Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:23](OCC)=[O:24])=[CH:4][CH:3]=1.[Al].[Li]>>[CH3:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:23][OH:24])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(-c3cccc(C)c3)ccc2n1Cc1ccc(C)cc1
Agent: [Al]
Agent: [Li]
Product: Cc1ccc(Cn2c(CO)cc3cc(-c4cccc(C)c4)ccc32)cc1

Procedure:
The title compound was prepared from ethyl 1-(4-methylbenzyl)-5-(3-methylphenyl)-1H-indole-2-Carboxylate and lithium aluminum in substantially the same manner, as described in step 3 of Example 1. The product was obtained as a white solid. Mass spectrum (ESI, [M+H]+) m/z 342. 1H NMR (400 MHz, DMSO-d6)δ 7.77 (s, 1H), 7.46 (s, 1H), 7.42 (d, 1H, J=7.79 Hz), 7.37 (d, 1H, J=8.55 Hz), 7.33 (d, 1H, J=8.56 Hz), 7.31 (d, 1H, J=7.02 Hz), 7.29 (d, 1H, J=7.48 Hz), 7.10–7.07 (m, 4H), 6.96 (d, 2H, J=7.94 Hz), 6.48 (s, 1H), 5.54 (s, 2H), 5.33 (s, 1H), 4.60 (s, 2H), 2.36 (s, 3H), and 2.23 ppm (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[H][H].[CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([CH:2]([CH3:4])[CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccccc1
Reactant: CC(C)=O
Reactant: [H][H]
Product: CC(C)c1ccccc1

Procedure:
The acetone from the step (b) is reacted with hydrogen and benzene to give cumene.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2cccc(F)c2)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B25 from 2-Iodo-5-methanesulfonyl-benzoic acid (example B19(b)) and 3-fluorobenzeneboronic acid. Yellow solid. MS (m/e): 293.2 ([M−H], 100%).
Reaction SMILES: [CH:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\CCCC.[CH3:18][C:19](OC(C)=O)=[O:20].N1C=CC=CC=1.C(O)CCCCCC/C=C\CCC>>[C:19]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH3:12])(=[O:20])[CH3:18]
Reactant: CCCC/C=C\CCCCCCCCCC=O
Reactant: CC(=O)OC(C)=O
Agent: CCC/C=C\CCCCCCCO
Solvent: c1ccncc1
Product: CCC/C=C\CCCCCCCOC(C)=O
Yield: 90 %

Procedure:
By acetylation of compound 2: According to the procedure for compound 6, Ac2O (0.29 mL, 3.0 mmol), pyridine (0.14 mL, 1.8 mmol), and alcohol 12 (0.28 g, 1.5 mmol) were reacted to provide 13 (19 g, 90% yield, 86% Z as determined by 1H-NMR) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[OH:11].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([OH:11])[CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)c(O)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 2-chloro-5-nitrophenol (20.0 g, 115.2 mmol) in ethanol (150 ml) and water (150 ml) was added iron powder (32.2 g, 576.2 mmol) and ammonium chloride (32.1 g, 599.3 mmol). The mixture was heated at reflux for two hours, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/9:1) gave 5-amino-2-chloro-phenol (15.85 g, 96%) as a white solid.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.[CH2:6]([O:13][CH2:14][CH2:15][CH2:16]CO)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:2][Br:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCCOCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCOCc1ccccc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
239 g of tetrabromomethane is added in portions to the solution of 105 g of 4-benzyloxy-butan-1-ol and 191 g of triphenylphosphine in 1 l of methylene chloride that is cooled to −15° C., and after the addition has been completed, it is stirred for 1 hour at 0° C. After the reaction mixture was concentrated by evaporation in a vacuum, the purification by chromatography on silica gel is carried out with a hexane-ethyl acetate gradient. 133 g of 4-benzyloxy-1-bromo-butane is obtained as an oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21]([CH3:23])=[O:22].C1CCN2C(=NCCC2)CC1>C1COCC1.C(OCC)(=O)C>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH:20]([C:21](=[O:22])[CH3:23])[C:19]([O:25][CH2:26][CH3:27])=[O:24])(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: CCOC(=O)CC(C)=O
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(P(=O)(OCC)OCC)P(=O)(OCC)OCC)C(C)=O

