Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][CH2:12][CH:13]=[C:14]([CH3:18])[C:15](Cl)=[O:16])(=[O:10])[CH3:9].[CH3:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH3:27])([CH3:26])[C:21]=1[CH2:28][CH:29]=[C:30]([CH3:33])[C:31]#[CH:32]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:8]([O:11][CH2:12][CH:13]=[C:14]([CH3:18])[C:15](=[O:16])[C:32]#[C:31][C:30]([CH3:33])=[CH:29][CH2:28][C:21]1[C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][CH2:25][C:20]=1[CH3:19])(=[O:10])[CH3:9]
Reactant: C#CC(C)=CCC1=C(C)CCCC1(C)C
Reactant: CC(=O)OCC=C(C)C(=O)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC=C(C)C(=O)C#CC(C)=CCC1=C(C)CCCC1(C)C
Reaction time: 0.08 h

Procedure:
Under inert gas atmosphere 59.9 mg (0.308 mmol) of copper(I) iodide and 110.3 mg (0.154 mmol) of bis(triphenylphosphine)palladium(II) dichloride [(PPh3)2PdCl2] were added to a 100 ml four-necked flask. At 23° C., 42.0 ml of anhydrous THF were added and the yellow suspension was stirred for 5 min. When 2.15 ml (15.4 mmol) of triethylamine were introduced drop wise via syringe an orange solution was obtained. Within 1 minute 3.10 g (15.4 mmol) of 4-chloro-3-methyl-4-oxobut-2-enyl acetate (compound of formula (IVa)) were added and the solution turned dark orange. Upon drop wise addition of 2.92 g (14.0 mmol) of 1,3,3-trimethyl-2-(3-methylpent-2-en-4-ynyl)cyclohex-1-ene (compound of formula (III))
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].N1C=CC=CC=1.[CH3:24][O:25][CH2:26][C:27](Cl)=O.[OH-].[Na+]>C1COCC1>[Cl:14][C:13]1[C:8]([C:6]2[CH:5]=[CH:4][C:3]3[C:15](=[O:16])[NH:17][C:27]([CH2:26][O:25][CH3:24])=[N:1][C:2]=3[N:7]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC(=O)c1ccc(-c2ncccc2Cl)nc1N
Reactant: COCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCc1nc2nc(-c3ncccc3Cl)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 6-amino-3′-chloro-[2,2′]bipyridinyl-5-carboxylic acid amide (0.5 g, 2.02 mmol) in anhydrous THF (10 mL) under N2 atmosphere. Add drop wise pyridine (0.36 g, 4.04 mmol) and methoxyacetyl chloride (0.48 g, 4.04 mmol) to the reaction mixture and stir at room temperature overnight. Add 10% aq. NaOH (10 mL) and reflux for 4 hours. Concentrate in vacuum, adjust the pH to 6.0 using AcOH, collect the solid by filtration and dry under vacuum to give 7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6](C(OCC)=O)[CH:7]2[C:12]([OH:14])=[O:13].[CH3:20]CO.[OH-].[Na+].S(Cl)(Cl)=O>O1CCOCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[C:12]([O:14][CH3:20])=[O:13]
Reactant: CCOC(=O)N1CCc2c(Br)cccc2C1C(=O)O
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)C1NCCc2c(Br)cccc21
Reaction time: 18 h
Yield: 80 %

