Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:66]=[CH:65][N:64]=[C:63]([N:67]3[CH2:71][CH2:70][CH2:69][CH2:68]3)[CH:62]=2)[C:50]=1[CH3:72].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:72])[C:51]([C:61]1[CH:66]=[CH:65][N:64]=[C:63]([N:67]3[CH2:68][CH2:69][CH2:70][CH2:71]3)[CH:62]=1)=[N:52]2
Reactant: Cc1c(-c2ccnc(N3CCCC3)c2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccnc(N3CCCC3)c2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.021 g, 0.044 mmol), 5-morpholinopyridin-3-amine (0.060 g, 0.33 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)quinoline (0.10 g, 0.28 mmol) and Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.067 g, 0.70 mmol) in toluene (2.8 mL) at 100° C. for 5 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/methanol/ammonium hydroxide (90/9/1)). The desired product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were concd then diluted with EtOAc. After washing twice with satd aqueous sodium bicarbonate solution, the solvent was removed under reduced pressure to yield pure product 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)quinolin-4-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.44 (1H, s), 8.43 (1H, d, J=2.0 Hz), 7.86 (1H, dd, J=8.8, 2.4 Hz), 7.79 (1H, d, J=2.4 Hz), 7.56-7.60 (2H, m), 7.34-7.39 (1H, m), 6.57 (1H, d, J=8.6 Hz), 6.54 (1H, t, J=2.3 Hz), 3.68-3.75 (4H, m), 3.47 (4H, t, J=6.5 Hz), 3.06-3.11 (4H, m), 2.19 (3H, s), 1.95-2.01 (4H, m). Mass Spectrum (ESI) m/e=503.1 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1N)([CH3:3])[CH3:2].N([O-])=O.[Na+].S(=O)(=O)(O)N.[BrH:20]>O>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[Br:20])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1N
Reactant: Br
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccccc1Br
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To an initial charge of 65 ml of 48% aqueous HBr are added, in portions, 13.5 g [0.1 mol] of 2-isopropylaniline. The resulting thick suspension is stirred at 80° C. for 15 minutes. It is then cooled to −10° C., and a solution of 8 g [0.116 mol] of NaNO2 in 35 ml of water is added dropwise within approx. 1 h at such a rate that the temperature does not exceed −5° C. 80 mg of sulphamic acid are added. Then the thin suspension of the diazonium salt, cooled to −10° C., is metered within about 30 minutes into a solution, heated to 70° C., of 13.9 g [0.05 mol] of FeSO4×7H2O in 65 ml of 62% aqueous HBr. The reaction mixture is then stirred for another 1 hour without further heating and allowed to cool to room temperature, and admixed with 125 ml of water, the phases are separated and the aqueous phase is extracted three times with 50 ml each time of methylene chloride. The combined organic phases are washed twice with 25 ml each time of water, dried and concentrated under reduced pressure. This gives 18.75 g of an oil which, according to GC, contains 82.3% 2-isopropylbromobenzene (77.5% of theory).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][NH2:10])[N:4]=1.[C:11](#[N:15])[C:12]([CH3:14])=[CH2:13]>C(O)C>[NH2:15][C:11]1[CH:12]([CH3:14])[CH2:13][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[N:4]=2)[N:10]=1
Reactant: C=C(C)C#N
Reactant: NNc1cccc(Cl)n1
Agent: [Na]
Solvent: CCO
Product: CC1CN(c2cccc(Cl)n2)N=C1N

Procedure:
As for Example 2 a 0.32 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 10.0 g. of 2-chloro-6-hydrazinopyridine is added, followed by 4.8 g. of methacrylonitrile in place of acrylonitrile. The procedure of Example 2 is followed to give 9.4 g. of crude product. The material is recrystallized from dichloromethane-hexane to give the product of the Example as pale yellow crystals, m.p. 175°-176° C.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=[O:38])(=[O:33])=[O:32]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:31]([C:34]3[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=3)[C:37]([OH:39])=[O:38])(=[O:33])=[O:32])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Product: O=C(O)c1cccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)c1

Procedure:
The title compound was prepared from of 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol and 3-chlorosulfonyl-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a white solid, mp 169-171° C.; MS m/e 559 (M−H)+;
Reaction SMILES: [O-][CH2:2]C.[CH3:4][C@@:5]12[C@H:15]3[CH2:16][CH2:17][C@:18]4([CH3:26])[C@:22]([OH:25])([C:23]#[CH:24])[CH2:21][CH2:20][C@H:19]4[C@@H:14]3[CH2:13][CH2:12][C:11]1=[CH:10][C:8](=[O:9])[CH2:7][CH2:6]2>C1C=CC=CC=1>[C:23]([C@:22]1([O:25][CH3:2])[CH2:21][CH2:20][C@H:19]2[C@H:14]3[C@H:15]([CH2:16][CH2:17][C@:18]12[CH3:26])[C@:5]1([CH3:4])[C:11](=[CH:10][C:8](=[O:9])[CH2:7][CH2:6]1)[CH2:12][CH2:13]3)#[CH:24]
Reactant: CC[O-]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Solvent: c1ccccc1
Product: C#C[C@]1(OC)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 2 h

