Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:35])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[CH:22][CH:21]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[ClH:36]>C1COCC1.O1CCOCC1>[ClH:36].[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:35])[NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][NH2:27])=[CH:24][CH:25]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NCc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 9-bromo-5-[(p-tert-butoxycarbonylaminomethylphenyl)carbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (180 mg, 0.3 mmol) in THF (6 mL) was added 4N HCl in dioxane (6 mL). The mixture was stirred for 3 h at room temperature and concentrated. The residue was collected by filtration, washed with diethyl ether, and dried in vacuo to give 140 mg of the title compound (97%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.11 (s, 1H), 10.27 (s, 1H), 8.27 (bs, 2H), 7.61 (d, 2H, J=8.6 Hz), 7.40 (d, 2H, J=8.6 Hz), 7.23 (bs, 1H), 7.20 (bs, 1H), 5.17~5.26 (m, 1H), 3.96 (br, 2H), 3.10 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.56~2.71 (m, 2H), 2.09 (dm, 1H, J=13.5 Hz), 1.82~1.96 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14](SC)=[N:15][CH:16]=2)[N:11]2[CH:22]=[CH:23][N:24]=[C:10]12.ClC1C=C(C=CC=1)C(OO)=O.[NH2:36][C:37]1[CH:38]=[N:39][C:40]2[CH2:41][CH2:42][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:44][C:45]=2[CH:46]=1>C(Cl)Cl.C(OCC)(=O)C>[C:50]([O:49][C:47]([N:43]1[CH2:42][CH2:41][C:40]2[N:39]=[CH:38][C:37]([NH:36][C:14]3[N:13]=[C:12]4[C:17]([C:18](=[O:19])[N:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[C:10]5[N:11]4[CH:22]=[CH:23][N:24]=5)=[CH:16][N:15]=3)=[CH:46][C:45]=2[CH2:44]1)=[O:48])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)N1CCc2ncc(N)cc2C1
Reactant: CSc1ncc2c(=O)n(-c3c(F)cccc3Cl)c3nccn3c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ncc(Nc3ncc4c(=O)n(-c5c(F)cccc5Cl)c5nccn5c4n3)cc2C1
Reaction time: 5 h

Procedure:
A mixture of Example 95C (70.0 mg, 0.193 mmol) and m-chloroperoxybenzoic acid (52.0 mg, 0.232 mmol) in CH2Cl2 (2 ml) was stirred for 20 minutes. tert-Butyl 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (57.9 mg, 0.232 mmol) was added to the reaction mixture. After 5 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with ethyl acetate to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][O:3]1.[Cl:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21](Cl)[N:20]=[CH:19][N:18]=1.CC(N(C)C)=O>>[Cl:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21]([O:14][C:11]2[CH:12]=[CH:13][C:8]([CH:5]3[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][CH2:6]3)=[CH:9][CH:10]=2)[N:20]=[CH:19][N:18]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CC1(C)OCC(c2ccc(O)cc2)CO1
Solvent: CC(=O)N(C)C
Product: CC1(C)OCC(c2ccc(Oc3ncnc(Cl)c3[N+](=O)[O-])cc2)CO1
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a solution of 4-(2,2-dimethyl-1,3-dioxan-5-yl)phenol (500 mg, 0.0026 moles) and 4,6 dichloro-5-nitropyrimidine (600 mg, 0.0028 mole) in dimethyl acetamide (10 ml) K2CO3 (776 mg, 0.00577 mole) was added −20° C. The reaction mixture was stirred for about 2 hours at −10° C. to −18° C. The reaction mixture was then poured into ice cold water and extracted with ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and evaporated under reduced pressure to yield crude product which was purified by column chromatography using 15% ethyl acetate in hexane as eluent to yield 500 mg product as pale yellow solid.
Reaction SMILES: NCC(O)=O.[C:6]([O:13]CC)(=O)[C:7]([O:9]CC)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].C(O)(=O)C(O)=O.OS(O)(=O)=O.OP(O)(O)=O>Cl>[NH:16]1[C:17]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:23][C:6](=[O:13])[C:7]1=[O:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1ccccc1N
Agent: Cl
Agent: NCC(=O)O
Agent: O=C(O)C(=O)O
Product: O=c1[nH]c2ccccc2[nH]c1=O