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I, 3.00 g), ethyl acetoacetate (II, 1.4 ml), and DBU (0.25 ml) are heated to 500 in THF (20 ml) for 1.5 hours. The reaction is cooled, diluted with ethyl acetate, filtered through magnesium sulfate and concentrated under reduced pressure. The concentrate is chromatographed eluting with ethyl acetate, ethyl acetate/acetone (1/1). The appropriate fractions are pooled and concentrated to give the title compound, MS (m/e) 430 (M+), 388, 339, 301 and 288; IR (neat) 2984, 1740, 1716, 1478, 1444, 1392, 1368 and 1250 cm- ; NMR (CDCl3) 4.20, 2.43, 2.29, 1.35 and 1.28 δ.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].OP(O)(O)=O.[OH2:18]>>[CH2:10]([OH:11])[C@H:8]1[O:9][C@H:1]([O:12][C@:8]2([CH2:10][OH:11])[O:18][C@H:2]([CH2:1][OH:12])[C@@H:4]([OH:5])[C@@H:6]2[OH:7])[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O
Agent: O=P(O)(O)O
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O

Procedure:
Mannitol (45.0 g) and H3PO4 (1.96 g) are dissolved into water for injectables (800 ml) in order to obtain the starting saccharose solution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=O)=[CH:13][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[C:30]([C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].[H-].[Na+]>C1COCC1.C1C=CC=CC=1>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([NH:38][C:23]([C:14]2[C:15]3[O:19][C:18]([CH3:20])=[N:17][C:16]=3[C:21]3[NH:22][C:10]([NH:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:11][C:12]=3[CH:13]=2)=[O:25])=[CH:39][CH:40]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(C(C)(C)C)cc1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 10.7 %

Procedure:
The title compound was prepared following the procedure as described for Example-177 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.100 g, 0.276 mmol), benzene (4 mL), thionyl chloride (5.0 mL), 4-tert-butylaniline (0.123 g, 0.828 mmol), THF (5.0 mL) and 60% NaH (0.033 g, 0.825 mmol). The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.28 (s, 9H), 2.65 (s, 3H), 6.54 (s, 1H), 7.37 (d, J=7.8 Hz, 3H), 7.60-7.68 (m, 4H), 9.43 (s, 1H), 9.93 (s, 1H), 11.56 (s, 1H); MS [M+H]+: 508.57.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9].[CH3:20]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[OH:61][C:54]1[C:53]([CH2:52][NH:51][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:2]3[CH:1]=[C:6]([CH3:20])[CH:5]=[CH:4][CH:3]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:58]([CH3:59])[CH:57]=[C:56]([CH3:60])[N:55]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1ccccc1OC(C)c1ccc(C(=O)O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(OC(C)c2ccc(C(=O)NCc3c(C)cc(C)nc3O)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.4 %

Procedure:
To the solution of 4-(1-(o-tolyloxy)ethyl)benzoic acid (124 mg, 0.48 mmol) in dichloromethane (80 mL) was added o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (274 mg, 0.72 mmol) and triethylamine (145 mg, 1.44 mmol). then the 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (73 mg, 0.48 mmol) was added, the solution was stirred at room temperature for 12 hours, then washed with water (50 mL*3), the organic layer was evaporated and purified by column chromatography (silica gel, dichloromethane/meth anol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(m-tolyloxy)ethyl)benzamide (57 mg, 30%). LRMS (M+H+) m/z: calcd: 390.19. found 390; 1H-NMR (300 MHz, CD3OD) δ 7.75 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.71-7.08 (m, 1H), 6.97-6.92 (m, 1H), 6.77-6.66 (m, 2H), 6.10 (s, 1H), 5.46-5.44 (m, 1H), 4.48 (s, 2H), 2.36 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 1.62 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[CH:8][CH:9]=1.O1CCCC1>[Fe].C(O)(=O)C>[CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:8][CH:9]=1
Reactant: CC(C)(C)C#Cc1ccc(-c2ccccc2[N+](=O)[O-])s1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1ccc(-c2ccccc2N)s1
Temperature: 80 °C

