Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].CCCCCC>C1COCC1>[CH3:27][S:28]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1)(=[O:30])=[O:29]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1(S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 7.7 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (2 g, 7.78 mmol) in THF (25 mL) was cooled to −78° C. followed by dropwise addition of LDA (1.8 M in THF, 8.8 mL, 15.56 mmol) and was stirred at the same temperature for 45 minutes followed by addition of methanesulfonyl chloride (1.3 g, 11.67 mmol) at −78° C. The temperature of the reaction was slowly raised to rt and left to stir for 6 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 30% EtOAc:hexane to obtain the product as an orange viscous liquid (0.20 g, 8.0% yield). MS: 336.18 [M+H]+.
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[S:11][C:10]([CH3:12])=[N:9][C:8]=2[CH2:13][CH2:14]\1)[CH3:3].[CH3:16][O:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2C(N)=[CH:26][CH:25]=[N:24]2)=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>O>[CH3:16][O:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[C:3]3[N:2]=[CH:4][C:5]4[CH2:14][CH2:13][C:8]5[N:9]=[C:10]([CH3:12])[S:11][C:7]=5[C:6]=4[C:26]=3[CH:25]=[N:24]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(Cn2nccc2N)cc1
Reactant: Cc1nc2c(s1)C(=O)/C(=C\N(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(Cn2ncc3c4c(cnc32)CCc2nc(C)sc2-4)cc1
Temperature: 100 °C
Yield: 13.1 %

Procedure:
To a mixture of (Z)-6-((dimethylamino)methylene)-2-methyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one (3.5 g, 16.9 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (3.5 g, 17.2 mmol) was added trifluoroacetic acid (2.3 mL, 29.2 mmol). The reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was then poured into ice-cooled water (100 mL) and extracted with dichloromethane (3×75 mL). The combined organic extracts were dried using sodium sulfate and concentrated under reduced pressure to give a dark residue. The crude product was purified by flash column chromatography (SiO2, gradient from 100% chloroform to 2% methanol in chloroform) to a residue, which was further purified by crystallization from methanol and isopropanol to give the pure desired product (0.8 g, 19%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 7.86 (s, 1H), 7.76 (s, 1H), 7.36 (d, J=8.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 5.59 (s, 2H), 3.75 (s, 3H), 3.17 (t, J=6.8 Hz, 2H), 3.09 (t, J=6.8 Hz, 2H), 2.77 (s, 3H); LCMS [M+H]: 363.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH2:23][CH3:24])[C:17]=2[CH:25]=1)=[O:12].[F:27][C:28]([Si](C)(C)C)([F:30])[F:29]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH2:23][CH3:24])[C:17]=2[CH:25]=1)([OH:12])[C:28]([F:30])([F:29])[F:27]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCN1C(=O)COc2ccc(C(=O)C(C)c3ccc(OC)cc3Cl)cc21
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(OC)cc3Cl)C(F)(F)F)cc21

Procedure:
In analogy to Example 56, step 3, 6-[2-(2-chloro-4-methoxy-phenyl)-propionyl]-4-ethyl-4H-benzo[1,4]oxazin-3-one (1.58 g) was reacted with (trifluoromethyl)-trimethylsilane. The product was purified by flash chromatography (silica gel, heptane/AcOEt 2:1) to give the title compound (1.58 g) as a white solid. MS (m/e)=444.3 [M+H+]
Reaction SMILES: BrCC.[Mg].Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[CH3:21].[CH3:22][C:23]1[CH:27]=[C:26]([C:28](Cl)=[O:29])[O:25][N:24]=1.[Cl-].[NH4+]>C1COCC1>[CH3:22][C:23]1[CH:27]=[C:26]([C:28]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:29])[O:25][N:24]=1
Reactant: Cc1cc(C(=O)Cl)on1
Reactant: Cc1ccc(C)c(OCc2ccccc2Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: C1CCOC1
Product: Cc1ccc(C)c(OCc2ccccc2C(=O)c2cc(C)no2)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 17.4 %

