Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH2:22])[CH2:19]2)=[N:14]1.Cl[CH2:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH2:34][C:33](=[O:36])[NH:32][C:31]=2[CH:37]=1)=[O:26].CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH:22][CH2:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]4[O:35][CH2:34][C:33](=[O:36])[NH:32][C:31]=4[CH:37]=3)=[O:26])[CH2:19]2)=[N:14]1
Reactant: O=C1COc2ccc(C(=O)CCl)cc2N1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCC(=O)c3ccc5c(c3)NC(=O)CO5)C4)c2c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 0.8 %

Procedure:
To a solution of 2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (50 mg, 0.2 mmol) in DMF (0.5 mL) was added 6-(2-chloro-acetyl)-4H-benzo[1,4]oxazin-3-one (0.05 g, 0.22 mmol) and Et3N (0.033 mL, 0.22 mmol). The reaction was heated to 50° C. and stirred for 12 h. The crude was purified directly by basic reverse phase HPLC to afford 0.8 mg (10%) of the title compound. HPLC: Rt=5.50 min. MS (ESI): exact mass calculated for C27H25N5O4, 483.19; m/z found, 484.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.78 (d, J=4.7, 1H), 8.06 (d, J=9.1, 1H), 7.69-7.61 (m, 3H), 7.42 (d, J=2.6, 1H), 7.40 (dd, J=9.1, 2.6, 1H), 7.32 (d, J=4.7, 1H), 7.04 (d, J=8.9, 1H), 4.70 (s, 2H), 4.21 (s, 1H), 3.89 (s, 3H), 3.11-2.80 (m, 5H), 2.62-2.58 (m, 1H), 2.26-2.17 (m, 1H), 1.93-1.86 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH2:26][OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[F:28][C:29]1[CH:34]=[C:33]([C:2]2[C:3]([N:22]3[CH2:23][CH:24]([CH2:26][OH:27])[CH2:25]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)[CH:32]=[N:31][CH:30]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 135.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. HPLC (Condition 4) tR=5.02 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=463.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.56-2.68 (m, 1H) 3.37-3.52 (m, 4H) 3.71 (t, J=8.60 Hz, 2H) 4.68 (t, J=1.00 Hz, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.77-7.90 (m, 3H) 8.04 (d, J=2.35 Hz, 1H) 8.49-8.55 (m, 1H) 8.60 (d, J=2.74 Hz, 1H) 8.76 (d, J=2.35 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14](=[O:16])[NH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>C(Cl)(Cl)Cl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[C:14]([C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1)(=[O:16])[NH2:15]
Reactant: CC(C)(C)OC(=O)N1CC=C(C(N)=O)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1=CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 20 ml of chloroform, 3.7 g of 1-tert-butoxycarbonyl-4-carbamoyl-1,2,3,6-tetrahydropyridine was dissolved, and 13 ml of trifluoroacetic acid were added thereto. The reaction mixture was stirred for 1 hour at room temperature, and subsequently was concentrated under reduced pressure to yield 4.1 g of crude 4-carbamoyl-1,2,3,6-tetrahydropyridine trifluoroacetate as a crystal.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH3:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a suspension of N-(tert-butoxycarbonyl)glycine (4.0 g, 23 mmol), N,O-dimethylhydroxylamine hydrochloride (3.0 g, 31 mmol) and N,N-dimethylpyridin-4-amine (300 mg, 2.5 mmol) in dry CH2Cl2 (100 mL) was added N-(3-dimethylaminopropyl)-W-ethylcarbodiimide hydrochloride (5.2 g, 27 mmol) followed by triethylamine (5.4 mL, 39 mmol) at 0° C. The mixture was stirred at that temperature 30 minutes and then at room temperature over 3 days. The suspension was washed with aqueous HCl (1 M, 2×40 mL) followed by a saturated aqueous solution of NaHCO3 (2×40 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to yield tert-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate as a white solid (4.5 g, yield 90%). 1H-NMR (400 MHz, CDCl3): δ 1.45 (s, 9H), 3.20 (s, 3H), 3.71 (s, 3H), 4.08 (br s, 2H), 5.26 (br s, 2H).
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:34]=[CH:33][C:23]([O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:38][OH:39].Cl>N1C=CC=CC=1>[OH:39][N:38]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:34]=[CH:33][C:23]([O:24][C:25]([CH3:31])([CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=NO)c4ccccc4)ccc32)cc1
Temperature: 0 °C

