Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[OH-].[Na+].C(N1C2C=CC=CC=2C2C1=CC=CC=2)CCCCCC>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:27]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCCCCCCCCCCCCBr
Agent: CCCCCCCn1c2ccccc2c2ccccc21
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCn1c2ccccc2c2ccccc21

Procedure:
N-Tridecylcarbazole was prepared from carbazole (62.43 g, 0.37 mol), 1-bromotridecane (100 g, 0.38 mol, commercially available from Aldrich, Milwaukee, Wis.), benzyltriethyl ammonium chloride (4.24 g. 0.018 mol), toluene (400 ml), and 50% aqueous NaOH (200 g) according to the procedure described for N-heptylcarbazole. The product was obtained as 120 g of brown liquid (96% yield).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]1[C@@H:9]([CH3:12])[CH2:10][OH:11].[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1.C(OCC)(=O)C>ClCCl.COC(OC)(C)C>[CH3:14][C:13]1([CH3:18])[O:11][CH2:10][C@H:9]([CH3:12])[C@H:4]2[C@@H:3]([C@@H:7]([CH3:8])[CH2:6][CH2:5]2)[CH2:2][O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@@H](CO)[C@H]1CC[C@H](C)[C@H]1CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: C[C@H]1COC(C)(C)OC[C@H]2[C@H]1CC[C@@H]2C
Temperature: 25 °C
Reaction time: 12 h
Yield: 162.2 %

Procedure:
(2R)-2-[(1R, 2R, 3S)-2-(hydroxymethyl)-3-methylcyclopent-1-yl]propan-1-ol (100 mg, 0.00058 mol) (obtained in Definite Example 45) was dissolved in 5 mι of dichloromethane, and 2 mι of 2, 2-dimethoxypropan and 5 mg of p-toluenesulfonic acid were added. After being stirred at room temperature for 12 hours, the reaction mixture was poured into 50 mι of ethyl acetate. After the organic layer was washed with an aqueous mixed solution of aqueous sodium bicarbonate (10 mι) and saturated sodium chloride solution (20 mι), it was dried by magnesium sulfate, filtered, and then concentrated under a reduced pressure. The residual substance was purified by a chromatography using silica gel. When the solvent of the fraction obtained from hexane:ether=8:2 eluent was distilled off, a colorless oily substance, i.e., (1R, 7R, 8S, 11S)-4, 4, 7, 11-tetramethyl-3, 5-dioxabicyclo[6. 3. 0]undecane (10 mg, yield=7.9%). This (1R, 7R, 8S, 11S)-4, 4, 7, 11-tetramethyl-3, 5-dioxabicyclo[6.3.0]undecane had the following physicochemical properties:
Reaction SMILES: [F:1][C:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([F:4])[CH3:3].C1C(=O)N([I:36])C(=O)C1.C(O)(C(F)(F)F)=O>CC#N>[F:1][C:2]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([I:36])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([F:4])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2I)CC1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
(R)-4-(6-(trans-4-(1,1-difluoroethyl)cyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (865 mg, 2.22 mmol) and NIS (550 mg, 2.45 mmol, 1.1 eq.) were dissolved in CH3CN (5 mL). Then CF3COOH (76 mg, 0.67 mmol, 0.3 eq.) was added to the mixture dropwise at 0° C. The mixture was warmed to 15° C. and stirred for another 1 h. Then the mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel chromatography using PE/EA (1/1) as eluent to give the title compound as a slight red solid (1.02 g, 90%). EDI-MS (M+1): δ 15.8. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, 1H), 7.73 (d, 2H), 7.48 (dd, 1H), 7.18 (d, 1H), 6.49 (s, 1H), 4.45-4.40 (m, 2H), 4.33-4.30 (m, 1H), 2.27-2.25 (m, 2H), 2.03-2.01 (m, 2H), 1.84 (s, 3H), 1.65-1.24 (m, 8H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](B(O)O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:15]3[CH:16]=[C:17]([NH2:18])[CH:19]=[CH:20][CH:21]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccc3c(c2)OCCO3)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
1,4-benzodioxane-6-boronic acid (0.125 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.079 g in 75% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15]([C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[CH:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)=[O:16])[C@H:10]([C:34](C)(C)[O:35][SiH2]C(C)(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(C)(C)C.CC#N.O>CCOC(C)=O.CCOC(C)=O.CO.O.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15]([C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[CH:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)=[O:16])[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCn1ccc2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(C)(C)O[SiH2]C(C)(C)C)C(C)C)cc21
Agent: CC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: COCCCn1ccc2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3CO)C(C)C)cc21

