Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].[CH2:13]([Mg]Br)[CH2:14][CH:15]=[CH2:16]>>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)([OH:5])[CH2:16][CH2:15][CH:14]=[CH2:13]
Reactant: C=CCC[Mg]Br
Reactant: O=C(CCCl)c1ccc(F)cc1
Product: C=CCCC(O)(CCCl)c1ccc(F)cc1

Procedure:
1-chloro-3-(4-fluorophenyl)hept-6-en-3-ol was prepared from 3-chloro-1-(4-fluorophenyl)propan-1-one and 3-butenylmagnesium bromide following a procedure analogous to that described in Example 110 Step 1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][C@@H:9]1[CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[ClH:34].[CH:23]1([O:22][C:16]2[CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][C@@H:9]([CH2:28][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[CH2:10]3)[CH:19]=[CH:18][C:17]=2[O:20][CH3:21])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(N2CCN(C(=O)OC(C)(C)C)[C@@H](CN3CCCC3)C2)cc1OC1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N2CCN[C@@H](CN3CCCC3)C2)cc1OC1CCCC1
Reaction time: 3 h

Procedure:
The intermediate (S)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)-2-pyrrolidin-1-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.65 mmol) was then dissolved in 1,4-dioxane (2 mL) and treated with a 4 N solution of hydrogen chloride in 1,4-dioxane (4 mL) and stirred for 3 h. The reaction was then evaporated to afford the title compound as a colorless solid. (280 mg, 99%). LC/MS (Method B) 1.05 min, [M+1]+ 360.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1)=[O:4].[C:15]([O:19][C:20](=[O:33])[CH2:21][C@H:22]([NH2:32])[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1)([CH3:18])([CH3:17])[CH3:16].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[C:15]([O:19][C:20](=[O:33])[CH2:21][C@@H:22]([C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1)[NH:32][C:12]([C:10]1[S:11][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:8][CH:9]=1)=[O:14])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)CCc1ccc(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1ccc2c(c1)OCO2
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C(=O)N[C@@H](CC(=O)OC(C)(C)C)c2ccc3c(c2)OCO3)s1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 130 %

Procedure:
214 mg (1 mmol) of 5-(2-methoxycarbonyl-ethyl)-thiophene-2-carboxylic acid (example 1, step b) were dissolved in 5 ml of anhydrous dimethylformamide. 265 mg (1 mmol) of (3S)-3-amino-3-(benzo[1,3]dioxol-5-yl)-propionic acid tert-butyl ester and 328 mg (1 mmol) of TOTU were added, and 3 mmol (0.51 ml) of N,N-diisopropyl-N-ethylamine were added to keep the pH of the mixture at 7.5 to 8. The reaction mixture was stirred for 4.5 hours at room temperature. Solvents were removed under reduced pressure to give a dark brown oil. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution, 10% citric acid and with water. Then the organic phase was dried with anhydrous magnesium sulfate. After filtration the solvents were removed in vacuo to give 600 mg of a brownish oil which was purified by chromatography (silica gel; ethyl acetate/heptane (1/2, v/v)). 425 mg of a resin were obtained.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=O)[CH3:8])[CH3:3].[CH3:12][C:13]([CH3:15])=[O:14]>[Cu]=O.[O-2].[Zn+2]>[CH3:3][C:2]([CH3:1])=[CH:4][CH2:5][CH2:6]/[C:7](/[CH3:8])=[CH:9]/[CH:10]=[CH:12]/[C:13]([CH3:15])=[O:14]
Reactant: CC(C)=O
Reactant: CC(C)=CCCC(C)=CC=O
Agent: O=[Cu]
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)/C=C/C=C(\C)CCC=C(C)C

