Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:26])[N:11]([C@H:21]2[CH2:24][C@H:23]([OH:25])[CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N-]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:26])[N:11]([C@H:21]3[CH2:22][C@H:23]([O:25][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:24]3)[C:12]3[N:13]([N:18]=[CH:19][N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:34]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](O)C2)c2ncnn12
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](OCC(=O)OCC)C2)c2ncnn12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3′-fluoro-4′-{[4-(trans-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.29 g), rhodium(II) acetate (dimer) (0.0028 g) and toluene (3 mL) was heated to 80° C. under an argon atmosphere, a solution of ethyl diazoacetate (0.16 g) in toluene (3 mL) was added dropwise, and the mixture was stirred at 80° C. for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.95 g, 27%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[CH2:12]([O:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13].C1(C2C=CC=CC=2)C(O)=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.[Cu](I)I.O>[CH2:12]([O:14][C:15](=[O:22])[CH:16]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13]
Reactant: Ic1ccc2nccnc2c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ccc2nccnc2c1
Temperature: 25 °C

Procedure:
A solution of 6-iodo-quinoxaline (0.323 g, 1.26 mmol), malonic acid diethyl ester (0.404 g, 2.52 mmol), copper iodide (0.012 g, 0.063 mmol), biphenyl-2-ol (0.021 g, 0.126 mmol) and cesium carbonate (0.616 g, 1.89 mmol) in THF (5 mL) was heated to 70° C. in a sealed tube for 24 hours. The solution was then cooled to room temperature, water was added and the crude product was extracted from ethyl acetate. The product was purified via silica gel column chromatography in hexane:ethyl acetate (1:1) to give 2-quinoxalin-6-yl-malonic acid diethyl ester. 2-quinoxalin-6-yl -malonic acid diethyl ester (0.066 g, 0.229 mmol) was added to a solution of sodium hydroxide [2N] (0.229 mL) in methanol (2 mL) and stirred for several hours at room temperature. The reaction was then evaporated in vacuo, 1N HCl was added and the product was extracted with ethyl acetate to give 0.030 g (70%) of quinoxalin-6-yl-acetic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.6 (bs, 1H), 8.93 (dd, 2H, J=2.0, 6.0 Hz), 8.05 (d, 1H, 8.8 Hz), 7.99 (m, 1H), 7.79 (dd, 1H, J=2.0, 8.8 Hz), 3.89 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3](=O)[CH2:4][C:5]1[N:9]2[C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:13][CH2:14][C:8]2=[N:7][N:6]=1.B>>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[N:9]2[C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[NH:13][CH2:14][C:8]2=[N:7][N:6]=1
Reactant: CN(C)C(=O)Cc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Agent: B
Product: CN(C)CCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)NC2

Procedure:
In the manner given in Example 1, N,N-dimethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-acetamide is reduced with borane to give 1-[2-(dimethylamino)ethyl]-5,6-dihydro-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:13])=[O:12])\[CH3:10])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:13])=[O:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C/C(=C\c1ccc(Cl)cc1)S(=O)(=O)Nc1ccccc1S(N)(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(Cc1ccc(Cl)cc1)S(=O)(=O)Nc1ccccc1S(N)(=O)=O
Yield: 37.6 %