Procedure:
Thallous ethoxide (0.8 ml.) is added to ethisterone (17α-ethinyl-17β-hydroxyandrost-4-en-3-one, 3.44 g.) in benzene (50 ml.). After mixing, the benzene is removed with the rotary evaporator and acetonitrile (50 ml.), benzene (40 ml.) and methyl iodide (1.7 ml.) are added. The mixture is refluxed and stirred for 2 hours. Additional methyl iodide (2 ml.) is added and the mixture refluxed another 2 hours. The precipitated thallous iodide is filtered off and the filtrate is concentrated to a residue which is taken up in boiling SSB and filtered thru Celite. After concentration the product is column chromatographed over silica gel eluting with increasing amounts of ethyl acetate in SSB. The appropriate fractions (TLC) are pooled and concentrated to give the title compound (recrystallized from SSB): m.p. 127°-131°; UV (ethanol) λ=240 nm (ε=16,500); MS (m/e) 326 and 311; IR (mull) 3240, 2100, 1670 and 1620 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[CH:7][C:6]=2[CH:14]=1.O1CCCC1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].N>O.C(OC)(C)(C)C>[CH2:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:14][C:6]=2[CH:7]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1cc2cc(N)ccc2o1
Agent: N
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Yield: 100 %

Procedure:
100 g of 5-amino-2-butylbenzofuran, 192 ml of tetrahydrofuran and 96 ml of methyl tert-butyl ether are introduced into a round-bottomed flask. 59.35 g of methanesulfonyl chloride are added, at 20° C., followed by 43.23 g of 20% aqueous ammonia. 44.51 g of methanesulfonyl chloride are then introduced, followed by 86.47 g of 20% aqueous ammonia. 48 ml of water are then added, the medium is separated by settling and the organic phase is washed twice with 211 g of 10% aqueous sodium chloride solution. The medium is separated by settling and concentrated at 400° C. under vacuum, to give the desired compound in crude form (weight yield: 100%).
Reaction SMILES: CCCC[O-].[Na+].Cl[CH2:8][CH:9]1[CH2:23][C@H:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[NH:16][CH:15]=3)[NH:11][CH2:10]1.Cl>>[CH2:8]=[C:9]1[CH2:23][C@H:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[NH:16][CH:15]=3)[NH:11][CH2:10]1
Reactant: ClCC1CN[C@@H]2Cc3c[nH]c4cccc(c34)[C@H]2C1
Agent: CCCC[O-]
Agent: Cl
Agent: [Na+]
Product: C=C1CN[C@@H]2Cc3c[nH]c4cccc(c34)[C@H]2C1

Procedure:
To date, only one 8-alkoxymethylergoline has been prepared and isolated. In particular, Zikan and Semonsky prepared D6-methyl-8-n-butoxymethylergoline by reaction of sodium butylate and the corresponding 8-chloromethylergoline. These workers reported that the reaction, when carried out with most sodium alcoholates, led primarily to elimination of hydrochloric acid and provided the corresponding 8-methylenergoline derivative; see Coll. Czech. Chem. Comm. 39, 614 (1974). Indeed, reaction of D-6-methyl-8-chloromethylergoline with sodium methoxide under the conditions taught by Zikan and Semonsky, effected only elimination of the elements of hydrochloric acid, affording exclusively the corresponding 8-methylenergoline.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]3[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][C:9]=3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1.Cl.[S:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])[CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[S:29]1[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][CH2:37][C:38]([O:1][C:2]2[C:11]3[C:10]4[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][C:9]=4[C:8]([CH3:17])([CH3:18])[O:7][C:6]=3[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=2)=[O:39])[CH2:33][CH2:34]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CC(C)CC1
Reactant: O=C(O)CCCN1CCSCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCSCC2)c2c(c1)OC(C)(C)C1=C2CC(C)CC1