Procedure:
5-Bromo-2-(ethoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1 g, 3.05 mmol) (Ortwine, et al., J. Med. Chem, 1992, 35, 1345), in two batches, was heated in a microwave to 150° C. in 1,4-dioxane (4 mL)/EtOH (2 mL)/2N NaOH (5 mL) for a total of 3 h. The combined reaction mixtures were concentrated, dissolved in MeOH (30 mL) and thionyl chloride (0.222 mL, 3.05 mmol) was slowly added. After 18 h, the solvent was removed and the residue was partitioned with EtOAc (50 mL)/saturated NaHCO3(30 mL), the phases separated and aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine (25 mL) and dried (MgSO4) to afford 0.56 g (80%) of Intermediate 4A as a yellow oil. MS (ESI) m/z: 270-272 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.ClC1C(C(O)=O)=C(C(=O)C2C=CC(Cl)=CC=2)C=CC=1.Cl.[N+:40]([C:43]1[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=1)([O-:42])=[O:41]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:3]=1[C:11]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([OH:19])[N:48]([CH2:47][C:46]1[CH:45]=[CH:44][C:43]([N+:40]([O-:42])=[O:41])=[CH:50][CH:49]=1)[C:5]2=[O:7]
Reactant: O=C(O)c1cccc(Cl)c1C(=O)c1ccc(Cl)cc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C(c1ccc(Cl)cc1)c1cccc(Cl)c1C(=O)O
Product: O=C1c2cccc(Cl)c2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 63 %

Procedure:
The named compound was synthesised from a mixture of 3-chloro-2-(4-chlorobenzoyl)benzoic acid and 6-chloro-2-(4-chlorobenzoyl)benzoic acid (2.15 g, 7.28 mmol) and 4-nitrobenzylamine hydrochloride (1.51 g, 8.01 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 10%-20% EtOAc/petrol) and obtained as a white solid (1.96 g, 63%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.C([Li])CCC.CN([CH:31]=[O:32])C>>[CH:31]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2)=[O:32]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3n2)CC1
Agent: [Li]CCCC
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3n2)CC1

Procedure:
6-bromo-2-hydroxyquinoline was treated with cis-4-tert-butylcyclohexanol under Mitsunobu conditions, affording 6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline. 6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline was then exposed to n-butyllithium and DMF, providing 6-formyl-2-((trans)-4-tert-butylcyclohexyloxy)quinoline. This aldehyde was then treated with 3-aminopropionic acid and sodium cyanoborohydride to afford the title compound, 3-((2-((trans)-4-tert-butylcyclohexyloxy)quinolin-6-yl)methylamino)propanoic acid.
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH3:13])[CH:7]=1.O.[NH2:17]N>C(O)(=O)C>[CH3:13][S:12][C:8]1[CH:7]=[C:6]([C:5]2[N:4]=[CH:3][NH:2][N:17]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CSc1cccc(C(=O)N=CN(C)C)c1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CSc1cccc(-c2nc[nH]n2)c1
Temperature: 90 °C

Procedure:
8 g of N-[1-dimethylaminomethylidene]-3-methylsulfanyl-benzamide were dissolved in 80 ml of glacial acetic acid. 2 ml of hydrazine hydrate were added and the mixture was heated to 90° C. for 2 h. The solvent was removed in vacuo. The crude product was purified by flash chromatography (300 g of silica gel; DCM/MOH, gradient from 100:0 to 95:5). 4.5 g of the title compound were obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[C:28]([S:32]([NH:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 0 °C
Yield: 39.7 %

