Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])[C:11]([C:13]2([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:40][N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:49]=2)[CH2:43][CH2:42]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][N:10]([CH2:9][C:4]3[CH:3]=[C:2]([C:52]4[CH:51]=[CH:50][CH:49]=[C:48]([CH2:47][CH:44]5[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]5)[CH:53]=4)[C:7]([F:8])=[CH:6][CH:5]=3)[C:11]([C:13]3([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]3)=[O:12])[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(F)c(Br)c1)C(=O)C1(C(N)=O)CC1
Reactant: CN1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(F)c(-c2cccc(CC3CCN(C)CC3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 100 °C
Yield: 2.1 %

Procedure:
A mixture of N1-[(3-bromo-4-fluorophenyl)methyl]-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (80 mg, 0.133 mmol), 1-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidine (53.4 mg, 0.133 mmol), Na2CO3 (42.3 mg, 0.399 mmol) and PdCl2(dppf) (9.73 mg, 13 μmol) was diluted in a mixture of 1,4-dioxane (3 mL) and water (1 mL) in a 2-5 mL Biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 min and was then heated in a Biotage microwave at normal absorption for 10 min at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and was then washed with ethyl acetate and water. The organic layer was concentrated under vacuum to obtain the crude residue. It was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({6-fluoro-3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide as a solid (2 mg, 2.12%). LC-MS m/z 712 (M+H)+, 0.79 min (ret time).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([OH:7])[C@@H:3]1[OH:8].[CH3:9][C:10]1([CH3:35])[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]2[CH:15]=[C:14]([C:22]3[N:27]=[C:26]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)[CH:25]=[CH:24][CH:23]=3)[CH:13]=[CH:12][C:11]1=2.Cl>>[CH3:9][C:10]1([CH3:35])[CH2:19][CH2:18][C:17]([CH3:20])([CH3:21])[C:16]2[CH:15]=[C:14]([C:22]3[N:27]=[C:26]([N:28]4[CH2:33][CH2:32][CH:31]([NH:1][C@@H:2]5[CH2:6][CH2:5][C@H:4]([OH:7])[C@@H:3]5[OH:8])[CH2:30][CH2:29]4)[CH:25]=[CH:24][CH:23]=3)[CH:13]=[CH:12][C:11]1=2
Reactant: N[C@@H]1CC[C@H](O)[C@@H]1O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(=O)CC4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(N[C@@H]5CC[C@H](O)[C@@H]5O)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS1007 starting from 31 mg (0.199 mmol) of (1S,2R,3R)-3-aminocyclopentane-1,2-diol and 80 mg (0.199 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyridinyl-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([OH:23])[CH:9]=[C:10]([C:12]2[NH:13][C:14]([C:17]3[O:18][C@@H:19]([CH3:22])[CH2:20][N:21]=3)=[CH:15][CH:16]=2)[CH:11]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([OH:23])[CH:9]=[C:10]([C:12]2[NH:13][C:14]([C:17]3[O:18][C@@H:19]([CH3:22])[CH2:20][N:21]=3)=[CH:15][CH:16]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN=C(c2ccc(-c3cc(O)cc(O[C@@H](C)CO)c3)[nH]2)O1
Reaction time: 1 h
Yield: 72 %

Procedure:
3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (60 mg, 0.18 mmol) synthesized in Example (116d) was dissolved in methylene chloride (4 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 0.38 mL, 0.38 mmol) was added at −78° C. under nitrogen atmosphere. Subsequently, the temperature was brought back to room temperature, followed by stirring for 1 hour. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: hexane/ethyl acetate=50%-70%) to afford the desired compound (41 mg, yield 72%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:18][C:5]2[N:6]=[C:7]([O:14][CH2:15][CH2:16][CH3:17])[N:8]([CH2:11][CH2:12][CH3:13])[C:9](=O)[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>O1CCOCC1>[Cl:1][C:2]1[S:18][C:5]2[N:6]=[C:7]([O:14][CH2:15][CH2:16][CH3:17])[N:8]([CH2:11][CH2:12][CH3:13])[C:9](=[S:28])[C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCOc1nc2sc(Cl)cc2c(=O)n1CCC
Solvent: C1COCCO1
Product: CCCOc1nc2sc(Cl)cc2c(=S)n1CCC