Procedure:
A mixture of 4.0 g. (10.8 mmole) of 1-hydroxy-3-(3-methyl-2-octyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H-dibenzo[ b,d] pyran, 2.4 g. (10.8 mmole) of γ-thiomorpholinobutyric acid hydrochloride, 2.38 g. (11.5 mmole) of dicyclohexylcarbodiimide and 250 ml. of methylene chloride was stirred and heated at reflux for 18 hours. After cooling the reaction mixture, the byproduct of dicyclohexylurea was removed by suction filtration. The solvent was evaporated to give a red-brown residue which was chromatographed using 90 g. of activated magnesium silicate (60-100 mesh) and chloroform as the solvent system. The fractions were monitored by thin layer chromatography, and the appropriate fractions were combined and evaporated to give 1.0 g. of a light yellow oil. The material was pure by thin layer chromatography, and the infrared and nuclear magnetic resonance spectra were in agreement with the designated structure.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:10]1[CH2:14][S:13][CH2:12][CH:11]1[C:15](OC)=[O:16].[Na].C(O)(=O)C>CO.O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]1[C:15](=[O:16])[C:11]2[CH2:12][S:13][CH2:14][C:10]=2[NH:2]1
Reactant: NNc1ccccn1
Reactant: COC(=O)C1CSCC1=O
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2c([nH]n1-c1ccccn1)CSC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
A mixture of 7 g (64.1 mmol) of 2-hydrazinopyridine and 10.3 g (64.1 mmol) of methyl 4-oxotetrahydrothiophene-3-carboxylate in 130 mL of MeOH is heated for 12 hours at 80° C. The medium is then concentrated under reduced pressure and the residue obtained is purified by chromatography on a column of silica gel, eluting with a DCM/MeOH gradient of from 0 to 10% MeOH. After concentrating under reduced pressure, 8.7 g (34.5 mmol) of hydrazone intermediate, in the form of a yellow powder, are isolated and are then added portionwise, at room temperature, to a solution of 0.8 g (34.5 mmol) of sodium in 46 mL of anhydrous MeOH. The reaction medium is stirred for 2 hours at room temperature, and the precipitate formed is then filtered off and washed successively with 10 mL of MeOH and 20 mL of pentane. The residue obtained is dissolved in 20 mL of water and 10 mL of acetic acid are added. The precipitate obtained is filtered off, washed with 10 mL of water, dried under vacuum and recrystallized from EtOH. 4.2 g of 2-pyridin-2-yl-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-one are obtained in the form of a whitish powder.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16]([N:18]1[C@H:22]([CH:23]=O)[CH2:21][CH2:20][C@H:19]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:17])([CH3:14])([CH3:13])[CH3:12].[C@H:32](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].O>C1(C)C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16]([N:18]1[C@H:22]([CH:23]=[CH2:32])[CH2:21][CH2:20][C@H:19]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](C=O)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C[C@@H]1CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
93.5 ml (61.69 mmol, 2.0 eq) of a solution of KHMDS in toluene (15 w %, ABCR) was added under argon at RT to a suspension of 22.037 g (61.69 mmol, 2.0 eq) Ph3PMeBr in 220 ml THF, and the substance was stirred for 1 h. Then, a solution of 9.234 g (30.88 mmol, 1.0 eq) of the aldehyde 111 in 70 ml THF was dropped in at −78° C., and the resulting solution was stirred for 2.5 h at RT. 160 ml saturated Rochelle salt solution and 100 ml water was added to the reaction mixture, then extracted 3× with 260 ml MTBE each, the combined organic phases were washed with saturated NaCl solution and dried over magnesium sulfate. The solvent was removed at reduced pressure and, after purification by means of column chromatography on silica gel with EtOAc/CyHex (1:9) as eluent, 8.091 g (27.21 mmol, 88%) of the vinyl proline 112 was obtained as an isomeric mixture (d.r.: 1.7:1 cis:trans).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:15](O)=O>O>[F:14][C:11]([F:12])([F:13])[C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:15][N:6]=[C:4]2[OH:5]
Reactant: O=CO
Reactant: NC(=O)c1cc(C(F)(F)F)ccc1N
Solvent: O
Product: Oc1ncnc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.6 %

Procedure:
2-Amino-5-trifluoromethyl-benzamide (ButtPark) (1.00 g, 4.90 mmol, 1 eq.) and formic acid (3.30 mL, 87.2 mmol, 17.8 eq.) were refluxed for 2.5 hours. Cooled to rt then added water (10 mL). Stirred 15 minutes then filtered off solids which were present. The solids were dried at 110° C. for 3 hours to give 520 mg of white solids as product. LCMS detects (M+H)+=215.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)(=O)OCC)C.[Cl:21][C:22]1[C:32]2[CH2:31][CH2:30][C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[C:27](=O)[C:26]=2[CH:25]=[CH:24][CH:23]=1.Cl[Sn]Cl.[OH-].[Na+]>CS(C)=O.C(O)C.C(OCC)C.O.C(OCC)(=O)C>[Cl:21][C:22]1[C:32]2[CH:31]=[CH:30][C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[C:27](=[CH:11][C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CCOP(=O)(Cc1cccc([N+](=O)[O-])c1)OCC
Reactant: O=C1c2ccccc2CCc2c(Cl)cccc21
Agent: Cl[Sn]Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Nc1cccc(C=C2c3ccccc3C=Cc3c(Cl)cccc32)c1
Temperature: 25 °C
Yield: 10.3 %

