Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N1CCC1.Cl.CN(C)CCCN=C=NCC.[OH:18]N1C2C=CC=CC=2N=N1.[CH2:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])C.[CH2:35]([O:42][C:43]1([CH:51]=[CH:50]C=[CH:48][CH2:47]1)C([O-])=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O.CN(C)C=O>[CH2:35]([O:42][C:43]1[CH:47]=[CH:48][C:34]([C:33]([N:30]2[CH2:28][CH2:32][CH2:31]2)=[O:18])=[CH:50][CH:51]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C([O-])C1(OCc2ccccc2)C=CC=CC1
Reactant: CCN(CC)CC
Reactant: On1nnc2ccccc21
Agent: C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCc2ccccc2)cc1)N1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
Azetidine hydrochloride (10.3 g, 110 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (25.2 g, 131 mmol), 1-hydroxybenzotriazole (20.1 g, 131 mmol), and triethylamine (33.6 ml, 241 mmol) were added to a N,N-dimethylformamide solution (500 ml) of 1-(benzyloxy)benzoate (25 g, 110 mmol), and this mixture was stirred overnight at room temperature. Water was added to this reaction solution, this mixture was extracted with ethyl acetate twice, followed by washing the organic layer with water and a saturated saline solution, drying the organic layer with anhydrous sodium sulfate, and thereafter concentrating this solvent under reduced pressure. The obtained residue was crystallized from chloroform-diethyl ether to obtain 1-[4-(benzyloxy)-benzoyl]azetidine (23.0 g, yield: 79%) as an ecru solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)([O:12][CH2:13][CH2:14][OH:15])[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:17]2)([O:12][CH2:13][CH2:14][O:15][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC[C@](OCCO)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC[C@](OCCOS(C)(=O)=O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-hydroxyethoxy)butyl)piperidine-1-carboxylate (750 mg, 1.82 mmol) in dry CH2Cl2 (10 mL) was added Et3N (550 mg, 5.46 mmol) at −5-0° C. Then a solution of MsCl (270 mg, 2.37 mmol) in dry CH2Cl2 (5 mL) was added dropwise at the same temperature. After addition, it was allowed to warm to rt gradually. Upon completion of the reaction, water (20 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers was washed with 10% citric acid, sat. NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-(methylsulfonyloxy)ethoxy)butyl)piperidine-1-carboxylate (900 mg, 99%), which was used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.[CH3:10][C@H:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[NH:12]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:12]2[C@@H:13]([CH3:17])[CH2:14][CH2:15][CH2:16][C@H:11]2[CH3:10])[CH:7]=1
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: ClCc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCC[C@H](C)N1Cc1cncc(Br)c1
Yield: 53.5 %

Procedure:
To a solution of 3-bromo-5-(chloromethyl)pyridine (XLVI) (1.17 g, 4.8 mmol) in MeCN (0.2 mL) and (2S,6R)-2,6-dimethylpiperidine (2.6 mL, 19.3 mmol) was added K2CO3 (667 mg, 4.8 mmol). The reaction was refluxed for 5 hrs. TLC showed the presence of starting material so additional (2S,6R)-2,6-dimethylpiperidine (2.0 mL, 14.8 mmol) was added and the reaction was refluxed for an additional 5 hrs. The solvent was removed and the residue was partitioned between EtOAc/water. The EtOAc was separated and washed with brine, dried over MgSO4 and concentrated under vacuum. The residue was purified on a silica gel column (100% hexanes→6:94 EtOAc:hexanes) to afford 3-bromo-5-(((2R,6S)-2,6-dimethylpiperidin-1-yl)methyl)pyridine (XLVII) as a clear oil (728 mg, 2.57 mmol, 53% yield). 1H NMR (DMSO-d6) δ ppm 0.92 (d, J=8 Hz, 6H), 1.21-1.32 (m, 3H), 1.52-1.55 (m, 2H), 1.59-1.63 (m, 1H), 2.42-2.46 (m, 2H), 3.73 (s, 2H), 7.97-7.98 (m, 1H), 8.50 (d, J=3 Hz, 1H), 8.55-8.56 (m, 1H); ESIMS found for C13H19BrN2 m/z 283 (M+H).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[Br:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH2:57])=[CH:52][CH:51]=1>CN(C=O)C.C(OCC)(=O)C>[Br:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH:57][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:5]=2)=[O:9])=[CH:52][CH:51]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: NCc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Br)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of biphenyl-4-carboxylic acid 10-2 (0.89 g, 4.5 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (1.7 g, 4.5 mmol) and DIEA (2.34 mL, 13.5 mmol) in DMF (15.0 mL) was added (4-bromophenyl)methanamine 10-1 (1.0 g, 4.5 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the resulting precipitate was collected by vacuum filtration to give N-(4-bromobenzyl)biphenyl-4-carboxamide 10-3 as a white solid. MS m/z 366.2 (M+1).
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH-].[Na+].C([O:24][CH2:25][CH3:26])(=O)C.[CH3:27]CCCCC>[Cl-].[Na+].O>[CH2:1]([O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[CH:27][C:25](=[O:24])[CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOc1ccccc1C=O
Reactant: CCOC(C)=O
Reactant: CCCCCC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCOc1ccccc1C=CC(C)=O

