Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH:14]=[CH:13][CH:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CN(C)C(=O)C>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1C=CC(c2c[nH]c3cc(F)ccc23)C=C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Temperature: 80 °C

Procedure:
A mixture of 95 parts of 1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-1,4-dihydropyridine and 540 parts of N,N-dimethylacetamide is hydrogenated in the Parr-apparatus with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over Hyflo and the filtrate is poured onto water while stirring: an oil is precipitated. The supernatant aqueous phase is decanted and the residual oil is washed with water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is washed successively with a mixture of petroleumether and 2,2'-oxybispropane, with a hydrochloric acid solution 2N and with water, and dissolved in trichloromethane. The latter is washed with a sodium hydroxide solution 1N and with water, dried, filtered and evaporated. The residue is heated in a small amount of N,N-dimethylacetamide at 80° C. and the mixture is allowed to stand over week-end. The solid product is filtered off, washed with a mixture of water and ethanol, and dried in vacuo at 80° C., yielding 25 parts of 1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-piperidine; mp. 220° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[N:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:8]([NH2:10])[CH3:9])[CH:7]=1.Br[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[N:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:8]([NH:10][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)[CH3:9])[CH:7]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Temperature: 130 °C

Procedure:
1-[8-Chloro-5-(3-fluorophenyl)imidazo[1,5-a]pyridine-6-yl]ethanamine (23 mg, 79 μmol), 6-bromo-9H-purine (32 mg, 0.16 mmol, Aldrich 104981) and N,N-diisopropylethylamine (69 μL, 0.40 mmol) were stirred in ethanol (1.0 mL) and heated to 130° C. for 30 minutes in a microwave. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as a racemic mixture (10 mg, 30%). LCMS calculated for C20H16ClFN7 (M+H)+: m/z=408.1. found: 408.0. 1H NMR (300 MHz, DMSO-d6): δ 8.09 (m, 3H), 8.65 (m, 3H), 7.42 (m, 4H), 5.02 (br s, 1H), 3.30 (m, 1H), 1.42 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:19]>C(Cl)(Cl)Cl>[N:4]1([CH2:3][CH2:2][NH:1][C:18](=[O:19])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: NCCN1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOC(=O)NCCN1CCCCC1
Temperature: 25 °C

Procedure:
7.3 Grams of N-(2-aminoethyl)piperidine, 5.2 g of triethylamine and 100 ml of chloroform were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with ice cooling. To the resulting solution was slowly added dropwise 15.8 g of hexadecyl chloroformate. After completion of the addition, the temperature of the solution was returned to room temperature, followed by refluxing with heating for 0.5 hour. The reaction mixture was cooled to room temperature, washed with water, dried over anhydrous magnesium sulfate and, then, concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 16.3 g of the desired product. m.p. 48° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.COCCOC.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1>O>[Cl:18][C:19]1[CH:24]=[C:23]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:22]=[CH:21][N:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1cccc(F)c1F
Solvent: O
Solvent: COCCOC
Product: Fc1cccc(-c2cc(Cl)ncn2)c1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 42 %

Procedure:
A reaction vessel was charged with 2.03 g of tetrakistriphenylphosphine palladium, 5.55 g of 2,3-difluorophenylboronic acid, and 14.9 g of tripotassium phosphate n-hydrate, to which 120 ml of 1,2-dimethoxyethane, 30 ml of water, and 5.20 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 12 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 3.32 g of 4-chloro-6-(2,3-difluorophenyl)pyrimidine.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.BrC1C=[C:14]([S:16]C)C=CN=1>>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([S:16][CH3:14])[CH:7]=1
Reactant: CSc1ccnc(Br)c1
Reactant: Fc1cc(I)ccn1
Product: CSc1cc(I)ccn1