Procedure:
A solution of the compound obtained in Step A of Example 31 (500 mg) and hydroxylamine hydrochloride (137 mg) in 10 ml of pyridine is heated at reflux for 3 hours. The reaction mixture is hydrolysed using 100 ml of ice-cold water and is acidified using 6N HCl. The precipitate obtained is then filtered off, washed with water and then with petroleum ether and purified on silica gel (eluant AcOEt/PE 2/8) to yield the title compound in the form of a white powder.
Reaction SMILES: C([O:3][C:4](=[O:13])[CH2:5][C@@H:6]([C:11]#[CH:12])[NH:7][C:8](=[O:10])[CH3:9])C.[OH-].[Na+]>CCO>[C:8]([NH:7][C@H:6]([C:11]#[CH:12])[CH2:5][C:4]([OH:13])=[O:3])(=[O:10])[CH3:9]
Reactant: C#C[C@H](CC(=O)OCC)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#C[C@H](CC(=O)O)NC(C)=O
Reaction time: 1 h

Procedure:
To a solution of 11-13 (70 mg, 0.1589 mmol) in EtOH (1 mL) was added 1N NaOH (0.175 ml, 0.164 mmol). After stirring for 1 h, the solvents were evaporated and the residue was chromatographed (silica gel, 25:10:1:1 to 15:10:1:1 ethyl acetate/EtOH/water/NH4OH to give 11-14 as a colorless foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]1[CH3:11].[CH3:12][N:13]=[C:14]=[S:15]>>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][N:4]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]1[CH3:11])=[S:15]
Reactant: CC1CCCC(C)N1CCN
Reactant: CN=C=S
Product: CNC(=S)NCCN1C(C)CCCC1C

Procedure:
By the general method described in Example 1, 1-(2-aminoethyl)-2,6-dimethylpiperidine is reacted with methyl isothiocyanate to give the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]O.C1(C)C=CC=CC=1>O>[Cl:3][CH2:22][C:21]1[CH:20]=[C:19]([CH:26]=[CH:25][CH:24]=1)[O:18][CH2:17][C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:10][C:6]=1[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CO)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Thionyl chloride (4.45 ml) was added dropwise to a mixture of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (15.0 g) and toluene (200 ml) at 0° C. After stirring at room temperature for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (13.4 g, yield 84%) as pale-yellow crystals. m.p. 79-80° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([Cl:20])[C:14]=2[Cl:21])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[C:15]([Cl:20])[C:14]=2[Cl:21])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:9])[F:10]
Reactant: COC(=O)CBr
Reactant: Cn1nc(Cc2ccc(O)c(Cl)c2Cl)c(Cl)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Cc2nn(C)c(OC(F)F)c2Cl)c(Cl)c1Cl

Procedure:
A solution of 0.6 g (1.7 mmol) of 4-[(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)methyl]-2,3-dichlorophenol, 0.35 g (2.5 mmol) of potassium carbonate, 0.42 g (2.5 mmol) of potassium iodide and 0.39 g (2.5 mmol) of methyl bromoacetate in 30 ml of dimethylformamide was stirred for 16 hours and then admixed with 20 ml of water. The aqueous phase was subsequently extracted with 100 ml of diethyl ether. The extract was washed with water, dried over sodium sulfate and finally concentrated. Yield: 0.4 g;
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[C:15]([S:19][C:20]1([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([OH:33])[CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([S:19][C:20]1([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([O:33][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)SC1(c2cc(O)cc(F)c2)CCOCC1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: Cn1c(=O)ccc2cc(COc3cc(F)cc(C4(SC(C)(C)C)CCOCC4)c3)ccc21
Yield: 30 %