Procedure:
From (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-({isopropyl-[1-(3-methoxy-propyl)-1H-indole-6-carbonyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (6.79 g, 11.3 mmol) and TBAF (5.35 g, 17.0 mmol) and purification by flash chromatography on silivca gel (chexane/AcOEt 50:50 to 0:100 to AcOEt/MeOH 90:10). TLC, Rf (AcOEt)=0.34. MS (LC-MS): 432 [M+H-tBu]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/15 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.73 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38]CC4C=CC=CC=4)=[CH:34][CH:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C.O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(O)cc2)cc1
Yield: 97.9 %

Procedure:
A mixture of 4-tert-butyl-N-{6-[2-(4-benzyloxyphenoxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzensulfonamide (3.95 g), 10% palladiumcarbon (1.5 g) and ethanol-tetrahydrofuran (80 ml-80 ml) is subjected to catalytic hydrogenation at room temperature under hydrogen atmosphere (1 atm) for 24 hours. The catalyst is removed by filtration, and the filtrate is concentrated. The residue is crystallized from ethyl acetate/diisopropyl ether to give 4-tert-butyl-N-{6-[2-(4-hydroxyphenoxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (3.31 g).
Reaction SMILES: [OH:1][C:2]1[C:13]2=[C:14]3[CH:9]([CH2:10][C:11]4[CH:18]=[C:17]([OH:19])[C:16]([O:20][CH3:21])=[CH:15][C:12]=42)[NH:8][CH2:7][CH2:6][C:5]3=[CH:4][C:3]=1[O:22][CH3:23].C(=O)(O)[O-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>CN(C)C=O>[CH2:31]([N:8]1[CH:9]2[C:14]3=[C:13]([C:2]([OH:1])=[C:3]([O:22][CH3:23])[CH:4]=[C:5]3[CH2:6][CH2:7]1)[C:12]1[CH:15]=[C:16]([O:20][CH3:21])[C:17]([OH:19])=[CH:18][C:11]=1[CH2:10]2)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: COc1cc2c(cc1O)CC1NCCc3cc(OC)c(O)c-2c31
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCc2cc(OC)c(O)c3c2C1Cc1cc(O)c(OC)cc1-3

Procedure:
582 mg. (1.85 mmol) (+)-5,6,6a,7-Tetrahydro-1,9-dihydroxy-2,10-dimethoxy-4H-dibenzo(de,g)quinoline are dissolved in 10 ml. dimethylformamide. After the addition of 385 mg. (4.58 mmol) sodium bicarbonate and 0.2 ml. (279.6 mg.; 2.31 mmol) allyl bromide, the reaction mixture is stirred for 30 minutes at ambient temperature and thereafter heated under reflux for 2 hours. Subsequently, the solvent is evaporated off in a vacuum and the residue is partitioned between chloroform and water. After working up and crystallising from chloroform/diethyl ether, there is obtained (+)-6-allyl-5,6,6a,7-tetrahydro-1,9-dihydroxy-2,10-dimethoxy-4H-dibenzo(de,g)quinoline; m.p. 161°-171° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:22]([CH3:23])[C:6]2=[N:7][C:8]([O:11][C:12]3[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[C:13]=3[CH3:21])=[CH:9][CH:10]=[C:5]2[N:4]=1>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:2]([O:1][CH2:2][C:3]1[N:22]([CH3:23])[C:6]2=[N:7][C:8]([O:11][C:12]3[CH:17]=[C:16]([CH3:18])[C:15]([O:19][C:8](=[O:11])[CH3:9])=[C:14]([CH3:20])[C:13]=3[CH3:21])=[CH:9][CH:10]=[C:5]2[N:4]=1)(=[O:1])[CH3:3]
Reactant: Cc1cc(Oc2ccc3nc(CO)n(C)c3n2)c(C)c(C)c1O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1nc2ccc(Oc3cc(C)c(OC(C)=O)c(C)c3C)nc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 163.9 %

Procedure:
To 400 ml of a solution of 38.0 g of 2-hydroxymethyl-5-(4-hydroxy-2,3,5-trimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine in pyridine, 69 ml of acetic anhydride were added dropwise under ice cooling. After stirring at room temperature for 3 hours, the reaction mixture was allowed to stand overnight at room temperature. The solvent was distilled off under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was separated and purified by chromatography through a silica gel column (eluting solvent n-hexane/ethyl acetate=1/2), whereby 39.5 g of the title compound were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)=O)=[C:7]([Cl:27])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[OH-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[C:7]([Cl:27])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)NCCc2cccc(OC(F)(F)F)c2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)(F)F)c2)c(Cl)c1
Yield: 77.8 %