Procedure:
Into a 1-neck round-bottom flask were added tert-butyl (3-aminophenyl)carbamate (2.0 g, 9.6 mmol) and tetrahydrofuran (30 mL) and triethylamine (2.0 mL, 14 mmol). The mixture was stirred at 0° C. and m-nitrobenzenesulfonyl chloride (2.1 g, 9.6 mmol) was slowly added. The reaction was warmed to rt and stirred for 1 h. The solvent was removed under vacuum and EtOAc and water were added. The aqueous phase was extracted again with EtOAc. The organics were combined, dried over Na2SO4 and the solvents were removed under vacuum. The crude was purified by combi-flash column chromatography to give the desired product (1.5 g, 39%). LCMS for C17H19N3O6S (M-tBu+H)+: m/z=338.0. 1H NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.35 (s, 1H), 8.51 (t, J=2.0 Hz, 1H), 8.43 (ddd, J=8.2, 2.2, 1.0 Hz, 1H), 8.12 (ddd, J=7.8, 1.8, 1.0 Hz, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.35 (br, 1H), 7.07 (m, 1H), 7.06 (s, 1H), 6.68 (dt, J=7.0, 2.0 Hz, 1H), 1.42 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29].C([O-])(=O)C.[Na+].[CH:36]([NH2:38])=O.C(OC(=O)C)(=O)C>[Cu]I.C(OCCCC)(=O)C>[C:36]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29])#[N:38]
Reactant: NC=O
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
2-Bromo-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino) azobenzene (479 parts), copper (I) iodide (19 parts), anhydrous sodium acetate (246 parts), formamide (180 parts), acetic anhydride (408 parts) and n-butyl acetate (2190 parts) are mixed together and heated, with stirring, to 110° C. during 15 minutes. The temperature is maintained at 110° for 30 to 50 minutes, when a solid is suddenly precipitated from the reaction mixture, indicating completion of the reaction. The mixture is allowed to cool to room temperature and the product is collected, washed with ethanol to remove residual n-butyl acetate and dried. 2-Cyano-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino)azobenzene is obtained in 88% yield and requires no purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[C:27]([O:29][CH3:30])=[O:28].C([O-])(O)=O.[Na+]>N1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[C:27]([O:29][CH3:30])=[O:28])(=[O:5])=[O:4]
Reactant: COC(=O)c1cccc2cc(O)cnc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.55 mL, 3.4 mmol) was added to a solution of methyl 3-hydroxyquinoline-8-carboxylate (650 mg, 3.2 mmol) in pyridine (2.3 mL) and CH2Cl2 (13 mL) at 0° C. The reaction mixture was allowed to warm to room temperature. After 3 h, additional trifluoromethanesulfonic anhydride (0.55 mL, 3.4 mmol) was added and the reaction was stirred for an additional 18 h. Saturated aqueous NaHCO3 (20 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×). The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified on silica gel eluting with CH2Cl2 to afford 971 mg (91%) of methyl 3-(((trifluoromethyl)sulfonyl)oxy)quinoline-8-carboxylate.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4](=[C:21]([CH3:24])[O:22][N:23]=2)[N:5]=[C:6]([C:17]([O:19]C)=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16].[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[C:3]2[C:4](=[C:21]([CH3:24])[O:22][N:23]=2)[N:5]=[C:6]([C:17]([OH:19])=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16]
Reactant: COC(=O)c1nc2c(C)onc2c(F)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc2c(F)c(Nc3ccc(I)cc3F)c(C(=O)O)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylisoxazolo[4,3-b]pyridine-5-carboxylate (250 mg, 0.56 mmol) in a mixture of THF (10 ml) and H2O (5 ml) is added a solution of LiOH (67 mg, 2.8 mmol) in H2O (2.4 ml). After stirring at room temperature for 4 h, the reaction is concentrated, acidified with 1 M HCl solution, and extracted with EtOAc (2×20 ml). The organic solution is dried over MgSO4 and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[O:26][CH2:27][CH2:28]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][CH2:27][O:26][C:25]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(OCCO)cc1OC
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(OC)c(OC)c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(3,4-dimethoxyphenoxy)ethanol (1.65 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-diethyl ether, 99:1) and crystallized from dichloromethane-hexane to provide 0.9 g of 4-[[2-(3,4-dimethoxyphenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 93°-94° C.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:13])(=[NH:12])[CH2:8][CH2:9][CH2:10][CH3:11].[N+:14]([C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]>C1C=CC=CC=1>[N+:14]([C:17]1[CH:18]=[C:19]([NH:23][C:24]([NH:12][C:7](=[NH:13])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1cccc([N+](=O)[O-])c1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 150 ml. dry acetone, 13.6 g. valeramidine hydrochloride, and 16.4 g. 3-nitrophenyl isocyanate in 300 ml. benzene, there was obtained after recrystallization from ethyl alcohol-ether 11.6 g. of the hydrochloride of 1-(3-nitrophenyl)-3-(pentanimidoyl)urea; m.p. 161°-163°C.
Reaction SMILES: BrC1C=CC(S([O:11][C@@H:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=O)=O)=CC=1.[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[C:34]([O:41][CH2:42][CH3:43])[CH:33]=[C:32]2O.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.O>[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[C:34]([O:41][CH2:42][CH3:43])[CH:33]=[C:32]2[O:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1
Reactant: CCOc1cc(O)c2cc(Br)c(OC)cc2n1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1cc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)c2cc(Br)c(OC)cc2n1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A suspension of 1-t-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (25.0 g, 53.8 mmol), 6-bromo-2-ethoxy-7-methoxyquinolin-4-ol (16.1 g, 53.8 mmol) and Cs2CO3 (52.6 g, 162 mmol) in NMP (300 mL) was stirred at 75° C., under N2, for 2 hours. At 22° C., the reaction was diluted with water (500 mL) and extracted with EtOAc (3×500 mL). The combined EtOAc layers were washed with water (3×100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60, eluting with 0 to 50% EtOAc in hexane, to give the title product. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H); 7.16 (s, 1H); 6.02 (s, 1H); 5.05 (m, 1H); 4.49 (m, 3H); 4.00 (s, 3H); 3.91 (m, 2H); 3.78 (s, 3H); 2.67 (m, 1H); 2.37 (m, 1H); 1.47 (s, 3H); 1.44 (s, 9H) ppm. LRMS (ESI) m/z 525.0 [(M+H)+; calcd for C23H30BrN2O7: 298.0].
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[N:5][N:4]=1.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1>C1(C)C=CC=CC=1>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:3]2[N:8]3[CH:9]=[N:10][CH:11]=[C:7]3[CH:6]=[N:5][N:4]=2)=[N:14]1
Reactant: Nc1cc[nH]n1
Reactant: CSc1nncc2cncn12
Solvent: Cc1ccccc1
Product: c1cc(Nc2nncc3cncn23)n[nH]1
Temperature: 0 °C

