Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[N:4]=1.[C-:27]#[N:28].[K+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[N:4]=[C:3]2[CH2:2][C:27]#[N:28]
Reactant: [C-]#N
Reactant: COc1ccc(Cn2nc(CCl)c3cc(OC)c(OC)cc32)cc1OC
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(CC#N)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C
Yield: 60.9 %

Procedure:
In 1000 ml of dimethyl sulfoxide was dissolved 187.0 g of 3-chloromethyl-5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazole, followed by stirring at room temperature. To the solution was added 134.0 g of potassium cyanide, having been ground to powder in a mortar, followed by stirring at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into 15000 ml of water, and stirred for 1 hour. A precipitated solid was collected, washed with three 1000 ml portions of water, dissolved in 5000 ml of chloroform, dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography using 2 kg of silica gel and chloroform:ethanol=50:1 and then 2 kg of silica gel and ethyl acetate:hexane=3:1, to yield 111.0 g of a pale brown solid. This solid was used in the subsequent reaction without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([N+:9]#[C-:10])[CH2:7][CH3:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20]Cl)=[CH:14][CH:13]=1>>[CH2:7]([C:6]([N+:9]#[C-:10])([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)[CH3:8]
Reactant: ClCCCc1ccc(Cl)cc1
Reactant: [C-]#[N+]C(CC)c1cccs1
Product: [C-]#[N+]C(CC)(CCCc1ccc(Cl)cc1)c1cccs1
Yield: 56.7 %

Procedure:
5.44 g of 1-(2-thienyl)propyl isocyanide and 6.81 g of 3-(4-chlorophenyl)propyl chloride are treated in the same manner as described in Example 1-(1) to give 6.2 g of 1-ethyl-4-(4-chlorophenyl)-1-(2-thienyl)butyl isocyanide as a colorless oil. yield; 56.7%
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[Li+:11].C[Si]([N-][Si](C)(C)C)(C)C.C1[CH2:25][O:24]CC1.C1C[O:29]CC1>>[O:2]=[C:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH:4]([C:25]([O-:24])=[O:29])[O:3]1.[Li+:11]
Reactant: O=C1OCc2ccccc21
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1OC(C(=O)[O-])c2ccccc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of phthalide (2.0 g, 14.9 mmol) in THF (60.0 ml) at −78° C. was added 1.0M LiHMDS/THF (15.7 ml) over 10 minutes. The reaction was stirred for 15 minutes at −78° C. and then the ice bath was removed. The reaction was quenched into dry ice using a cannula and then allowed to warm to room temperature. After adding 40 ml hexane, the cloudy mixture was rotary evaporated and chased with hexane to give lithium 3-oxo-1,3-dihydro-2-benzofuran-1-carboxylate as a yellow solid (2.86 g, 100%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:10][CH:11]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:12]1([C:9]2[S:10][CH:11]=[C:7]([CH2:6][CH2:5][CH2:4][OH:3])[N:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCc1csc(-c2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1csc(-c2ccccc2)n1
Yield: 76 %

Procedure:
In analogy of the procedure described in example 12 b], 0.44 g (1.68 mmol) of 3-(2-phenyl-thiazol-4-yl)-propionic acid ethyl ester was reacted with lithium aluminium hydride, yielding 0.28 g of 3-(2-phenyl-thiazol-4-yl)-propan-1-ol as colorless liquid (75.8% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].Cl.[CH3:31][NH:32][CH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([N:32]([CH3:33])[CH3:31])=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(Cl)cc3Cl)cc1CCO2

Procedure:
2-[(2,4-Dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and dimethylamine hydrochloride salt were reacted in the general amide coupling procedure to give 288. NMR: (CDCl3): 2.73-3.04 (6 H, br m), 2.95-3.00 (2 H, m), 3.29 (3 H, s, Me), 4.17-4.20 (2 H, m), 6.79 (1 H, s, Ar), 6.93 (1 H, d, J 8.3, Ar), 7.19-7.29 (3 H, m, Ar) and 7.47-7.48 (2 H, m, Ar). MS: (ESI+) MH+=475.04
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:24](I)[CH3:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:15]1)[CH2:24][CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN1CCC(CNC(=O)OC(C)(C)C)CC1
Reactant: CCI
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(CN(CC)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl [4-(tert-butoxycarbonylamino-methyl)-piperidin-1-yl]-acetate (1.86 g) is dissolved in N,N-dimethylformamide (10 ml), and thereto are added sodium hydride (63%) (1.19 g) and ethyl iodide (6.0 ml), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is made weak basic with a 10% aqueous citric acid solution and a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give ethyl {4-[(tert-butoxycarbonyl-ethyl-amino)-methyl]-piperidine-1-yl}-acetate (905 mg). MS (m/z): 329 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:38][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NC1CCCC1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Cyclopentylamine (2.38 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to dryness and the residue was treated with water. The solid was collected by filtration, washed with water, and dried under high vacuum overnight. The solid was recrystallized from isopropyl alcohol-ethanol, collected by filtration, washed with cold isopropyl alcohol, and dried under high vacuum over the weekend to give 3.67 g (74%) of crystals, mp 260°-261° C.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:13][NH:14]2)=[CH:10][CH:9]=1.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>O1CCCC1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([S:17]([CH3:20])(=[O:18])=[O:19])=[N:13][N:14]2[CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CS(=O)(=O)c1n[nH]c2cc(Br)ccc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(S(C)(=O)=O)c2ccc(Br)cc21
Temperature: 0 °C

