Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[C:15]1([N:21]2[CH2:26][CH2:25][N:24]([C:2]3[N:3]=[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]4[S:10][CH2:9][CH2:8][C:6]=4[N:7]=3)[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: NCCCc1nc(Cl)nc2c1SCC2
Solvent: C1COCCO1
Product: NCCCc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Yield: 55 %

Procedure:
9.7 g (42.3 mmol) of 2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine (VIII) and 25.7 mL (169.2 mmol) of 1-phenylpiperazine (III) are placed in 200 mL of dioxane (carried out in 10 batches), then reacted for 1 hour at 160° C. in the microwave. The reaction mixture is concentrated by evaporation, the residue is combined with 250 mL of water. Then the mixture is suction filtered, washed with water, and dried. The residue is stirred with acetonitrile, then recrystallized from isopropanol. 8.3 g of the product (I) (55%) is obtained as a powder (m.p. 121° C.). 1H NMR (400 MHz, DMSO): 7.22 (2H, t); 6.97 (2H, d); 6.79 (1H, t); 6.43 (2H, t); 3.81-3.69 (4H, m); 3.37-3.19 (4H, m); 3.19-3.09 (4H, m); 2.99 (2H, t); 1.62-1.47 (2H, m); 0.87 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][C:13]([OH:15])=[O:14])=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c2cnccc12
Solvent: ClCCl
Solvent: O=CO
Product: O=C(O)Cc1ccc(F)c2cnccc12
Reaction time: 16 h

Procedure:
To a solution of the above ester (200 mg) in DCM (2 mL) was added formic acid (3 mL). The reaction was sealed with a Teflon cap and heater to 50° C. for 16 h. The solvent was removed and the crude product was used without further purification. LCMS showed an m/z of 206.1 with a retention time of 0.437 min, method [1].
Reaction SMILES: [Br:1]Br.[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=1>C(O)(=O)C>[Br:1][C:11]1[C:12](=[O:15])[NH:13][CH:14]=[C:9]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][N:3]=2)[CH:10]=1
Reactant: BrBr
Reactant: O=c1ccc(-c2cnccn2)c[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]cc(-c2cnccn2)cc1Br
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3 ml of bromine are added to a stirred suspension of 5-(2-pyrazinyl)-2(1H)-pyridone (9.0 g) in 300 ml of glacial acetic acid warmed to a temperature of 50° C. The mixture is stirred at RT overnight, cooled in an ice bath to 16° C. and filtered. The filtered yellow solid is suspended in 100 ml of distilled H2O, to which sodium bisulfite is gradually added until the solid appears tan. A saturated potassium carbonate solution is slowly added until the pH is adjusted to 7.4, and the suspension is filtered. The filtered solid is washed with H2O and dried under high vacuum at 100° C. for 4 hours, giving the desired 3-bromo-5-(2-pyrazinyl)-2(1H)-pyridone which is recrystallized from methanol, M.P. >250° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@H:13]2[C@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([CH2:20][O:21][CH3:22])[O:14]2)=[C:6]([NH:23][CH2:24][CH:25]([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)[N:5]=1.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>>[OH:18][C@@H:17]1[C@H:16]([OH:19])[C@@H:15]([CH2:20][O:21][CH3:22])[O:14][C@H:13]1[N:10]1[CH:9]=[N:8][C:7]2[C:11]1=[N:12][C:4]([CH2:3][CH2:2][NH:1][S:44]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:46])=[O:45])=[N:5][C:6]=2[NH:23][CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNS(=O)(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Yield: 56.2 %

Procedure:
The title compound was prepared by a similar method to example 3 using (2R,3R,4S,5R)-2-{2-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)-tetrahydro-3,4-furandiol (example 11) (200 mg, 0.40 mmol), phenylsulfonyl chloride (70 mg, 0.40 mmol) and triethylamine (0.15 ml, 1.08 mmol). The compound was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (95:5) to give the title compound (145 mg) as a powder. MS: 645 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:46]=[CH:45][C:37]([CH2:38][N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:42]4[CH2:41][CH2:40][N:39]([CH2:38][C:37]5[CH:45]=[CH:46][C:34]([O:33][CH3:32])=[CH:35][CH:36]=5)[CH2:44][CH2:43]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: COc1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: COc1ccc(CN2CCN(C(=O)c3ccc(-c4cnc5c(c4)N(Cc4cc(Cl)ccc4C(F)(F)F)CCN5)cc3)CC2)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-methoxybenzyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=636.02 (M+H+); retention time=0.61 minutes.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH:21]1([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30](B4OC(C)(C)C(C)(C)O4)[CH:31]=3)[N:26](C(OC(C)(C)C)=O)[N:25]=2)[CH2:23][CH2:22]1>>[CH:21]1([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:2]4[CH:3]=[CH:4][N:5]5[C:10]([C:11]=4[CH3:12])=[C:9]([CH:13]4[CH2:15][CH2:14]4)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]5=[O:20])[CH:31]=3)[NH:26][N:25]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)n1nc(C2CC2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]nc(C5CC5)c4c3)ccn2c1=O
Yield: 78.1 %

