Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:16][C:3]=1[O:4][C:5]1(C(OC)=O)[CH2:10][CH:9]=[CH:8][NH:7][C:6]1=[O:11].[Cl-].[Li+].CS(C)=O>O>[Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:16][C:3]=1[O:4][CH:5]1[CH2:10][CH:9]=[CH:8][NH:7][C:6]1=[O:11]
Reactant: COC(=O)C1(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)CC=CNC1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC3CC=CNC3=O)c(Cl)cc2F)c1=O
Temperature: 120 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A mixture of 202 mg of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-3-methoxycarbonyl-3,4-dihydro-1H-pyridin-2-one, 52 mg of lithium chloride, 2 ml of dimethyl sulfoxide and 10 μl of water was stirred at 120° C. for one hour. The reaction mixture was cooled to room temperature, and then water was poured therein and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 70 mg of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-3,4-dihydro-1H-pyridin-2-one.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1([C:15]2[C:16]([O:21][CH2:22][CH3:23])=[N:17][CH:18]=[CH:19][CH:20]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]1=[O:14].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[S:34](Cl)(=[O:36])=[O:35]>CN(C)C=O>[NH2:3][C:4]1([C:15]2[C:16]([O:21][CH2:22][CH3:23])=[N:17][CH:18]=[CH:19][CH:20]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]([S:34]([C:27]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=2[O:25][CH3:24])(=[O:36])=[O:35])[C:5]1=[O:14]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOc1ncccc1C1(N)C(=O)Nc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
3.2 g (79 mmol) of sodium hydride (60% dispersion in mineral oil) were added in portions to a solution of 20 g (66 mmol) of 3-amino-5-chloro-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one in 50 ml of anhydrous dimethylformamide under a nitrogen atmosphere and while cooling in an ice bath. The mixture was stirred at 0° C. for 10 min and then 18.7 g (79 mmol) of 2,4-dimethoxybenzenesulfonyl chloride were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ice-water and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by chromatography on silica gel (120 g Redisep cartridge, mobile phase gradient from 2 to 25% dichloromethane in ethyl acetate). 34 g of the title compound were obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:19]([CH:20]=O)=[CH:18][C:17]2[C:12](=[C:13]([CH3:22])[CH:14]=[CH:15][CH:16]=2)[N:11]=1.[CH2:23]([NH2:32])[C:24]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:29][O:28][C:27]1[CH:30]=[CH:31][C:24]([CH2:23][NH:32][CH2:20][C:19]2[C:10]([C:3]3[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:22])=[CH:25][CH:26]=1
Reactant: COc1cccc(F)c1-c1nc2c(C)cccc2cc1C=O
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CNCc2cc3cccc(C)c3nc2-c2c(F)cccc2OC)cc1

Procedure:
Prepared according to Procedure F using 2-(2-fluoro-6-methoxyphenyl)-8-methylquinoline-3-carbaldehyde (1.086 g, 3.68 mmol), DCE (18 mL), PMBNH2 (0.95 mL, 7.36 mmol, 2.0 eq), and NaBH(OAc)3 (2.3387 g, 11.03 mmol, 3 eq) After purification, N-(4-methoxybenzyl)(2-(2-fluoro-6-methoxyphenyl)-8-methylquinolin-3-yl)methanamine was obtained as yellow syrup. 1H NMR (DMSO-d6) δ ppm 8.42 (1 H, s), 7.84 (1 H, d, J=7.4 Hz), 7.55-7.62 (1 H, m), 7.43-7.54 (2 H, m), 7.13 (2 H, d, J=8.6 Hz), 6.90-7.01 (2 H, m), 6.77-6.85 (2 H, m), 3.71 (3 H, s), 3.65 (3 H, s), 3.47-3.62 (4 H, m), 2.64 (3 H, s), 2.43 (1 H, s). Mass Spectrum (ESI) m/e=417.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:33])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31](O)[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:36]1([S:42]([N:45]=[C:46]=[O:47])(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:33])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([C:46](=[O:47])[NH:45][S:42]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)(=[O:43])=[O:44])[C:19]=4[CH2:18]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 39.5 %

