Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:9][CH:8]2[CH:4]([CH:5]([CH2:18][OH:19])[O:6][CH:7]2[N:10]2[C:16](=[O:17])[NH:15][C:13](=[O:14])[CH:12]=[CH:11]2)[O:3]1.[CH2:21]([O:23][C:24](Cl)=[O:25])[CH3:22].C(Cl)(Cl)Cl.CO>N1C=CC=CC=1>[CH2:21]([O:23][C:24]([C@@:7]1([N:10]2[CH:11]=[CH:12][C:13](=[O:14])[NH:15][C:16]2=[O:17])[O:6][C@H:5]([CH2:18][OH:19])[C@@H:4]([OH:3])[C@H:8]1[OH:9])=[O:25])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: CC1(C)OC2C(CO)OC(n3ccc(=O)[nH]c3=O)C2O1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)[C@@]1(n2ccc(=O)[nH]c2=O)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C

Procedure:
To an ice cold solution of 0.5 grams (1.76 millimoles) grams of 2′,3′-isopropylidene uridine in 10 ml pyridine, 2.64 mmoles (1.5 equivalents) of ethylchloroformate was added dropwise while stirring. The reaction was allowed to warm up to room temperature (25° C.) and stirred overnight (18 hours), at which point TLC (9:1 chloroform/methanol) showed complete conversion of starting material to a single product. The solvent was removed by rotary evaporation under high vacuum, giving a light beige syrup which was carried over into the subsequent deprotection step.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Br:39][C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[CH:37][CH:36]=1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C[C@@H](N)c1cccc(Br)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cccc(Br)c1

Procedure:
Compound 65 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-bromo-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound. LC/MS [401,403 (M+H)]1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.19 (s, 1H), 9.01 (d, 1H), 8.55 (s, 1H), 8.39 (d, 1H), 8.19 (s, 1H), 7.70 (m, 1H), 7.52-7.38 (m, 3H), 7.29 (m, 1H), 5.48 (s, 1H), 3.15 (dd, 1H), 2.91 (dd, 1H), 2.31 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([N:19]2[CH2:20][CH:21]([CH3:23])[CH2:22][CH:17]([CH3:16])[CH2:18]2)(=[O:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CC1CNCC(C)C1
Reactant: O=C(O)c1cc(Cl)cc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CC(C)CN(S(=O)(=O)c2cc(Cl)cc(C(=O)O)c2)C1
Reaction time: 1.5 h

Procedure:
3-Chloro-5-chlorosulfonylbenzoic acid (770 mg., 3 m moles) is added to a solution of 3,5-dimethylpiperidine hydrochloride in 30 ml. of water followed by the portionwise addition of 12 ml. of 1N sodium hydroxide solution with stirring. After 1.5 hrs. at room temperature the reaction mixture is filtered and the filtrate acidified with 12N hydrochloric acid.The product, 600 mg., m.p. 226°-231° C., is recrystallized from acetone-hexane, 390 mg., m.p. 232.5°-234° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11]([OH:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:1]([S:8][C:9]1[NH:10][C:11](=[O:18])[C:12]2[NH:13][CH2:14][N:15]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1nc(SCc2ccccc2)nc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(SCc2ccccc2)nc2c1NCN2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (3.88 mmol) of 2-benzylthio-6-hydroxypurine was dissolved in 20 ml of dimethylformamide and 0.816 ml (5.82 mmol) of triethylamine was added to the solution. Under ice cooling, 1.62 g (5.82 mmol) of tritylchloride was added to the mixture following stirring at room temperature overnight. After 400 ml of water was added, a precipitate was collected by filtration and washed with n-hexane and with ethyl acetate. Recrystallization from ethanol afforded 0.785 g (yield, 40%) of Compound o as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:28][CH2:29][CH2:30][F:31])(=O)=O)=CC=1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[F:31][CH2:30][CH2:29][CH2:28][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: Cc1ccc(S(=O)(=O)OCCCF)cc1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCCF)c(O)c1
Temperature: 0 °C
Reaction time: 37 h
Yield: 50 %

Procedure:
Commercially available 3,4-dihydroxybenzaldehyde (6.5 g, 47.1 mmol) and potassium carbonate (6.83 g, 49.4 mmol) were suspended in N,N-dimethylformamide (30 mL), then 3-fluoropropyl 4-methylbenzenesulfonate described in Production Example 5-1 (11.3 g, 48.4 mmol) was added under nitrogen atmosphere at loom temperature, and the mixture was stirred for 37 hours. The mixture was cooled to 0° C. and then 2 M hydrochloric acid, ethyl acetate, and water were added for partition. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The solvent was evaporated and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=4:1-2:1-1:1). The target fraction was concentrated under vacuum to obtain the title compound (4.62 g, 50%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[CH:12]2)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[CH:12]2
Reactant: [H][H]
Reactant: Cn1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Product: Cn1ccc2cc(O)ccc21
Yield: 90.9 %