Procedure:
2-[[(E)-1-(4-Chlorophenyl)prop-1-en-2-yl]sulfonylamino]benzenesulfonamide (100 mg, 0.26 mmol) was dissolved in ethyl acetate (3 ml) and subjected to the H-cube (1 ml/min, full hydrogen. 10% Pd/C, 3 runs). The material obtained was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (38 mg, 38%). The compound of Example 8 was also obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[NH2:45][C@H:46]1[CH2:51][CH2:50][C@H:49]([OH:52])[CH2:48][CH2:47]1>ClCCl>[OH:52][C@H:49]1[CH2:50][CH2:51][C@H:46]([NH:45][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:19]=2)=[O:23])[CH2:47][CH2:48]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@H](O)CC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
In a 100 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.150 g, 0.295 mmol), EDC (61 mg, 0.32 mmol), DIEA (52 μl, 0.295 mmol) were combined with dichloromethane (3 ml) to give a yellow solution. Stirred for 30 min then trans-4-aminocyclohexanol (48 mg, 0.42 mmol) was added. The reaction mixture was stirred at room temperature for 24 h then diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 5% MeOH in DCM) and recrystallized from ethyl acetate to afford 60 mg of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-4-hydroxy-cyclohexyl)amide as a white solid. MS: [M+H]+=555.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2.N1CCCCC1>C(O)C>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:9]1[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=1[CH3:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1CCC(=O)O
Yield: 88 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 106 mg 5-bromo-2-oxindole, and 75 μL piperidine in 3 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 171 mg (88%) of the title compound as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[K+]>CN(C=O)C.O>[CH2:17]([N:1]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1)[CH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#CCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 153.2 %

Procedure:
A solution of 4-aminophenylacetonitrile (20 g, 151.3 mmol) in dry DMF (150 ml) was treated with potassium carbonate (50.1 g, 363.1 mmol), benzyl bromide (54.4 g, 318 mmol), and potassium iodide (5 g, 0.2 30.3 mmol). The reaction mixture was stirred at room temperature for 12 h. Water (100 ml) was added to the mixture and the organic was extracted with ether (3×200 ml). The combined organic fraction was washed with brine (200 ml), dried over sodium sulfate and concentrated. The crude product was further purified by flash chromatography (SiO21 20% EtOAc:Hexanes) to give 36.2 g (76%) of the pure product. NMR was consistent with the proposed title structure. Field Desorption Mass Spectrum:M+=312.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[N:13]([CH:18]=[CH:19][N:20]=3)[C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:6][CH:5]=1.ClC1N2C=CN=C2C(NC2C=CC(N3CCN(C(C)C)CC3)=CC=2)=CC=1.O.[OH-].[Li+]>O1CCOCC1.O>[Cl:17][C:14]1[N:13]2[CH:18]=[CH:19][N:20]=[C:12]2[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(Nc2ccc(Cl)n3ccnc23)cc1
Agent: CC(C)N1CCN(c2ccc(Nc3ccc(Cl)n4ccnc34)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(Nc2ccc(Cl)n3ccnc23)cc1
Temperature: 60 °C

Procedure:
A mixture of 4-(5-chloro-imidazo[1,2-a]pyridin-8-ylamino)-benzoic acid methyl ester (450 mg, 1.495 mmol), prepared using methods similar to those described for compound 12, step 1, and lithium hydroxide hydrate (250.9 mg, 5.98 mmol) in solution in dioxane/water (2/1: 30 mL) is heated at 60° C. for 2 hours. The mixture is concentrated and then acidified to pH 1 with aqueous 2N HCl. The resulting precipitate is filtrated to yield the title compound, which is used as such for the next step.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:17])[CH:12](Br)[C:13](=O)[CH3:14])[CH3:9]>CC(C)=O>[CH2:8]([O:10][C:11]([C:12]1[N:4]2[C:5]([S:6][C:2]([CH3:1])=[CH:3]2)=[N:7][C:13]=1[CH3:14])=[O:17])[CH3:9]
Reactant: CCOC(=O)C(Br)C(C)=O
Reactant: Cc1cnc(N)s1
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C)nc2sc(C)cn12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 5-methyl-2-aminothiazole (7.09 mmol) and 2-bromo-3-oxo-butyric acid ethyl ester (8.51 mmol) in acetone (17 mL) is stirred for 16 h at RT and for additional 7 h at reflux. The solvents are removed in vacuo, chloroform and sat aq. NaHCO3 solution are added, the layers are separated and the aq. layer is extracted with chloroform. The combined organic layers are dried over MgSO4 and concentrated in vacuo to give a crude product which is purified by FC (heptane to heptane/EtOAc 6/4). LC-MS: tR=0.80 min; [M+H]+=225.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.Cl[CH2:18][CH2:19][C:20]1[C:25](=[O:26])[N:24]2[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:23]2=[N:22][C:21]=1[CH3:32].C(NC(C)C)(C)C.[I-].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:18][CH2:19][C:20]2[C:25](=[O:26])[N:24]3[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:23]3=[N:22][C:21]=2[CH3:32])[CH2:15][CH:16]=1
Reactant: Cc1nc2c(C)cccn2c(=O)c1CCCl
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: Cc1nc2c(C)cccn2c(=O)c1CCN1CC=C(c2c[nH]c3ccc(F)cc23)CC1