Procedure:
A mixture of 6.0 gm. of 4-(methylthio)-imidazo[1,5-d]-as-triazine, 4.15 gm. of 3-aminopyrazole and 150 ml. of toluene is refluxed for 26 hours. The mixture is evaporated and the residue is heated with a mixture of 150 ml. of ethanol and 40 ml. of dimethylformamide. The mixture is cooled to 0° C. and the desired product is collected as a solid, m.p. 271°-274° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]2[CH2:7][CH:8]3[CH2:22][NH:21][CH2:20][CH2:19][N:9]3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1.C(N(CC)CC)C.[CH2:32]([O:39][CH2:40][C:41](Cl)=[O:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]2[CH2:7][CH:8]3[CH:22]([C:41](=[O:42])[CH2:40][O:39][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[NH:21][CH2:20][CH2:19][N:9]3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNCC1C2
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNC(C(=O)COCc3ccccc3)C1C2
Reaction time: 0.5 h

Procedure:
8,9-Dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (the compound obtained in Example 1-(6)) (1.6 g) is dissolved in methylene chloride (10 ml), and thereto are added triethylamine (0.8 ml) and benzyloxyacetyl chloride (0.8 ml) under ice-cooling, and the mixture is stirred for 30 minutes. The reaction solution is washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent; chloroform:ethyl acetate=9:1) to give 8,9-dimethoxy-2-benzyloxyacetyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (1.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][CH2:23][C:10]2([O:14][C:13](=[O:15])[N:12]([C:16]3[CH:17]=[N:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]([CH3:45])[C:28]([C:30]1[N:39]([CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:33]2[N:34]=[C:35](Cl)[N:36]=[CH:37][C:32]=2[CH:31]=1)=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][CH2:23][C:10]2([O:14][C:13](=[O:15])[N:12]([C:16]3[CH:17]=[N:18][C:19]([NH:22][C:35]4[N:36]=[CH:37][C:32]5[CH:31]=[C:30]([C:28](=[O:29])[N:27]([CH3:26])[CH3:45])[N:39]([CH:40]6[CH2:44][CH2:43][CH2:42][CH2:41]6)[C:33]=5[N:34]=4)=[CH:20][CH:21]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)CN(c1ccc(N)nc1)C(=O)O2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5(CCCN(C(=O)OC(C)(C)C)C5)OC4=O)cn3)nc2n1C1CCCC1