Procedure:
THF (2 ml) and bromoethane (0.1 ml) were added to magnesium (0.49 g, 0.02 mol) in a stream of nitrogen, and the mixture was stirred at 50° C. for 10 minutes. Then, a mixture of 1-bromo-2-(2,5-dimethylphenoxymethyl)benzene (2.91 g, 0.01 mol) and THF (8 ml) was added at 50 to 60° C. over 30 minutes, and the mixture was stirred at 50 to 60° C. for 1 hour. After completion of the reaction, the reaction mixture was added to a mixture of 3-methylisoxazol-5-carbonyl chloride (1.45 g, 0.01 mol) and THF (15 ml) at −70 to −60° C. over 15 minutes, and then the mixture was stirred at −70 to −60° C. for 0.5 hours. After completion of the reaction, saturated aqueous ammonium chloride solution (150 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl 3-methylisoxazol-5-yl ketone (0.56 g, 17.4%) as colorless crystals. mp. 106-108° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([S:25]([C:28]3[CH2:29][O:30][C:31]4[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:32]=4[CH:33]=3)(=[O:27])=[O:26])[CH2:21][C:20]2=[O:39])([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CO>[ClH:38].[Cl:38][C:36]1[CH:35]=[CH:34][C:32]2[CH:33]=[C:28]([S:25]([N:22]3[CH2:23][CH2:24][N:19]([CH2:18][C:11]4([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:20](=[O:39])[CH2:21]3)(=[O:27])=[O:26])[CH2:29][O:30][C:31]=2[CH:37]=1
Reactant: COC(=O)C1(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 196.8 %

Procedure:
To 1-[1-(tert-butoxycarbonyl)-4-methoxycarbonylpiperidin-4-ylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone (260 mg) was added 4N hydrochloric acid in ethyl acetate (10 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give colorless solid of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(4-methoxycarbonylpiperidin-4-ylmethyl)-2-piperazinone hydrochloride (228 mg). A solution of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(4-methoxycarbonylpiperidin-4-ylmethyl)-2-piperazinone hydrochloride (228 mg), chloropyridine hydrochloride (80 mg) and triethylamine (225 mg) in ethanol (14 ml) was allowed to react in a sealed tube at 150% for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=20:1) to give colorless solid of the title compound (126 mg).
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:39]=[CH:38][C:15]([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[C:19]([C@@H:27]3[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]3[OH:29])=[CH:18]2)=[CH:14][CH:13]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[C@@H:27]1([C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[N:17]([CH2:16][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:39][CH:38]=3)[CH:18]=2)[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]1[OH:29]
Reactant: Cc1ccc2c(c1)c([C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)cn2Cc1ccc(OCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc2c(c1)c([C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)cn2Cc1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
1-{4-[2-(Benzyloxy)ethoxy]benzyl}-3-(β-D-glucopyranosyl)-5-methyl-1H-indole (32 mg) was dissolved in a mixed solvent of methanol (1 mL) and ethyl acetate (2 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure to give the title compound (17 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.I[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>O1CCCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Ic1ccncc1
Reactant: C#Cc1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ccncc2)cc1

Procedure:
A mixture of 4-methoxyphenylacetylene (2.86 g, 21.7 mmol), 4-iodopyridine (4.44 g, 21.7 mmol), cuprous iodide (206 mg, 1.08 mmol), bis(triphenylphosphine)palladium(II) dichloride (758 mg, 1.08 mmol) in tetrahydrofuran (40 mL) and triethylamine (20 mL) was heated at reflux for 2 h. The mixture was filtered, concentrated, and the residue chromaptographed on silica in 1:1 ethyl acetate-hexanes giving 2.45 g (54%) of a yellow solid. 1H NMR (CDCl3, 400 mHz) δ 9.2 (very broad, 2H), 7.57 (br, 2H), 7.48 (d, 2H, J=8.7 Hz), 6.88 (d, 2H, J=8.7 Hz), 3.82 (s, 3H). MS (AP+) m/e 210 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C@H:23]([CH2:27]C)[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:24](=[O:25])[C@H:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:27])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C(=O)O)c1ccccc1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Product: C[C@H](C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and substituting (S)-2-phenylpropanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (500 MHz, CDCl3) δ ppm 7.38-7.26 (m, 8H), 7.25-7.20 (m, 2H), 5.20 (d, J=6.7, 1H), 4.03-3.91 (m, 1H), 3.60 (d, J=13.0, 1H), 3.52-3.43 (m, 2H), 2.54 (dd, J=5.7, 13.8, 2H), 2.43 (dd, J=7.1, 16.0, 1H), 2.29-2.23 (m, 1H), 2.22-2.08 (m, 2H), 1.98 (ddd, J=5.8, 11.9, 15.7, 1H), 1.74-1.60 (m, 1H), 1.50 (t, J=6.4, 3H), 1.44-1.30 (m, 2H); MS (ESI+) m/z 349 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH:22]=[CH2:23]>C(O)C>[CH2:21]([N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:26][CH2:25]1)[CH:22]=[CH2:23]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: C=CCN1CCNCC1
Solvent: CCO
Product: C=CCN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1