Procedure:
The title compound was prepared from 2-fluoro-4-iodo-pyridine following a procedure analogous to that described for 2-bromo-4-methylsulfanyl-pyridine in Example 184. Mass spectrum (ESI+): m/z=252 [M+H]+.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][CH2:5][CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1.C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:3][O:4][CH2:5][CH:6]1[CH2:11][N:10]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COCC1CNCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
Compound 12 (2.14 g, 10.5 mmol) was dissolved in dry CH2Cl2 (60 ml), in the presence of dry triethylamine (5.9 ml, 42.3 mmol). The solution was cooled (0° C.) and triphenylmethyl chloride (2.94 g, 10.6 mmol) in dry CH2Cl2 (10 ml) was added drop-wise. Once the addition was complete the reaction was warmed to room temperature and stirred for 16 h. The reaction mixture was washed with saturated NaHCO3 (75 mL), water (75 mL), and brine (75 mL). The organic portion was dried (K2CO3), and concentrated in vacuo to give 13 as an amorphous foam (3.96 g, 99% yield). 1H NMR (400 MHz, CDCl3): δ 1.3 (m, 3H), 1.9 (s, 3H), 3.0 (m, 3H), 3.2 (m, 1H), 3.3 (s, 3H), 7.16 (m, 4H), 7.27 (m, 7H), 7.49 (m, 4H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.O.C1COCC1>[OH:1][C@H:2]1[CH2:6][N:5]([C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:21])[C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A suspension of cis4-hydroxy-D-proline (10.0 g) in THF-water (1:1, 100 mL) was added 1N NaOH solution (50 mL) at 5° C. To the mixture was added a solution of benzyloxycarbonyl chloride (12.5 mL) in THF (10 mL) keeping pH to 8.5-10 by the addition of 2N NaOH solution at 5-10° C. After stirring at the same temperature for 1 h, the reaction mixture was washed with EtOAc (50 mL), adjusted to pH 2 by the addition of 4N HCl, and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and evaporated in vacuo to give cis4-hydroxy-N-benzyloxycarbonyl-D-proline (18.74 g).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]21[CH2:12][C:11](=[O:13])[O:10][C:8](=O)[CH2:7]2.[NH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C1(C)C(C)=CC=CC=1>O>[N:18]1[CH:19]=[CH:20][C:15]([N:14]2[C:8](=[O:10])[CH2:7][C:2]3([CH2:1][CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:12][C:11]2=[O:13])=[CH:16][CH:17]=1
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CC2(CCCCC2)CC(=O)N1c1ccncc1

Procedure:
The starting material is prepared as follows: The mixture of 25 g of 2,2-cyclohexane diacetic anhydride, 12.92 g of 4-aminopyridine, and 400 ml of xylene is refluxed for 25 hours using a water separator. The hot, supernatant xylene solution is decanted from an oily precipitate (which is discarded), cooled, filtered and the residue recrystallized from ethanol, to yield the 3-(4-pyridyl)-3-azaspiro[5,5]undecan-2,4-dione melting at 213°-215°.
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].[CH2:13]([O:20][C:21](=[O:26])[CH2:22][C@@H:23]([CH3:25])[NH2:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCCCC.CCOC(C)=O>[CH2:13]([O:20][C:21](=[O:26])[CH2:22][C@@H:23]([CH3:25])[NH:24][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C[C@@H](N)CC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C

Procedure:
N-(t-Butoxycarbonyl)glycine 14-3 (Aldrich) was coupled with 3(R)-methyl-β-alanine benzyl ester 0.5 H2SO4. 11-7 (Celgene) according to the procedure described for the preparation of 14-5. The title product 15-1 was then obtained by chromatography (silica, hexane/EtOAc 2:3).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=O>ClCCl>[Cl:20][C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:22]=1[CH2:23][N:7]1[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C1CCCNc2ncccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCN(Cc2ccc([N+](=O)[O-])cc2Cl)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,7,8,9-tetrahydro-5Hpyrido[2,3-b]azepin-5-one and 0.234 g of triethylamine in 6 ml of dichloromethane is added 0.506 g of 2-chloro-4-nitrobenzoyl chloride in 2 ml of dichloromethane. The mixture is stirred at room temperature overnight under argon. The solution is washed with H2O, 10% NaHCO3 and dried (MgSO4). The solvent is removed to give a brown oil which crystallizes. The mixture is chromatographed on silica with a waters Prep-500 instrument with ethyl acetate-hexane (1:1) as solvent to Give 2.4 g of off-white crystals, m.p. 162°-164 C. (identified as O-2-chloro-4-nitrobenzoyl derivative (2-chloro-4-nitro-benzoyl enolate of product) and 0.80 g of product as crystals, m.p. slowly decomposes 160°-220° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][CH2:11]2)=[O:8])[CH:4]=[N:3][CH:2]=1.[OH-].[Na+]>C1COCC1.O>[N:1]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11]2)=[O:8])[CH:4]=[N:3][CH:2]=1
Reactant: CCOC(=O)C1(NC(=O)c2cncnc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)O)CCC1)c1cncnc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 90.7 %