Procedure:
To a solution of the compound of Example 44 (0.511 g, 1.1 mmol) in dry THF (20 mL) was added sodium hydride (60% in mineral oil, 48 mg, 1.2 mmol), and the slurry heated at 40° C. under argon with stirring for 20 minutes. Phenylsulfonylisocyanate (160 μL, 1.2 mmol) was added and the mixture was stirred for 14 hours. The solvent was then removed by rotary evaporation to give the crude product. The solid material was washed twice with 20 mL CH2Cl2, and then twice with 20 mL MeoH: CH2Cl2 (1:1) to give the title compound (274 mg). MS m/z: 647
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][N:33]=1)[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]2[CH2:12][CH2:13][C:14]3[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:18]=3[C:10]=2[CH:9]=1)=[O:6].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.O>CN(C)C(=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([N:17]2[C:18]3[C:10]4[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]5[CH:31]=[CH:32][N:33]=[C:2]([N:38]6[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]6)[CH:3]=5)[CH:30]=[CH:29][C:11]=4[CH2:12][CH2:13][C:14]=3[C:15]([C:26]([NH2:28])=[O:27])=[N:16]2)=[CH:20][CH:21]=1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3ccnc(Cl)c3)cc1-2
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2cc(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc(F)cc3)CC4)ccn2)CC1
Temperature: 100 °C
Reaction time: 88 h

Procedure:
The material from step 1 (2.17 mmoles) and N-methyl piperazine (32.9 mmoles) were dissolved in 5.0 mL N,N-dimethylacetamide. The reaction mixture was then placed under nitrogen and stirred in an oil bath at 100° C. for 88 h. The mixture was partially stripped of solvent then added to water, filtered, and washed with water. The solid was then dissolved in acetonitrile, decolorized with decolorizing carbon, and dried over anhydrous MgSO4. The solvent was stripped, then the solid residue was recrystallized from acetonitrile. Mp: 277–279° C. 1H NMR (400 MHz, d6-DMSO): δ 2.17 (s, 3H); 2.35 (t, 4H, J=5 Hz); 2.82–2.95 (m, 4H); 3.47 (t, 4H, J=5 Hz); 6.85 (d, 1H, J=5 Hz); 7.01 (s, 1H); 7.21–7.44 (m, 6H); 7.50–7.59 (m, 3H); 8.16 (d, 1H, J=5 Hz); 10.10 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 20.32, 29.69, 45.20, 46.46, 55.00, 105.43, 111.23, 115.50, 117.07, 117.30, 120.66, 121.37, 126.54, 128.60, 128.69, 129.48, 133.36, 136.82, 136.85, 137.70, 139.71, 143.19, 144.36, 148.89, 159.88, 161.37, 163.81, 164.44, 165.15. M+1=526.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7][CH2:6][NH:5]1)=[CH:15][CH:14]=[CH:13][CH:12]=3.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:6]([N:5]1[CH2:2][CH2:1][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH2:4]1)[CH3:7]
Reactant: CCI
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCc2c([nH]c3ccccc23)C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Ethyl iodide (2.4 ml) was added to a solution of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (5.17 g) and sodium hydrogencarbonate (3.0 g) in 50 ml of acetonitrile and the solution was stirred at 70° C. over a bath for 3 hrs. After removal of the solvent by evaporation, water (60 ml) was added and the solution was extracted with chloroform. The extract was washed with brine and dried over magnesium sulfate. Purification of the crude product by silica gel column chromatography and crystallization from ethyl acetate of the eluates with methanol/chloroform (1/4) gave 1.5 g of 2-ethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[CH3:37]>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=3)=[CH:26][C:25]=2[CH3:37])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Reactant: Cc1cc(-c2ccc(=O)[nH]n2)ccc1OCCN