Procedure:
The compounds synthesized for testing as potential glycine antagonists which are not substituted on the amide (1 or 4) position are summarized below (Table I). Most were available by simple condensation of diethyl oxalate with the corresponding diaminobenzene according to Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962). The 1,4-dihydro-2,3-quinoxalinediones may be easily prepared in high yield by heating oxalic acid and the corresponding o-diamine to about 100° to 140° C. for 1 to 10 hr. in the presence of a strong mineral acid such as HCl, H2SO4, H3PO4 and the like. See, Mager and Berends, Rec. Trav. Chim. 77:842 (1958). In a preferred embodiment, oxalic acid and the o-diamine are heated to 125° C. in 2N HCl for 2.5 hours to give the corresponding 1,4-dihydro-2,3-quinoxalinedione in high yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]3[CH2:13][C:14]([CH3:19])([CH3:18])[CH2:15][C:16](=[O:17])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:20]([Mg]Cl)=[CH2:21].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]3[CH2:13][C:14]([CH3:19])([CH3:18])[CH2:15][C:16]([CH:20]=[CH2:21])([OH:17])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=C[Mg]Cl
Reactant: CC1(C)CC(=O)c2cc(-c3cccc(Br)c3)sc2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC1(O)CC(C)(C)Cc2sc(-c3cccc(Br)c3)cc21
Temperature: -30 °C
Reaction time: 18 h
Yield: 118.4 %

Procedure:
2-(3-Bromophenyl)-6,6-dimethyl-6,7-dihydrobenzo[b]thiophen-4(5H)-one (0.36 g, 1.0 mmol) was dissolved in anhydrous THF (10 mL) and the solution was cooled to −30° C. under a nitrogen atmosphere. Vinyl magnesium chloride (2.8 mL, 1.6 M solution in THF, 5.4 mmol) was added to the ketone portion-wise whilst maintaining the temperature at −30° C. Upon completion of the addition, the reaction was allowed to warm to 25° C. and then stirred for 18 hr. Monitoring of the reaction by LC/MS indicated starting material was still present so further vinyl magnesium chloride (2.8 mL, 1.6 M solution in THF, 5.4 mmol) was added. After 2 hr the solution was treated with saturated aqueous ammonium chloride solution. The product was extracted into ethyl acetate (×3) and this was back extracted with water and saturated brine. The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (0.43 g, quant.).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[C:14]=1[C:21]1[N:26]=[C:25]([CH3:27])[C:24]([CH:28]([CH:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32][CH2:31]2)[OH:29])=[C:23]([O:40][CH3:41])[CH:22]=1)[CH3:12].C(N(CC)CC)C>ClCCl>[CH2:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:11][CH3:12])[C:14]=1[C:21]1[N:26]=[C:25]([CH3:27])[C:24]([C:28]([CH:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32][CH2:31]2)=[O:29])=[C:23]([O:40][CH3:41])[CH:22]=1)[CH3:20]
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(O)C2CCCc3ccccc32)c(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)C2CCCc3ccccc32)c(C)n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Dimethyl sulfoxide (60 μL, 0.85 mmol) is added at −78° C. to a solution of oxalyl chloride (36 μL, 0.41 mmol) in dichloromethane (2 mL). After stirring at −78° C. for 10 minutes, a solution of [6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-pyridin-3-yl]-(1,2,3,4-tetrahydro-naphthalen-1-yl)-methanol (138 mg) in dichloromethane (2 mL) is added and the mixture is stirred for 40 minutes more. Triethylamine (0.24 mL, 1.7 mmol) is then added. After 10 minutes, the mixture is allowed to warm to room temperature and quenched with water. Extraction with dichloromethane, drying (Na2SO4), and concentration followed by flash chromatography provides [6-(2,6-diethylphenyl)-4-methoxy-2-methylpyridin-3-yl]-(1,2,3,4-tetrahydronaphthalene-1-yl)methanone. 1H NMR (CDCl3) 7.30 (dd, 1H), 7.16-7.12 (m, 4H), 7.0 (t, 1H), 6.9 (d, 1H), 6.6 (s, 1H), 4.4 (s, 1H), 3.8 (s, 3H), 2.90-2.76 (m, 2H), 2.43-2.33 (m, 4H), 2.3 (s, 3H), 2.03-1.84 (m, 4H), 1.15-1.04 (m, 6H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[S:14][CH:13]=[N:12][CH:11]=1.[CH:15]1([CH2:18]/[C:19](=[N:21]/[S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])/[CH3:20])[CH2:17][CH2:16]1.C[Al](C)C.CCCCCCC>C1COCC1.C1(C)C=CC=CC=1>[CH:15]1([CH2:18][C:19]([NH:21][S:22]([C:24]([CH3:25])([CH3:27])[CH3:26])=[O:23])([CH3:20])[C:13]2[S:14][C:10]([CH3:9])=[CH:11][N:12]=2)[CH2:16][CH2:17]1
Reactant: C/C(CC1CC1)=N\S(=O)C(C)(C)C
Reactant: Cc1cncs1
Agent: CC(C)[N-]C(C)C
Agent: C[Al](C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cc1cnc(C(C)(CC2CC2)NS(=O)C(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
A 2.0M solution of lithium diisopropylamide in THF (745 μl, 1.49 mmol) was added dropwise to a solution of 5-methylthiazole (148 mg, 1.49 mmol) in dry THF (0.5 ml) cooled to −78° C. and once the addition was complete the reaction was stirred for 30 minutes at −78° C. followed by addition of dry toluene (1.5 ml). To a solution of (NE)-N-(2-cyclopropyl-1-methyl-ethylidene)-2-methyl-propane-2-sulfinamide (CAN 1426426-70-1, 150 mg, 745 μmol) in dry toluene (1.5 mL) was added a 2.0M solution of trimethylaluminum in heptane (410 μl, 820 μmol). The previous solution was then added to the reaction mixture cooled at −78° C. The reaction was allowed to warm up to room temperature overnight. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and was then diluted with ethyl acetate. The bi-phasic mixture was poured into a separatory funnel and extracted. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (123 mg, 55%). MS (ESI, m/z): 301.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]([CH3:36])[CH2:31][CH2:32][CH2:33][NH:34][CH3:35]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:34]([CH2:33][CH2:32][CH2:31][N:30]([CH3:36])[CH3:29])[CH3:35])=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CNCCCN(C)C
Solvent: CCO
Product: CN(C)CCCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 85 °C
Yield: 78.7 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (550 mg, 1.40 mmol) in ethanol (2 ml) was treated with N,N,N′-trimethyl-1,3-propanediamine (1.02 ml, 7.00 mmol) and the resulting mixture was heated at 85° C. in a sealed tube for 3 hours. The solvent removed under reduced pressure. The residue was purified by column chromatography on silica eluting with a gradient system of 97:3:0.3 (dichloromethane:methanol:ammonia) gradually changing to 90:10:1 (dichloromethane:methanol:ammonia) to afford the title compound as a colourless oil (512 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1>CC(O)C>[N+:27]([C:22]1[CH:21]=[C:20]([NH:19][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:25]=[CH:24][C:23]=1[OH:26])([O-:29])=[O:28]
Reactant: Clc1ccnc2ccccc12
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(Nc2ccnc3ccccc23)ccc1O
Temperature: 130 °C