Procedure:
2-(nonyloxy)benzaldehyde (62 dissolved in acetone 500 mL) was treated with aqueous sodium hydroxide (100 mL, 1M) at room temperature for 18 h. Brine and ethyl acetate/hexane (1:1 parts by volume) was then added. Concentration of the organic phase followed by crystallization from hexane gave 4-(2-nonyloxyphenyl)-3-butene-2-one (53 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:56])=[N:14][C:15]2[N:16]([N:50]=[C:51]([C:53](O)=[O:54])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(Cl)(=O)OCC.[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:56])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH2:53][OH:54])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CO)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a stirred solution of 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (6.4 g, 8.13 mmol) and Et3N (1.473 mL, 10.57 mmol) in THF (80 mL) was added ethyl carbonochloridate (1.011 mL, 10.57 mmol) at 0° C. After 1 h, a solution of NaBH4 (1.538 g, 40.7 mmol) in cold water (80 mL) was added at once and stirred for additional 1 h at 0° C. Then the reaction was quenched with MeOH (5 mL), diluted with Et2O (100 mL), washed with water (2×50 mL) and brine (25 mL). The organic layer dried (Na2SO4), filtered and concentrate. The residue was then purified by Biotage (5-30% EtOAc/hexane) to afford (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (4.5 g, 5.82 mmol, 71.6% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.74-7.70 (m, 4H), 7.46-7.35 (m, 6H), 6.48 (s, 1H), 5.90 (br. s., 1H), 4.91-4.83 (m, 2H), 4.29-4.11 (m, 2H), 3.94-3.84 (m, 1H), 3.41-3.29 (m, 3H), 2.61 (s, 3H), 2.17 (q, J=5.8 Hz, 1H), 1.94-1.87 (m, 2H), 1.87 (br. s., 1H), 1.66 (br. s., 1H), 1.59 (s, 3H), 1.58-1.40 (m, 5H), 1.33-1.26 (m, 3H), 1.26-1.21 (m, 12H), 1.09 (d, J=6.1 Hz, 3H), 1.07 (s, 9H). LCMS (M+H)=773.4.
Reaction SMILES: Cl.[Cl:2][CH:3]1[CH2:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:6]=2[N:5]([CH3:22])[CH2:4]1.[Na].[CH3:24][OH:25]>>[ClH:2].[Cl:21][C:18]1[CH:19]=[CH:20][C:6]2[N:5]([CH3:22])[CH:3]([CH2:4][O:25][CH3:24])[CH2:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:7]=2[CH:17]=1
Reactant: CN1CC(Cl)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COCC1CN=C(c2ccccc2)c2cc(Cl)ccc2N1C

Procedure:
500 mg of 3,8-dichloro-1-methyl-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine hydrochloride were heated in a solution of 110 mg sodium in 70 ml methanol under reflux for 12 hours. After evaporation of the methanol in a vacuum the mass was further processed with water/chloroform and the chloroform solution was evaporated and concentrated in a vacuum. The residue was taken up in isopropanol and reacted with an ether solution of hydrogen chloride. There was obtained 7-chloro-1-methyl-2-methoxymethyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine hydrochloride which product also was identical with the product obtained directly by reaction of N-methyl-N-(2-hydroxy-3-benzoylaminopropyl)-4'-chloroaniline in phosphoroxychloride at 120° C. and subsequent reaction with sodium and methanol as disclosed in Examples 4 and 8 of application Ser. No. 355 986; m.p. 198°-210° C.
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[CH3:41][S:42][C:43]1[CH:44]=[C:45]([N:49]=[C:50]=[O:51])[CH:46]=[CH:47][CH:48]=1.[C:52]([O:56][CH2:57][CH2:58][OH:59])(=[O:55])[CH:53]=[CH2:54].[N-]=C=O>>[C:52]([O:56][CH2:57][CH2:58][O:59][C:50](=[O:51])[NH:49][C:45]1[CH:46]=[CH:47][CH:48]=[C:43]([S:42][CH3:41])[CH:44]=1)(=[O:55])[CH:53]=[CH2:54]
Reactant: C=CC(=O)OCCO
Reactant: CSc1cccc(N=C=O)c1
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [N-]=C=O
Product: C=CC(=O)OCCOC(=O)Nc1cccc(SC)c1
Temperature: 60 °C