Product: Cc1cc(-c2ccc(=O)[nH]n2)ccc1OCCNCC(O)COc1ccc(COCCOC(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-3(2H)-pyridazinone.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[S:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=3[C:29]3[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=3)=[CH:15][NH:16]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[H-].[Na+].[C:48](OC(=O)C)(=[O:50])[CH3:49].C(Cl)(=O)C>O.CCOC(C)=O.[Cl-].[Na+].O.CN(C=O)C>[C:48]([N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([S:7]([NH:6][C:35]3[S:39][N:38]=[CH:37][N:36]=3)(=[O:9])=[O:8])[CH:18]=2)[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[CH:15]1)(=[O:50])[CH3:49]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)c[nH]c3c2)c(OC)c1
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)n1cc(-c2ccc(C(F)(F)F)cc2-c2ccnn2C)c2ccc(S(=O)(=O)Nc3ncns3)cc21
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
A 10-mL round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate B) (85.95 mg, 0.131 mmol) and DMF (1.3 mL) to give a clear, light-yellow solution. Sodium hydride (60% in mineral oil) (7.88 mg, 0.197 mmol) was added, and the resulting mixture was stirred for 15 min. Acetic anhydride (24.77 μl, 0.263 mmol) was added dropwise to give a thick slurry. After 15 min of stirring, the mixture was diluted with water, EtOAc, and a small amount of brine. The layers were separated, and the aq. layer was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, and concentrated. The residue was dissolved in MeOH (1 mL) and treated dropwise with acetyl chloride (46.7 μl, 0.656 mmol) for 1.5 h. The reaction mixture was concentrated in vacuo, and the residue was suspended in DCM (2 mL) and triethylamine (0.5 mL). The resulting solution was again concentrated, and the crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM) to give 1-acetyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (48.77 mg, 0.089 mmol, 68.0% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.82 (dd, J=0.5, 1.7 Hz, 1 H), 8.42 (s, 1 H), 8.06-7.97 (m, 1 H), 7.93-7.85 (m, 3 H), 7.60 (dd, J=1.8, 8.4 Hz, 1 H), 7.41 (d, J=8.4 Hz, 1 H), 7.33 (s, 1 H), 6.31 (d, J=1.9 Hz, 1 H), 3.43 (s, 3 H), 2.59 (s, 3 H). m/z (ESI) 547.2 (M+H)+.
Reaction SMILES: CB(O)O.[C:5]([O-])([O-])=O.[Na+].[Na+].[C:11]([NH:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[C:27](Br)[CH:26]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[C:11]([NH:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[C:27]([CH3:5])[CH:26]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)NC(=O)C1CCN(Cc2cc(Br)cc([N+](=O)[O-])c2)CC1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(CN2CCC(C(=O)NC(C)(C)C)CC2)cc([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
Methylboronic acid (23.2 mg, 0.377 mmol) and a solution of 2 M Na2CO3 (0.088 mL, 0.502 mmol) is added to a solution of 1-(3-bromo-5-nitro-benzyl)-piperidine-4-carboxylic acid tert-butylamide BB-10a (100 mg, 0.251 mmol) in anhydrous toluene (3 mL) The mixture is purged under argon for 15 min. Tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.0502 mmol) is added and the mixture is heated to 100° C. overnight. Water (10 mL) and AcOEt (10 mL) are added and the aqueous phase is extracted twice with AcOEt (10 mL). The combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The title compound is obtained by prep. LC-MS F as a colorless powder (61 mg, 73%); LC-MS A: tR=0.63 min; [M+H]+=334.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[C:6]2=[CH:7][N:8]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:11][CH2:10][NH:9][C:6]2=[CH:7][N:8]=1
