Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:20]([O-])([OH:22])=[O:21].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH:1]1([S:7][C:8]2[CH:13]=[C:12]([N+:20]([O-:22])=[O:21])[CH:11]=[CH:10][C:9]=2[NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCS(=O)(=O)Nc1ccccc1SC1CCCCC1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1SC1CCCCC1
Temperature: 0 °C
Yield: 63.8 %

Procedure:
In 20 ml of acetic acid was dissolved 1.5 g of N-[2-(cyclohexylthio)phenyl]ethanesulfonamide, 0.33 g of 61% nitric acid was added dropwise on heating at 80°-85° C., and then the mixture was stirred on heating for 1 hour. The reaction solution was poured into ice water, neutralized with a saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The dichloromethane layer was washed, in turn, with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude crystals were purified by silica gel column chromatography (eluent: n-hexane:dichloromethane:ethyl acetate=20:10:1) and recrystallized from carbon tetrachloride-n-hexane to give 1.1 g of N-(2-cyclohexylthio-4-nitrophenyl)ethanesulfonamide.
Reaction SMILES: CO[CH2:3][C:4](=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)[CH3:5].[BrH:21]>C(O)(=O)C.O>[CH3:5][C:4](=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)[CH2:3][Br:21]
Reactant: COCC(C)=C1c2ccccc2CCc2ccccc21
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(CBr)=C1c2ccccc2CCc2ccccc21

Procedure:
The above ether (3.6 g, 13.6 mmol) was dissolved in acetic acid (40 ml) and 48% hydrobromic acid (20 ml) was added. After 7 days the mixture was diluted with water (200 ml) and extracted with benzene (100 ml). The organic phase was dried (MgSO4), filtered and the solvent was evaporated in vacuo to give 3.8 g of crude 5-(1-methyl-2-bromoethylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene.
Reaction SMILES: [OH:1][C:2]1([C:15]([OH:17])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH2:18](O)[CH2:19][CH2:20][CH3:21].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1>[OH:1][C:2]1([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CCCCO
Reactant: O=C(O)C1(O)c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C1(O)c2ccccc2-c2ccccc21
Yield: 80 %

Procedure:
To a reactor were added 0.05 mol of 9-hydroxyfluorene-9-carboxlic acid, 0.075 mol of butanol, 40 ml of toluene and 0.4 ml of concentrated sulfuric acid. The reaction was heated to reflux for 6 hrs, while water was separated by a water segregator. At the end of the reaction, the reaction mixture was neutralized with sodium bicarbonate, washed with saturated saline, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Removing the solvent gave the product with a yield of 80%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]([CH3:25])[CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][N:17]([CH3:25])[CH3:16])[CH2:20][CH2:21]1
Reactant: CN(C)CC1CCNCC1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN(C)C)CC1
Yield: 8.1 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (160 mg, 0.560 mmol) was reacted with N,N-dimethyl-1-(piperidin-4-yl)methanamine (172 mg, 0.800 mmol) to afford the desired product (17.7 mg, 8%) as an off-white solid: ESI MS m/z 390 [C19H24BrN3O+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=3[NH:16][C:15](=[O:25])[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](I)[CH3:29]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=3[N:16]([CH2:28][CH3:29])[C:15](=[O:25])[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2CC(=O)Nc3cc(Cl)ccc3C2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(=O)CN([C@@H]2CCN(C(=O)OC(C)(C)C)C2)Cc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
(R)-3-(8-Chloro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.258 g, 0.70 mmol) was dissolved in THF (7 mL) and cooled to 0° C. To the solution was added NaH (0.042 g, 1.0 mmol) and stirred for 15 min, followed by ethyl iodide (0.085 mL, 1.0 mmol). The solution was allowed to warm to room temperature slowly and stir at room temperature for 14 h. The reaction was quenched with water and extracted with EtOAc (3×). The organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (75% ethyl acetate/25% ethyl acetate to 100% ethyl acetate) to yield the title compound (0.130 g, 47%). 1H-NMR (CDCl3): δ 1.16 (t, 3H), 1.43 (s, 9H), 1.75 (sextet, 1H), 2.18 (pentet, 1H), 3.05–3.9 (m, 1H), 7.20 (m, 3H). ESI-MS m/z: 394 (M+1), retention time 2.25.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([N:12]=[C:13]([C:16]4[CH:33]=[CH:32][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=O)[O:26]C(C)(C)C)[CH3:23])=[CH:18][C:17]=4[F:34])[C:14]=3[F:15])[CH:11]=2)[CH2:3][CH2:2]1.Cl.[C:36](OCC)(=O)C>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([N:12]=[C:13]([C:16]4[CH:33]=[CH:32][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:26])[CH3:36])[CH3:23])=[CH:18][C:17]=4[F:34])[C:14]=3[F:15])[CH:11]=2)[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1ccc(-c2nn3cc(OCC4CC4)ccc3c2F)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc(-c2nn3cc(OCC4CC4)ccc3c2F)c(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-3-fluoropyrazolo[1,5-a]pyridin-2-yl]-3-fluorophenoxy}-1-methylethyl]carbamate (67 mg), 4 M hydrogen chloride/ethyl acetate (2 mL), and ethyl acetate (1 mL) was stirred at room temperature for 6 hr. The mixture was concentrated under reduced pressure. The residue was mixed with pyridine (1 mL) and acetic anhydride (1 mL). The mixture was stirred at room temperature overnight. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (33.4 mg) as white crystals.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)(=O)=O)=CC=1>COCCOC>[Br:7][C:8]1[CH:13]=[CH:12][N:11]([CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[C:10](=[O:14])[CH:9]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(Br)cc2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
Potassium tert-butoxide (7.09 g) was added at room temperature to a mixture of 4-bromopyridin-2(1H)-one (10 g) in DME (287 mL). The reaction mixture was stirred at room temperature for 10 minutes. Then, potassium carbonate (15.9 g) and tert-butyl 4-(((4-methylphenyl)sulfonyl)oxy)piperidine-1-carboxylate (37.8 g) were added thereto, and the mixture was stirred at 85 C for 1 day, at 95 C for 1 day, and at 100 C for 1 day in a nitrogen atmosphere. Saturated saline was added to the reaction mixture, followed by extraction with ethyl acetate twice. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (14.7 g).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1)C1C=CC=CC=1.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1
Reactant: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1CC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CC(N)CC1CC
Yield: 98.9 %