Procedure:
TFA (0.57 mL) was added to a suspension of 4-chloroquinoline (0.48 mg, 2.9 mmol) and 4-amino-2-nitrophenol (0.45 g, 2.9 mmol) in i-PrOH (4 mL) was added at RT. The reaction was heated to 130° C. in a sealed tube for 2 h. A solid precipitated upon cooling. The solid was filtered out and washed with i-PrOH to give 2-nitro-4-(quinolin-4-ylamino)-phenol.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[C:7]1([CH2:13][CH2:14][NH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:1][O:2][CH2:3][C:4]([NH:15][CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: NCCc1ccccc1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)NCCc1ccccc1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Methoxyacetyl chloride (19.57 g, 0.18 mol) was added over 10 minutes to a stirred, ice-cooled solution of 2-phenylethylamine (21.85 g, 0.18 mol) and N-ethyldiisopropylamine (23.26 g, 0.18 mol) in dichloromethane (200 ml). After 2 hours at room temperature, the solvent was removed under reduced pressure and the residue partitioned between ether and water. The organic phase was washed successively with 1M aqueous citric acid solution, water, saturated aqueous sodium bicarbonate solution and water, dried (MgSO4) and evaporated under reduced pressure to provide the required product (29.65 g) as an oil, Rf 0.32 (SS 2), which was used without further purification in the next step.
Reaction SMILES: [K].[C:2]([NH:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10])([CH3:5])([CH3:4])[CH3:3].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[C:16]([CH3:24])=[CH:15][N:14]=1>C(O)(C)(C)C>[OH:11][CH:8]([CH2:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:9][O:10][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[C:16]([CH3:24])=[CH:15][N:14]=1
Reactant: Cc1cnc(Cl)c2cc(Cl)ccc12
Reactant: CC(C)(C)NCC(O)CO
Agent: [K]
Solvent: CC(C)(C)O
Product: Cc1cnc(OCC(O)CNC(C)(C)C)c2cc(Cl)ccc12
Reaction time: 24 h

