
Agent: Cl
Agent: OO
Solvent: CC(=O)O
Product: COc1cc(CC[C@@](C)(N)CO)cc(Cl)c1OCCCC(F)(F)C(F)(F)F

Procedure:
A solution of {(R)-1-Hydroxymethyl-3-[3-methoxy-4-(4,4,5,5,5-pentafluoro-pentyloxy)-phenyl]-1-methyl-propyl}-carbamic acid tert-butyl ester (32 mg, 0.07 mmol) in acetic acid (1 ml), conc. HCl (0.027 ml) and H2O2 (30%, 0.074 ml) is stirred at RT for 2 h. After evaporation of the solvent at RT, the oily residue is treated with toluene (1 ml), which is distilled off at RT. Et2O is added and the white precipitate is filtered off to yield the title compound. MS (ESI+): m/z=420/422 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K].O>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:31]3[C:27](=[O:37])[C:28]4=[CH:36][CH:35]=[CH:34][CH:33]=[C:29]4[C:30]3=[O:32])=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(CN3C(=O)c4ccccc4C3=O)c(=O)n(CC3CC3)n2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one (220 mg, 0.57 mmol) in N,N-dimethylformamide (5 mL) was added potassium phthalimide (160 mg, 0.87 mmol), and the mixture was stirred at 80° C. for 2 hours. Water (30 mL) was added to the reaction mixture. After stirring under cooling over ice water, precipitated crystals were collected by filtration, dried in air, and recrystallized from chloroform-hexane to yield the title compound as colorless needles (202 mg, 81.0%).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](OCC)=[O:24].Cl>O.O1CCCC1>[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:2][OH:3])=[O:24]
Reactant: NO
Reactant: CCOC(=O)CCCCCC(c1ccccc1)c1c(O)ccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCCCC(c1ccccc1)c1c(O)ccc2ccccc12)NO
Reaction time: 4 h
Yield: 38.4 %

Procedure:
Hydroxylamine hydrochloride (1.4 g) was dissolved in water (14 ml) followed by addition of sodium hydroxide (93%, 2 g) and water (7 ml). To this mixture was added a solution of ethyl 7-(2-hydroxy-1-naphthyl)-7-phenylheptanoate (1.08 g) in tetrahydrofuran (3 ml) and the mixture was stirred for 4 hours. This reaction mixture was neutralized with 1N-HCl and extracted with ethyl acetate. The organic layer was washed, dried, and concentrated, and the residue was purified using a silica gel column (chloroform-methanol) to provide the title compound (0.4 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C:10]([C:12]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH:13]=1)=[O:11]>ClCCl>[CH3:8][NH:9][C:10]([C:12]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:13]=1)=[O:11]
Reactant: CNC(=O)C1=CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C1=CC2(CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 146 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a stirred solution of tert-butyl 3-(methylcarbamoyl)spiro[indene-1,4′-piperidine]-1′-carboxylate (C5) (0.45 g, 1.30 mmol) in dichloromethane (5 mL) and the solution was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and dried under high vacuum for 18 h to provide N-methylspiro[indene-1,4′-piperidine]-3-carboxamide (C6) as an oil (0.46 g). LC/MS (10-90% over 3 min with 0.9% FA) m/z 243 (M+1), Rt 1.2 minutes.
Reaction SMILES: [Br-].[C:2]([N:5]([CH:23]1[CH2:25][CH2:24]1)[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N+:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1)(=[O:4])[CH3:3].[CH3:26][Mg]Cl.[Cl-].[NH4+]>O1CCCC1.CO>[CH2:16]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([N:5]([CH:23]2[CH2:25][CH2:24]2)[C:2](=[O:4])[CH3:3])=[CH:7][CH:8]1[CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)N(c1cc[n+](Cc2ccccc2)c2ccccc12)C1CC1
Reactant: C[Mg]Cl
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N(C1=CC(C)N(Cc2ccccc2)c2ccccc21)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a mixture of 4-(acetyl-cyclopropyl-amino)-1-benzyl-quinolinium bromide (9.6 g) in tetrahydrofuran (200 ml), under nitrogen and under cooling at 0° C., a solution of methyl magnesium chloride 1 Mol/l (12 ml) was added during 15 minutes. After 2 hours, a solution of ammonium chloride in methanol (100 ml) was added. The solvent was removed under reduce pressure and then washed with dichloromethane and water. The organic layer was separated and the solvent was removed under reduce pressure. The crude compound was purified by flash chromatography on silicagel with an eluent of dichloromethane/methanol (98/2) to give the N-(1-benzyl-2-methyl-1,2-dihydro-quinolin-4-yl)-N-cyclopropyl-acetamide (7.9 g, 98.6% yield).
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]1([C:12]2[O:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].CN([CH:22]=[O:23])C>>[C:6]1([C:12]2[O:13][C:14]([CH:22]=[O:23])=[CH:15][N:16]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(-c2ncco2)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnc(-c2ccccc2)o1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a 50 mL flask charged with DMF (5 mL) was added POCl3 (0.7 g, 4.6 mmol) dropwise at 0° C. After stirring for 10 min, a solution of 2-phenyloxazole (0.6 g, 4.1 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was heated to 100° C. and stirred for 48 h. After cooling to room temperature, the reaction mixture was poured into ice water and the pH was adjusted to 10 with 10% aqueous NaOH. The aqueous mixture was extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated and purified by column chromatography to give 240 mg of the desired product. LC-MS: m/z 174 (M+H+).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:21]Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Cl>C1COCC1>[Si:1]([O:18][CH2:19][C@H:20]1[CH2:21][CH2:27][S:24](=[O:26])(=[O:25])[NH:23]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC[C@@H](CCl)NS(C)(=O)=O)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC[C@H]1CCS(=O)(=O)N1)(c1ccccc1)c1ccccc1
Temperature: -62 °C
Yield: 58.8 %