Procedure:
In a sulfonation flask, a mixture of 1.15 g 6-chloro-2-propoxy-3-propyl-4-oxo-thieno[2,3-d]pyrimidine, 0.97g Lawesson reagent and 50 ml of dioxane is heated at reflux temperature for 3.5 hours. After removal of the solvent in the water jet vacuum, the residue is taken up in ethylacetate and the organic phase is washed twice with water. The organic phase is dried over sodium sulfate and the solvent removed in the water jet vacuum. The crude material is purified twice by column chromatography over silica gel (eluant: tert. butylmethylether/hexane 1:9). Yield: 0.3 g pure 6-chloro-2-propoxy-3-propyl-4thioxo-thieno[2,3-d]pyrimidine in the form of a yellow powder; m.p. 81-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH:10]([O:12][C:13]1[NH:17][N:16]=[C:15]([CH3:18])[C:14]=1[N:19]1[C:23]([CH3:24])=[N:22][C:21]([CH3:25])=[N:20]1)[CH3:11]>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:17]2[N:16]=[C:15]([CH3:18])[C:14]([N:19]3[C:23]([CH3:24])=[N:22][C:21]([CH3:25])=[N:20]3)=[C:13]2[O:12][C:10]=1[CH3:11]
Reactant: Cc1nc(C)n(-c2c(C)n[nH]c2OC(C)C(=O)c2ccc(Cl)cc2Cl)n1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc(Cl)cc4Cl)c(C)oc23)n1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a dispersion of 1-(2,4-dichlorophenyl)-2-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-methyl-1H-pyrazol-5-yloxy)propan-1-one (120 mg, 0.304 mmol) in 1,2-dichloroethane (1.217 ml) is added titanium tetrachloride (0.080 ml, 0.73 mmol). The reaction mixture is heated to 85° C. for 4 hours and then left at RT overnight. The mixture is quenched carefully with sat. NH4Cl (50 ml) and extracted with EtOAc (2×50 ml). The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo to afford a white solid. Purification by recrystallisation from EtOAc (˜3 ml) yields the title compound as a white crystalline solid; MS: m/z 376.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (1H, d), 7.77 (1H, d), 7.69 (1H, d), 2.38 (3H, s), 2.30 (3H, s), 2.28 (3H, s), 2.12 (3H, s).
Reaction SMILES: Br[C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:12]1[CH:13]=[CH:14][C:8]2[C:7](=[O:16])[NH:6][C:5]3[CH:17]=[C:18]([O:19][CH3:20])[C:2]([CH:23]=[CH:22][C:21]([O:25][CH3:26])=[O:24])=[CH:3][C:4]=3[NH:10][C:9]=2[CH:11]=1
Reactant: COc1cc2c(cc1Br)Nc1cc(Cl)ccc1C(=O)N2
Reactant: C=CC(=O)OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1cc2c(cc1OC)NC(=O)c1ccc(Cl)cc1N2
Yield: 83.6 %

Procedure:
A mixture of Example 223G (71 mg, 0.2 mmol), methyl acrylate (64 mg, 0.8 mmol), Pd(dppf)Cl2 (33 mg, 0.04 mmol) and 1 mL Et3N in 3 mL of DMF was heated at 110° C. overnight. The reaction mixture was diluted with EtOAc when it was still warm, and poured onto water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The residue was triturated with 20 mL of 1:1 EtOH/Aceton to give 60 mg of the title compound. MS (DCI) m/e 359 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.91 (s, 1H), 7.86-7.75 (m, 2H), 7.25 (s, 1H), 7.03 (d, J=1.53 Hz, 1H), 6.93 (dd, J=8.59, 1.84 Hz, 1H), 6.75 (s, 1H), 6.35 (d, J=15.96 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][C@@H:6]([CH3:8])[C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:1][C@@H:2]1[CH2:7][C@@H:6]([CH3:8])[C:5](=[O:9])[C:4]([CH3:10])([CH3:11])[CH2:3]1)(=[O:14])[CH3:13]
Reactant: C[C@@H]1C[C@@H](O)CC(C)(C)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1C[C@@H](C)C(=O)C(C)(C)C1
Temperature: 25 °C
Reaction time: 4.25 h
Yield: 99.4 %