Procedure:
50 Parts of citral and 100 parts of acetone are reacted for 45 minutes at 200° C and a pressure of 80 atmospheres in the presence of 12 parts of a catalyst consisting of 12% by weight of copper(II) oxide and 88% by weight of zinc oxide. 45.6 parts of pseudoionone having a boiling point of 90° C at 0.01 mm is obtained analogously to Example 1. The conversion is 82% of theory and the yield based on citral is 88% of theory.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH:16]=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:18]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+]>CN(C)C(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:16]([C:14]1[N:15]=[C:8]2[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:12][CH:11]=[N:10][N:9]2[C:13]=1[C:27]1[CH:28]=[CH:29][C:24]([C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:31])=[CH:25][CH:26]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: O=Cc1cn2nccc(N3CCOCC3)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
To a mixture of compound 5e (0.57 g, 2.5 mmol), tert-butyl-4-bromobenzoate (0.97 g, 3.7 mmol), palladium acetate (38 mg, 0.17 mmol), triphenylphosphine (45 mg, 0.17 mmol) and potassium acetate (0.72 g, 7.3 mmol) were added while under an argon atmosphere and in dry N,N-dimethylacetamide (5 mL). The reaction mixture was stirred at 110° C. for 22 h, allowed to cool to rt, diluted with water (100 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The obtained residue was purified by flash chromatography on silica gel (10-60% EtOAc/heptane) to give compound 5f as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 10.13 (s, 1H), 8.13-8.21 (m, J=8.1 Hz, 2H), 8.09 (d, J=5.6 Hz, 1H), 7.85 (d, J=8.3 Hz, 2H), 6.15 (d, J=5.6 Hz, 1H), 4.02-4.14 (m, 4H), 3.90-4.00 (m, 4H), 1.62 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH:20]([O:22][C:23](=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH3:21])=[O:18].N1C=CC=CC=1.[C:47]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80](Cl)=[O:81])(=[O:63])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]>C1COCC1>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH:20]([O:22][C:23](=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:80](=[O:81])[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75][CH2:74][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][O:64][C:47](=[O:63])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH3:21])=[O:18]
Reactant: CC(OC(=O)CCCCCCCCCCCCCCCO)OC(=O)CCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)OC(C)OC(=O)CCCCCCCCCCCCCCCO
Reaction time: 2 h
Yield: 29.4 %