Procedure:
Sodium tert-butoxide (0.057 g) was added to an ice-cold solution of 6-bromo-3-(methylsulfonyl)-1H-indazole (Intermediate 75) (0.14 g) in tetrahydrofuran (1.5 ml). 2-(Trimethylsilyl)ethoxymethyl chloride (0.11 ml) was then added and the mixture was warmed to room temp. over 1 h. The reaction was quenched using 2M aqueous ammonia (1 ml) and methanol (1 ml) the solvent was evaporated and the aqueous residue was extracted with ethyl acetate. The organic extracts were dried using a hydrophobic filter tube and concentrated under vacuum to give the title compound (0.67 g).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14](O)=[O:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1.F[P-](F)(F)(F)(F)F.[N:29]1([O:38]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.Cl.NO>CN(C=O)C>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([NH:29][OH:38])=[O:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NO)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To 1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (0.15 g, 0.52 mmol) in DMF (10 mL) were added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU; 0.20 g, 0.52 mmol), triethylamine (0.15 mL, 1.05 mmol), and hydroxylamine hydrochloride (0.036 g, 0.52 mmol). The resulting mixture was stirred for 16 hours at ambient temperature. It was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water (2×30 mL), dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC to provide the title compound as a white powder (0.075 g, 48% yield). 1H NMR (DMSO-d6) δ ppm 11.14 (s, 1H), 8.92 (s, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 7.78 (s, 1H), 7.26-7.38 (m, 2H), 7.08 (t, 1H, J=8.3 Hz), 6.71 (d, 1H, J=3.0 Hz), 5.64 (s, 2H). LCMS (API-ES, M+H+): 304.1 HRMS (M+H): 304.0886; cal: 304.0898 with C15H12N3O2F2. HPLC: 98% purity.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
A mixture of 4-chloro-3-nitrobenzaldehyde (1.00 g, 5.389 mmol), 4-(benzyloxy)phenol (1.187 g, 5.928 mmol), and potassium carbonate (0.744 g, 5.389 mmol) in anhydrous pyridine (10 mL) was heated at reflux under a nitrogen atmosphere for 30 minutes. The reaction was cooled to room temperature and the solvent removed by rotary evaporation under vacuum. The residue was taken up in ethyl acetate (100 mL) and washed with 1N aqueous hydrochloric acid (2×50 mL), water (50 mL), and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel flash chromatography using methylene chloride as eluent provided the title compound as a yellow solid (1.625 g, 86%).
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]([F:19])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16].CC(C)([O-])C.[K+]>CS(C)=O.CCOC(C)=O>[Cl:9][C:10]1[C:11]([O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]2)=[CH:12][C:13]([F:19])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Reactant: OCC1CC=CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)c(OCC2CC=CCC2)cc1F
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
To a solution of cyclohex-3-en-1-ylmethanol (1.00 g) and 5-chloro-2,4-difluoro-benzoic acid (1.72 g) in DMSO (36 mL) at 14° C. (bath) was added potassium tert-butoxide (2.20 g) gradually. The mixture was stirred at that temp for 5 min then at rt for 30 min. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (3×) and brine, and dried (Na2SO4). After filtration and concentration, the product was obtained as white solid (2.48 g).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][N:11]([C:16](=[O:27])[CH2:17][N:18]1[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]1=[O:20])[CH2:12][C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)Cl.[F:31][C:32]1[C:37](O)=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:33]=1[F:42]>CN(C=O)C>[F:31][C:32]1[C:37]([O:14][C:13](=[O:15])[CH2:12][N:11]([CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:16](=[O:27])[CH2:17][N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:33]=1[F:42]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Cc1cn(CC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cn(CC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
N-(N-Boc-2-aminoethyl)-N-[(1-thyminyl)acetyl]glycine (5) (2.00 g; 5.20 mmol) was dissolved in DMF (5 ml) and methylene chloride (15 ml) was added. Pentafluorophenol (1.05 g; 5.72 mmol) was added and the solution was cooled to 0° C. in an ice bath. DDC then was added (1.29 g; 6.24 mmol) and the ice bath was removed after 2 min. After 3 h with stirring at ambient temperature, the precipitated DCU was removed by filtration and washed with methylene chloride. The combined filtrate was washed twice with aqueous sodium hydrogen carbonate and once with saturated sodium chloride, dried over magnesium sulfate, and evaporated to dryness, in vacuo. The solid residue was dissolved in dioxane (150 ml) and poured into water (200 ml) at 0° C. The title compound was isolated by filtration, washed with water, and dried over an appropriate drying agent, in vacuo. Yield: 2.20 g (77%). An analytical sample was obtained by recrystallisation from 2-propanol. M.p. 174–175.5° C. Analysis for C22H23N4O7F5, found(calc.): C, 48.22(48.01); H: 4.64(4.21); N: 9.67(10.18). 