Procedure:
300 g of (4R,6R)-4-hydroxy-2,2,6-trimethylcyclohexanone were dissolved in 154.7 ml of pyridine. The solution was treated dropwise at -3° C. to 0° C. within 10 minutes with 1.2 l of acetic anhydride and then stirred at room temperature for a further 4.25 hours. The reaction mixture was subsequently concentrated on a rotary evaporator at 60° C./16 mbar, whereby there were obtained 394.7 g of crude product as a yellow oil. Distillation of the crude product gave at about 95° C./0.07 mbar 378.4 g (99.4%) of (4R,6R)-4-acetoxy-2,2,6-trimethylcyclohexanone as a colourless oil.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([C:28]([F:31])([F:30])[F:29])[C:5]=1[OH:32])(=[O:3])[CH3:2].[SiH](CC)(CC)CC.B(F)(F)F>C(Cl)Cl>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([C:28]([F:30])([F:31])[F:29])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(C#N)c3)cc2)c(C(F)(F)F)c1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Product: CC(=O)c1ccc(OCc2ccc(Cc3cccc(C#N)c3)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To 3-{[4-(4-acetyl-3-hydroxy-2-trifluoromethyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile (211 mg, 0.48 mmol) in anhydrous CH2Cl2 (5 mL) at room temperature under Ar is added Et3SiH (0.61 mL, 3.8 mmol) and BF3.ether complex (0.12 mL, 0.96 mmol). The reaction mixture is stirred at room temperature for 2 h and quenched into saturated aqueous NH4Cl (20 mL). The aqueous mixture is extracted with CH2Cl2 (3×25 mL). The organic layers are combined, washed with brine, dried over sodium sulfatesodium sulfate, and concentrated. The residue is purified by flash column chromatography using 50% ethyl acetate/hexane as eluent to give the title compound (108 mg, 53%). LC-MS (m/e): 424 (M−1)
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=[C:6]([O:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[CH:5]=1)=[N+]=[N-]>O1CCCC1.CO.[Pd]>[NH2:1][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=[C:6]([O:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[CH:5]=1
Reactant: CC(C)(O)COc1cc(N=[N+]=[N-])nc(N2CCOCC2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)COc1cc(N)nc(N2CCOCC2)n1
Reaction time: 24 h

Procedure:
1-(6-azido-2-morpholin-4-yl-pyrimidin-4-yloxy)-2-methyl-propan-2-ol was dissolved in a mixture of tetrahydrofuran (200 mL) and methanol (20 mL). To the solution was added 10% palladium on carbon (2 g) and the reaction was stirred under an atmosphere of hydrogen for 24 hours. The reaction was then filtered through celite and evaporated to give 1-(6-amino-2-morpholin-4-yl-pyrimidin-4-yloxy)-2-methyl-propan-2-ol (2.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([OH:19])=O)[N:3]=1.Cl.C([O:25][C:26](=[O:35])[C@@H:27]([NH2:34])[CH2:28][O:29]C(C)(C)C)(C)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([NH:34][C@@H:27]([CH2:28][OH:29])[C:26]([OH:35])=[O:25])=[O:19])[N:3]=1
Reactant: CC(C)Oc1ccc2c(Cl)nc(C(=O)O)c(O)c2c1
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)N[C@@H](CO)C(=O)O)c(O)c2c1

Procedure:
Prepared in analogy to Example A-2 e) and f) from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and (S)-2-amino-3-tert-butoxy-propionic acid tert-butyl ester hydrochloride; MS-(+)-ion: M+1=369.0 amu.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:13]([OH:14])[C@@:12]([OH:17])([CH2:15][OH:16])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@H:3]1[OH:22]>O>[CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]([C@H:13]([OH:14])[C@@H:12]([OH:17])[CH2:15][OH:16])[C@H:10]([OH:11])[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@H:3]1[OH:22].[OH2:7].[CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]([C@H:13]([OH:14])[C@@H:12]([OH:17])[CH2:15][OH:16])[C@H:10]([OH:11])[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@H:3]1[OH:22].[OH2:7].[OH2:7]
Reactant: OC[C@H]1O[C@@H](O[C@@H]2[C@@H](CO)O[C@](O)(CO)[C@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Solvent: O
Product: OC[C@@H](O)[C@@H](O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)[C@H](O)[C@@H](O)CO