Procedure:
8.62 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 8.3 gm of 1-allyl-piperazine were refluxed in 100 ml of ethanol for 2 hours. The reaction mixture was then evaporated, and the crystalline precipitate was subsequently recrystallized from 30 ml of isopropanol and then from 94% ethanol in the presence of activated charcoal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]2=[C:11]([NH2:13])[CH:12]=1>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:13]([C:8]([CH3:7])=[O:9])[C:3](=[O:2])[CH3:12])[C:6]2[CH2:7][CH:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(c(N(C(C)=O)C(C)=O)c1)CC(C)O2

Procedure:
A reaction mixture consisting of 2.4 grams of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine, 10 cc of acetic anhydride and one drop of pyridine is heated to 130°-140° C. for 90 minutes. After cooling and evaporating the excess of acetic anhydride, the residue is distilled under reduced pressure yielding 2.4 grams (69 percent of theoretical) of the compound of the title. B.p./0.4 mmHg 160° C. The distillate which solidifies is crystallized from ethyl ether-petroleum ether. M.p. 56°-57° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]([C:12](=[O:27])[CH2:13][CH2:14][C:15]1[S:16][C:17]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[C:20]([F:26])[C:18]=2[N:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>O.O1CCOCC1>[F:26][C:20]1[C:18]2[N:19]=[C:15]([CH2:14][CH2:13][C:12]([N:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:4][C:3]([OH:28])=[O:2])=[O:27])[S:16][C:17]=2[C:23]([F:24])=[CH:22][C:21]=1[F:25]
Reactant: COC(=O)CN(C(=O)CCc1nc2c(F)c(F)cc(F)c2s1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN(C(=O)CCc1nc2c(F)c(F)cc(F)c2s1)c1ccccc1
Yield: 53.2 %

Procedure:
To a solution of N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-phenylglycine methyl ester (420 mg, 1 mmol) in a mixture of water (3 ml) and dioxane (6 ml) was added dropwise 2N sodium hydroxide (1.2 ml) with stirring under ice cooling and the mixture was stirred for 1 hour at room temperature. The reaction mixture was then diluted with water and washed with ether. The aqueous layer was acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, then dried and evaporated to yield a residue, which was recrystallized from ethyl acetate-isopropyl ether to give N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-phenylglycine 210 mg, 52%) as a colorless powder.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH:38]2[CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH:38]3[CH2:39][CH2:40][CH2:41]3)=[O:37])=[CH:34][CH:35]=2)[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(c1ccc(O)cc1)C1CCC1
Product: O=C(c1ccc(OCCCc2c[nH]cn2)cc1)C1CCC1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of cyclobutyl 4-hydroxyphenyl ketone are treated as described in Example 76.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1.Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCC(c3cccnc3)C2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N1CCC(c2cccnc2)C1)N1CCNc2ccccc21
Yield: 92.6 %