1H-NMR (250 MHz, CDCl3):Due to the limited rotation around the secondary amide bond several of the signals were doubled in the ratio 6:1 (indicated in the list by mj. for major and mi. for minor). 7.01 ppm (s, mi., ArH); 6.99 ppm (s, mj., ArH); 5.27 ppm (unres. t, BocNH); 4.67 ppm (s, mj., T-CH2—CO—); 4.60 ppm (s, mi., T-CH2—CO—); 4.45 ppm (s, mj., CONRCH2CO2Pfp); 4.42 ppm (s, mi., CONRCH2CO2Pfp); 3.64 ppm (t,2H,BocNHCH2CH2-); 3.87 ppm (“q”,2H,BocNHCH2CH2—); 1.44(s,9H,t-Bu). FAB-MS: 551 (10; M+1); 495 (10; M+1-tBu); 451 (80; -Boc).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([CH2:7][NH:8][C:9](=[O:25])[CH:10]([O:22][CH2:23][CH3:24])[N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:20])[C:12]2=[O:21])=[C:5]([N+:28]([O-])=O)[CH:4]=1)#[N:2]>C(OCC)(=O)C.[Pd]>[NH2:28][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:27]=[CH:26][C:6]=1[CH2:7][NH:8][C:9](=[O:25])[CH:10]([O:22][CH2:23][CH3:24])[N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:20])[C:12]1=[O:21]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1[N+](=O)[O-])N1Cc2c(C)cccc2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(C(=O)NCc1ccc(C#N)cc1N)N1Cc2c(C)cccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of (RS)-N-(4-cyano-2-nitro-benzyl)-2-ethoxy-2-(4-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide (0.382 g) in ethyl acetate (9 ml) was added 10% Pd/C (190 mg) and the mixture vigorously stirred at r.t. under a hydrogen atmosphere for 16 h. The catalyst was filtered over a celite pad and the cake was carefully washed with ethyl acetate. The filtrate was evaporated to yield (RS)-N-(2-amino-4-cyano-benzyl)-2-ethoxy-2-(4-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide (0.354 g) as off-white foam, MS 379.4 ([M+H]+).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:14]=[N:13][CH:12]=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:14]=[N:13][CH:12]=[CH:11][C:8]=1[CH:9]=[CH2:1]
Reactant: O=Cc1ccncc1Br
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccncc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.14 g, 6.00 mmol) in THF (27 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 1.8 mL, 4.5 mmol). The resulting yellow reaction mixture was stirred for 30 min at −78° C. In a separate flask THF (6 ml) was added to 3-bromoisonicotinaldehyde (CAS#113118-81-3, 558 mg, 3.00 mmol). The resulting 3-bromoisonicotinaldehyde solution was the transferred, via cannula, to the phosphonium ylide mixture followed by a 2 mL THF wash. The reaction was allowed to warm to room temperature over 60 minutes and then permitted to stir for an additional 30 minutes. The reaction was then quenched with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate. The organic layer was concentrated to near dryness. The resulting residue was then diluted with ethyl acetate and 1M sodium bisulfate and the layers were separated. The organic layer was extracted two additional times with 1M sodium bisulfate. The aqueous layers were combined, diluted with dichloromethane, and neutralized via the careful addition of saturated aqueous sodium bicarbonate and solid sodium carbonate. The layers were separated and the now basic aqueous layer was extracted three additional times with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0 to 16%) to furnish 3-bromo-4-vinyl-pyridine; MS: (ES+) m/z 183.9 (M+H)+
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([F:16])=[CH:6][C:7]2[O:12][CH:11]([CH3:13])[C:10](=[O:14])[NH:9][C:8]=2[CH:15]=1.[CH2:17](Br)[C:18]#[CH:19].O>CN(C)C=O>[NH2:3][C:4]1[C:5]([F:16])=[CH:6][C:7]2[O:12][CH:11]([CH3:13])[C:10](=[O:14])[N:9]([CH2:19][C:18]#[CH:17])[C:8]=2[CH:15]=1
Reactant: CC1Oc2cc(F)c(N)cc2NC1=O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)C(C)Oc2cc(F)c(N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
While kept under N2, 0.30 g (7.4 mmol) of sodium hydride (60% dispersion in oil) was washed with 1 ml pentanes and then suspended in 2 ml anhydrous dimethylformamide. A solution of 1.36 g (6.9 mmol) of 6-amino-7-fluoro-2-methyl-2H-1,4-benzoxazin-3(4H)-one in 10 ml of dimethylformamide was added to the sodium hydride slurry slowly by syringe with ice cooling and the reaction mixture was stirred at room temperature for 0.5 hr. There was then added 0.77 ml (8.6 mmol) of propargyl bromide by syringe with ice bath cooling. The reaction mixture was allowed to warm to room temperature, stirred for 84 hours and then poured into 50 ml of water. The resulting mixture was extracted with EtOAc (2×50 ml) and the organic layers were combined and washed with water (3×50 ml), dried over MgSO4 and filtered. The solvent was removed in vacuo to yield a golden solid which was recrystallized from chloroform to yield 0.66 g of 6-amino-7-fluoro-2-methyl-4-propargyl-2H-1,4-benzoxazin-3(4H)-one as a brown solid, m.p. 142°-145° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)=[O:17]>CC(C)=O.C(OCC)(=O)C>[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 19 °C