Procedure:
Following general N—C coupling procedure 1, 3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.084 g, 0.287 mmol, 1.0 eq) and gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester which was used directly in the following BOC deprotection.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[Na].[C:11](O)(=[O:13])C>C[O-].[Na+].CO>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:8](=[NH:9])[O:13][CH3:11]
Reactant: N#Cc1cccc(Br)n1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=N)c1ccccn1
Reaction time: 0.25 h

Procedure:
6-Bromo-2-cyano-pyridine (20 g) was dissolved in a solution of sodium methoxide in methanol prepared from methanol (300 ml) and metallic sodium (1.26 g). After the solution was left to stand for 15 minutes, acetic acid (3.3 g) was added thereto, followed by concentration under reduced pressure. The resulting residue was dissolved in ether (300 ml) and insoluble materials were filtered out. The filtrate was concentrated under reduced pressure to obtain methyl 2-picoline imidate derivative.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:15])[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.N12CCCN=C1CCCCC2.[CH3:27][N:28]=[C:29]=[O:30]>C(Cl)Cl>[CH3:27][NH:28][C:29]([O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:15])[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1)=[O:30]
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=O
Reactant: CN=C=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)C(=O)CC1
Reaction time: 8 h

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol3(2H)-one (5.0 g) was suspended in EtOH (100 ml), and thereafter 10% NaOH solution (50 ml) was added and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, CH2Cl2 (100 ml) was added followed by 10% HCl until the aqueous layer was neutralized. The layers were separated and the aqueous phase extracted with CH2Cl2 (2×100 ml). The organic portion was dried (Na2SO4) and concentrated and the residue was recrystallized from 95% EtOH to provide 1,4-dihydro-7-hydroxy-4-methylcyclopent[b]indol-3(2H)-one as an off-white solid. The phenol was dissolved in CH2Cl2 (100 ml), and thereafter 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 g) was added followed by methyl isocyanate (1.4 g) and the mixture was stirred overnight. The mixture was concentrated in vacuo to afford an oily solid which was crystallized from EtOH to provide 1,4-dihydro-7-methylaminocarbonyloxy-4-methylcyclopent[b] indol-3(2H)-one (1.1 g).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=2[F:24])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH3:3].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:3][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:25])[S:11]([C:14]2[C:15]([F:24])=[C:16]([F:23])[C:17]([F:22])=[C:18]([F:21])[C:19]=2[F:20])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH3:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN(C)c1ccc(NS(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C)c1ccc(N(C)S(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
4-(N,N-Dimethylamino)-1-(pentafluorophenylsulfonamido)benzene (100 mg, 0.273 mmol) was dissolved in dry THF (2.5 mL) and to the system was added under N2 at room temperature a 1M solution of lithium bis(trimethylsilyl)amide (0.274 mL). The reaction mixture was stirred for 10 min followed by addition of MeI (65 mg, 0.028 mL). The reaction mixture was stirred overnight, the solvent was evaporated under reduced pressure and the crude product purified by HPLC using silica as the stationary phase and eluting with 20%EtOAc/Hex (v/v) to afford the product as a white solid in 60% yield (62 mg). EI m/z: 380(35, M+), 149(100). 1H NMR (CD3OD) 7.05(d, J=8 Hz, 2H), 6.68(d, J=8 Hz, 2H), 3.33(s, 3H) 2.93(s, 6H). Anal. calcd. for C15H13F5SO2N2: C, 47.37, H, 3.45, N, 7.37. Found: C, 47.37, H, 3.49, N, 7.32.