Procedure:
Because the mixture according to the invention is a liquid, it is preferable to start from the lactitol reaction mixture obtained after the hydrogenation of lactose. Said reaction is usually performed in an aqueous medium in the presence of a suitable hydrogenation catalyst. The lactitol solution in water obtained after filtration, purification and possibly concentration by evaporation is very suitable as a source of lactitol for the preparation of the mixture according to the invention. The condition for using such a solution is, however, that the lactitol solution is sufficiently pure, that is to say at least 90% by weight, and preferably 95% by weight, of the content of dissolved solids is composed of lactitol. The advantage of using such a lactitol is that no crystallization step is necessary to obtain crystalline lactitol monohydrate or crystalline lactitol dihydrate which then has to be redissolved. The advantage of using a crystalline lactitol hydrate is the high purity (usually more than 97% by weight of lactitol).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.S(Cl)(C)(=O)=O.C([N:17](CC)CC)C.[N-]=[N+]=[N-].[Na+]>C1COCC1.C(OCC)(=O)C.[Pd]>[NH2:17][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1
Reactant: CCN(CC)CC
Reactant: OCC1CCC(O)CC1
Agent: [Pd]
Agent: CS(=O)(=O)Cl
Agent: [N-]=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCC1CCC(O)CC1
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxymethylcyclohexanol (2 mmol) in THF (10 mL) were added Ms-Cl (2.2 mmol) and triethylamine (3 mmol) at 0° C. and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 10 mL of DMF, and then NaN3(6 mmol) was added. After overnight stirring at 60° C., the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Then, the obtained compound was dissolved in methanol, and 10% Pd—C (0.2 mmol) was added. After overnight stirring under hydrogen atmosphere, the reaction mixture was filtered, washed with methanol and concentrated under reduced pressure to provide 4-aminomethyl-cyclohexanol. To a solution of 4-aminomethyl-cyclohexanel in dichloromethane (10 mL) were added 1-pyrrolidinecarbonyl chloride (2 mmol) and triethylamine (3 mmol). After overnight stirring at room temperature, the reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:1) to provide a pyrrolidine-1-carboxylic acid (4-hydroxy-cyclohexylmethyl)-amide. The pyrrolidine-1-carboxylic acid (4-hydroxy-cyclohexylmethyl)-amide compound was dissolved in acetonitrile (10 mL), and then CDI (2.2 mmol) was added. After 1 hours stirring at 80° C., methyl iodide (10 mmol) was added and stirred for additional 1 hour at 80° C. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (10 mL) and C-pyridine-2-yl-methylamine (3 mmol) was added. After 4 hours stirring at 80° C., the reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:3), thereby completing the preparation of a target compound (180 mg, 25% yield).
Reaction SMILES: C(OC([N:6]1[CH2:17][CH:9]2[C:10]3[CH:11]=[C:12]([Br:16])[S:13][C:14]=3[CH2:15][CH:8]2[CH2:7]1)=O)C.I[Si](C)(C)C>C(Cl)Cl.CO>[Br:16][C:12]1[S:13][C:14]2[CH2:15][CH:8]3[CH2:7][NH:6][CH2:17][CH:9]3[C:10]=2[CH:11]=1
Reactant: CCOC(=O)N1CC2Cc3sc(Br)cc3C2C1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CO
Product: Brc1cc2c(s1)CC1CNCC21