Procedure:
0.60 ml (0.60 mmol) of a 1M borane-THF complex solution in THF were added under nitrogen at rt to 80 mg (0.20 mmol) of 4-tert-butyl-2-chloro-N-[2-(3-trifluoromethoxy-phenyl)-ethyl]-benzamide dissolved in 1 ml THF. The reaction mixture was heated to reflux over night. At rt 2 ml 2N aqueous HCl solution were added and the reaction mixture was heated to reflux for 3 h. The reaction mixture was basified with 3 ml 2N aqueous NaOH solution and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (25 g silica gel; DCM/methanol 19:1) to yield 60 mg (78%) (4-tert-butyl-2-chloro-benzyl)-[2-(3-trifluoromethoxy-phenyl)-ethyl]-amine as a colorless oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.40-7.19 (m, 7H), 3.74 (s, 2H), 2.78 (s, 4H), 1.26 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]1)C.O.[OH-].[Li+]>CO.O>[C:17]([O:16][C:14]([NH:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([O:6][CH2:5][C:4]([OH:21])=[O:3])[CH2:8][CH2:9]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
A solution of trans (4-tert-butoxycarbonylamino-cyclohexyloxy)-acetic acid ethyl ester (720 mg, 2.40 mmol) in methanol (18 mL) and water (6 mL) as treated with lithium hydroxide monohydrate (210 mg, 5.00 mmol) and stirred at ambient temperature for 2.25 hours. Methanol was removed under vacuum and the residue partitioned between ethyl acetate and 1M HCl. The phases were separated and the aqueous phase extracted into ethyl acetate (2×). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under vacuum to afford 600 mg (92%) of trans (4-tert-butoxycarbonylamino-cyclohexyloxy)-acetic acid as a white solid. LCMS (Method Q, ESI): RT=2.96 min, m+H=296.0; 1H NMR (400 MHz, CDCl3) δ: 4.38 (br s, 1H), 4.12 (s, 2H), 3.41 (m, 2H), 2.04 (m, 4H), 1.44 (m, 11H), 1.15 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH3:6])[CH:12]1[C:8]1[S:7][CH:11]=[CH:10][CH:9]=1
Reactant: CNCCNC
Reactant: O=Cc1cccs1
Solvent: Cc1ccccc1
Product: CN1CCN(C)C1c1cccs1

Procedure:
23.5 g (267 mmol) of N,N′-dimethylethylenediamine were dissolved in 300 ml of toluene and treated with 29.8 g (266 mmol) of thiophene-2-carbaldehyde. The clear mixture was refluxed for 4 hours using a Dean-Stark trap. After that time 4.9 ml of water had separated in the trap. After cooling, the solution was filtered and evaporated. The oily residue was destined in vacuo. Yield: 45 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[C:11]([F:15])[CH:10]=[CH:9][CH:8]=3.[OH-].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[C:11]([F:15])[CH:10]=[CH:9][CH:8]=3
Reactant: BrCC1CO1
Reactant: Fc1ccc2[nH]c3cccc(F)c3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)c1c(F)cccc1n2CC1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a stirred solution of 3,5-difluoro-9H-carbazole (0.300 g, 1.5 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added 85% potassium hydroxide (0.117 g, 1.8 mmol) and the mixture was stirred for 1 hr. Epibromohydrin (0.244 mL, 3.0 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 4 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as an off-white solid (0.36 g, 94%). 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, 1H, J=8.7, 2.7 Hz), 7.46-7.36 (m, 2H), 7.29-7.20 (m, 2H), 6.92 (dd, 1H, J=9.9, 7.8 Hz), 4.68 (dd, 1H, J=15.9, 3.0 Hz), 4.35 (dd, 1H, J=15.9, 5.1 Hz), 3.36 (m, 1H), 2.85 (t, 1H, J=4.5 Hz), 2.56 (dd, 1H, J=4.5, 2.7 Hz).
Reaction SMILES: NC1C(Cl)=CC(C(NCCN(CC)CC)=O)=C(OC)C=1.[NH2:21][C:22]1[C:49]([Cl:50])=[CH:48][C:25]([C:26]([NH:28][C@H:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH2:31][C@H:30]2[O:46][CH3:47])=[O:27])=[C:24]([O:51]C)[CH:23]=1>>[NH2:21][C:22]1[C:49]([Cl:50])=[CH:48][C:25]([C:26]([NH:28][C@H:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[CH2:31][C@H:30]2[O:46][CH3:47])=[O:27])=[C:24]([OH:51])[CH:23]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC
Agent: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Product: CO[C@@H]1CN(CCCOc2ccc(F)cc2)CC[C@@H]1NC(=O)c1cc(Cl)c(N)cc1O
Yield: 54 %