Procedure:
Ethylidene bis (16-hydroxyhexadecanoate) (4.38 g, 7.67 mmol) was dissolved in THF (80 ml) and pyridine (0.61 g, 7.71 mmol) was added. 16-hexadecanoyloxyhexadecanoyl chloride (4.18 g, 7.90 mmol) was dissolved in THF (20 ml) and added dropwise. After 3 days at room temperature the mixture was filtered and the filtrate was left -20° C. for 2 hours. The precipitated product was filtered and purified by flash chromatography (silicagel, chloroform) to give 2.4 g (29%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 0.85 (t, 3H, CH3), 1.2-1.4 (s, 90H, --CH2 --), 1.45 (d, 3H, --O--CH(CH3)--O--), 1.5-1.7 (m, 14H, --CH2 --), 2.25 (m, 8H, --CH2 --C(O)--O--), 3.60 (t, 2H, --CH2 --OH), 4.05 (t, 4H, --C(O)--O--CH2 --), 6.85 (q, 1H, --O--CH(CH3)--O--). 13C NMR (75 MHz, CDCl3): δ 13.7, 19.1, 22.2, 24.2, 24.6, 25.2, 25.5, 28.2, 28.5, 28.7, 28.8, 29.0, 29.2, 31.5, 32.3, 33.7, 34.0, 62.5, 64.0, 88.0, 171.5, 173.5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39]O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CN1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][O:1][C:2]2[CH:3]=[C:4]([O:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=2[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=S(=O)(Oc1ccc(Cc2ccccc2)c(O)c1)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cc(OS(=O)(=O)c3ccccc3Cl)ccc2Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To 294 mg (0.787 mmol) of 2-chlorobenzenesulfonic acid 3-hydroxy-4-benzylphenyl ester, as prepared in the preceding step, in tetrahydrofuran (5 mL) containing 236 μL (1.10 mmol) of N-tert-butoxycarbonyl-4-piperidinemethanol, as prepared in step f of Example 1, 300 μL (2.72 mmol) of N-methylmorpholine, and 309 mg (1.18 mmol) of triphenylphosphine was added 185 μL (1.18 mmol) of diethyl azodicarboxylate. The reaction mixture was stirred at ambient temperature for 1 h, quenched with saturated NaHCO3, and extracted into ether. The organic phase was dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (ethyl acetate/hexane (1:2)) gave 382 mg of the title compound as a colorless foam. 1H-NMR (300 MHz, CDCl3) δ 7.95 (dd, 1H, J=1.5, 8 Hz), 7.55-7.64 (m, 2H), 7.35-7.40 (m, 1H), 7.08-7.26 (m, 5H), 6.93 (d, 2H, J=8 Hz), 6.65 (d, 2 Hz), 6.53 (dd, 1H, J=2, 8 Hz), 3.87 (s, 2H), 3.67 (d, 2H, 6 Hz), 2.69 (t, 2H, J=13 Hz), and 1.47 (s, 9H). Mass spectrum (MALDI-TOF; gentisic acid matrix) calcd. for C30H34ClNO6S: 594.2 (M+Na). Found: 594.0, 472.0 (M - (tert-butoxycarbonyl)+H).
Reaction SMILES: C1([C:7]([C:19]2[CH:24]=[CH:23]C=[CH:21][CH:20]=2)(C2C=CC=CC=2)[S:8][CH2:9][CH2:10][O:11][CH3:12])C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+].C([O:44][CH:45]1[NH:48]C(=O)C1(CC)CC)(=O)C>ClCCl.CC(C)=O>[CH3:12][O:11][CH2:10][CH2:9][S:8][CH:7]1[NH:48][C:45](=[O:44])[C:19]1([CH2:20][CH3:21])[CH2:24][CH3:23]
Reactant: CCC1(CC)C(=O)NC1OC(C)=O
Reactant: COCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCC1(CC)C(=O)NC1SCCOC
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To S-triphenylmethyl 2-methoxyethanethiol (1.37 g, 4.1 mmol) in dichloromethane (30 ml) under nitrogen were added triethylsilane (0.953 g, 1.31 ml, 8.2 mmol) and trifluoroacetic acid (0.632 ml, 0.935 g, 8.2 mmol). The mixture was stirred at room temperature for 16 hours. Acetone (50 ml) was added and the mixture neutralised with 2 M aqueous sodium hydroxide. 1 M Aqueous sodium hydroxide (24 ml, 24 mmol), 4-acetoxy-3,3-diethyl-2-azetidinone (J. Med. Chem., 35, 3745-3754 (1992)) (0.690 g, 6.00 mmol) and acetone (10 ml) were then added and the mixture stirred at room temperature for 23 hours. The solvents were removed in vacuo and to the residue were added water (50 ml) and dichloromethane (50 ml). The organic layer was isolated and the water layer extracted further with dichloromethane (3×30 ml). The 4 organic layers were combined and washed with water (30 ml) and saturated brine (30 ml), dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (gradient from petrol/EtOAc, 9:1 to EtOAc) gave the title compound (0.51 g, 63%) as an oil.
Reaction SMILES: OC(C1C=CC2C(=CC=CC=2)C=1)[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[N:11]1[CH:10]=[CH:9][C:8]([C:6]2[S:5][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][CH:7]=2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1sc(-c2ccncc2)cc1C(O)c1ccc2ccccc2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.7 %

Procedure:
Ethyl 3-[hydroxy(2-naphthyl)methyl]-5-pyridin-4-ylthiophene-2-carboxylate (118.0 mg, 0.3030 mmol), methylene chloride (2.4 mL), trifluoroacetic acid (140.0 uL, 1.818 mmol), and triethylsilane (84.7 uL, 0.530 mmol) were combined in a round bottomed flask equipped with a stirbar. The reaction was stirred overnight at room temperature under an atmosphere of nitrogen. An aliquot was taken from the reaction, quenched into water, basified with sodium carbonate, and extracted with ethyl acetate. TLC analysis (2:1 ethyl acetate:DCM) indicated that the starting ester was ˜50% converted to a slightly higher Rf product. Additional trifluoroacetic acid (300 uL, 4 mmol) and triethylsilane (200 uL, 1 mmol) were added and the reaction was stirred at room temperature under an atmosphere of nitrogen for another 4 hours. LCMS analysis showed one major peak with correct ES+ for product with a small amount of SM remaining. The reaction was quenched into water, basified, and extracted into ethyl acetate. The extract was washed with saline, dried over sodium sulfate, filtered, and evaporated to leave crude product as an oil. The crude product was dissolved in minimal DCM then was purified by column chromatography on silica gel (gradient 100% DCM to 50% ethyl acetate) to afford product 86 mg (76% yield) as a white solid. LC/MS (FA) ES+ 374. 1H NMR (400 MHz, DMSO) δ 8.64-8.55 (m, 2H), 7.90-7.80 (m, 4H), 7.80-7.75 (s, 1H), 7.73-7.66 (m, 2H), 7.52-7.40 (m, 3H), 4.57-4.49 (s, 2H), 4.39-4.27 (q, J=7.1 Hz, 2H), 1.35-1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([CH:3]([CH2:4][CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC/C=C/C(=O)OC
Reactant: C1CCNC1
Product: CCC(CC(=O)OC)N1CCCC1
Temperature: 100 °C