Procedure:
Methyl 8-(3-cyclopropyl-1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A′ from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (75 mg, 0.26 mmol) and tert-butyl 3-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate (157.9 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (84 mg, 60%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])=O)(C)(C)C.[ClH:22]>C(OCC)(=O)C>[ClH:22].[NH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21]
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-(2-tert-butoxycarbonylaminoethyl)phthalimide (2.5 g) and 4N solution of hydrogen chloride in ethyl acetate (25 ml) was stirred for 1 hour at ambient temperature. The resulting precipitates were collected by filtration and washed with ethyl acetate to give N-(2-aminoethyl)phthalimide hydrochloride (1.89 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Li+].Cl[C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[CH:16]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:15]3[CH:16]=[C:17]([O:23][CH3:24])[N:18]=[C:19]([O:21][CH3:22])[N:20]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COc1cc(Cl)nc(OC)n1
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C2C(=O)Nc3cc(Cl)ccc32)nc(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 6-chlorooxindole (0.94 g, 5.34 mmol) (Cresent Chem.) in N,N-dimethylformamide (20 mL) at room temperature was added lithium hydride (86 mg, 10.7 mmol) (Aldrich). The mixture was stirred at room temperature for 10 minutes, then 6-chloro-2,4-dimethoxy-pyrimidine (0.93 g, 5.34 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The mixture was cooled to room temperature. Water (100 mL) was added, and mixture was extracted with ethyl acetate (2×100 mL). The organic layers were separated, combined, washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate) to give rac-6-chloro-3-(2,6-dimethoxy-pyrimidin-4-yl)-1,3-dihydro-indol-2-one as a brown solid. (Yield 0.23 g, 14%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.Br[CH2:20][CH2:21][O:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOC(C)=O>[CH3:23][O:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (400 mg, 1.65 mmol), 1-bromo-2-methoxyethane (436 mg, 3.14 mmol), potassium carbonate (434 mg, 3.14 mmol), and dimethyl sulfoxide (5 mL) was stirred at 135° C. overnight. After cooling, the mixture was diluted with EtOAc and washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-100% EtOAc/hexane) to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([C:7]([NH:9][C:10](=[O:34])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:14]([O:27][CH2:28][O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:43]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:34])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:14]([O:27][CH2:28][O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:13]=2)=[O:8])=[CH:35][CH:36]=1)(=[S:43])[NH2:2]
Reactant: S
Reactant: CC(C)(C)OCOc1cc(NC(=O)NC(=O)c2ccc(C#N)cc2)ccc1OCC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OCOc1cc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)ccc1OCC(=O)OC(C)(C)C

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (c) (2.2 g), pyridine (186 ml), triethylamine (26 ml) and H2S gas were reacted to give t-butyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]-2-(t-butoxymethoxy)phenoxyacetate (2.6 g) as a yellow solid: m.p. 198°-199° C.; NMR Spectrum (DMSO-d6) 1.43 (9H, s), 1.44 (9H, s), 4.61 (2H, s), 4.66 (2H, s), 6.89 (1H, d), 7.09 (1H, dd), 7.27 (1H, d), 7.98 (4H, m), 9.68 (1H, s), 10.02 (1H, s), 10.66 (1H, s), 11.07 (1H, s); Mass Spectrum m/Z 582 (M +Na)+.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]([NH:22][C:23]2[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][N:27]([C@H:35]([CH3:38])[CH2:36][OH:37])[C:28]3=[O:34])=[O:21])[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16].[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(Cl)Cl>CN(C)C1C=CN=CC=1>[CH3:39][S:40]([O:37][CH2:36][C@H:35]([N:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[C:32]([CH3:33])[C:23]=2[NH:22][C:20](=[O:21])[CH2:19][C:11]2[CH:12]=[CH:13][C:14]([C:15]([F:18])([F:16])[F:17])=[C:9]([F:8])[CH:10]=2)[C:28]1=[O:34])[CH3:38])(=[O:42])=[O:41]
Reactant: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(=O)n([C@H](C)COS(C)(=O)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.2 g, 0.002 mol) was added to a solution of (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-N-(2-(1-hydroxypropan-2-yl)-6-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)acetamide (0.5 g, 0.001 mol), methanesulfonyl chloride (0.16 g, 0.0014 mol) and 4-dimethylaminopyridine (10 mg, 0.0001 mol) in methylene chloride (10 mL, 0.2 mol). The mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the mixture was purified via flash chromatography to afford the desired product as a white solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:28][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH2:26][CH3:27])[CH:20]=[CH:19]4)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH:39]=[C:38]([C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=2)[CH2:37][CH2:36]1>C1COCC1.CN(C=O)C>[CH2:26]([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][CH:13]([CH2:12][N:35]4[CH2:36][CH:37]=[C:38]([C:41]5[C:49]6[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=6)[NH:43][CH:42]=5)[CH2:39][CH2:40]4)[O:28][C:17]3=2)[N:22]=1)[CH3:27]
Reactant: CCc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O3
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1ccc2c3c(ccc2n1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 25 °C