Procedure:
The general procedure of Preparation No. 1 was repeated except that the 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide utilized therein was replaced by cis-4-amino-5-chloro-N-{1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl}-2-methoxybenzamide (2 g, 4.3 mmoles) [prepared according to the procedure described in Published European Patent Application No. 76,530 (1983)]. The product was crystallized from 2-propanol to give the title product in 54% yield, mp. 146°-148° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]([N:26]([C:34](=[O:36])[CH3:35])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:18][C@@H:17]2[CH3:37])=[O:15])=[CH:10][CH:9]=1.[C:39](=[N:42]O)([NH2:41])[CH3:40].[H-].[Na+]>C1COCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([N:26]([C@H:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]([C:14](=[O:15])[C:11]3[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]4[O:2][N:42]=[C:39]([CH3:40])[N:41]=4)=[CH:13][CH:12]=3)[C@@H:17]([CH3:37])[CH2:18]2)[C:34](=[O:36])[CH3:35])=[CH:32][CH:31]=1
Reactant: CC(N)=NO
Reactant: COC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCc3nc(C)no3)cc2)c2ccccc21

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-(2-methyl-1-{4-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-propoxy]-benzoyl}-1,2,3,4-tetrahydro-quinolin-4-yl)-acetamide was prepared from (2S,4R)-4-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid methyl ester. Acetamide oxime (0.043 g, 0.58 mmol) was suspended in THF under N2 and NaH (60% dispersion in oil) (0.025 g, 1.0 mmol) was added followed by 4A° molecular sieves and heated to 60° C. for 1 h. (2S,4R)-4-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid methyl ester was added and heated to reflux for 4.5 h. The reaction was filtered and concentrated down and partitioned between CH2Cl2 and water. The aqueous layer was extracted 3×CH2Cl2 and dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (100% EtOAc) to afford (2S,4R)-N-(4-Chloro-phenyl)-N-(2-methyl-1-{4-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-propoxy]-benzoyl}-1,2,3,4-tetrahydro-quinolin-4-yl)-acetamide in 44% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:35]2[CH2:36][CH2:37][CH:32]([CH2:31][CH2:30][CH2:29][CH2:28][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:33][CH2:34]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: c1ccc(CCCCC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCCCc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a mixture of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(R)-pyrrolidinyl]methoxy]pyridine (125 mg, 350 μmol) and 4-(4-phenylbutyl)piperidine (83.4 mg, 384 μmol, 1.1 equiv.) in anhydrous toluene (2 mL) were added successively potassium tert-butoxide (64 mg, 0.52 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (6.4 mg, 7.0 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 12.1 mg, 21 μmol, 55 mequiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed by microwave irradiation under Ar. After reaction for 30-40 minutes at 130° C., the mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The solution was dried over Na2SO4 and evaporated, and the residue was purified by CC on SiO2 with CH2Cl2/EtOAc 3:2. 3-[[1-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-(4-phenylbutyl)-1-piperidinyl]pyridine (128 mg, 74%) was obtained as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([N+:23]([O-:25])=[O:24])=[C:18](F)[CH:17]=2)[CH2:11][S:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:36])([F:35])[C@H:30]([OH:34])[CH2:31][O:32][CH3:33].C(O[K])(C)(C)C.C(OC(C)(C)C)=O>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:17]=[C:18]([O:34][C@H:30]([CH2:31][O:32][CH3:33])[C:29]([F:36])([F:35])[F:28])[C:19]([N+:23]([O-:25])=[O:24])=[C:20]([F:22])[CH:21]=2)[CH2:11][S:10][CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC[C@@H](O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)[C@@H]1O
Agent: CC(C)(C)OC=O
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC[C@@H](Oc1cc(C[C@@H]2CSC[C@H](NC(=O)OC(C)(C)C)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of [(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (1 g, 2.47 mmol) and (R)-1,1,1-trifluoro-3-methoxy-propan-2-ol (392 mg, 2.72 mmol) in THF (13 mL) was added tert-BuOK (277 mg, 2.47 mmol) in small portions at 0° C. over a period of 30 min. After 1 h the cooling bath was removed and the orange solution was stirred at room temperature for 5 h. The reaction mixture was diluted with EtOAc (500 mL) and washed with ice cooled K2CO3 solution and cold brine. The organic phase was dried over Na2SO4, filtered and evaporated to yield a brown-yellowish foam: TLC Rf=0.50 (toluene-ETA 85:15); HPLC RtE=1.157 min; ESIMS [M+H-Boc]+=429; 1H NMR (600 MHz, DMSO-d6): δ 7.28 (s, 1H), 7.10 (d, 1H), 6.71 (d, 1H), 5.65 (broad, 1H), 4.95 (d, 1H), 3.83 (dd, 1H), 3.73 (dd, 1H), 3.42 (m, 1H), 3.31 (s, 3H), 3.25 (dd, 1H), 2.93 (m, 1H), 2.54 (d, 1H), 2.48-2.35 (m, 2H), 2.32-2.20 (m, 2H), 1.94 (m, 1H), 1.37 (s, 9H).