Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[CH3:5][N:6]([C:14]1[S:15][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][N:18]=1)[C:7](=[O:13])[CH2:8][CH2:9][C:10](=O)[CH3:11].C([O-])(=O)C.[Na+]>C(O)C>[CH3:5][N:6]([C:14]1[S:15][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][N:18]=1)[C:7](=[O:13])[CH2:8][CH2:9]/[C:10](=[N:4]/[O:3][CH3:2])/[CH3:11]
Reactant: CON
Reactant: CC(=O)CCC(=O)N(C)c1nnc(-c2cccnc2)s1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CO/N=C(\C)CCC(=O)N(C)c1nnc(-c2cccnc2)s1
Yield: 37.1 %

Procedure:
4-[(E)-methoxyimino]-pentanoic acid methyl-(5-pyridin-3-yl-[1,3,4]thiadiazol-2-yl)-amide was prepared as described in J F W Keana et al. in J. Org. Chem., 1985, 50, 2346. A suspension of O-methylhydroxylamine hydrochloride (0.065 g, 0.9 mmol), 4-oxo-pentanoic acid methyl-(5-pyridin-3-yl-[1,3,4]thiadiazol-2-yl)-amide (0.18 g, 0.6 mmol) and sodium acetate (0.076 g, 0.9 mmol) in anhydrous ethanol was refluxed under nitrogen for 14 hours, cooled, concentrated under reduced pressure and chromatographed on silica to afford the title compound as an amorphous yellow solid (0.071 g, 36%): mp 114-121° C.; 1H NMR (400 MHz, CDCl3) δ 9.15 (d, J=1.8 Hz, 1H), 8.70 (dd, J=4.8, 1.8 Hz, 1H), 8.29 (dt, J=5.9, 1.8 Hz, 1H), 7.43 (dd, J=7.7, 5.2 Hz, 1H), 3.92 (s, 3H), 3.86, 3.83 and 3.77 (all s, 1H), 2.95 (q, J=7.0 Hz, 2H), 2.71 (q, J=7.4 Hz, 2H), 2.11, 1.98 and 1.89 (all s, 3H); ESIMS m/z 320 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])C)[CH:9]=[CH:10][CH:11]=1.[Se](=O)=O.[C:23]([O-:26])(O)=[O:24].[Na+]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[C:23]([OH:26])=[O:24])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)c1cccc(OCc2c(C)cccc2C)c1
Reactant: O=C([O-])O
Agent: O=[Se]=O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cccc(C)c1COc1cccc(C(=O)C(=O)O)c1
Temperature: 100 °C

Procedure:
To a stirred solution of 1-(3-(2,6-Dimethylbenzyloxy)-phenyl)-ethanone (WO 02/100341, 5 g, 20 mmol) in pyridine (20 ml) was added selenium dioxide (3.492 g, 31 mmol) diluted in pyridine (20 ml). The reaction mixture was heated at 100° C. for 3 hours, decanted from selenium metal and concentrated in vacuo to give orange oil, which solidified at room temperature. The solid was dissolved in saturated NaHCO3 (40 ml) and stirred with decolorizing carbon (0.5 g) for an hour at room temperature. The reaction mixture was filtered through celite and aqueous filtrate was acidified using 6N HCI (6 ml). A gray precipitant (6.3 g) was filtered and dried in vacuo at 40° C. for 2 hours. The acidified filtrate was washed with ether (2×75 ml), dried over Na2SO4, filtered, and concentrated to yield a white solid (0.5 g). Recrystallization using carbon tetrachloride afforded 4.9 g of the title compound with pyridine as an impurity. The semipure material (4.2 g) was dissolved in ethyl acetate (150 ml) and washed with 5% HCl (2×50 ml). The organic layer was dried over Na2SO4, filtered and concentrated to yield a yellow solid (3.9 g). The solid was recrystallized with carbon tetrachloride (30 ml) to afford the title compound (3.03 g) as a light yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]#[N:22])=[O:15])[CH2:3]1.[ClH:23].O1CCOCC1>>[ClH:23].[ClH:23].[NH2:1][C@@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]#[N:22])=[O:15])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: C1COCCO1
Product: N#C[C@@H]1CCCN1C(=O)[C@@H]1C[C@H](N)CN1