Procedure:
To a solution of (2R)-8-ethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.60 g, 1.5 mmole) and potassium carbonate (0.65 g, 4.70 mmole) in 30 mL of 1:1 THF/DMF was added 0.90 g (4.5 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The mixture was heated at reflux under nitrogen for 6 hours. After cooling to room temperature, the mixture was concentrated to dryness under vacuum and the residue column chromatographed on silica gel using first methylene chloride to elute impurities and then 3% methanol in methylene chloride to elute the product. The product-containing fractions were concentrated in vacuum and the residue recrystallized from ethanol to give 0.42 g of the (S)-enantiomer of the title compound as a yellow solid (m.p. 190° C.).
Reaction SMILES: [NH2:1]OS(C1C(C)=CC(C)=CC=1C)(=O)=O.[Cl:15][C:16]1[C:21]2[CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:23][O:24][C:20]=2[C:19]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[NH:33][C:32]2=[O:42])=[C:18]([F:43])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:15][C:16]1[C:21]2[CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:23][O:24][C:20]=2[C:19]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([NH2:1])[C:32]2=[O:42])=[C:18]([F:43])[CH:17]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(F)cc(Cl)c2c1ONC2c1ccccc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2ONC3c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
1-Aminooxysulfonyl-2,4,6-trimethylbenzene (0.5 g, 0.002 mole) was added all at once to a stirred solution of 3-[4-chloro-6-fluoro-3-phenyl-1,2(2H)-benzisoxazol-7-yl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.8 g, 0.002 mole) and potassium carbonate (0.4 g, 0.003 mole) in THF (50 mL). Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time, the reaction mixture was filtered and the filtrate was concentrated to a residue. The residue was subjected to silica gel column chromatography using 4:1 hexane and ethyl acetate. The product-containing fractions were combined and concentrated, yielding 0.6 gram of Compound 34, m.p. 171-173° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Na+].[Na+].[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([F:19])[CH:13]=1>C(Cl)(Cl)Cl>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]=[C:1]=[S:2])=[C:14]([F:19])[CH:13]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1cc(Br)ccc1N=C=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiophosgene (22 mL, 289 mmol) was added to a suspension of sodium carbonate (61.0 g, 579 mmol) and 4-bromo-2-fluoroaniline (50.0 g, 263 mmol) in CHCl3 (1 L). The reaction mixture was stirred overnight at RT, the inorganic salts were filtered off, and the filtrate was concentrated to give 4-bromo-2-fluoro-1-isothio-cyanatobenzene as a tan solid which was converted to 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-bromobenzo[d]thiazole as described in Reference A above.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[N+](=[CH2:15])=[N-].CO>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH3:15])=[O:8])([O-:3])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-Nitrobenzoic acid (1.00 g; 5.98 mmol; 1.00 eq.) is dissolved in toluene (15 ml). Timethylsilyl diazomethane in toluene and MeOH (1/1) (8.98 ml; 2.00 M; 17.95 mmol; 3.00 eq.) is added dropwise. The solution is stirred at RT for 1.5 h. Solvents are removed affording methyl 3-nitrobenzoate as a yellow powder (940.70 mg; 86.79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[CH:11][CH3:12])=[CH:5][CH:4]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C(OCC)C>[C:13]([N:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[N:10]=[CH:11][CH3:12])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC=NNc1ccc(OC)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC=NN(C(=O)c1ccccc1)c1ccc(OC)cc1
Reaction time: 24 h