Procedure:
0.74 g of Potassium is dissolved in 40 ml of tert.-butylalcohol and 3.0 g of 1-tert.butylamino-2,3-dihydroxypropane and subsequently 4 g of 1,7-dichloro-4-methylisoquinoline are added. After stirring for one day, heating up to 50° is effected for a further day. The reaction solution is concentrated by evaporation under vacuum. The residue is taken up with 1N hydrochloric acid and ether, the aqueous phase neutralised with 2N caustic soda solution and extracted with methylene chloride. After drying over magnesium sulphate and concentration by evaporation the title compound is obtained in free base form. M.p. 116°-117°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH:28]([CH3:30])[CH3:29])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18]CC2C=CC(OC)=CC=2)[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)=[O:34])=[C:4]([F:43])[CH:3]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[NH2:18][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:8]([C:7]3[C:2]([Cl:1])=[CH:3][C:4]([F:43])=[C:5]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=4)=[O:34])[CH:6]=3)[C:9](=[O:31])[N:10]2[CH:28]([CH3:30])[CH3:29])=[CH:15][N:14]=1
Reactant: COc1ccc(CNc2cc3c(cn2)cc(-c2cc(NC(=O)Nc4cccc(F)c4)c(F)cc2Cl)c(=O)n3C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)n1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2Cl)cc2cnc(N)cc21
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A mixture of 1-(4-chloro-2-fluoro-5-(1-isopropyl-7-((4-methoxybenzyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (0.094 g, 0.156 mmol) and anisole (0.085 mL, 0.778 mmol) was stirred in TFA (1 mL) at RT for 3 h. The mixture was concentrated to dryness, treated with EtOAc and satd. NaHCO3 and stirred for 1 h. The resulting solid was collected via filtration and dried to afford 1-(5-(7-amino-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-(3-fluorophenyl)urea (70 mg, 93% yield). MS (ESI) m/z: 484.1 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.[N:40]1([S:45](Cl)(=[O:47])=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:24][CH2:25][N:26]([S:45]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)(=[O:47])=[O:46])[CH2:27][CH2:28]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)N3CCCC3)CC2)c1C
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 81.4 %

Procedure:
To a 0° C. solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 102 mg, 0.237 mmol) and N,N-diisopropylethylamine (124 μL, 0.711 mmol) in methylene chloride (10.0 mL) was added pyrrolidine-1-sulfonyl chloride (80.4 mg, 0.474 mmol). The reaction mixture was stirred at 0° C. for 25 minutes, and then warmed to room temperature and stirred overnight. During this time period the solvent evaporated to dryness. Additional methylene chloride (10 mL) was added in the morning. The reaction mixture was diluted with water (25 mL). The resulting mixture was extracted with ethyl acetate (2×30 mL). The organic phase was dried over MgSO4, filtered, and concentrated. Silica gel chromatography (33% ethyl acetate in hexanes) provided {6-fluoro-3-methyl-4-[1-(pyrrolidine-1-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (86.5 mg, 81%). MS cald. for C23H30FN2O4S [(M+H)+]: 449, obsd. 449.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.[C:17]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCC1
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccccc2C(F)(F)F)CCCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 48.9 %