Procedure:
0.02 g of 2,6-di-tert-butyl-4-methylphenol, 0.01 g of Desmorapid Z, 11.7 g of 3-(methylthio)phenyl isocyanate were initially introduced into a 100 ml round-bottomed flask and heated to 60° C. Thereafter, 8.2 g of 2-hydroxyethyl acrylate were added dropwise and the mixture was kept farther at 60° C. until the isocyanate content had fallen below 0.1%. Cooling was then effected. The product was obtained as a light yellow liquid.
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15](C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:17][CH2:18][NH2:19])=[CH:11][CH:10]=1)[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8]>C(O)C.[Pd]>[O:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:13][CH:14]=1)[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8]
Reactant: COCCOCCOc1ccc(C(CCCN)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COCCOCCOc1ccc(CCCCN)cc1
Reaction time: 5 h
Yield: 99.1 %

Procedure:
Compound 106 (800 mg, 2.0 mmol) in ethanol (20 mL), was subjected to 1 atmosphere of H2 in the presence of 10% palladium on carbon (100 mg, cat.) with stirring for 5 h. After standing overnight, the reaction was purged with N2 then suction filtered through celite and washed off the celite with methylene chloride. The solvents were evaporated and chromatographed (silica gel, 200:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford 530 mg (>99%) of amine 107. 1H NMR (300 MHz, CDCl3) d 1.31 (br s, 2H), 1.41-1.52 (m, 2H), 1.55-1.67 (m, 2H), 2.56 (t, J=7.7 Hz, 2H), 2.70 (t, J=7.0 Hz, 2H), 3.39 (s, 3H), 3.58 (m, 2H), 3.72 (m, 2H), 3.84 (t, J=4.9 Hz, 2H), 4.12 (t, J=5.3 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H). CI MS m/z=268 [C15H25NO3+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]([C:15]2[S:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=3)=[CH:18][CH:19]=2)=[CH:13][C:12]([CH2:30][OH:31])=[N:11]1.Br.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1.CN(C=[O:45])C>>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]([C:15]2[S:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:21]=3)=[CH:18][CH:19]=2)=[CH:13][C:12]([CH2:30][O:31][O:45][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[N:11]1
Reactant: BrCc1ccccn1
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CO)nn3-c3ccccc3Cl)s2)c1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(COOCc4ccccn4)nn3-c3ccccc3Cl)s2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
NaH (60% in mineral oil, 90 mg, 2.25 mmol) was added at 0° C. to a stirred mixture of [1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methanol (222 mg, 0.5 mmol), 2-(bromomethyl)pyridine hydrobromide (190 mg, 0.75 mmol), and anhydrous DMF (5 mL) under N2, the resulting mixture was stirred at it for 4 h. The reaction mixture was poured into ice-water, and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-100% EtOAc/hexanes) to give the title compound as a colorless semi-solid (179 mg, 67%). 1HNMR (CDCl3): δ 8.58 (m, 1H), 8.04 (m, 1H), 7.82 (m, 1H), 7.74-7.71 (m, 2H), 7.57-7.44 (m, 6H), 7.20 (m, 2H), 6.76 (m, 2H), 4.78 (m, 4H), 3.08 (s, 3H). MS(ES): 536 [M+H]+.
Reaction SMILES: [Cl-].[Cl-].[CH:3]([O:6][Ti+2:7][O:8][CH:9]([CH3:11])[CH3:10])([CH3:5])[CH3:4].[CH:12](=[O:14])[CH3:13].C1C[O:18][CH2:17][CH2:16]1>>[CH:3]([O:6][Ti:7]([O:8][CH:9]([CH3:11])[CH3:10])([O:18][CH:17]=[CH2:16])[O:14][CH:12]=[CH2:13])([CH3:5])[CH3:4]
Reactant: CC(C)O[Ti+2]OC(C)C
Reactant: C1CCOC1
Reactant: CC=O
Agent: [Cl-]
Product: C=CO[Ti](OC=C)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diisopropoxytitanium dichloride (0.262 g, 1.10 mmol) was dissolved in 20 ml of THF (dry, nitrogen atmosphere) in a 100 ml Schlenk flask. This solution was cooled to -78° C. at which point the lithium enolate of acetaldehyde, CH2 =CHOLi, in THF solution (2.20 mmol) was added to the stirred solution via syringe. This solution was allowed to warm to room temperature. After two hours of stirring, the solvent was evaporated by trap-to-trap distillation, leaving a yellow solid. This solid was extracted with pentane yielding a yellow pentane-soluble solid (crude yield 0.19 g, 70%). 1H NRM (CDCl3) δ 1.19 (d, J=6.4 Hz, 6.7H, CH--(CH3)2), 3.10 (d, J=28 Hz, 1H, OCH=CH2), 3.62 (s, 1H, OCH=CH2), 4.00 (sept, J=6.45 Hz, 1H, CH--(CH3)2), 6.55 (d, J=10.3 Hz, 1H, OCH=CH2), 7.01 (d, J=19.7, 1H, OCH=CH2).
Reaction SMILES: C(OCC)(OCC)[O:2][CH2:3][CH3:4].[O:11]=[C:12]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].O.[C:28]1(C)C=CC(S(O)(=O)=O)=C[CH:29]=1>CCO>[CH2:28]([O:11][C:12]([O:2][CH2:3][CH3:4])([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:29]
Reactant: CCOC(=O)CCC(=O)CCC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(OCC)OCC
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCC(CCC(=O)OCC)(OCC)OCC
Temperature: 77 °C
Reaction time: 20 h