Procedure:
A solution of 5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)indole (5.5 g, 0.025 mol), 3-(2-chloroethyl)-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (7.2 g, 0.030 mol), diisopropylamine (5 ml) and potassium iodide (1 g) in acetonitrile (100 ml) was heated under reflux for 24 h. After cooling the precipitate was collected and washed with acetonitrile (20 ml), isopropyl alcohol (3×20 ml) and petroleum ether (25 ml) respectively. Yield 7.13 g (67%) of a pale yellow solid. M.p.: 229-230° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:16][C:17](=[O:30])[CH2:18][O:19][C:20]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]2[C:21]=1[CH2:22][CH2:23][CH2:24]2>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][S:29][C:26]3[CH:27]=[CH:28][C:20]([O:19][CH2:18][C:17]([OH:30])=[O:16])=[C:21]4[C:25]=3[CH2:24][CH2:23][CH2:22]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Product: O=C(O)COc1ccc(SCc2cc(-c3ccc(Cl)cc3)on2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole and 12C. mp 112-114° C.; MS m/z 430 (M+1).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[N:11]=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:20][CH2:21][CH2:22][CH3:23]>C(O)C>[CH2:20]([O:9][C:7]1[CH:6]=[C:5]([CH3:10])[C:4]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH3:2])[CH:8]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCBr
Reactant: Cc1cc(O)cc(C)c1N=Nc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCCCOc1cc(C)c(N=Nc2ccccc2)c(C)c1

Procedure:
To a solution of sodium (2.0 g, 0.09 mole) in absolute ethanol (119 ml) was added 2,6-dimethyl-4-hydroxyazobenzene (18.3 g, 0.08 mole) prepared according to B. C. Saunders and G. H. R. Watson, Biochem. J. 46:629-233 (1950). To the resulting orange-red solution was added 1-bromobutane (22.3 g, 0.162 mole) slowly from a separatory funnel and the mixture was refluxed for five hours. When cool, the precipitated sodium bromide was filtered off and the filtrate was evaporated to dryness. The residue was taken up in ether and the ether solution was extracted, first with 0.5 M sodium hydroxide and then once with water. The ether phase was dried (Na2SO4), filtered, and evaporated to dryness. The yield was over 90%. This material is satisfactory for the next step. After recrystallization from 95% ethanol, it melted at 47°-47.5° C. Calcd. for C18H22N2O: C 76.6, H 7.85, N 9.92. Found: C 76.7, H 7.84, N 9.86.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11].[CH3:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22](Cl)=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][C:22](=[O:23])[CH2:21][C:16]1[CH:15]=[C:14]([CH3:13])[CH:19]=[C:18]([CH3:20])[CH:17]=1
Reactant: Cc1cc(C)cc(CC(=O)Cl)c1
Reactant: COC(=O)c1ccc(Cl)cc1N
Product: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of (3,5-dimethylphenyl)acetyl chloride (2.58 g in 20 mL dry dichloroethane) was added 2.5 g 2-amino-4-chlorobenzoic acid methyl ester and the mixture heated to reflux on an oil bath. After 2 hours, the pot was cooled to room temperature and the solvent removed in vacuo. Recrystallization of the crude product from methanol gave the title compound (4.05 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([NH:15][CH3:16])=[CH:8][C:7]=1[N:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]1.C1COCC1>[Pd].CO>[F:29][C:2]([F:1])([F:28])[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([NH:15][CH3:16])=[CH:8][C:7]=1[N:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]1
Reactant: CNc1cc(N2CCC(C(C)(C)O)CC2)c(C(=O)NCC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(N2CCC(C(C)(C)O)CC2)c(C(=O)NCC(F)(F)F)cc1N
Reaction time: 7 h