Procedure:
Combine N-(4-methoxyphenyl)-N'-ethylidene hydrazine (6.0 g, 43 mmol), benzoyl chloride (5.2 mL. 44 mmol), pyridine (3.7 mL, 46 mmol), and diethyl ether (25 mL). After 24 hours, add diethyl ether (100 mL), remove the solid by filtration and dry in vacuo to give N-benzoyl-N-(4-methoxyphenyl)-N'-ethylidene hydrazine as a solid.
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[CH2:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH:11]=[O:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccc1CCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1ccccc1CCc1ccccc1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
A mixture of 2-phenethylbenzoic acid (11.3 g), oxalyl chloride (5.2 ml), DMF (0.2 ml) and dichloromethane (100 ml) was stirred for 1.5 hours. The solvent was evaporated, diglyme (75 ml) added and the mixture cooled to −70° C. Lithium tri-(tert-butoxy)aluminium hydride (100 ml, 0.5M solution in diglyme) was added dropwise over 45 minutes maintaining the reaction temperature below −60° C. The reaction was stirred at −70° C. for 1 hour and poured into a 2N HCl and ice mixture. The mixture was extracted with iso-hexane (3×100 ml). The extracts were washed with saturated aqueous sodium hydrogen carbonate, water and brine, dried (MgSO4), filtered and evaporated. The residue was purfied by MPLC eluting with dichloromethane/iso-hexane (1:1) to give 2-(phenethyl)benzaldehyde (7.77 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:6]([Cl:14])[CH:5]=1)(=[O:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].S(=O)(=O)(O)O>C(#N)C.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:15](=[O:17])[CH3:16])(=[O:12])=[O:11])=[C:6]([Cl:14])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(N)(=O)=O)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: CC(=O)NS(=O)(=O)c1ccc(C(C)=O)cc1Cl
Reaction time: 0.67 h

Procedure:
To a solution of the product obtained in step 2 (0.40 mg, 1.71 mmol) in ACN (3 ml) was added acetic anhydride. Concentrated sulphuric acid (2.8 μl, 5 mg, 51 μM) was added at 60° C. and the reaction mixture was stirred for 40 min at that temperature. The cooled reaction mixture was diluted with water, extracted with dichloromethane, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The desired product was obtained (yield: 460 mg, 97%) and used in the following step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][OH:21]>C(O)C>[F:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]([CH:7]=1)[NH:16][C:17]1[CH:18]=[C:19]([CH2:20][OH:21])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(CO)c1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(F)cc1F
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(F)cc1Nc1cccc(CO)c1
Yield: 88.5 %

Procedure:
With ice-cooling, 1,5-difluoro-2-nitro-4-trifluoromethylbenzene (1.50 g) and 3-aminobenzyl alcohol (1.62 g) were dissolved in ethanol (50 ml) and subjected to 3 hours of the reaction at room temperature. The reaction solution was concentrated and the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=100:1) to give [3-(5-fluoro-2-nitro-4-trifluoromethylanilino)phenyl]methanol (1.93 g). The resulting anilinophenylmethanol (1.75 g) and imidazole (3.61 g) were allowed to react with each other in DMF (50 ml) at 140° C. for 30 minutes, and the resulting reaction solution was spontaneously cooled down to room temperature. Then, saturated sodium chloride aqueous solution (150 ml) was added. The thus formed orange solid was collected by filtration, washed with water and then dried under a reduced pressure. The resulting crude crystals were purified by a silica gel column chromatography (chloroform:methanol=10:1) to give [3-[5-(1H-imidazol-1-yl)-2-nitro-4-trifluoromethylanilino]phenyl]methanol (1.46 g). In an atmosphere of hydrogen, the thus formed product (1.37 g) in methanol was subjected to reduction under ordinary pressure using palladium-carbon as the catalyst. The reaction solution was filtered and concentrated under a reduced pressure to give amorphous residue. Then, oxalic acid (0.13 g) and 1 N hydrochloric acid aqueous solution (10 ml) were added, followed by heating at 100° C. for 15 hours. When the reaction solution was concentrated to about half in volume, the thus formed crystals were collected by filtration, washed with ethyl acetate and then dried under a reduced pressure to give 1-(3-hydroxymethylphenyl)-7-(1H-imidazol-1-yl)-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione hydrochloride (1.20 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(Cl)(Cl)=O.[CH3:17]O>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(O)c(F)c1
Temperature: 85 °C

Procedure:
(3-Fluoro-4-hydroxy-phenyl)-acetic acid (25 g, 150 mmol) was dissolved in methanol (100 mL), and thionyl chloride (5 mL) was added dropwise to the solution. The solution was heated to 85° C. for 16 hours. The reaction mixture was allowed to cool and evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and the filtrate was evaporated to dryness under reduced pressure to yield the crude title compound as an off white solid (25.3 g). 1H NMR (500 MHz, CDCl3): δ 7.07 (d, J=7.07 Hz, 1H), 7.00-6.97 (m, 2H), 3.74 (s, 3H), 3.73 (s, 2H).