Procedure:
A mixture of 2-(3,3-dimethyl-but-1-ynyl)-5-(2-nitro-phenyl)-thiophene (22 g, 76 mmol), tetrahydrofurane (100 ml) and acetic acid (425 ml of a 5% aqueous solution) was heated to 80° C. Iron powder (66 g, 1.2 mol) was added in small portions at this temperature. The reaction mixture was heated for 5 hours to reflux. After cooling, it was poured on ice and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated, delivering Compound No. 5.030.i (20 g).
Reaction SMILES: C(OC1C(=O)N=C(CC2C(C3C=CC=CC=3)=CC=CN=2)N2CCN(C(C)C)C(=O)C=12)C1C=CC=CC=1.[CH2:37]([O:44][C:45]1[C:46]([C:58]([N:60]([CH2:64][CH2:65]O)[CH:61]([CH3:63])[CH3:62])=[O:59])=[N:47][C:48]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)=[N:49][C:50]=1[OH:51])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:44][C:45]1[CH:46]2[C:58](=[O:59])[N:60]([CH:61]([CH3:62])[CH3:63])[CH2:64][CH2:65][N:47]2[C:48]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)=[N:49][C:50]=1[OH:51])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(-c2ccccn2)nc(O)c1OCc1ccccc1
Agent: CC(C)N1CCn2c(Cc3ncccc3-c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CC(C)N1CCN2C(c3ccccn3)=NC(O)=C(OCc3ccccc3)C2C1=O

Procedure:
The title compound was prepared in analogy to (167) from 5-benzyloxy-6-hydroxy-N-(2-hydroxyethyl)-N-isopropyl-2-(2-pyridyl)pyrimidine-4-carboxamide (194) as a light yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][OH:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:10]2.I[CH2:32][CH3:33].FC1C=C(F)C=CC=1[C@]12CO[C@@H](COC)C[C@H]1[C@@H](C)SC(NC(=O)C1C=CC=CC=1)=N2.CO>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH2:32][CH3:33])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[N:10]2
Reactant: CCI
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@@H]12
Agent: COC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Solvent: ClCCl
Solvent: CO
Product: CCOC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P2) was reacted with iodoethane according to the method described for synthesis of N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(methoxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C20) in Example 2. In this case, additional silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) was carried out. The product was obtained as a white solid. Yield: 24.8 mg, 53.8 μmol, 41%. LCMS m/z 461.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.12 (br d, J=7 Hz, 2H), 7.51-7.57 (m, 1H), 7.39-7.48 (m, 3H), 7.01-7.11 (m, 2H), 4.14 (br d, J=12 Hz, 1H), 3.89 (d, J=11.9 Hz, 1H), 3.82-3.89 (m, 1H), 3.47-3.61 (m, 4H), 3.19-3.27 (br m, 1H), 2.97-3.04 (m, 1H), 1.74-1.82 (m, 1H), 1.51-1.63 (m, 1H), 1.25 (d, J=6.8 Hz, 3H), 1.17 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.[OH-].[Na+].O>C(O)C.C(O)(=O)C>[O:20]1[CH2:19][CH:18]1[CH2:16][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(OCC3CO3)cccc2[nH]1

Procedure:
4.2 g of 4-hydroxy 2-ethoxycarbonyl indole and 40 ml of epichlorohydrine are dissolved by heating in an inert atmosphere in 40 ml of absolute ethanol then 0.82 g of sodium hydroxide in pellet form is added and the mixture is taken to reflux for 5 hours. Water is added to the reaction mixture and it is neutralized by the addition of acetic acid. The solvents are evaporated in vacuo then extracted with methylene chloride. The organic solution is dried over sodium sulfate and the solvent is evaporated to dryness in vacuo. The residue is chromatographed over a column of silica gel. By elution with the ether-pentane (80-20 vol/vol) mixture, the expected compound is obtained (3.5 g), m.p.: 142°-144° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]#[C:19][Si](C)(C)C)[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]3([CH3:17])[CH3:16])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([C:4]2[CH:5]=[C:6]([C:18]#[CH:19])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]3([CH3:17])[CH3:16])[CH2:3][CH2:2]1
Reactant: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)cc(C3CC3)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2