Procedure:
14.5 cm3 of benzyl bromide and 16.75 g of potassium carbonate were added, at a temperature in the region of 19° C., to 15 g of 4-hydroxyacetophenone dissolved in 180 cm3 of acetone. The reaction medium was heated and maintained at the reflux temperature of the acetone for 4 hours. After cooling to a temperature in the region of 19° C., the reaction medium was suction-filtered through a sinter funnel and the insoluble material was rinsed again with 10 cm3 of acetone. The organic phase was evaporated under reduced pressure (2 kPa; 45° C.) and the solid obtained was dissolved in 300 cm3 of ethyl acetate. The organic solution was washed with twice 100 cm3 of water and then with 100 cm3 of saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 45° C.). The solid residue was triturated in 20 cm3 of pentane, suction-filtered through a sinter funnel and oven-dried under reduced pressure (10 kPa; 20° C.). 23.1 g of 4-benzyloxyacetophenone were obtained in the form of a white solid melting at 99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17](Cl)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Nc1nccnc1Cl)c1ccccc1Cl
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1
Yield: 83 %

Procedure:
Following the general method as outlined for Intermediate 4, starting from 2-chloro-N-(3-chloropyrazin-2-yl)benzenesulfonamide and 4-carboxybenzene boronic acid, the title compound was isolated, after evaporation and recrystallization, as a yellowish solid in 83% yield (96% purity by HPLC).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[C@H:10]([CH3:24])[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:24][C@@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][N:15]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)CCN1c1ccc(C(F)(F)F)cn1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CNCCN1c1ccc(C(F)(F)F)cn1
Yield: 91.4 %

Procedure:
A solution of 4-benzyl-2-(R)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (175 mg, 0.522 mmol) and 10% Pd/C (cat) in ethanol (5 mL) was stirred under a hydrogen atmosphere (50 psi) for 3 d. The reaction mixture was then filtered through Celite and purified by silica gel column chromatography (gradient eluent: 0-20% MeOH in dichloromethane) to provide the desired product (117 mg, 99%). 1H NMR (400 MHz, MeOH-D4) 8.39 (s, 1H), 7.60 (dd, 1H), 7.39-7.28 (m, 5H), 6.58 (d, 1H), 4.49 (br s, 1H), 4.10 (br d, 1H), 3.62 (br d, 1H), 3.47 (br d, 1H), 3.24 (br t, 1H), 2.95 (br d, 1H), 2.77 (br d, 1H), 2.35-2.15 (m, 2H), 1.25 (d, 3H); LCMS: 246.1 (M+1)+.