Procedure:
To EtOH (27.8 L), triethyl orthoformate (9.26 L, 55.6 mol) and diethyl 4-oxopimelate (5.93 L, 27.8 mol) was added p-toluenesulfonic acid monohydrate (0.053 kg, 0.278 mol), and the reaction mixture was heated to 77.0° C. with stirring for 20 h. Heating was discontinued, and ethanol was removed by distillation under vacuum, starting with the batch at 63° C. The remaining orange ketal solution was dissolved in toluene (32 L) and transferred to a 100-L extractor that had been charged with 2% NaHCO3 (24 L), with stirring.
Reaction SMILES: CN([P:4]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)C.[ClH:19]>>[C:8]1([CH3:11])[CH:9]=[CH:10][C:5]([P:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[Cl:19])=[CH:6][CH:7]=1
Reactant: Cl
Reactant: Cc1ccc(P(c2ccc(C)cc2)N(C)C)cc1
Product: Cc1ccc(P(Cl)c2ccc(C)cc2)cc1

Procedure:
U.S. Pat. No. 2,934,564 relates to compounds of the general formula R2PX wherein R represents an alkyl or aryl group and X represents chlorine, bromine or iodine. For example, the reaction of Me2NPCl2 (0.42 mole) with p-tolylmagnesium bromide (0.84 mole) produces dimethylamino-di-p-tolylphosphine. The isolated dimethylamino-di-p-tolylphosphine (31.88 mmoles) was treated with 1428 cc (63.75 mmoles) of anhydrous HCl yielding di-p-tolylchlorophosphine, which was purified by distillation. Similarly, Burg, et al. (J.A.C.S. 80, 1107-09, 1958) disclose the preparation of chlorodimethylphosphine from Me2NPCl2 and suggest the viability of a Grignard route to R2PR'-type phosphines. K. Issleib, et al. (Chem. Berichte 29, 2682-3008, 1959) have shown that Et2NPCl2 (Et=ethyl) and cyclohexylmagnesium chloride react in a 1:1.25 molar ratio to form diethylaminocyclohexylchlorophosphine in 57.5% yield. The authors suggest this reaction can be exploited to prepare unsymmetrical chlorophosphines of the type RR'PCl, but no mention is made of the possibility of further reaction to unsymmetrical tertiary phosphines of the type RR'R"P.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][N:20]([C:22](OCC4C=CC=CC=4)=O)[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[O:43]C(O)[CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C(OCC)(=O)C.[Pd]>[F:17][C:14]1[CH:15]=[CH:16][C:11]2[N:7]([C:8]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[C:6]3[CH2:5][CH2:21][N:20]([CH2:22][CH2:41][CH2:40][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[OH:43])[CH2:19][C:18]=3[C:12]=2[CH:13]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1
Reactant: OC1CCC(c2ccc(F)cc2)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: OC(CCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1)c1ccc(F)cc1
Reaction time: 20 h