Procedure:
Using a similar procedure to that described in Example 11, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 4-tert-butylthio-4-(5-fluoro-3-hydroxyphenyl)tetrahydropyran to give 4-tert-butylthio-4-[5-fluoro-3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 30% yield, m.p. 54°-56° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O.[NH2:18][NH2:19]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[NH:19][N:18]=1
Reactant: CCCCCCC(=O)CC(=O)c1cccs1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCCCCc1cc(-c2cccs2)n[nH]1
Yield: 59.5 %

Procedure:
In ethanol (20 ml), 1-(2-thienyl)-1,3-nonanedione (1.30 g) and hydrazine hydrate (1.26 g) are refluxed for 3 hours by heating. After the reaction is completed, the solvent is distilled off. The obtained residue is added to petroleum ether and crystallized to obtain the objective 3-(2-thienyl)-5-n-hexylpyrazole (0.76 g) as colorless crystals. mp. 53-55° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[S:14][C:13]([C:15]([O:17]C)=[O:16])=[CH:12][C:11]=1[C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1.[OH-].[Na+]>O1CCCC1>[Br:8][C:20]1[CH:21]=[N:22][N:23]([CH3:24])[C:19]=1[C:11]1[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[S:14][C:10]=1[Cl:9]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
NBS (1.243 g, 6.98 mmol) was added in portions to a 150 mL sealed tube reactor containing methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (1.47 g, 5.73 mmol) [Prepared according to the procedure of Example 151] in Tetrahydrofuran (THF) (40 ml) at room temperature. The mixture was heated to 70° C. for 1 h. 6N NaOH (20 ml, 120 mmol) was then added and the mixture stirred at 70° C. for an additional 2 h. The mixture was partitioned between CHCl3 and H2O, the organic layer dried with Na2SO4 and concentrated affording the title compound which was used without further purification (385 mg, 1.4 mmol, 30%): LC-MS (ES) m/z=302 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>[Ni].O1CCCC1>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:12][CH2:13][NH:14][C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(CCNC(=O)C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1cc(CCNC(=O)C(F)(F)F)ccc1N
Yield: 89.1 %

Procedure:
In the presence of 15.0 g of Raney nickel, 12.5 g of N-[2-(3-methoxy-4-nitrophenyl)ethyl]-trifluoroacetamide is hydrogenated in 250 ml of tetrahydrofuran. The product is recrystallized from ethyl acetate/hexane, thus obtaining 10.0 g of N-[2-(4-amino-3-methoxyphenyl)ethyl]trifluoroacetamide, mp 80°-81° C.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O-:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Amixtureofmethyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1N LiOH (15 mL), and methanol (50 mL) was stirred at 0° C. for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification. 1H NMR (CDCl3): δ 0.87 (t, 3H); 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.25 (m, 1H); 3.53 (dd, 2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:6]2[CH:7]=[N+:8]([O-:26])[CH:9]=[CH:10][C:5]=2[N:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)n1cc(Cl)c2cnccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)n1cc(Cl)c2c[n+]([O-])ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
A stirred suspension of benzyl 3-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2.4 g, 8.37 mmol) in dichloromethane (20 mL) was treated portion wise with 3-chloroperoxybenzoic acid (2.165 g, 12.55 mmol) followed by stirring at room temperature for about 1.5 hours. The reaction was neutralized with saturated aq. sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to afford benzyl 3-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate 5-oxide (2.45 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:15])[CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2=[CH:37][CH:38]=[CH:39][NH:40][C:35]2=[CH:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:12][CH2:13]2)=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C1(O)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)C1=CC=CNC1=CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: Cc1cc(Cl)ccc1C1(O)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 42.4 %