Procedure:
Heat a suspension of NaH (60% suspension in mineral oil, 49 mg, 1.2 mmol) in DMSO (6 mL) to 80° C. under N2 until evolution of H2 stops. Dissolve (3-nitro-benzyl)-phosphonic acid diethyl ester (prepared according to procedures as described in Okamoto et. al., Bull. Chem. Soc. Jpn. (1987), 60(1), 277-82) (338 mg, 1.2 mmol) in DMSO (1 mL) and add to reaction mixture. Add 1-chloro-10,11-dihydro-dibenzo[a,d]cyclohepten-5-one (prepared according to procedures as described in Humber et al., J. Med. Chem. (1978), 21(12), 1225-31) (200 mg, 0.824 mmol) at once and heat to 100° C. for 48 h. Cool to room temperature. Dilute reaction mixture with ethyl acetate (50 mL) and wash twice with H2O. Dry (MgSO4) and concentrate organics to a brown oil. Chromatograph on silica gel (10 g), eluting with 2% to 4% ethyl acetate/hexanes to afford a mixture of compounds. Dissolve this mixture in ethanol (10 mL) and add SnCl2 (dihydrate, 508 mg, 2.25 mmol). Heat to reflux for 3 h and cool to room temperature. Concentrate reaction mixture, then dissolve residue in diethyl ether. Wash organics with H2O, 1.00N aqueous NaOH, then twice with H2O. Dry (MgSO4) and concentrate organics to a yellow oil. Chromatograph on silica gel (10 g), eluting with 5% to 10% ethyl acetate/hexanes to afford 28 mg (10%) of the title compound as a colorless oil. MS (ES) 330 (M+H); HPLC reveals 36:64 mixture of geometric isomers—36% at 4.977 min, 64% at 5.218 min—overall 100% purity.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.Cl.[NH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]3([C:33]4[C:24](=[CH:25][C:26]5[O:31][CH2:30][CH2:29][O:28][C:27]=5[CH:32]=4)[O:23][CH2:22]3)[C:14]2=[O:34])[CH2:8][CH2:7]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][CH:2]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]3([C:33]4[C:24](=[CH:25][C:26]5[O:31][CH2:30][CH2:29][O:28][C:27]=5[CH:32]=4)[O:23][CH2:22]3)[C:14]2=[O:34])[CH2:8][CH2:7]1)[CH3:4]
Reactant: CC(C)=O
Reactant: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of acetone (0.19 mL, 2.5 mmol) and 1,2-dichloroethane (5.0 mL), were added 1′-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrochloride (0.36 g, 0.84 mmol), triethylamine (0.35 mL, 2.5 mmol) and sodium triacetoxyborohydride (0.534 g, 2.52 mmol). The mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. The residue was purified by column chromatography and eluted with ethyl acetate/methanol/ammonium hydroxide (20/1/0.2) to afford 1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one. To a solution of this compound in methanol (5 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) and the mixture was stirred at ambient temperature for 30 min and concentrated in vacuo. Sequential trituration of the residue in hexanes and diethyl ether afforded 1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrochloride (0.21 g, 53%) as an off-white solid: mp 213-216° C.; 1H NMR (300 MHz, DMSO-d6) δ10.02-9.80 (br s, 1H), 7.40-7.02 (m, 4H), 6.51 (s, 1H), 6.18 (s, 1H), 4.74 (d, J=9.3 Hz, 1H), 4.62 (d, J=9.3 Hz, 1H), 4.23-4.06 (m, 4H), 3.73-3.21 (m, 4H), 3.00-2.78 (m, 2H), 2.20-1.52 (m, 5H), 1.32-1.12 (m, 7H); 13C NMR (75 MHz, DMSO-d6) δ176.8, 154.7, 144.0, 142.5, 137.7, 131.6, 128.7, 123.5, 122.8, 121.0, 111.1, 109.2, 98.6, 79.7, 64.1, 63.5, 57.1, 56.7, 47.1, 44.2, 32.1, 26.6, 26.4, 16.1; MS (ES+) m/z 435.1 (M+1).
Reaction SMILES: [PH:1](=[O:16])([O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[O:2][CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([O:33][N:34]2[C:39]([CH3:41])([CH3:40])[CH2:38][CH2:37][CH2:36][C:35]2([CH3:43])[CH3:42])[CH3:32])=[CH:27][CH:26]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:13][Si:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][O:9][P:1]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([O:33][N:34]2[C:39]([CH3:41])([CH3:40])[CH2:38][CH2:37][CH2:36][C:35]2([CH3:42])[CH3:43])[CH3:32])=[CH:27][CH:26]=1)(=[O:16])[O:2][CH2:3][CH2:4][Si:5]([CH3:7])([CH3:8])[CH3:6]
Reactant: C[Si](C)(C)CCO[PH](=O)OCC[Si](C)(C)C
Reactant: CC(ON1C(C)(C)CCCC1(C)C)c1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(ON1C(C)(C)CCCC1(C)C)c1ccc(CP(=O)(OCC[Si](C)(C)C)OCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound I, that is, bis[2-(trimethylsilyl)ethyl] phosphonate (582 mg, 2.05 mmol) is dissolved in dimethylformamide (“DMF”) (25 ml) to manufacture a solution III-1. Cesium carbonate (Cs2CO3)) (2 g, 6.13 mmol) and tetrabutylammonium iodide (“TBAI”) (2.26 g, 6.13 mmol) are added to the solution III-1, and stirred at room temperature for approximately 1 hour under a nitrogen atmosphere to manufacture a solution III-2. After approximately 1 hour, compound II, that is, 1-[1-(4-chloromethylphenyl)ethoxy]-2,2,6,6-tetramethyl-piperidine (1.9 g, 6.13 mmol), is added to the solution III-2, and stirred for approximately 24 hours to manufacture a suspension III-3. The suspension III-3 is purified with ethyl acetate (“EtOAc”), washed with distilled water, dried over anhydrous magnesium sulfate (MgSO4), and then condensed under a vacuum to obtain non-purified {4-[1-(2,2,6,6-tetramethyl-piperidine-1-yloxy)-ethyl]-benzyl}-phosphonic acid bis-(2-trimethylsilylethyl) ester.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]([CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[CH:10][C:9]([CH3:24])=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[S:25]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>C1(C)C=CC=CC=1.O=[Mn]=O>[O:23]=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:13]1[CH2:12][C:11]1[CH:10]=[C:9]([CH3:24])[C:8]2[N:7]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=3)(=[O:27])=[O:26])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:2]=[O:1]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CO)c(CN4C(=O)c5ccccc5C4=O)cc(C)c32)cc1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(CN4C(=O)c5ccccc5C4=O)cc(C)c32)cc1
Temperature: 80 °C
Reaction time: 11 h