Procedure:
To a vessel containing a slurry of 20 wt % Pd(OH)2 on C (12.9 g, 18.4 mmol) in EtOH (1.0 L) was added ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (129 g, 352 mmol). The reaction was shaken for about 90 min at about 50° C. under about 30 psi of hydrogen. After removal of the hydrogen source, a nitrogen atmosphere was introduced and the resulting mixture was filtered through a pad of Celite® and the filtrate was coned under reduced pressure to give ethyl 4-amino-2-ethylcyclopentanecarboxylate (64.5 g, 99%) as a yellow syrup: 1H NMR (CDCl3) δ 4.03-3.88 (m, 2H), 3.17 (m, 1H), 2.68 (m, 1H), 2.09-2.02 (m, 2H), 2.02-1.94 (m, 2H), 1.84 (m, 1H), 1.58-1.48 (m, 1H), 1.32-1.18 (m, 1H), 1.09 (m, 3H), 1.03 (m, 2H), 0.78-0.69 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]=[C:7]2O.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]=1
Reactant: CCOC(=O)c1nc(O)c2cccc(F)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Cl)c2cccc(F)c2n1
Yield: 65 %

Procedure:
A mixture of ethyl 8-fluoro-4-hydroxyquinazoline-2-carboxylate (530 mg, 2.2 mmol) and POCl3 (3 mL) was heated under reflux for 5 h. The mixture was concentrated under reduced pressure, and then toluene was twice added and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-25% EtOAc/hexanes to afford ethyl 4-chloro-8-fluoroquinazoline-2-carboxylate (365 mg, 65%). 1H NMR (300 MHz, DMSO-d6) δ 1.39 (t, J=7.1 Hz, 3H), 4.46 (q, J=7.1 Hz, 2H), 7.97-8.06 (m, 1H), 8.07-8.16 (m, 1H), 8.18-8.24 (m, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(F)cc1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (53.30 g, 0.219 mol) and benzenesulfonyl chloride (44 g, 0.25 mol) in 500 mL of pyridine was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was extracted with dilute H2SO4 and then dried (MgSO4). The volume was reduced to 400 mL, hexane was added, and 39.20 g (50.6%) of the title compound was collected as a white crystalline solid, mp 156.5°-158° C.
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH:40](=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:40]([N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(N[C@@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(N[C@H](Cc1ccccc1)CN(Cc1ccccc1)C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)OCc1cncs1
Yield: 18.4 %