Procedure:
A mixture of 171 g of methyl 2-trans-pentenoate and 106.5 g of pyrrolidine was heated for 20 hours at 100° C. After distillation over a Vigreux column, 198.7 g (72% of theory) of methyl 3-pyrrolidinovalerate of boiling point 65° C./0.4 mbar, nD20 =1.4580, were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[CH2:8][C:7]2([CH3:17])[CH3:16])(=[O:3])[CH3:2].[I:18]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([I:18])[CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[CH2:8][C:7]2([CH3:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: II
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(=O)c1cc(I)c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
A solution of 6-acetyl-2,2,4,4-tetramethyl chroman (Compound 34, 0.36 g, 1.55 mmol) in anhydrous dichloromethane (5 mL) was treated with silver(I)trifluoromethanesulfonate (0.398 g, 1.55 mmol) and iodine (0.393 g, 1.55 mmol) and the resulting solution was stirred at ambient temperature for 4 h. The reaction mixture was treated with saturated, aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 4-10% ethyl acetate in hexane as the eluent to afford the title compound (0.47 g, 85%) as a viscous oil.
Reaction SMILES: C(OC1C=CC(N2CCN(CCCC3CCCCC3)CC2)=CC=1Cl)C1C=CC=CC=1.C([O:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:47][CH2:46]2)=[CH:41][C:40]=1[F:60])C1C=CC=CC=1>>[F:60][C:40]1[CH:41]=[C:42]([N:45]2[CH2:46][CH2:47][N:48]([CH2:51][CH2:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH2:49][CH2:50]2)[CH:43]=[CH:44][C:39]=1[OH:38]
Reactant: Fc1cc(N2CCN(CCCc3ccccc3)CC2)ccc1OCc1ccccc1
Agent: Clc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Product: Oc1ccc(N2CCN(CCCc3ccccc3)CC2)cc1F
Yield: 73.1 %

Procedure:
Production Example 30 was repeated except that 1-(4-benzyloxy-3-chlorophenyl)-4-(3-cyclohexylpropyl)piperazine was replaced with 1-(4-benzyloxy-3-fluorophenyl)-4-(3-phenylpropyl)-piperazine (394 mg). The resulting crude product was purified on TLC (developer, chloroform: methanol=10:1) to provide 2-fluoro-4-[4-(3-phenylpropyl)piperazin-1-yl]phenol (224 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[C:52]([O:53][CH3:54])=[CH:51][C:49]([NH2:50])=[C:48]([O:55][CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.N>CC(O)C.Cl.CO>[N:34]1([CH:40]2[CH2:41][CH2:42][N:43]([C:46]3[C:52]([O:53][CH3:54])=[CH:51][C:49]([NH:50][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]6=[N:10][C:9]=5[C:17]5[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=5)[C:20]([NH:22][C:23]5[C:24]([F:30])=[CH:25][CH:26]=[CH:27][C:28]=5[F:29])=[O:21])[CH:5]=[CH:4][N:3]=4)=[C:48]([O:55][CH3:56])[CH:47]=3)[CH2:44][CH2:45]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COc1cc(N2CCC(N3CCCCC3)CC2)c(OC)cc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cl
Agent: N
Solvent: CC(C)O
Solvent: CO
Product: COc1cc(N2CCC(N3CCCCC3)CC2)c(OC)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 40.3 %