Procedure:
Ethyl 1-[(pyrimidin-5-ylcarbonyl)amino]cyclobutanecarboxylate (0.939 g, 3.77 mmol) was dissolved in THF (36.0 mL) prior to addition of aqueous sodium hydroxide (6.03 mL, 1M). The reaction mixture was then allowed to stir over the weekend (ca. 64 h) at ambient temperature. Most of the THF was then removed under reduced pressure to yield an oily aqueous layer, which was diluted with additional water, prior to three-fold extraction with diethyl ether. The aqueous layer was then made neutral by the addition of HCl (6.00 mL, 1H) and then saturated with sodium chloride. Repeated extraction of this aqueous layer with EtOAc (ca. 500 mL total) followed by concentration of the organic layers provided 1-[(pyrimidin-5-ylcarbonyl)-amino]cyclobutanecarboxylic acid (0.756 g) as a white solid giving proton NMR and LC/MS data consistent with theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:12]([CH3:14])[CH3:13])[N:5]=[C:6]([O:10][CH3:11])[CH:7]([CH3:9])[N:8]=1.C([Li])(C)(C)C.Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29].[Cl-].[NH4+]>O1CCCC1>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][C@@:7]1([CH3:9])[C:6]([O:10][CH3:11])=[N:5][C@H:4]([CH:12]([CH3:14])[CH3:13])[C:3]([O:2][CH3:1])=[N:8]1
Reactant: Clc1ccccc1CCBr
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1=N[C@@](C)(CCc2ccccc2Cl)C(OC)=N[C@@H]1C(C)C
Reaction time: 1 h

Procedure:
A solution of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine (1.0 g, 5.0 mmol) in tetrahydrofuran (23 ml) was cooled to −70° C., then tert.butyllithium (1.7 M in pentane, 3.26 ml, 5.55 mmol) was added and the mixture was stirred for 1 hour. A solution of 1-(2-bromo-ethyl)-2-chlorobenzene (1.44 g, 6.56 mmol) in tetrahydrofuran (10 ml) was added slowly and the mixture was stirred overnight at −70° C. At room temperature saturated ammonium chloride solution was added and the mixture was extracted three times with ether. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, heptane/EtOAc=1:1 to yield an orange solid, (1.22 g, 72%); MS (ISP): 337.1; 339.1 ((M+H)+.).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([P:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][CH:12]=2)OCC[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:2]([C:7]1[CH:8]=[C:9]([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:3])[CH3:1]
Reactant: CC1(c2cccc(P(c3ccccc3)c3ccccc3)c2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cccc(P(c2ccccc2)c2ccccc2)c1
Yield: 70 %