Procedure:
A solution of 5-benzyloxy-1-methylindole (3.5 g, 15.7 mmol), in ethanol (100 ml) was hydrogenated at ambient temperature and 1 atmosphere pressure hydrogen for 4 hours using 10% palladium on carbon (0.5 g) as catalyst. The catalyst was filtered off and the filtrate evaporated in vacuo. The residue was purified by silica column chromatography eluting with ethyl acetate/dichloromethane (10/90) to give 5-hydroxy-1-methylindole (2.1 g, 97%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[C:6]([O:13]C([O-])=O)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O>C(Cl)Cl>[CH3:12][C:9]([O:8][C:6](=[O:13])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CNCCO
Solvent: ClCCl
Product: CN(CCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
A mixture of 2-(methylamino)ethanol (5.2 g, 69.2 mmol) and tert-butyl dicarbonate (15.8 g, 72.7 mmol) in methylene chloride (200 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with methylene chloride, and the organic layer was then washed with water, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give (2-hydroxyethyl)methylcarbamic acid 1,1-dimethylethyl ester (12.1 g, yield 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=[C:10]3[CH2:9][N+:8]([O-:31])=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=[N+]([O-])C2
Temperature: 0 °C

Procedure:
A stirred solution of 1.0 g. of 8-chloro-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine (Ia) in absolute ethanol in an ice bath is treated with 1.0 g. of m-chloroperbenzoic acid. The mixture is allowed to stand in the ice bath for about 8 hous and at room temperature at about 24° C. for approximately 18 hours. It is then concentrated in vacuo, the residue thus obtained is suspended in aqueous, cold, dilute potassium carbonate solution and extracted with methylene chloride. The extract is washed with water, dried and concentrated in vacuo. The residue thus obtained is chromatographed on 100 g. of silica gel to give 8-chloro-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-5-oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH:38]([CH2:48][CH3:49])[C:39]([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)=[O:40].O>O1CCCC1.CN(C)C=O>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([C:39]([CH:38]([N:23]2[C:22](=[O:26])[N:21]([C:18]3[CH:17]=[N:16][C:15]([N:12]4[CH2:11][CH2:10][N:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[CH2:14][CH2:13]4)=[N:20][CH:19]=3)[CH:25]=[N:24]2)[CH2:48][CH3:49])=[O:40])=[CH:46][CH:45]=1
Reactant: CCC(Br)C(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(N2CCN(c3ncc(-n4cn[nH]c4=O)cn3)CC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C(=O)c1ccc(Cl)cc1)n1ncn(-c2cnc(N3CCN(c4ccc(OC)cc4)CC3)nc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
2,4-Dihydro-4-[2-[4-(4-methoxyphenyl)-1-piperazinyl]-5-pyrimidinyl]-3H-1,2,4-triazol-3-one (0.019 mol) and N,N-dimethylformamide (200 ml) were stirred. A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1M) (21 ml) was added dropwise under N2 and the mixture was stirred for 30 minutes at room temperature. 2-Bromo-1-(4-chlorophenyl)-1-butanone (0.021 mol) dissolved in a little N,N-dimethylformamide was added dropwise and the mixture was stirred for 3 hours at room temperature. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water, dried and evaporated. The residue was crystallized from 1-propanol. The precipitate was faltered off and dried in vacuo at 75° C., yielding 6 g (60%) of (±)-2-[1 -(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[2-[4-(4-methoxyphenyl)-1-piperazinyl]-5-pyrimidinyl]-3H-1,2,4-triazol-3-one; mp. 184.6° C. (comp. 8).
Reaction SMILES: CCCCCC.S(Cl)([Cl:10])(=O)=O.C(O)(=O)C.[F:16][C:17]([F:43])([F:42])[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[NH:28][C:29]1[N:34]([CH2:35][CH3:36])[C:33](=[O:37])[CH:32]=[C:31]([C:38]([F:41])([F:40])[F:39])[N:30]=1>CCOCC>[F:43][C:17]([F:42])([F:16])[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][C:19]=1[NH:28][C:29]1[N:34]([CH2:35][CH3:36])[C:33](=[O:37])[C:32]([Cl:10])=[C:31]([C:38]([F:39])([F:40])[F:41])[N:30]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOCC
Product: CCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)c(Cl)c1=O
Temperature: 0 °C
Yield: 53.2 %