Procedure:
In a Parr bottle were combined 5% Pd/C (5 g of 50% water-wet), 8-fluoro-5-(p-fluorophenyl)-2-carbobenzoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (5.0 g, 0.0119 mole) in 100 ml ethyl acetate, and 5.5 grams (0.03 mole) 5-(p-fluorophenyl)-2-hydroxytetrahydrofuran in 100 ml ethyl acetate. The mixture was agitated and hydrogenated at 30-40 psig for 20 hours. The solution was filtered to recover catalyst, with ethyl acetate and CH2Cl2 wash. The filtrate and washes were concentrated in vacuo to a viscous oil. The oil was dissolved in 400 ml ethyl acetate and filtered. The solution was concentrated to an oil, diluted with 150 ml ether, and filtered to yield title product, 3.8 gm, m.p. 145°-149° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C@H:19]([C:21]2[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=2)[CH3:20])=[N:4][C:5]([NH:11][C:12]2[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=2)=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.O.Cl[Sn]Cl.[CH:33](OCC)(OCC)OCC>CCO>[F:1][C:2]1[CH:7]=[C:6]2[N:8]=[CH:33][N:11]([C:12]3[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=3)[C:5]2=[N:4][C:3]=1[NH:18][C@H:19]([C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1)[CH3:20]
Reactant: CCOC(OCC)OCC
Reactant: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)c(F)cc2[N+](=O)[O-])n[nH]1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(-n2cnc3cc(F)c(N[C@@H](C)c4ncc(F)cn4)nc32)n[nH]1
Temperature: 70 °C

Procedure:
To a solution of 3-fluoro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N6-(5-methyl-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine (Intermediate 42, 3.05 mmol) in EtOH (5 ml) were added SnCl2.2H2O (1.74 g, 9.18 mmol) and triethyl orthoformate (0.652 ml). The resulting solution was heated to 70° C. overnight. The mixture was allowed to cool to room temperature and filtered through Celite® and washed with EtOAc. Evaporation of the volatiles under reduced pressure gave a colored residue that was purified by Gilson (5%→95% MeCN/H2O) to give the title compound. LC-MS: 357 [M+1]. 1H NMR δ 2.01 (d, 3H) 2.34 (s, 3H) 6.46-6.55 (m, 1H) 8.20 (s, 1H) 8.72 (s, 1H) 8.87 (s, 2H) 9.72 (s, 1H) 9.86 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:34]=[CH:33][C:24]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[C:23]([CH3:35])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]>CO>[CH2:1]([C:3]([C:21]1[CH:34]=[CH:33][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[C:23]([CH3:35])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(C=C2SC(=O)NC2=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Solvent: CO
Product: CCC(CC)(c1ccc(CC2SC(=O)NC2=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Yield: 34 %

Procedure:
To a mixture of enantiomer 2 of 5-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzylidene)-thiazolidine-2,4-dione (example Rupp-7) (0.25 g, 0.50 mmol) and MeOH (10 mL) is added Mg (0.12 g, 5.04 mmol). The solution is heated at a reflux for 4 hours. The solution is filtered thru Celite®, rinsed with MeOH (2 mL), and the solution concentrated. The residue is purified by ISCO (15%-30% EtOAc gradient) to furnish the title compound (0.084 g, 0.17 mmol, 34%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[C:4](Cl)[N:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18][CH2:19][CH3:20])=[CH2:17])CCC.[F-].[K+].CC(OC)(C)C>CN(C=O)C.O.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>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[CH2:17])[N:3]=1
Reactant: Cc1c(Cl)nc(Cl)nc1Cl
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: C=C(OCC)c1nc(Cl)nc(Cl)c1C
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
2,4,6-Trichloro-5-methylpyrimidine (2.0 g, 10.13 mmol) and bis(triphenylphosphine)palladium chloride (0.142 g, 0.20 mmol) in DMF (40 mL) was degased. Tributyl(1-ethoxyvinyl)stannane (3.59 mL, 10.64 mmol) was added. The mixture was heated at 100° C. for 1.5 h under nitrogen atmosphere. The mixture was poured into a solution of KF (6 g) in water (100 mL). MTBE (100 mL) was added mixture was for stirred 10 min. The solid was removed by filtration and was washed with MTBE (60 mL). The organic phase was washed with water, dried over sodium sulfate and evaporated. The mixture was purified by column chromatography eluting with DCM to give the title compound as a solid, 1.15 g (49%).