Procedure:
(S)-1-((2S,4S)-4-Amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine (title compound of Reference Example 3, 308 mg) was dissolved in 4 mol/L hydrochloric acid-1,4-dioxane (1.25 mL), and the mixture was stirred at room temperature for 27 hr. The solvent was evaporated under reduced pressure and tetrahydrofuran was added thereto. The precipitated solid was collected by filtration to give the title compound (214 mg).
Reaction SMILES: [CH2:1]([S:4]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCCS(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CCC)n1

Procedure:
A mixture of 5.25 g. 3-propylsulphonyl-1,2,4-triazole, 5.3 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The reaction mixture was worked up as described in Example 1 to give a solid product which was recrystallized from petroleum ether (b.p. 60° - 80°C.) to give 1-diallylcarbamoyl-3-propylsulphonyl-1,2,4-triazole, m.p. 41° - 42°C. Elemental analysis satisfactory.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([N:8]2[CH2:11][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9]2)[CH2:6][CH2:5][NH:4][CH2:3]1.[F:37][C:38]1[C:46]([C:47]([F:50])([F:49])[F:48])=[N:45][CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[F:1][C@H:2]1[C@@H:7]([N:8]2[CH2:9][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][NH:23][C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:11]2)[CH2:6][CH2:5][N:4]([C:40](=[O:41])[C:39]2[CH:43]=[CH:44][N:45]=[C:46]([C:47]([F:50])([F:48])[F:49])[C:38]=2[F:37])[CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CCNC[C@H]5F)C4)c3)ncnc21
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN([C@H]2CCN(C(=O)c3ccnc(C(F)(F)F)c3F)C[C@H]2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
Into a 20 mL vial were added {1-[cis-3-fluoropiperidin-4-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (200 mg, 0.4 mmol) in DMF (3 mL), 3-fluoro-2-(trifluoromethyl)isonicotinic acid (99 mg, 0.47 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (225 mg, 0.509 mmol) and triethylamine (0.14 mL, 1.0 mmol). The mixture was stirred at room temperature overnight and purified with prep-LCMS to give 50 mg of the desired compound as a white solid. LC/MS found: 702.2 (M+1)+.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7](O)=[O:8])=[CH:5][N:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[N:3]=1>C1COCC1>[I:1][C:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[N:3]=1
Reactant: O=C(O)c1cn(C2CCCCO2)nc1I
Solvent: C1CCOC1
Product: OCc1cn(C2CCCCO2)nc1I
Yield: 47.3 %

Procedure:
To a solution of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carboxylic acid (28 g, 86.93 mmol, 1.00 equiv) in anhydrous THF (300 mL) maintained under nitrogen at 5° C. was added a 1M solution of BH3 in THF (300 mL) dropwise with stirring. The reaction was stirred overnight at room temperature and then quenched by the addition of 300 mL of saturated NH4Cl solution. The resulting mixture was extracted with 3×1000 mL of dichloromethane. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1:1) to give 12.67 g (47%) of (3-iodo-1-(oxan-2-yl)-1H-pyrazol-4-yl)methanol as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.73 (s, 1H), 5.37-5.34 (m, 1H), 4.92 (s, 1H), 4.20 (d, J=3.6 Hz, 2H), 3.89-3.88 (m, 1H), 3.65-3.57 (m, 1H), 2.09-2.00 (m, 1H), 1.99-1.90 (m, 2H), 1.69-1.61 (m, 1H), 1.49-1.46 (m, 2H) ppm. LCMS (method A, ESI): RT=1.16 min, m/z=309.0 [M+H]+.
Reaction SMILES: C([C:3]1([C:18]2[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=2)[C:7]2=[N:8][CH:9]=[CH:10][C:11]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)=[C:6]2[C:5](=[O:17])[O:4]1)#N.[O:28]1CCCC1.[OH-].[Na+]>O>[CH3:25][O:24][C:22]1[CH:21]=[C:20]([O:26][CH3:27])[N:19]=[C:18]([C:3]2([OH:28])[C:7]3=[N:8][CH:9]=[CH:10][C:11]([C:12]4[O:13][CH:14]=[CH:15][CH:16]=4)=[C:6]3[C:5](=[O:17])[O:4]2)[N:23]=1
Reactant: COc1cc(OC)nc(C2(C#N)OC(=O)c3c(-c4ccco4)ccnc32)n1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)nc(C2(O)OC(=O)c3c(-c4ccco4)ccnc32)n1
Yield: 94.6 %