Procedure:
While stirring under ice-cooling, 10% hexane solution of sulfuryl chloride (0.019 ml, 0.24 mmol) was added to acetic acid (3 ml) solution of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-ethyl-6-trifluoromethyl-4(3H)-pyrimidinone (0.10 g, 0.24 mmol), followed by stirring for 1.5 hours while gradually returning to room temperature. After completion of the reaction, ice-water (10 ml) and ether (10 ml) were added to the reaction solution to separate the organic layer, and the resulting aqueous layer was extracted with ether (10 ml×3). The organic layers were combined, washed with water (20 ml×2) and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. By recrystallizing the thus obtained crude product from chloroform/hexane, 2-{2,5-bis(trifluoromethyl)phenyl}amino-5-chloro-3-ethyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 49] was obtained.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][CH3:15])=[C:10]([CH:13]=1)[C:11]#[N:12])[CH3:3].[CH2:16]([OH:18])[CH3:17]>>[ClH:1].[CH2:2]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][CH3:15])=[C:10]([CH:13]=1)[C:11](=[NH:12])[O:18][CH2:16][CH3:17])[CH3:3]
Reactant: CCO
Reactant: CCOCc1ccc(OC)c(C#N)c1
Agent: Cl
Product: CCOCc1ccc(OC)c(C(=N)OCC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride gas was passed through a solution of 5-ethoxymethyl-2-methoxy-benzonitrile (181 mg, 0.947 mmol) in anhydrous ethanol (30 mL) at room temperature. After 2 h, hydrogen chloride gas was stopped and the reaction vessel was sealed. After stirring at room temperature for 12 h, the reaction vessel was cooled to 0° C. and opened. The solvent was evaporated in vacuo to dryness to afford crude ethyl 5-ethoxymethyl-2-methoxy-benzimidate hydrochloride. meso-1,2-Bis-(4-chloro-phenyl)-ethane-1,2-diamine (253 mg, 0.9 mmol), triethylamine (186 μL, 1.5 mmol) and ethanol (10 mL) were added and the resulting mixture was heated at reflux for 12 h. The solvent was removed and the residue was taken up in methylene chloride (2 mL) and sodium bicarbonate solution (2 mL). The product was extracted with methylene chloride (2×30 mL). The organic layers were washed with brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 70-100% ethyl acetate in hexanes to afford 4,5-bis-(4-chloro-phenyl)-2-(5-ethoxymethyl-2-methoxy-phenyl)-4,5-dihydro-1H-imidazole (136 mg, 33%). LR-MS (APCI): 455 [(M+H)+].
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([OH:14])=O)=[CH:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[CH:36]=1>CN(C)C=O.CN(C)C(=O)C>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:28]=[C:27]([NH:26][C:12]([C:5]5[C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][N:3]([CH2:1][CH3:2])[CH:4]=5)=[O:14])[CH:48]=[CH:47][CH:46]=4)=[CH:36][N:35]3[N:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: CCn1cc(C(=O)O)c(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCn1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C(F)(F)F)c1
Yield: 73.9 %

Procedure:
In the same manner as in Example 18-4 and using 1-ethyl-4-(trifluoromethyl)-1H-pyrrole-3-carboxylic acid (268 mg, 1.29 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (238 mg, 74%) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([NH2:16])([C:13]([OH:15])=[O:14])[CH2:8]2.C(N(CC)CC)C.[C:25](=O)([O:41]N1C(=O)CCC1=O)[O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2>C(#N)C.O>[C:25]([CH:8]1[C:9]2[C:4](=[C:3]([N:2]([CH3:17])[CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1([NH2:16])[C:13]([OH:15])=[O:14])([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:41]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CN(C)c1cccc2c1CCC(N)(C(=O)O)C2
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)c1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
A mixture of 5-dimethylamino-2-aminotetraline-2-carboxylic acid (1.33 g, 2.15 mmole theoretical), triethylamine (0.40 ml, 2.87 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 0.92 g, 2.73 mmole) in acetonitrile (10 ml) and water (10 ml) was stirred at room temperature for one day. TLC analysis of the reaction indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (400 mg) and triethylamine (0.2 ml) were added and the mixture was stirred at room temperature for another day. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile and the almost neutral mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate. Filtration and concentration gave a crude which was purified by column chromatography (eluted with 2.5→6→10→15→20% methanol/methylene chloride) to give racemic Fmoc-5-dimethylamino-2-aminotetraline-2-carboxylic acid (602 mg, 61% yield over 2 steps) as an off-white solid. HRMS (FAB): C28H28N2O4 (M) calc. 456.2049; observed: 456.2056.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([NH:17]C(OC(C)(C)C)=O)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10]CC)=[O:9])([O-:3])=[O:2].Cl.[CH3:26][CH2:27]OC(C)=O>>[CH2:26]([CH:7]([O:6][C:5]1[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:4]=1[N+:1]([O-:3])=[O:2])[C:8]([OH:10])=[O:9])[CH3:27]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: Cl
Product: CCC(Oc1ccc(N)cc1[N+](=O)[O-])C(=O)O
Temperature: 0 °C