Procedure:
The product from Example 31D (80 mg, 0.141 mmol), benzaldehyde (17 μl, 0.170 mmol), acetic acid (10 μl, 0.166 mmol), and sodium triacetoxyborohydride (48 mg, 0.226 mmol) were processed as described in Example 27 to provide the title compound (17 mg, 18%). 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.78 (s, 2H), 7.32-7.08 (m, 15H), 5.12 (br s, 2H), 4.84 (brs, 2H), 4.12 (s, 2H), 3.13 (dd, 2H), 3.05-2.87 (m, 6H), 2.80-2.70 (m, 2H); MS (ESI+) m/z 656 (M+H)+.
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[F:7][C:8]([F:30])([F:29])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([CH2:18][C:19](OCC)=[O:20])[N:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:12]2=[O:28]>C(O)C.C(OCC)C>[F:30][C:8]([F:7])([F:29])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([CH2:18][C:19]([NH:5][C:4]([NH2:6])=[NH:3])=[O:20])[N:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:12]2=[O:28]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2ccc(C(F)(F)F)cc2C(=O)N1CC(C)C
Agent: [Cl-]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)CN1C(=O)c2cc(C(F)(F)F)ccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 16 h
Yield: 17.6 %

Procedure:
N-[2-(2-Isobutyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is prepared as described in Example 9, starting with 10 cm3 of absolute ethanol, 0.19 g of sodium, 0.78 g of guanidinium chloride and 1.86 g of ethyl (5-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihyrdo-1H-isoindol-1-yl)acetate in 10 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is then taken up in a mixture of 5 cm3 of water and 15 cm3 of diethyl ether and then concentrated to dryness again under the same conditions. The residue is taken up in 100 cm3 of ethyl acetate and the organic phase is washed with twice 60 cm3 of aqueous 1N sodium hydroxide solution and then with twice 60 cm3 of 4N hydrochloric acid solution. The acidic aqueous extracts are combined, treated with aqueous 30% sodium hydroxide solution to pH 14, and then extracted with 3 times 50 cm3 of ethyl acetate. The organic extracts are combined, washed with 100 cm3 of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The yellow solid thus obtained is taken up in 20 cm3 of diethyl ether, stirred at a temperature in the region of 20° C. for 1 hour and then filtered off. The solid is washed with twice 20 cm3 of diethyl ether and then dried in a desiccator under reduced pressure (2 Pa) at a temperature in the region of 35° C. 0.34 g of N-[(5-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is thus obtained in the form of a yellow powder melting at 224° C. (Analysis: C16 H19 F3 N4 O2% calculated C, 53.93; H, 5.37; F, 15.99; N, 15.72; O, 8.98%. found C, 53.95; H, 5.15; F, 15.00; N, 15.59).
Reaction SMILES: N1CCCCC1.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:16].[N:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH:34]=O)[CH:32]=3)[N:27]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:26]=2)=[CH:19][CH:18]=1>CCO>[N:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH:34]=[C:9]4[C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[NH:7][C:8]4=[O:16])[CH:32]=3)[N:27]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:26]=2)=[CH:19][CH:18]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2cc(C=O)ccc21
Solvent: CCO
Solvent: C1CCNCC1
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2cc(C=C3C(=O)Nc4ccccc43)ccc21
Temperature: 75 °C