Procedure:
25.7 g (73.9 mmol) of [3-(2-methyl-1,3-dioxolane-2-yl)phenyl]diphenylphosphane are dissolved under cover gas in 240 mL of a THF/water mixture (1:1) and mixed with 0.9 g of 4-toluenesulphonic acid. The mixture is boiled under reflux until the original compound is completely reacted. After the addition of 50 mL of a degassed 0.5 M NaHCO3 solution it is washed and after extraction with degassed toluene, the organic phase is separated off and dried over anhydrous MgSO4. The solvent is removed at the rotary evaporator and the residue is purified by column chromatography. The product is obtained in a yield above 70% as colorless oil (purity: >98%, GC). C20H17OP.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][C:12]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:13][CH:14]=3)[C:9](=[O:25])[C:8]=2[CH:7]=1.[C:27](=O)([O-])[O-].[Na+].[Na+].CN(N=O)C(=O)OCC>CO.CCOCC.Cl>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][O:19][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[C:8](=[CH:7][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:26])[CH3:1])=[CH:18][CH:17]=3)[C:9]([OH:25])=[CH:27][C:10]=2[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)CCOc1ccc2c(c1)C(=O)c1cc(OCCN(C)C)ccc1-2
Agent: CCOC(=O)N(C)N=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CN(C)CCOc1ccc2c(c1)cc(O)c1cc(OCCN(C)C)ccc12
Reaction time: 24 h

Procedure:
A solution of 8.1 g (0.023 mole) of 2,7-bis[2-(dimethylamino)ethoxy]fluoren-9-one in 50 ml of methanol and 25 ml of ether is stirred and treated with 0.5 gram of finely powdered sodium carbonate. To this mixture is added 75 g (0.06 mole) of ethyl N-methyl-N-nitrosocarbamate in 20 ml of methanol over a period of 2 hours. The temperature of this reaction mixture is kept below 30° C. for a period of 24 hours. The reaction mixture is then freed of most of the volatile materials in vacuo, dissolved in an aqueous solution of hydrochloric acid, and extracted several times with diethyl ether. The resulting aqueous solution is made strongly alkaline with an aqueous sodium hydroxide solution and extracted with ether. The remaining aqueous solution is neutralized to an approximate pH of 10 using a 10% hydrochloric acid solution and extracted with ether. Evaporation of the combined ether extracts in vacuo and recrystallization from a methanol-water mixture yields the desired 2,7-bis[2-(dimethylamino)ethoxy]- 9-phenanthrol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([F:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][C:12]([F:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)c1cnc2c(OC)cc(F)cc2c1Cl
Product: CCCCNc1c(C(=O)OCC)cnc2c(OC)cc(F)cc12

Procedure:
4-Chloro-6-fluoro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.88 mmol) was treated with butylamine following general procedure B to afford 4-butylamino-6-fluoro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (282 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E. The above ethylamide (0.170 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 1-butyl-3-ethyl-9-fluoro-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (105 mg). LCMS: m/z 346 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+]([O-])=O)[CH:3]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:15]1([S:21][C:4]2[CH:3]=[C:2]([S:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Sc2ccccc2)cc1Sc1ccccc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 9.2 %

Procedure:
A mixture of methyl 4-chloro-2-nitrobenzoate (25 g), thiophenol (20.4 g) and potassium carbonate (17.6 g) in N,N-dimethylformamide was stirred at 120° C. for five hours. Water was added and the mixture extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulphate, filtered and evaporated. The product was recrystallised from cyclohexane to give 3.0 g of methyl 2,4-bis(phenylsulphenyl)benzoate as a beige solid, m.p. 123.9° C.
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CCCCCC[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CN(C)CCO[C:38]1[CH:47]=[CH:46][C:45]2[CH2:44][CH2:43][CH2:42][CH2:41][C:40]=2[CH:39]=1.C(OCOCC)C.C1(C)C(C2C(C)=CC=CC=2)=CC=CC=1.CC1C=CC(O)=CC=1>>[CH3:32][C:31]1[CH:26]=[CH:27][C:28]([C:38]2[CH:39]=[C:40]3[C:45](=[CH:46][CH:47]=2)[CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:29][CH:30]=1
Reactant: CCCCCCCCCCCCC
Reactant: CN(C)CCOc1ccc2c(c1)CCCC2
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1ccc(O)cc1
Agent: Cc1ccccc1-c1ccccc1C
Solvent: CCOCOCC
Product: Cc1ccc(-c2ccc3c(c2)CCCC3)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
In a reaction flask was placed NiCl2(PCy3)2 (69.0 mg, 0.0999 mmol), PCy3 (57.8 mg, 0.206 mmol), tridecane (328 mg, 1.778 mmol, as an internal standard), and N,N-dimethyl-N-[2-(5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl]amine (409 mg, 1.867 mmol). The solvent in the Grignard reagent (1 M in ether, 6.0 mmol) was exchanged with diethoxymethane (6.0 mL) and this solution added to the above catalyst mixture under a nitrogen atmosphere at room temperature. The resulting solution was stirred for several minutes at room temperature and then warmed to 95° C. for 15 hours. A sample was withdrawn and quenched with an aqueous sodium citrate solution (1 M) and was extracted with ethyl acetate. GC analysis of the organic phase showed the presence of 6-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene (1.851 mmol, 99% yield) and bitoluene (0.654 mmol) and p-methylphenol (0.575 mmol) in the reaction mixture.
Reaction SMILES: [CH3:1][N+:2]([O-:16])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH3:15].[N+:17]([CH:20]=[CH2:21])([O-:19])=[O:18]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:5]1[C:6]([O:12][CH3:13])=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[CH:3]1[CH:20]([N+:17]([O-:19])=[O:18])[CH2:21][O:16][N:2]1[CH3:1]
Reactant: C=C[N+](=O)[O-]
Reactant: COc1ccc(C=[N+](C)[O-])c(OC)c1OC
Solvent: Cc1ccccc1
Product: COc1ccc(C2C([N+](=O)[O-])CON2C)c(OC)c1OC