Procedure:
To a solution of the 4-(4-chloro-2-methyl-phenyl)-piperidin-4-ol (0.160 g, 0.71 mmol) in isopropanol was added 2,6-lutidine (0.24 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,1-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.221 g, 0.59 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.130 g, 36%). 1H-NMR (CDCl3): δ 1.57 (s, 6H), 1.92 (d, 2H), 2.30 (t, 2H), 2.49 (s, 3H), 2.48-2.63 (m, 2H), 2.74-3.11 (m, 6H), 3.40 (s, 1H), 5.21 (bs, 2H), 6.09 (t, 1H), 6.75 (d, 1H), 7.06 (d, 1H), 7.08 (s, 1H), 7.20 (d, 2H), 7.22-7.36 (m, 1H), 7.57 (d, 1H), 8.36 (dd, 1H). ESI-MS m/z: 519 (M+1), retention time 1.61.
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH2:12])([CH2:6]3)[CH2:4]2.Cl[CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]#[N:23])=[O:16].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH:12][CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]#[N:23])=[O:16])([CH2:6]3)[CH2:4]2
Reactant: COC12CC3CC(C1)C(N)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC12CC3CC(C1)C(NCC(=O)N1CCC[C@H]1C#N)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
To a stirred solution of the amino compound obtained by step V (0.16 g, 0.95 mmol) in DMSO (4.0 mL) was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 0.96 mmol) and K2CO3 (0.4 g, 2.9 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with EtOAc and washed with water ad brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{[(1-methoxytricyclo[3.3.1.03,7]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile (0.12 g) in 41% yield. m/z (M+1) 304; 1H NMR (CDCl3) 300 MHz δ 4.82-4.75 (m, 1H), 3.75-3.40-m, 4H), 3.27 (s, 3-H), 2.47-2.40 (m, 1H), 2.35-1.68 (13H), 1.57-1.41 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].[CH:44]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH2:45]>C(O)(C)C>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([CH2:45][CH2:44][S:46]([CH3:49])(=[O:48])=[O:47])[CH2:23]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: C=CS(C)(=O)=O
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCNC2)cn1
Solvent: CC(C)O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCN(CCS(C)(=O)=O)C2)cn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 63.6 %

Procedure:
(R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(piperidin-3-yl)-1,4-dihydroquinoline-3-carboxylate (Example 262, 0.150 g, 0.24 mmol) was taken up in isopropanol (2 mL) and methyl vinyl sulfone (0.026 mL, 0.29 mmol) was added. The reaction mixture was stirred at 100° C. for 18 h in a sealed vessel, then cooled to room temperature and the solvent was removed in vacuo and loaded directly onto silica. Purified by flash column chromatography on silica gel using (dichloromethane-methanol) gave (R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.110 g, 62.5%).
Reaction SMILES: [Na].C(O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.[C:15](OCC)(=[O:19])[CH2:16][CH2:17][CH3:18]>>[C:15]([CH:12]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)[C:13]#[N:14])(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: N#CCc1ccc(F)cc1
Reactant: CCCC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCC(=O)C(C#N)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
10.9 g of sodium are added to 150 ml of absolute ethanol. While maintaining reflux, a solution of 49.5 g of 4-fluorophenylacetonitrile in 65.2 g of ethyl butyrate is added. The reaction mixture is refluxed for 4 hours and then left to stand overnight at room temperature. The solvents are concentrated under vacuum and the residue is taken up in water and washed with ether. The aqueous phase is cooled in an ice bath and acidified to pH 5-6 by the addition of concentrated acetic acid to give crystals, which are filtered off, washed with water and dissolved in methylene chloride.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[C:11](=[O:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25]>ClCCl>[C:18]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]3[CH:12]([CH2:13][N:14]([C:11](=[O:17])[CH2:10][C:25]4[CH:4]=[CH:3][CH:2]=[CH:7][C:24]=4[N:26]4[CH2:29][CH2:30][CH2:28][CH2:27]4)[CH2:15]3)[C:11](=[O:17])[CH2:10][CH2:9]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3N3CCCC3)CC12
Reaction time: 0.67 h

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-[2-(1-pyrrolydinyl)phenyl]acetic acid (1.42 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 40 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 1 hour at +5° C. and then for 1 hour at 20° C. It is washed with distilled water (2×20 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 2 cm, height 25 cm), eluting with a mixture of ethyl acetate and cyclohexane (70/30 by volume) and collecting 100 cc fractions. Fractions 3 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from a mixture of acetonitrile (5 cc) and isopropyl ether (5 cc). The crystals are drained, washed with ethylene oxide (10 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-[2-(1-pyrrolidinyl)phenyl]acetyl]-4-perhydroisoindolone (2.2 g) melting at 178° C. is obtained.