Procedure:
A solution of 1-bromo-2-(trifluoromethyl)benzene (0.5 g, 2.222 mmol) in anhydrous THF (10 mL) was cooled to −78° C. (dry ice IPA bath) under argon atmosphere. BuLi (2.5 M in hexanes, 1.068 mL, 2.67 mmol) was added in drops with efficient stirring. The reaction mixture was stirred at −78° C. for 40 min. A solution of cyclopentanone (0.243 g, 2.89 mmol) in anhydrous THF (1.5 mL) was added slowly (in drops) at −78° C. The reaction mixture was stirred at −78° C. for 30 min, gradually brought to room temperature, and stirred for 1 h. The reaction mixture was cooled by an ice bath, quenched with water, and acidified to pH 4-5 by addition of concentrated HCl. The solvent was removed under reduced pressure. The residue was dissolved in methylene chloride, washed with water (2 times), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as an oil (250 mg). LCMS m/z=213.1 [M−H2O+H]+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@H:14]1[C@@H:18]2[O:19][C:20]([CH3:23])([CH3:22])[O:21][C@@H:17]2[C@@H:16]([C:24]([OH:26])=[O:25])[O:15]1)([CH3:3])[CH3:2].[CH2:27](OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>CO>[CH3:27][O:25][C:24]([C@@H:16]1[C@@H:17]2[C@@H:18]([O:19][C:20]([CH3:22])([CH3:23])[O:21]2)[C@H:14]([N:9]2[CH:8]=[N:7][C:6]3[C:10]2=[N:11][CH:12]=[N:13][C:5]=3[NH:4][CH:1]([CH3:3])[CH3:2])[O:15]1)=[O:26]
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: CC(C)Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@H]2OC(C)(C)O[C@H]21
Solvent: CO
Product: COC(=O)[C@H]1O[C@@H](n2cnc3c(NC(C)C)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A mixture of (3aS,4S,6R,6aR)-6-(6-isopropylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (4.82 g) and 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ, 3.36 g) in methanol (150 ml) was heated under reflux for 60 h. After cooling to room temperature, the solution was concentrated in vacuo and the resulting residue partitioned between ethyl acetate (100 ml) and citric acid solution (0.5M, 75 ml). The aqueous layer was extracted with ethyl acetate (4×25 ml) and the combined organic extracts were washed with water (50 ml) and brine (75 ml), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel, eluting with ethyl acetate: cyclohexane (1:1) to afford the title compound as a white solid (3.76 g).
Reaction SMILES: [H][H].[CH3:3][CH:4]([CH3:13])[CH2:5]/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C.[C].[Pd]>[CH3:3][CH:4]([CH3:13])[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)/C=C/CC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCC(C)C

Procedure:
In 15 ml of ethanol was dissolved ethyl (E)-5-methyl-2-hexenoate, to which was added 0.50 g of 5% palladium-carbon. Under a stream of hydrogen, the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered with Celite, and the solvent was distilled off under reduced pressure. Thus, 2.2 g of ethyl 5-methylhexanoate was obtained as a colorless oily product.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].ClC(O[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH3:16])=O>>[CH3:16][C:10]1[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:9]=1[Cl:1]
Reactant: Cc1cccc(OC(=O)Cl)c1C
Reactant: [Cl-]
Agent: [Al+3]
Product: Cc1cccc(Cl)c1C
Temperature: 200 °C
Yield: 18 %

Procedure:
0.4 g of anhydrous aluminium chloride was added to 20 g of 2,3-dimethylphenyl chloroformate and the mixture was heated at 200° C. for 4.5 hours at normal pressure. The reaction mixture was then cooled and worked up as described in Example 1. 2,3-Dimethylchlorobenzene was obtained in a yield of 18%, which is considerable despite the unfavourable substitution pattern.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]2[CH:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][O:9]2)[CH:4]=1)[CH3:2].[CH2:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[O:25][CH:24]=[C:23](C=O)[C:22]2=[O:31])[CH3:18].[OH:32]OS([O-])=O.[K+].CCOC(C)=O>CN(C=O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]2[CH:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][O:9]2)[CH:4]=1)[CH3:2].[CH2:17]([C:19]1[CH:28]=[CH:27][CH:26]2[CH:21]([C:22](=[O:31])[C:23]([OH:32])=[CH:24][O:25]2)[CH:20]=1)[CH3:18]
Reactant: O=S([O-])OO
Reactant: CCc1ccc2occ(C=O)c(=O)c2c1
Agent: CCC1=CC2C(=O)C(C(=O)O)=COC2C=C1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC1=CC2C(=O)C(O)=COC2C=C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To prepare 6-ethyl-4-oxo-4a,8a-dihydro-4H-chromene-3-carboxylic acid, 6-ethyl-3-formyl chromone (0.25 g) was dissolved in DMF (10 mL), and OXONE (0.76 g) was added and stirred at room temperature for 3 hours with the reaction having a final volume (12 mL). The reaction was monitored by TLC or GC analysis. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (30 mL×3) and brine (30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 6-ethyl-4-oxo-4a,8a-dihydro-4H-chromene-3-carboxylic acid in 52% yield and 6-ethyl-3-hydroxy-4a,8a-dihydro-chromene-4-one in 34% yield after purification by silica gel column chromatography.