Procedure:
The product of step c) (20.9 mg, 0.07 mmol) in CH2Cl2 (330 μl) was treated with iodotrimethylsilane (19.8 mg, 0.099 mmol) at 50° C. for 16 hours. The solvent was evaporated in vacuo leaving a brown residue that was dissolved in MeOH and a portion purified by preparative LC/MS to give the title compound. 1H NMR (300 MHz, CDCl3, ppm) 2.76-2.81 (m, 1H); 2.95-3.03 (m, 1H); 3.12-3.22 (m, 2H); 3.44-3.61 (m, 3H); 3.81-3.85 (m, 1H); 6.78 (s, 1H); 9.20-9.4 (br s, 2H); MS calculated for C9H10BrNS+H 244, observed 244, 246.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:21]=[CH:20][C:7]([C:8]([N:10]2[CH2:19][CH2:18][CH2:17][CH:12]([C:13](OC)=O)[CH2:11]2)=O)=[CH:6][CH:5]=1.[OH-:22].[Na+]>CO.O>[CH3:2][O:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:10]2[CH2:19][CH2:18][CH2:17][C:12](=[CH2:13])[C:11]2=[O:22])=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: COC(=O)C1CCCN(C(=O)c2ccc(OC)cc2)C1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C1CCCN(Cc2ccc(OC)cc2)C1=O
Yield: 74.7 %

Procedure:
A solution of methyl N-(p-methoxybenzoyl)nipecotate hydrochloride (30.7 g) and 8.4 g of sodium hydroxide in 900 ml of methanol and 45 ml of water is stirred at room temperature for seventeen hours. The solution is evaporated to dryness in vacuo, the residue diluted with toluene, and this again evaporated in dryness in vacuo. To the residue is added 1 liter of acetic anhydride and 140 ml of triethylamine, and the resulting mixture is heated under reflux for four hours. The reaction mixture is evaporated to dryness in vacuo, the residue taken up in chloroform, washed with water, dried and concentrated in vacuo. The residual oil is chromatographed on silica gel using 1:1 hexane-ethyl acetate as the eluant, and yields 16.9 g of N-(p-methoxybenzyl)-3-methylene-2-piperidone as a chromatographically pure yellow oil. Alternatively, the oil can be distilled to give analytically pure N-(p-methoxybenzyl)-3-methylene-2-piperidone, m.p. 145°-155°/0.05 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[OH:11][CH2:12][CH2:13]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:11][CH2:12][CH2:13][O:6]2)[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc(C2OCCO2)cc1Br
Yield: 90.1 %

Procedure:
3-Bromo-4-hydroxybenzaldehyde (2a, 10.0 g, 49.8 mmol) was heated at reflux with 1,2-dihydroxyethane (25 g, 0.4 mol) in toluene (150 mL) in the presence of p-toluenesulfonic acid (950 mg) for 48 h in an apparatus fitted with a Dean-Stark trap. The reaction mixture was concentrated by reduced pressure evaporation, washed with aqueous sodium hydrogen carbonate, water, brine, dried over Na2SO4, evaporated to dryness and then passed through a short silica gel column using a hexanes-ethyl acetate mixture (5:1) with a few drops of triethylamine as eluent to afford the protected product 3a (11.0 g, 95%) as a crystalline solid. Rf=0.38 (25% EtOAc-hexanes): mp 76-78° C. IR (neat) 3351, 2954, 2891, 1608, 1499, 1431, 1284, 1100 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=1.8 Hz, 1H), 7.28 (dd, J=8.4, 2.4 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 5.69 (s, 1H), 4.03 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 152.9, 131.5, 130.2, 127.5, 115.8, 110.0, 102.7, 65.2; CIMS (m/z, rel intensity) 247 (MH++2, 7), 245 (MH+, 7), 203 (100), 201 (100), 175 (4), 173(5), 94 (1).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:29])[NH:6][C:7]1[C:8]([CH3:28])=[C:9]([O:26][CH3:27])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:32][CH2:33][CH2:34][OH:35]>CCCCCC.C(OCC)(=O)C>[OH:35][CH2:34][CH2:33][NH:32][C:5]([NH:6][C:7]1[C:8]([CH3:28])=[C:9]([O:26][CH3:27])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=3)[C:11]=2[C:24]=1[CH3:25])=[O:29]
Reactant: NCCO
Reactant: COc1c(C)c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1c(C)c(NC(=O)NCCO)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 59 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 140 and 2-aminoethanol, the title compound was synthesized in the same manner as in Example 143. Yield: 59%. Melting point: 127-129° C. (hexane-ethyl acetate).