Reactant: COc1cc2c(cn1)N(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cn1)NCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To 500 mg of tert-butyl 5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate was added 1.5 mL of trifluoroacetic acid, followed by stirring at room temperature for 0.5 hours. The reaction mixture was poured into ice water, neutralized with a 1 M aqueous sodium hydroxide solution, and then chloroform was added to the mixture. The aqueous layer was separated, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 262 mg of 5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:15][C:16]2C=CC=CC=2)[CH2:9][C:10]([F:14])([F:13])[C:11]=1[OH:12])=[O:5])[CH3:2].C(=O)C>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:15][CH3:16])[CH2:9][C:10]([F:13])([F:14])[C:11]=1[OH:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(O)C(F)(F)CN(Cc2ccccc2)C1
Agent: [Pd]
Agent: CC=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)C(F)(F)CN(CC)C1
Reaction time: 3 h

Procedure:
A solution of 1-benzyl-5,5-difluoro-4-hydroxy-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester was (59.46 g, 0.2 mol, prepared according to EP2123651 A1) in ethyl acetate (600 ml) was degassed and charged with acetaldehyde (13.22 g, 0.3 mol) and 10% palladium on activated carbon (6 g). This mixture was allowed to stir for three hours under an atmosphere then filtered through Celite, washed with copious methanol and concentrated under vacuum to give 1-ethyl-5,5-difluoro-4-hydroxy-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester that was immediately taken up into a 3N solution of hydrochloric acid (470 ml) and heated to reflux for four hours. Upon completion, the reaction was cooled to room temperature and concentrated under vacuum to yield 43.5 g 1-ethyl-3,3-difluoro-4,4-dihydroxy-piperidinium as a pale yellow powder (100%) LCMS (Method F): RT=0.13 min, m+H=182.0 1H NMR (400 MHz, DMSO) δ 10.84 (s, 1H), 6.93 (s, 2H), 3.82 (s, 1H), 3.60-3.32 (m, 2H), 3.15 (d, J=41.5, 2H), 3.09 (s, 1H), 2.07 (dd, J=30.7, 17.4, 2H), 1.25 (t, J=7.2, 3H).
Reaction SMILES: Br[CH2:2][C@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].[OH-].[Na+]>C1COCC1>[O:4]1[CH2:2][C@@H:3]1[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: O[C@H](CBr)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1cncc([C@H]2CO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a solution of (S)-2-Bromo-1-pyridin-3-yl-ethanol (134 mg, 0.66 mmol) in THF (10 mL) was added 4N NaOH solution (8.3 mL). The reaction mixture was stirred at room temperature for 1 h. The organic phase was separated, dried over Na2SO4 and concentrated. Silica gel prep TLC of the resulting residue using 99:1 CH2Cl2:MeOH as an eluant afforded 34 mg of (S)-3-Oxiranyl-pyridine as a colorless oil (42%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][O:21][C:17]1[C:18]([O:19][CH3:20])=[CH:2][C:3]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH3:29])=[C:4]([CH:5]=[C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH:16]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1cc(C=C2C(=O)Nc3ccccc32)cc(Br)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C=C2C(=O)Nc3ccccc32)c(-c2ccccc2OC)cc1OC
Reaction time: 12 h
Yield: 64.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added to a solution of 3-(3-bromo-4,5-dimethoxybenzylidene)-1,3-dihydroindol-2-one (0.20 g, 0.56 mmol) in toluene (1 ml) and ethanol (1 ml), followed by addition of 2M aqueous sodium carbonate (1.1 ml, 2.2 mmol). To this mixture was added 2-methoxyphenylboronic acid (0.09 g, 0.62 mmol), and the mixture was held at 100° C. in a sealed tube for 12 hours. The reaction mixture was added to water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and concentrated. Chromatography (silica, 30-40% ethyl acetate/hexanes) afforded 0.14 g (64%) of 3-(4,5,2′-trimethoxy-biphenyl-2-ylmethylene)-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: O1C2C=CC([CH:10]3[C:22]4[C:13](=[N:14][C:15]5[CH:16]=[C:17](C(OCC)=O)[C:18]6[O:25][CH:24](C(OCC)=O)[O:23][C:19]=6[C:20]=5[CH:21]=4)[C:12](=[O:36])[O:11]3)=CC=2OC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH2:43]>C1COCC1>[O:43]1[C:18]2[CH:17]=[CH:16][C:15]([C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]5[O:25][CH2:24][O:23][C:19]5=4)[N:14]=[C:13]4[C:12](=[O:36])[O:11][CH2:10][C:22]=34)=[CH:20][C:19]=2[O:23][CH2:24]1