Procedure:
A mixture of N-(2,2,2-trifluoroethyl)-2-[4-(1-hydroxy-1-methyl-ethyl)-piperidinyl]-4-methylamino-5-nitro-benzoic acid amide (crude product from the reaction above), Pd/C (10 mg), THF (5 ml) and MeOH (5 ml) is stirred under 3 bar H2-atmosphere for 7 h. The mixture is filtered and the filtrate is concentrated and directly used in the next step.
Reaction SMILES: [C:1]([C@H:3]1[CH2:6][C@H:5]([NH:7]C(=O)OC(C)(C)C)[CH2:4]1)#[N:2].[C:15]([OH:21])([C:17]([F:20])([F:19])[F:18])=[O:16]>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:15]([OH:21])=[O:16].[NH2:7][C@H:5]1[CH2:6][C@H:3]([C:1]#[N:2])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@H]1C[C@H](N)C1

Procedure:
tert-Butyl (trans-3-cyanocyclobutyl)carbamate (0.061 g, 0.31 mmol) was stirred with TFA (2 mL) in DCM (4 mL) for 1 hour. The solvents were removed in vacuo and the residue was reconstituted in DCM and subjected to rotary evaporation an additional 2 times to rid of excess TFA in the product, which was used without further purification in Step 5.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15])=[CH:5][CH:4]=1)#[N:2].C(OC(=O)C)(=O)C.[N+:28]([O-])([OH:30])=[O:29]>C(O)(=O)C>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15])=[C:5]([N+:28]([O-:30])=[O:29])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(=O)Nc1ccc(C#N)c2ccccc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(C#N)c2ccccc12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 4.2 g (15.7 mmol) 4-cyano-1-ethoxalylaminonaphthalene in 125 ml glacial acetic acid was added 125 ml acetic anhydride. At 15° C. a solution of 12 ml 100% nitric acid in 60 ml glacial acetic acid was added dropwise. Stirring was continued at 25° C. for 24 h and then at 50° C. for 1.5 h. The reaction mixture was poured into 500 ml ice-water to give 3.5 g (72%). M.p. 178.0° C.
Reaction SMILES: C(=O)(OC1C=CC(S(N2C3C(=CC=C(F)C=3)NC(=O)[C@@H]2C)(=O)=O)=CC=1)OCC.ICC.[CH2:32]([C@@H:34]1[N:43]([S:44]([C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:54])[CH:41]=2)[N:36]([CH2:55][CH2:56]C)[C:35]1=[O:58])C>>[CH2:55]([N:36]1[C:37]2[C:42](=[CH:41][C:40]([F:54])=[CH:39][CH:38]=2)[N:43]([S:44]([C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[C@@H:34]([CH3:32])[C:35]1=[O:58])[CH3:56]
Reactant: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Agent: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(F)ccc3NC(=O)[C@@H]2C)cc1
Solvent: CCI
Product: CCN1C(=O)[C@H](C)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21