Procedure:
0.42 g of 7-cyano-7-(4,6-dimethoxypyrimidin-2-yl)-4-(2-furyl)furo[3,4-b]pyridin-5(7H)one was weighed out, and 14 ml of tetrahydrofuran was added thereto. The mixture was stirred under cooling with ice. 14 ml of 0.25N sodium hydroxide aqueous solution was added thereto dropwise, and the mixture was stirred at room temperature for 30 minutes. The mixture was poured into water, and the aqueous layer was washed with ethyl acetate twice, acidified with 10% hydrochloric acid and extracted with 100 ml of ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crystals were washed with methyl alcohol to obtain 0.40 g (yield 94.6%) of the desired compound as yellow crystals. m.p.: 198°-204° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([CH3:34])[CH:18]=[CH:17][C:16]([S:19]([O:22][CH2:23][C@@H:24]([OH:33])[CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:54](O)(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>O1CCCC1>[C:13]1([CH3:34])[CH:18]=[CH:17][C:16]([S:19]([O:22][CH2:23][C@H:24]([O:33][C:54](=[O:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)CCc2cccnc2)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)OC(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 64.7 %

Procedure:
Diethyl azodicarboxylate (0.61 ml) was added to a solution of (2S)-2-hydroxy-4-(3-pyridyl)-1-butyl para-toluenesulfonate (1.4 g), triphenylphosphine (1.31 g) and benzoic acid (0.61 g) in tetrahydrofuran (30 ml) at 0° C. and the resulting solution stirred for 1 hour. The mixture was concentrated under reduced pressure and the residue obtained purified by column chromatography over silica eluting with diethyl ether to give the sub-title compound as a white solid (1.2 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)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>[C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:10])=[O:9])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1sccc1NS(=O)(=O)c1cccc(-c2ccccc2)c1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
To a solution of 81 (318 mg; 0.85 mmol) in toluene (8.5 mL) was added a solution of phenylboronic acid (152 mg; 1.12 mmol) in ethanol (5.6 mL). Bis(triphenylphosphine)palladium(II) dichloride (32 mg; 0.05 mmol) was then added, followed by the addition of aqueous saturated sodium bicarbonate (3.3 mL). The reaction was placed under a nitrogen atmosphere and then heated at 80° C. for 17 hours. After cooling to room temperature, the reaction was extracted with dichloromethane (70 mL) and washed with aqueous hydrochloric acid (40 mL; 2N), water (40 mL), and aqueous saturated sodium chloride (40 mL). The dichloromethane extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by a silica gel chromatography (9% to 16% ethyl acetate in hexanes gradient) to yield the title compound as a white solid (217 mg).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Br:6][C:7]1[CH:8]=[N+:9]([O-])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH-].[Na+]>>[Br:6][C:7]1[C:8]([Cl:3])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: [O-][n+]1cc(Br)cc2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1nc2ccccc2cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To POCl3 (7.5 ml, 80 mmol) was added in portions solid 6 (2.25 g, 10 mmol). The mixture was stirred at room temperature for 30 min and then 60° C. for 10 min. The mixture was then poured into cold 1M NaOH extracted with CH2C2. The combined extracts were dried (K2CO3) and concentrated to a residue which was purified by flash chromatography (EtOAc) to afford 3-Bromo-2-chloroquinoline 7 (1.95 g, 80%). 1H NMR d (ppm): 7.6 dd (CH atom), 7.7 m (2 CH atom), 8.0 d (CH atom), 8.5 s (CH arom)
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:9]=1.CI>CC(C)=O>[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([N:18]([CH3:1])[S:19]([CH3:22])(=[O:20])=[O:21])[CH:9]=1
Reactant: COC(=O)c1ccc(Cl)cc1NS(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccc(Cl)cc1N(C)S(C)(=O)=O
Reaction time: 0.25 h
Yield: 62 %