Procedure:
To a 1 L three neck flask fitted with a thermometer, mechanical stirrer, addition funnel, under argon was added the chlorosulfonamide 7 (35 g, 0.082 mol) dissolved in THF (500 mL). The reaction mixture was cooled to −62° C. LDA (Lithium diisopropylamide, 2.0 M in heptanes/THF/ethylbenzene, 193 mL, 0.385 mol) was added drop wise over 90 min. The reaction mixture warmed to −30° C. The cooling bath was turned off and 1M HCl (1 L) was added slowly initially, then the solution was transferred to a reparatory funnel where the remaining HCl was added to pH 2. The layers were separated and the aqueous layer was extracted with ethyl acetate (400 mL). The organic layers were combined and washed with sat. NaHCO3 (250 mL) and brine (250 mL). The organic layer was dried over MgSO4 (10 g) filtered and concentrated under reduced pressure to 37.2 g of an orange oil. The oil was flash chromatographed over flash silica gel (400 g) with anhydrous Na2SO4 (100 g) on top of the column packed with hexanes. Fractions of 500 mL were collected. Fractions 1-17 were eluted with pure hexanes up to 12% ethyl acetate in hexanes, 18-26 with 20% ethyl acetate in hexanes, 27-30 with 50% ethyl acetate in hexanes. Fractions were monitored by TLC (EtOAc:hexanes; 1:1) and HPLC. Fractions 21-29 were combined and concentrated under reduced pressure and further dried submersed in a warm water bath at 50° C. under high vacuum over night to give 18.8 g (59%) of the final product 8 as a viscous honey colored oil. HPLC analysis showed a purity of 95%. 1H NMR (300 MHz, CDCl3) δ 7.3-7.7 (m, 10H), 4.4-4.6 (br s, 1H), 3.6-3.9 (m, 3H), 3.2 (m, 2H), 2.1-2.6 (m, 2H), 1.1 (s, 9H). This batch was sent as lot #07-OC-FP-019.