Procedure:
In a 5 mL microwave vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 4-(1,4′-bipiperidin-1′-yl)-2,5-bis(methyloxy)aniline (0.166 g, 0.520 mmol) were taken up in iPrOH (3 mL) and concentrated HCl (4 drops) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo. The resulting residue was taken up in DCM and purified by column chromatography using basic alumina. The desired combined fractions were concentrated and the resulting solid was triturated with DCM and hexane, filtered and air dried to give the title compound (0.130 g, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.41 (br. s., 1H), 8.50 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=5.1 Hz, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.73 (d, J=9.2 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.43-7.50 (m, 1H), 7.36-7.42 (m, 1H), 7.34 (s, 1H), 7.20 (t, J=8.1 Hz, 2H), 6.94-7.00 (m, 1H), 6.66 (s, 1H), 6.50 (d, J=5.1 Hz, 1H), 3.76 (s, 3H), 3.64 (s, 3H), 3.43 (d, J=11.7 Hz, 2H), 2.51-2.58 (m, 2H), 2.26-2.35 (m, 1H), 1.77 (d, J=13.6 Hz, 2H), 1.53-1.64 (m, 2H), 1.48 (s, 4H), 1.38 (s, 2H). MS (M+H, ES+) 745.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[F:22])=[CH:7][C:8]([C:12]#N)=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:24][OH:25].C[OH:27]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[F:22])=[CH:7][C:8]([C:12]([O:25][CH3:24])=[O:27])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc(C#N)nc3cc(Cl)ccc23)c(F)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(-c2ccc(OC)cc2F)c2ccc(Cl)cc2n1
Temperature: 60 °C
Yield: 90 %

Procedure:
7-Chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carbonitrile (4.4 g, 14.07 mmol) was suspended in MeOH (70.3 ml), added 200 ml sat HCl/MeOH and then heated to 60° C. for 4 hours. The reaction was allowed to cool to ambient temperature and then was concentrated. The residue was dissolved in EtOAc and then washed with 1:1 1N NaOH/sat NaHCO3, brine, dried (MgSO4) and concentrated to afford methyl 7-chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate (4.4 g, 12.73 mmol, 90% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[C:22]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.N1C(C)=CC=CC=1C>BrC1C=CC=CC=1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[C:22]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Reactant: CS(=O)(=O)c1cccnc1Cl
Solvent: Cc1cccc(C)n1
Solvent: Brc1ccccc1
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncccc3S(C)(=O)=O)cc12
Yield: 13 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)-1H-indole and 2-chloro-3-methylsulfonylpyridine were used. 2,6-Lutidine was used as base, bromobenzene was used as solvent, and the reaction was heated at reflux for 3.5 hours. Column chromatography afforded the title compound (13%) as a yellow solid: top, 66.0°-68.0° C.; 1H NMR (CDCl3) δ8.46 (s, NH), 8.33 (dd, J=4.8 and 1.9 Hz, 1H), 8.33 (br s, NH), 8.06 (dd, J=7.8 and 1.9 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.29 (d, J=8.5 Hz, 1), 7.20 (dd, J=8.6 and 2.0 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.78 (dd, J=7.8 and 4.8 Hz, 1H), 3.15 (s, 3H), 2.94-2.88 (m, 2H), 2.68-2.60 (m, 2H), 2.34 (s, 6H); HRMS calculated for C18H22N4O2S 358.1459, found 358.1490.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[CH2:10][C@H:9]1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Yield: 77.8 %

Procedure:
To a solution of (2R,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[(E)-2-ethoxycarbonylvinyl]-pyrrolidine (20 g, 50 mmol) in ethanol (500 ml) was added 10% palladium-carbon (5 g), and the mixture was stirred under atmospheric pressure in a hydrogen atmosphere at room temperature for 2 h. Further, 10% palladium-carbon (2 g) was added thereto, and the mixture was stirred under atmospheric pressure in a hydrogen atmosphere at room temperature for 1.5 h. The catalyst was filtered off, and the solvent was removed in vacuo. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate) to give (2R,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2-ethoxycarbonylethyl)pyrrolidine (15.62 g, yield: 78%).