Procedure:
Potassium carbonate (12.5 g) was added to a stirred solution of methyl 4-chloro-2-(N-methylsulphonylamino)benzoate (7.5 g) in acetone. The mixture was stirred for 15 minutes and methyl iodide (8.0 g) was added. The resultant mixture was stirred at room temperature for 1 hour and left to stand overnight. The mixture was evaporated to dryness and the residue was dissolved in ethyl acetate and washed with sodium hydroxide solution (2M) and water, dried (anhydrous MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl 4-chloro-2-(N-methyl-N-methylsulphonylamino)benzoate (4.9 g) as a white solid, m.p. 73°-75° C.
Reaction SMILES: [O:1]=[C:2]([NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].FC(F)(F)C(O)=O>O1CCCC1>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:29][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2](=[O:1])[NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:12]=1
Reactant: O=C(COc1ccc(C(=O)O)cc1)NCc1cccnc1
Reactant: Nc1ccccc1N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1ccccc1NC(=O)c1ccc(OCC(=O)NCc2cccnc2)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
0.34 g (2.1 mmole) of N,N′-carbonyldiimidazole was added to a tetrahydrofuran (10 ml) suspension including 0.6 g (2.1 mmole) of 4-{2-oxo-2-[(pyridin-3-ylmethyl)amino]ethoxy}benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling to room temperature, 2.1 g (19.4 mmole, 8 equivalents) of 1,2-phenylenediamine and 0.4 ml of trifluoroacetic acid were added, and reaction was further carried out for 15 hours. After completion of the reaction, a post-treatment was performed in the same manner as in Example 6 to obtain 0.67 g (yield: 53%) of N-(2-aminophenyl)-4-{2-oxo-2-[(pyridin-3-ylmethyl)amino]ethoxy}-benzamide.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]([C:16]1[N:28]=[CH:27][C:19]2[NH:20][C:21]3[C:26]([C:18]=2[CH:17]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:15])[CH3:12].Br[CH:30]([CH3:32])[CH3:31]>C1COCC1>[CH2:11]([O:13][C:14]([C:16]1[N:28]=[CH:27][C:19]2[N:20]([CH:30]([CH3:32])[CH3:31])[C:21]3[C:26]([C:18]=2[CH:17]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: CC(C)Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c3ccccc3n(C(C)C)c2cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
Potassium bis-(trimethylsilyl)amide (5.48 g, 27.5 mmol) was added portionwise over 5 minutes under an atmosphere of argon to a stirred solution of 3-ethoxycarbonyl-9H-pyrido[3,4-b]indole (6 g, 25 mmol) in THF (60 ml) at 0° C. After 1 hour, 2-bromopropane (19 ml, 0.2 mol) was added dropwise over 10 minutes at room temperature and the reaction mixture was then heated to 60° C. for 18 hours. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The solution was washed with water and then brine. The organic phase was separated, dried, filtered and concentrated in vacuo. The crude product was purified by flash eluting over a gradient of 0-70% EtOAc in isohexane. The product was obtained as a yellow solid (2.91 g) after evaporation of the appropriate fractions. NMR (300 MHz) 9.21 (s, 1H), 8.92 (s, 1H), 8.41 (d, 1H), 7.86 (d, 1H), 7.62 (t, 1H), 7.33 (t, 1H), 5.28 (m, 1H), 4.37 (q, 2H), 1.69 (d, 6H), 1.37 (t, 3H); m/z 283.5.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.I[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(OC(C)(C)C)=O>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cn2)CC1
Yield: 27 %