Procedure:
3.72 g of tert-butyl 4-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-3,4-dihydroquinoxaline-1(2H)-carboxylate, dissolved in 18.2 ml of dioxane, are introduced into a 250 ml round-bottomed flask. 34.1 ml of a 4N solution of hydrochloric acid in dioxane are subsequently added. Stirring is maintained for three hours. After evaporating, the residue is taken up in dichloromethane and a saturated aqueous sodium hydrogencarbonate solution and then the aqueous phase is extracted three times with dichloromethane. The organic phases are combined and dried over sodium sulfate and the solvent is evaporated under reduced pressure. 2.6 g of 1-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinoxaline are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>CCOCC>[Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:19])=[O:6]
Reactant: Cc1c(Cl)cccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COC(=O)c1cccc(Cl)c1C
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 3-chloro-2-methylbenzoic acid (1 g, 5.86 mmol) and sulfuric acid (0.312 mL, 5.86 mmol) in Methanol (5 mL) was charged into a round bottom flask. The reaction was stirred at reflux overnight and cooled to RT. 1N NaOH was added to adjust pH to 7. The mixture was diluted with ether, which was washed with brine. The organic layer was dried over MgSO4 and the solvent was removed to afford 1.07 g of crude product (99%). 1H NMR (400 MHz, CDCl3) δppm 7.71 (m, 1H), 7.52 (m, 1H), 7.20 (m, 1H), 3.92 (s, 3H). 2.62 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38].Cl>CN(C=O)C.O>[CH2:40]([O:39][C:37]([C:24]1[CH:25]=[N:26][C:27]2[C:32]([C:23]=1[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:38])[CH3:41]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1Cl
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a solution of 1.85 g (6.67 mmol) of N-benzyl 4-methoxyphenyl-sulphonamide in 15 mL of DMF was added, in one portion, 0.267 g (6.67 mmol) of 60% sodium hydride and the resulting mixture was stirred at room temperature under nitrogen for 15 min. Ethyl 4-chloro-7-trifluoromethyl-3-quinolinecarboxylate (2.02 g, 6.67 mmol) was then added to the solution in one portion and the resulting mixture was heated at 85° C. for 24 h. The reaction mixture was then cooled to room temperature, poured into a mixture of water (300 mL) and HCl (1N, aqueous, 100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was then chromatographed on silica gel eluting with 15%-50% ethyl acetate/hexane to give 3.11 g (88%) of the desired product. Electrospray Mass Spec 545.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:23][CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1>CS(C)=O>[O:26]1[CH2:27][CH2:28][O:29][CH:25]1[CH2:24][CH2:23][N:8]1[CH2:7][C@@H:6]2[CH2:12][O:13][CH2:14][CH2:15][N:5]2[C:4]2[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]1=2
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: BrCCC1OCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ncc2c(n1)N1CCOC[C@H]1CN2CCC1OCCO1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 250 mg, 1.103 mmol) in DMSO (7 mL), sodium tert-butoxide (127 mg, 1.324 mmol), and 2-(2-bromoethyl)-1,3-dioxolane (220 mg, 1.213 mmol) (200 mg, 56%). ESI-MS m/z [M+H]+ calc'd for C14H19ClN4O3, 327.12; found 327.2.
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([NH:13][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(F)c(Cl)c2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cc(F)c(Cl)c2cccnc12)c1ccccc1
Yield: 15.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-chloro-6-fluoroquinolin-8-amine (Intermediate 53) (100 mg, 0.51 mmol), benzenesulfonyl chloride (100 mg, 0.61 mmol) and DMAP (cat.) gave the title compound (27 mg, 16%) after purification by column chromatography with DCM as the eluent followed by preparative HPLC (neutral conditions).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][C:14](=[O:16])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:18])=[O:17].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+].Cl>CN(C)C=O>[CH3:1][N:2]1[C:15]([C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])=[C:14]([OH:16])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:18])=[O:17]
Reactant: CN1CC(=O)c2c(c3ccccc3n2C)S1(=O)=O
Reactant: O=C=Nc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(C(=O)Nc2ccccc2)=C(O)c2c(c3ccccc3n2C)S1(=O)=O
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A solution of 1.0 gm (3.7 millimols) of 2,5-dihydro-2,5-dimethyl-1,2-thiazino[5,6-b]indole-4(3H)-one-1,1-dioxide and 0.44 ml (4.0 millimols) of phenyl isocyanate in 20 ml of dimethylformamide was added to a suspension of 230 mgm of a 55% sodium hydride-in-oil dispersion (5.0 millimols) in 15 ml of dimethylformamide, while cooling on ice. The reaction mixture was stirred for 30 min. on an ice bath and then for 4 hours at room temperature. Afterwards, it was stirred into 100 ml of aqueous 3 N hydrochloric acid. The precipitate formed thereby was filtered off, washed with water, dried and recrystallized from xylene, yielding 340 mgm (27% of theory) of 2,5-dihydro-2,5-dimethyl-4-hydroxy-N-phenyl-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide; M.p.: 269°-270° C. (decomposition).
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH2:24]>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:24][C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=1)#[CH:3]
Reactant: O=C([O-])OCC=Cc1ccccc1
Reactant: Nc1ccc2ccccc2c1
Product: C#CC(Nc1ccc2ccccc2c1)c1ccccc1
Reaction time: 16 h
Yield: 89.3 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and 2-napthylamine (0.170 g, 1.18 mmol). The reaction was conducted at room temperature for 16 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 99/1. The mixture was purified by flash column chromatography on silica gel (1.5% ethyl acetate in hexanes) to give the title compound (0.225 g, 89%). [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.53 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.31-7.11 (m, 6H), 7.06 (t, J=7.6 Hz, 1H), 6.76 (dd, J=9.0, 2.2 Hz, 1H), 6.64 (d, J=2.0 Hz, 1H), 5.95 (ddd, J=17.2, 10.4, 6.0 Hz, 1H), 5.20 (d, J=17.6 Hz, 1H), 5.13 (d, J=9.6 Hz, 1H), 4.94 (d, J=5.6 Hz, 1H), 4.06 (br s, 1H). 13C NMR (100.59 MHz, CDCl3) δ 144.65, 141.52, 138.63, 134.90, 128.74, 128.73, 127.53, 127.48, 127.45, 127.14, 126.18, 125.99, 122.04, 118.02, 116.16, 105.82, 60.18. Anal. Calcd for C19H17N: C, 87.99; H, 6.61; N, 5.40. Found: C, 88.16; H, 6.58; N, 5.41.