Procedure:
A solution of 5-2 (0.3 g, 0.88 mmol) was dissolved in EtOAc (10 mL), cooled to -78° C. and saturated with HCl gas, warmed to 0° C. for 1 hour and concentrated to give ethyl 2-(2-nitro-4-aminophenoxy)acetic acid as a white solid that was coupled immediately (0.26 g, 0.88 mmol) to 1-5 (0.29 g, 0.95 mmol) as described for 5--5 to give 5-9 as a yellow solid after chromatography in a gradient of 40 to 100% EtOAc/hexanes.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:21]([O:23]CC)=[O:22])[C:6](=[O:20])[N:7]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:21]([OH:23])=[O:22])[C:6](=[O:20])[N:7]2[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1nc2c(F)cccc2n(-c2ccc(OC)cc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-n2c(=O)c(C(=O)O)nc3c(F)cccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
14.3 g (41.8 mmol) of ethyl 5-fluoro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate was dissolved in ethanol (100 ml), and 10.0 g (62.5 mmol) of a 25% aqueous solution of sodium hydroxide was added thereto. The mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue thus obtained. The mixture was acidified using 10% hydrochloric acid. A solid precipitated therefrom was separated by filtration, washed with water, and then dried, to obtain 11.1 g (yield: 84%) of 5-fluoro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid as a pale yellow powder.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15]([F:18])([F:17])[F:16].CN(CCN(C)C)C.CN([CH:30]=[O:31])C.Cl>C(OCC)C>[Cl:6][C:7]1[C:8]([C:15]([F:16])([F:17])[F:18])=[CH:9][C:10]([O:13][CH3:14])=[C:11]([CH:12]=1)[CH:30]=[O:31]
Reactant: COc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C(F)(F)F)c(Cl)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 1.61 M hexanes solution of n-BuLi (18.7 mL, 30.1 mmol) was added to a −78° C. diethyl ether solution (45 mL) of 1-chloro-4-methoxy-2-(trifluoromethyl)benzene (5.3 g, 25.1 mmol) and TMEDA (4.5 mL, 30.1 mmol). After 30 min at −78° C. the reaction was transferred to an ice bath and stirred at 0° C. After 5 min DMF (5.0 mL, 65.0 mmol) was added and the reaction was maintained in the ice bath. After 2 hrs at 0° C. 6 M aqueous HCl (aq) (17.0 mL, 102 mmol) was added and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with 4 M NaCl and 5 M K2CO3, dried (Na2SO4), and concentrated to yield the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([SH:10])=[CH:5][C:3]=1[NH2:4].[F:11][C:12]([F:16])([F:15])[CH2:13]I.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+]>O.CN(C)C=O>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10][CH2:13][C:12]([F:16])([F:15])[F:11])=[CH:5][C:3]=1[NH2:4]
Reactant: FC(F)(F)CI
Reactant: Cc1cc(C)c(S)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(SCC(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.4 %

Procedure:
To a mixed solution of 20 g of 2,4-dimethyl-5-mercaptoaniline and 150 ml of N,N-dimethylformamide, 41 g of 2,2,2-trifluoroethyl iodide and 24 g of potassium carbonate were added, and 4 g of Rongalit was further added, followed by stirring at room temperature for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent hexane:ethyl acetate=5:1) to obtain 29 g of 2,4-dimethyl-5-(2,2,2-trifluoroethylthio)aniline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]([F:24])([F:23])[F:22])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][C:30]#[N:31]>CN(C=O)C>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:29][C:30]#[N:31])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]([F:22])([F:23])[F:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1-c1ccccc1OC(F)(F)F
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC#N)c1cnccc1-c1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of [4-(2-trifluoromethoxy-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (190 mg, 0.54 mmol) in DMF (5 mL) was added sodium hydride (24 mg, 0.59 mmol, 60% dispersion in mineral oil) at 0° C. The reaction mixture was stirred at 25° C. for 30 minutes. Then bromoacetonitrile (71 mg, 0.59 mmol) was added to the reaction mixture and it was stirred at 25° C. for 24 hours. The reaction mixture was quenched with 10 mL saturated NH4Cl solution and extracted with EtOAc (2×40 mL). The combined EtOAc part was dried over Na2SO4 and evaporated. The residue crude was purified by silica gel column chromatography eluting with a gradient of n-hexane:EtOAc (85:15 to 70:30) to get the desired compound as a light yellow sticky liquid (185 mg, 88%). LC-MS (ESI): m/z=394.4 [M+H]+.