Procedure:
This compound was synthesized from 6-bromonicotinonitrile and tert-butyl 4-iodopiperidine-1-carboxylate as described for example 49 step 1 (150 mg, yield 27%). 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J=2.0 Hz, 1H), 7.91 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 4.28 (m, 2H), 2.97-2.81 (m, 3H), 1.91 (m, 2H), 1.78-1.67 (m, 2H), 1.48 (s, 9H). MS (ESI) m/z: Calculated for C16H21N3O2: 287.16. found: 188.2 (M+H-Boc)+
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:24])[NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[C:1]([N:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:12](=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)[CH2:9][CH2:10]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)N1CCC(NC(=O)Nc2ccc(C(=O)OC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(=O)N1CCC(NC(=O)Nc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
Compound 21 (85 mg, 0.25 mmol) was refluxed in ethanol (10 mL) containing 1M NaOH (300 μl, 1.2 eq) for 5 hours. Additional base (300 μl) was added and the reaction continued for 2 hours before cooling to RT The reaction was quenched with 1N HCl (20 mL), the organic solvent removed and the remaining suspension filtered to give compound 22 (49 mg, 60%) as a white solid: MP 201-204° C. 1H NMR (500 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.73 (s, 1H), 7.80 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 6.32 (d, J=7.6 Hz, 1H), 3.13 (t, J=12.1 Hz, 1H), 2.80 (t, J=11.8 Hz, 1H), 2.32 (q, J=7.4 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). Purity 94%. HRMS calculated for C16H21N3O4−H+ 318.1454. found (ESI(−), [M−H]) 318.1498.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10]
Reactant: Clc1cccc(CBr)c1
Reactant: O=C1NCc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1Cc1cccc(Cl)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.066 g, 0.5 mmol), 1-bromomethyl-3-chloro-benzene (0.123 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (3 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(3-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.107 g, 85%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.28 (s, 2H), 4.78 (s, 2H), 7.16-7.52 (m, 7H), 7.90 (d, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:44]=[CH:43][C:21](/[CH:22]=[CH:23]/[C:24]3[C:32]4[C:27](=[CH:28][C:29]([CH:33]=O)=[CH:30][CH:31]=4)[N:26]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1>>[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH:22]=[CH:23][C:24]3[C:32]4[C:27](=[CH:28][C:29](/[CH:33]=[C:3]5/[C:2](=[O:10])[NH:1][C:9]6[C:4]/5=[CH:5][CH:6]=[CH:7][CH:8]=6)=[CH:30][CH:31]=4)[N:26]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[N:25]=3)=[CH:43][CH:44]=2)[CH2:13][CH2:12]1
Reactant: O=C1Cc2ccccc2N1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccc(CN3CCOCC3)cc2)c2ccc(C=O)cc21
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccc(CN3CCOCC3)cc2)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21

Procedure:
According to the method of A57B, oxindole (39 mg, 0.29 mmol) was reacted (E)-3-(4-(morpholinomethyl)styryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (116 mg, 0.25 mmol) to give the title compound as a yellow solid upon silica gel purification (95:5 CH2Cl2/MeOH) (95 mg, 64%). MS ESI 593.5 [M+H]+, calcd for [C35H40N4O3Si+H]+ 593.3
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1COCC1.[NH4+].[Cl-].[CH3:17][C:18]([Si:21]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[O:22][CH2:23][C@@H:24]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:25]/[CH:26]=[CH:27]\[C:28](OC)=[O:29])([CH3:20])[CH3:19]>C(Cl)Cl>[CH3:20][C:18]([Si:21]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[O:22][CH2:23][C@@H:24]([NH:32][C:33](=[O:34])[O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH2:25]/[CH:26]=[CH:27]\[CH2:28][OH:29])([CH3:17])[CH3:19]
Reactant: COC(=O)/C=C\C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H](C/C=C\CO)NC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
In a 500 ml round-bottomed flask methyl (2Z,5S)-6-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-5-({[(phenylmethyl)oxy]carbonyl}amino)-2-hexenoate D5 (3.58 g) was dissolved in dry DCM (122 ml) and the solution cooled at −78° C. To this solution DIBAL-H 1 M in THF (33.7 ml, 33.7 mmol) was added dropwise and the mixture left under stirring at −78° C. for 5 hours. After this time a saturated NH4Cl aqueous solution (250 ml) was added and the reaction mixture filtered through a celite pad the solid was washed with DCM (5×200 ml) and the resulting filtrate transferred into a separatory funnel. The phases were separated and the aqueous one back extracted with DCM (3×100 mls). The collected organic phases were dried (Na2SO4) and solvent removed under reduced pressure to give an oil. This crude was purified by column chromatography on silica gel (SP4 SNAP 340 g, Cy/EtOAc from 100/0 to 80/20). Collected fractions gave the title compound D6 (3.3 g) as colorless thick oil. HPLC (walk-up): rt=7.30 min. C30H37NO4Si requires 503. 1H NMR (400 MHz, CDCl3-d6) δ (ppm): 7.74-7.30 (m, 15 H), 5.71 (m, 1 H), 5.52 (m, 1 H), 5.80-5.61 (m, 1 H), 561-3.36 (m, 1 H), 5.20-4.94 (m, 2 H), 4.25-3.98 (m, 2 H), 3.91-372 (m, 1 H), 3.72-3.58 (m, 2 H), 2.50-2.26 (m, 2 H), 1.07 (s, 9 H)