Procedure:
Following general procedure E and using 8-cyclopropyl-6-trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman (Intermediate 33, 0.1 7 g, 0.68 mmol), methanol and potassium carbonate (0.2 g, 1.47 mmol) the title compound was obtained as an oil (0.064 g, 47%).
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[O:4].Cl.[CH3:22][NH:23][CH3:24].C(N(CC)CC)C>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH:2]([N:23]([CH3:24])[CH3:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)#[N:14]
Reactant: CNC
Reactant: N#Cc1ccc(CNC(=O)C(Br)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(C(=O)NCc1ccc(C#N)cc1)c1ccccc1
Reaction time: 19 h
Yield: 92.6 %

Procedure:
To a stirred solution of (RS)-2-bromo-N-(4-cyano-benzyl)-2-phenyl-acetamide (200 mg) in THF (10 ml) at rt under an Ar atmosphere were added dimethylamine, hydrochloride (149 mg), triethylamine (0.42 ml) and tetrabutylammonium iodide (34 mg). The reaction mixture was stirred for 19 hrs, then treated with additional dimethylamine, hydrochloride (149 mg) and triethylamine (0.42 ml). After another 8 hrs stirring at rt, the solids were filtered off and washed with EtOAc. The filtrate was washed with water and brine, dried over MgSO4 and concentrated. The product was isolated by chromatography (silica gel, gradient dichloromethane=>dichloromethane/MeOH 9:1) to give (RS)-N-(4-cyano-benzyl)-2-dimethylamino-2-phenyl-acetamide (165 mg). Orange solid. MS 294.3 ([M+H]+)
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH2:29])[CH2:20][C:21]2[CH:26]=[C:25](F)[CH:24]=[C:23](F)[CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3].[C:31]([NH:34][C@:35]1([CH:48]([CH2:50][CH3:51])[CH3:49])[CH2:39][CH2:38][N:37]([C@@H:40]([CH2:44][CH:45]=[CH2:46])[C:41](O)=[O:42])[C:36]1=[O:47])(=[O:33])[CH3:32].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:31]([NH:34][C@:35]1([CH:48]([CH2:50][CH3:51])[CH3:49])[CH2:39][CH2:38][N:37]([C@@H:40]([CH2:44][CH:45]=[CH2:46])[C:41]([NH:29][C@H:19]([C@H:18]([OH:30])[CH2:17][NH:16][C@@H:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=3)[C@H:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH2:6]2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:42])[C:36]1=[O:47])(=[O:33])[CH3:32]
Reactant: C=CC[C@@H](C(=O)O)N1CC[C@](NC(C)=O)(C(C)CC)C1=O
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(OC)ccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC=C)N2CC[C@](NC(C)=O)(C(C)CC)C2=O)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
Step N (1): (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-difluorophenyl)butan-2-ol (20 mg, 0.05 mmol) from step E (2), (S)-2-((S)-3-acetamido-3-sec-butyl-2-oxopyrrolidin-1-yl)pent-4-enoic acid (14 mg, 0.048 mmol) from step L (7), EDC (10 mg, 0.05 mmol), HOBt (7 mg, 0.05 mmol), DIEA (40 μL, 0.24 mmol) were mixed in 2 mL of DMF. The mixture was stirred at RT for 24 h. Purified with reverse phase Prep-HPLC to give 14.1 mg of (S)-2-((S)-3-acetamido-3-sec-butyl-2-oxopyrrolidin-1-yl)-N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-yl)pent-4-enamide as a light brown viscous residue (TFA salt): LC-MS (M+H)+=661.37, 1H NMR (300 MHz, CDCl3) δ ppm 0.82 (t, J=5.86 Hz, 2H) 0.89-1.69 (m, 5H) 1.86-2.04 (m, 4H) 2.35-2.90 (m, 5H) 3.05-4.17 (m, 19H) 4.57 (d, J=6.59 Hz, 1H) 4.75 (d, J=4.76 Hz, 1H) 4.87-4.98 (m, 1H) 5.12-5.34 (m, 1H) 5.38-5.57 (m, 1H) 5.78-5.94 (m, 1H) 6.01 (s, 1H) 6.84-6.95 (m, 1H) 7.02-7.36 (m, 8H) 7.70 (d, J=9.15 Hz, 1H).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([OH:16])[CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1.O>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([O:16][CH:7]([CH2:8][S:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:21]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: OC(CSc1ccccc1)Cn1ccnc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(OC(CSc1ccccc1)Cn1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(1-imidazolyl)-3-phenylthiopropan-2-ol and 5 g (0.213 mole), in pyridine (15 ml) was cooled in an ice and water bath; then 4.9 g [3.3 ml (0.0235 mole)] 2,4-dichlorobenzoyl chloride was added dropwise. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with a sodium bicarbonate solution, then several times with water and once with brine, dried, treated with activated charcoal, filtered and concentrated to give a brown gum (8.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:25][C:26](=[CH2:30])[C:27](Cl)=[O:28]>C(OCC)C>[F:25][C:26](=[CH2:30])[C:27]([O:17][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)([C:9]([F:11])([F:12])[F:10])[C:13]([F:14])([F:15])[F:16])=[O:28]
Reactant: C=C(F)C(=O)Cl
Reactant: OC(c1ccc(F)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(F)C(=O)OC(c1ccc(F)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
A solution of 40 g (0.153 mol) of 2-(4-fluorophenyl)-hexafluoro-2-propanol and 15.5 g (0.153 mol) of triethylamine in 75 ml of dry diethyl ether were added dropwise with stirring at a temperature of 25° C. to a solution of 18 g (0.166 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 25 ml of dry diethyl ether in the course of 45 minutes. The reaction mixture was then stirred at a temperature of 25° C. for a further 2 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.01 g of hydroquinone monomethyl ether. 42.5 g (83 percent of theory) of 2-(4-fluorophenyl)-hexafluoro-2-propyl α-fluoroacrylate having a boiling point of 70° to 73° C. (under 0.5 mbar) were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:8])[CH2:4][CH2:3]1.[C:22]([Cl:26])(=[O:25])[CH2:23][CH3:24]>CCOCC>[ClH:26].[CH3:1][N:2]1[CH2:3][CH2:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([O:8][C:22](=[O:25])[CH2:23][CH3:24])[CH2:6][CH2:7]1
Reactant: CCC(=O)Cl
Reactant: CN1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Solvent: CCOCC
Product: CCC(=O)OC1(c2ccccc2Cc2ccccc2)CCN(C)CC1
Product: Cl
Reaction time: 137 h