Procedure:
Ethyl 4-{[(2S)-7-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]sulfonyl}phenyl carbonate was treated with iodoethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-1-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-3-methyl-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−67° (c=0.005 G/ML, DMSO); MS (ESI) m/z 365 ([M+H]+); MS (ESI) m/z 363 ([M−H]−); Anal. Calcd for C17H17FN2O4S: C, 56.03; H, 4.70; N, 7.69. Found: C, 54.80; H, 4.47; N, 7.39.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19]O)[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Br)(Br)[Br:22].O.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][Br:22])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN2CCCC(CO)C2)cc1OC
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(CCN2CCCC(CBr)C2)cc1OC
Temperature: 0 °C
Reaction time: 15 h

Procedure:
4.4 g (0.0157 mol) of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-3(hydroxymethyl)-piperidine are dissolved in 70 ml of carbon tetrachloride and cooled to 0° C. Then 1.63 ml (0.0173 mol) of phosphorus tribromide is added, whereupon a bulky precipitate is immediately formed. The mixture is stirred for 15 hours at ambient temperature, water is added and the mixture is neutralized with 2 molar sodium hydroxide solution. The organic phase is separated off, washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over 310 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 5%). Yield: 2.0 g (37.2% of theory), Rf value: 0.5 (aluminium oxide neutral, eluant: 2% ethanol in methylene chloride).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:19][C@H:18](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:17][C@H:12]2[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:19][C@@H:18]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:17][C@H:12]2[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Product: COC(=O)[C@@H]1C[C@H](N2CCCCC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 15.0 g of 1-[(phenylmethoxy)carbonyl]-trans-4-tosyloxy-L-proline, methyl ester (J.A.C.S., 79, 191 (1957)) and 75 ml of piperidine is stirred at room temperature for 24 hours. The excess piperidine is removed under reduced pressure and the residue is dissolved in 50 ml of chloroform. The latter solution is extracted twice with 10 ml portions of water, dried (MgSO4), filtered and the solvent evaporated to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH:4]([NH2:7])[CH2:5][CH3:6].[C:10](Cl)(=[O:13])[CH:11]=[CH2:12]>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:8][CH3:9])[CH:4]([NH:7][C:10](=[O:13])[CH:11]=[CH2:12])[CH2:5][CH3:6]
Reactant: CCC(N)C(OC)OC
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)NC(CC)C(OC)OC
Yield: 68.9 %

Procedure:
Using the standard procedure for ABDA-Et, 16.5 g (0.124 mol) of the above aminobutyraldehyde dimethyl acetal was reacted with 11.2 g (0.124 mol) of acryloyl chloride in 40 mL of CH2Cl2 /30 g of 14N NaOH. The product mixture was adjusted to pH 10.0 and worked up as usual to yield 16 g of oil showing predominantly a single component by gc at 7.00 min.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:10]=[C:9]([C:11]3[C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)[CH:8]=[C:7]([CH3:30])[C:6]2=[O:31])[CH2:3][CH2:2]1.[CH2:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH3:33]>>[CH:1]1([CH2:4][N:5]2[C:6](=[O:31])[C:7]([CH3:30])=[CH:8][C:9]([C:11]3[C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])=[CH:15][N:14]=[C:13]([NH:37][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])[N:12]=3)=[CH:10]2)[CH2:2][CH2:3]1
Reactant: CCS(N)(=O)=O
Reactant: Cc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(CC2CC2)c1=O
Product: CCS(=O)(=O)Nc1ncc(Oc2ccc(F)cc2F)c(-c2cc(C)c(=O)n(CC3CC3)c2)n1

Procedure:
The title compound of Example 248, step 3 was treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 248, step 4 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 9.09 (s, 1H), 8.60 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.04-6.96 (m, 2H), 6.91-6.89 (m, 1H), 3.87 (d, J=7.2 Hz, 2H), 3.64 (q, J=7.2 Hz, 2H), 2.22 (s, 3H), 1.44 (t, J=7.2 Hz, 3H), 1.25-1.23 (m, 1H), 0.62-0.60 (m, 2H), 0.38-0.37 (m, 2H). LCMS: 477.2 (M+H)+