Reactant: CCOC(=O)c1cc2nc3c(cc2c2c1OC(C(=O)OCC)O2)C(c1ccc2c(c1)OCO2)OC3=O
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OCc2c1nc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl 9-(1,3-benzodioxole-5-yl)-1,3-dioxolo[4,5- f]furo[3,4-b]quinoline-7(9H)-one dicarboxylate (2.4 g) was added gradually to a suspension of LAH (lithium aluminium hydride (2.0 g) in THF (50 ml) at 0° C. The mixture was stirred at room temperature for one hour, followed by addition of water to stop the reaction. The resulting precipitate was filtered off through Celite®. The filtrate was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (100 ml) and, with addition of 10% Pd-C (2.5 g), stirred at room temperature overnight. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform (300 ml), followed by addition of manganese dioxide (20 g). The mixture was stirred at room temperature for 3 hours. The manganese dioxide was filtered off through Celite®. The filtrate was concentrated under reduced pressure. The resulting crude crystals were washed with diisopropyl ether to yield the title compound (0.9 g). Some portions of the compound were recrystalized from THF to be used for elemental and instrumental analysis.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[C:18]([NH2:19])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1>O1CCCC1>[C:5]([NH:19][C:18]1[C:9]([NH2:8])=[N:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:17]=1)(=[O:7])[CH3:6]
Reactant: Nc1nc2ccccc2nc1N
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccccc2nc1N
Reaction time: 20 h

Procedure:
A solution of 20.8 parts of acetic anhydride in 100 parts of tetrahydrofuran was added to a slurry of 24.0 parts of 2,3-diaminoquinoxaline in 900 parts of tetrahydrofuran. The heterogeneous reaction mixture was stirred at 25° for 20 hrs and then concentrated in vacuo to give 25 parts of 2-acetamido-3-aminoquinoxaline, mp 319° (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH2:19](I)[CH3:20]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][CH3:20])[C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Cl)c(Cl)ccc2[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(Cl)c(Cl)ccc2n1CC
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a mixture of 4,5-dichloro-1H-indole-2-carboxylic acid ethyl ester (207 mg, 0.80 mmol) in DMF (2 mL) was added drop wise a suspension of NaH (41.2 mg, 60% dispersion in mineral oil, 1.03 mmol) in DMF (5 mL). The reaction mixture was stirred for 30 min, then ethyl iodide (156 mg, 1.0 mmol) diluted in 1 mL of DMF was added drop wise at room temperature and the mixture was stirred for an additional 1 hr. The reaction mixture was diluted with 100 mL of EtOAc and washed with saturated ammonium chloride (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified on a flash chromatography column with EtOAc/hexanes to afford 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (160 mg, 70% yield). The 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (160 mg, 0.56 mmol) was diluted in 10 mL of methanol and 4 mL of 1N NaOH and placed in a sealed tube. The reaction mixture was heated under microwave condition at 120° C. for 25 min. The reaction mixture was diluted with 150 mL of EtOAc and washed with 100 mL of 1N HCl, brine (50 L) and dried. The solvent was removed to afford the product 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid (120 mg, 84% yield) as a white solid. LCMS for C11H9Cl2NO2 calcd. (m/e) 257, observed 256 (M−H).