Procedure:
1.41 g of 1-methyl-4-(α-phenyl-2-tolyl)-4-piperidinol, Example 1, is treated with 5.0 ml of propionyl chloride with stirring and cooling. The reaction mixture, at ambient temperature, is stirred for 30 minutes and then permitted to stand for 137 hours under nitrogen. The mixture is diluted with 5.0 ml of ether, stirred for 5 minutes and the resulting precipitate collected by suction filtration. The filter cake is washed thoroughly with ether and recrystallized twice from isopropyl alcohol to give colorless crystals, mp 191°-193° C. of 1-methyl-4-(α-phenyl-2-tolyl)-4-propionyloxypiperidine hydrochloride.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH3:30][N:26]1[CH2:27][CH2:28][CH2:29][C@@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN1CCC[C@@H]1c1nnc2ccc(F)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC[C@@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Intermediate A (245 mg, 1.50 mmol) in DMF (4 mL) was added NaH (60% dispersion in oil, 180 mg, 4.50 mmol) and the mixture stirred at RT for 0.5 h. A solution of Intermediate 60a (330 mg, 1.50 mmol) in DMF (5 mL) was added and the mixture stirred at 60° C. for 2 h. The cooled solution was diluted with water and extracted with DCM (5×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-15% [2M NH3 in MeOH] in DCM, to give the title compound as a brown solid after freeze-drying (408 mg, 74%). LCMS (Method 3): Rt 0.44 min, m/z 364 [MH+].