Procedure:
A suspension of 2-((4-(hydroxymethyl)-7-methyl-1-tosyl-1H-indol-5-yl)methyl)isoindoline-1,3-dione (180 mg, 0.38 mmol) and MnO2 (165 mg, 1.9 mmol) in toluene (20 mL) was stirred at 80° C. for 11 h. The reaction mixture was cooled to room temperature. The reaction mixture was filtered off through Celite®. The Celite® cake was washed with CH2Cl2. The combined filtrate was concentrated to give the title compound, with no need of further purification. MS (ESI+) m/z 473.1 (M+H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([O:14]C)=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.BrC1C=CC(CN)=CC=1.N>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[CH3:24])=[CH:19][CH:18]=1
Reactant: CC(N)c1ccc(Br)cc1
Reactant: COC(=O)Cc1cccc2cnccc12
Agent: N
Agent: NCc1ccc(Br)cc1
Product: CC(NC(=O)Cc1cccc2cnccc12)c1ccc(Br)cc1

Procedure:
The title compound was prepared using the procedure described in Example 132C using the product from Example 133B and 1-(4-bromophenyl)ethanamine instead of the product from Example 132B and 4-bromobenzylamine. 1H NMR (300 MHz, d6-DMSO) 9.81 (s, 1H), 9.00 (d, 1H), 8.70 (d, 1H), 8.48 (d, 1H), 8.40 (d, 1H), 8.04 (d, 1H), 7.92 (m, 1H), 7.51 (d, 2H), 7.23 (d, 2H), 4.84 (m, 1H), 4.10 (s, 2H), 1.35 (d, 3H). MS (DCI/NH3) m/e 369 (M+H)+; Anal. Calcd. For C19H17N2OBr.1.0HCl.1.0H2O: C, 53.86; H, 4.76; N, 6.61. Found: C, 53.47; H, 4.53; N, 6.76.