Procedure:
A 5.88 g (26.1 mmol) portion of N-methyl-C-(2,3,4-trimethoxyphenyl)nitrone was added to 50 mL of 0.76 molar (38 mmol) nitroethylene in toluene. The mixture was heated at reflux for 2 h. The solvent was removed in vacuo to leave a brown tar which was purified by flash chromatography on a column of 50 g of silica gel eluted successively with 100 mL portions of 0, 10, 20, 30, 40 and 50% ether in hexanes to yield 4.53 g of an orange oil. This material was crystallized from 20 mL of ice-cold 1:1 ether:hexanes to give 3.16 g of 2-methyl-4-nitro-3-(2,3,4-trimethoxyphenyl)-isoxazolidine (Example 38) as a low melting solid.
Reaction SMILES: [CH3:1][C:2](N(C)C)=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][O:12][CH2:13][CH:14]1[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15]1.C(Cl)(=O)C>>[CH3:11][O:12][CH2:13][CH:14]1[CH2:15][O:16][C:17]2[CH:23]=[CH:22][C:21]([C:2]([CH3:1])=[O:3])=[CH:20][C:18]=2[O:19]1
Reactant: CC(=O)N(C)C
Reactant: COCC1COc2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)Cl
Product: COCC1COc2ccc(C(C)=O)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dimethyl acetamide (16.65 mol, 1.31 ml) was added slowly to anhydrous aluminum chloride (33.3 mmol, 4.44 g) at 0° C. in the presence of nitrogen and stirred for 30 min at a room temperature, and then, the titled compound prepared in Example 1 (3.77 mmol, 500 mg) was added slowly to the resulting mixture, followed by stirring for 15 min. Then, acetyl chloride (3.33 mmol, 0.28 ml) was added and stirred for 5 hours at a room temperature. Ice was added slowly to the mixture to destroy and remove the remaining aluminum chloride. The reaction mixture was neutralized with NaHCO3, extracted with ethylacetate, followed by removing the solvent. And then, the resultant was dried to prepare the titled compound (520 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)cccc12
Reactant: COc1ccncc1B(O)O
Product: COc1ccncc1-c1cccc2c(N)c(C(=O)NC3CCC3)nnc12
Yield: 19.7 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclobutyl-cinnoline-3-carboxamide (145 mg) and 4-methoxypyridin-3-yl boronic acid (172 mg) were reacted to afford the title compound (31 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.24 (d, 1H), 8.52 (m, 1H), 8.44 (m, 1H), 8.33 (s, 1H), 7.78 (m, 2H), 7.18 (d, 1H), 4.49 (m, 1H), 3.72 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=350 (M+H).