Procedure:
A solution of piperidine (0.2M in EtOH, 0.10 mL, 0.02 mmol) was added to a suspension of oxindole (16.5 mg, 0.12 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-carbaldehyde (42.5 mg, 0.11 mmol) in EtOH (4 mL). The reaction was then heated to 75° C. for 15 hrs. The solvent was evaporated in vacuo. MeOH was added and the resulting suspension was sonicated, but the solution was still cloudy even after EtOAc was added. The solid was removed by filtration and the solvent evaporated in vacuo. Chromatography (5 g silica SPE tube, Silicycle, 2% MeOH in CH2Cl2) gave a yellow solid (35 mg, 64%, 55:45 mixture of E/Z isomers). 1H NMR (400 MHz, CDCl3 plus a drop of CD3OD) δ 9.77 (s, 0.45H), 8.63 (m, 1.9H), 8.42 (s, 0.55H), 8.18 (s, 0.45H), 8.14 (dd, J=8.8, 1.2 Hz, 0.45H), 8.00 (s, 1H), 7.83-7.42 (m, 7H), 7.26 (t, J=7.6 Hz, 1H), 7.09 (t, J=7.6 Hz, 0.45H), 6.94-6.88 (m, 1.6H), 5.80 (s, 0.55H), 5.77 (s, 0.45H), 3.64 (m, 2H), 0.95 (m, 2H), −0.02 (s, 5H), −0.03 (s, 4H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[C:12]2[NH:14][C:15](=[O:47])[C:16]3([CH:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[O:29][C:30]4([C:34](OC)=[O:35])[CH2:33][CH2:32][CH2:31]4)[CH2:20][C:19](=[O:38])[NH:18][CH:17]3[C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=3[CH3:46])[C:11]2=[CH:10][CH:9]=1>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]2[NH:14][C:15](=[O:47])[C:16]3([CH:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[O:29][C:30]4([CH2:34][OH:35])[CH2:33][CH2:32][CH2:31]4)[CH2:20][C:19](=[O:38])[NH:18][CH:17]3[C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=3[CH3:46])[C:11]2=[CH:10][CH:9]=1
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2(CO)CCC2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 1.5 h
Yield: 24.6 %

Procedure:
To a mixture of LiAlH4 (15 mg, 0.4 mmol) in THF (2 mL) was added racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (RO5247453-000) (60 mg, 0.1 mmol). The mixture was stirred in a ice bath for 1.5 h, quenched with MeOH, purified by Prep-HPLC to give title compound (14 mg, 24%). m/z (M+H)+: 569
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2([C:43](O)=[O:44])[CH2:42][CH2:41][CH2:40]2)=[O:38])=[CH:32][CH:31]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][N:23]([CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:43]([C:39]4([C:37]([NH:36][C:33]5[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=5)=[O:38])[CH2:42][CH2:41][CH2:40]4)=[O:44])=[CH:3][C:4]=3[F:28])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1)[CH3:25]
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CCC1
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: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CCC4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 10.7 %

Procedure:
4-(Dimethylaminomethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (114 mg) was dissolved in N,N-dimethylformamide (4.0 ml). 1-(4-Fluorophenylcarbamoyl)cyclobutanecarboxylic acid (279 mg), triethylamine (0.164 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (520 mg) were added under a nitrogen atmosphere at room temperature and stirred overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with 0.5N hydrochloric acid (4 times), water, a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of a mixture of diethyl ether and heptane (1:3) to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (19.1 mg, 11%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[CH:11]#[C:12][CH2:13][CH3:14]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[CH:11]=[C:12]([CH2:13][CH3:14])[O:10][C:3]=2[CH:4]=1
Reactant: C#CCC
Reactant: COc1ccc(I)c(O)c1
Product: CCc1cc2ccc(OC)cc2o1
Yield: 81 %

Procedure:
This material was prepared from 2-iodo-5-methoxyphenol (1 g, 4 mmole) and 1-butyne in a manner as previously described for example 12a to give 570 mg (81%) of a brown oil. 1H NMR (CDCl3) δ 7.33 (1H, d, J=8.6 Hz), 6.97 (1H, d, J=2.2 Hz), 6.80 (1H, dd, J=2.2, 8.6 Hz), 6.26 (1H, s), 3.83 (3H, s), 3.04 (2H, q, J=7.3 Hz), 1.28 (3H, t, J=7.3 Hz).
Reaction SMILES: [N+](C1C=CC(COC([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[CH2:26][CH:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:24]4[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=4[CH2:22][C:21]=3[CH:37]=2)=O)=CC=1)([O-])=O>[Pd].C(O)C>[NH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[CH2:26][CH:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[CH2:22][C:21]=2[CH:37]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)cc2Cc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1Cc2ccc(OCCCN)cc2Cc2ccccc21
Reaction time: 3 h
Yield: 113.2 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-[3-(4-nitrobenzyloxycarbonylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (1.6 g 3 mmol), 10% palladium on charcoal (0.8 g, 1 mmol), and ethanol (50 mL) was shaken under H2 (48 psi) for 3 hr, then the catalyst was removed by filtration through celite®D. The filtrate was concentrated to give the title compound (1.2 g, 100%) as a yellow oil: MS (ES) 348.2 (M+H)+.