Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][CH:21]([C:23]#[N:24])[CH2:20]1>C1COCC1>[C:7]([CH:9]=[C:19]1[CH2:22][CH:21]([C:23]#[N:24])[CH2:20]1)#[N:8]
Reactant: N#CC1CC(=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of 1 M of potassium tert-butoxide in THF (67.4 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (11.4 mL, 0.0706 mol) in tetrahydrofuran (100 mL, 1 mol). The reaction mixture was warmed up to room temperature and cooled to 0° C. again. To the resulting mixture, a solution of 3-oxocyclobutanecarbonitrile (6.10 g, 0.0641 mol) in tetrahydrofuran (20 mL, 0.2 mol) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. After quenching with water, the mixture was extracted with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by flash silica gel column, eluting with 0-10% MeOH/dichloromethane to give the titled product (5.40 g, 71.26%). LCMS (M+Na) 141.3. 1H NMR (400 MHz, CDCl3): δ 5.30 (1H, m), 3.40 (2H, m), 3.14 (3H, m) ppm.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[C:8]([CH3:14])=[C:7]([CH3:15])[C:6]=1[O:16][CH3:17])[CH2:2][CH:3]=[CH2:4].C12BC(CCC1)CCC2.[OH-].[Na+].OO.B.C([O-])([O-])=[O:33].[K+].[K+].C(OC(C)C)(=O)C>C1COCC1>[CH3:17][O:16][C:6]1[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]([O:12][CH3:13])=[C:10]([CH3:11])[C:5]=1[CH2:1][CH2:2][CH2:3][CH2:4][OH:33]
Reactant: O=C([O-])[O-]
Reactant: C=CCCc1c(C)c(OC)c(C)c(C)c1OC
Agent: B
Agent: B1C2CCCC1CCC2
Agent: OO
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(CCCCO)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
1-(But-3-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (5.08 g) in 50 mL THF was treated with 9-borabicyclo[3.3.1]nonane (9-BBN) (2.96 g) and stirred overnight at room temperature. A chilled solution of 10 M NaOH (10 mL) and 35% w/w H2O2 (10 mL) was added to cold borane (0° C.) such that the internal temperature never exceeded 36° C. The cloudy solution was stirred vigorously and treated with 2 g K2CO3 until the layers clarified. Isopropyl acetate (100 mL) was added followed by separation and extraction of the aqueous phase 3×60 mL isopropyl acetate. The combined organics were washed with 50 mL saturated NaCl, dried over Na2SO4 and concentrated to a pale yellow oil. Flash chromatography yielded 3.3 g of 4-(2,5-dimethoxy-3,4,6-trimethylphenyl)butan-1-ol as a white powder (60.3%). Mp 85.1-87.1° C.; 1H NMR (400 MHz, CDCl3) δ=3.67 (m, 5H), 3.64 (s, 3 H), 2.63 (q, 2 H), 2.22 (s, 3 H), 2.17 (s, 6 H), 1.68 (m, 2 H), 1.55 (m, 2 H) ppm.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:28][C:29]([F:32])([F:31])[F:30])[S:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:19])=[C:12]([F:33])[CH:11]=1.IC>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:28][C:29]([F:30])([F:31])[F:32])[S:18]([CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:1])(=[O:20])=[O:19])=[C:12]([F:33])[CH:11]=1
Reactant: CC(C)NC(C)C
Reactant: O=S(=O)(Cc1ccccc1)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Agent: [Li]
Solvent: C1CCOC1
Solvent: CI
Product: CC(c1ccccc1)S(=O)(=O)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of lithium diisopropylamine (2.0 M in THF/heptane/ethylbenzene) (1.2 mL, 2.5 mmol) at −78° C. was slowly added a solution of N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide (1 g, 2.3 mmol) in tetrahydrofuran (11 mL) and the reaction was stirred at −78° C. for 1 hour. Iodomethane (0.16 mL, 2.5 mmol) was then added and the reaction was warmed to ambient temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc, washed with 1 N aqueous HCl, and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-30% EtOAc in heptane) to give N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)ethanesulfonamide (614 mg, 60% yield). LCMS (m/z) ES+ 471 [M+18]+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13](=O)[CH3:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O1CCOCC1.[C:22]([NH2:26])(=[O:25])[CH:23]=[CH2:24].CC(C)([O-])C.[K+]>O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:24][CH2:23][C:22](=[O:25])[NH:26][C:13]=3[CH3:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Cc1ccc(-n2ccnc2)cc1
Reactant: C=CC(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1=C(c2ccc(-n3ccnc3)cc2)CCC(=O)N1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 3 g 1-[4-(1-imidazolyl)-phenyl]-2-propanone (EPA 102 227, example 4), 30 ml 1,4-dioxane, 1,2 g acrylic acid amide and 1.73 g potassium tert-butoxide is stirred for 40 minutes at room temperature and subsequently for 2 hours at 100° C. After cooling it, water is added, the precipitated solid is sucked off, washed with water, dried and purified by column chromatography (silica gel/dichloromethan/methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-])=O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>[Pd].CO>[OH:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=1[NH:1][C:15](=[O:17])[CH3:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1O
Reaction time: 2 h
Yield: 100.7 %

Procedure:
A mixture of 2-nitro-4-(trifluoromethyl)phenol (310 mg, 1.5 mmol), palladium on carbon (10%, 125 mg) and acetic anhydride (306.3 mg, 3.0 mmol) in methanol was hydrogenated for 2 h at atmospheric pressure. The catalyst was filtered off, the filtrate was concentrated in vacuo to give crude N-[2-hydroxy-5-(trifluoromethyl)phenyl]acetamide (331 mg). A part (219.16 mg, 1.0 mmol) of N-[2-hydroxy-5-(trifluoromethyl)phenyl]acetamide was treated with [(2S)-2-methyloxiran-2-yl]methyl3-nitrobenzenesulfonate (273.27 mg, 1.0 mmol) in the presence of Cs2CO3 (406.25 mg, 1.25 mmol) in DMF (5 mL) at room temperature for 5 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, concentrated. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum ether) to give the subtitled compound (230 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1>CS(C)=O>[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[N:18]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1ccc(COc2cncc(Cl)n2)cc1

Procedure:
4-Fluorobenzylalcohol (200 μL, 1.85 mmol) and potassium tert-butoxide (122.1 mg, 1.00 mmol) in anhydrous DMSO (1 mL) were reacted with 2,6-dichloropyrazine (156.8 mg, 1.05 mmol) as described in Example 19B to afford the title compound. MS (DCI/NH3) m/z 239 (M+H)+.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11](=[O:22])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCO>[C:1]1(/[CH:7]=[CH:8]\[C:9]2[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11](=[O:22])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1c(C)cc(C#Cc2ccccc2)cc1=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CCOC(=O)Cn1c(C)cc(/C=C\c2ccccc2)cc1=O
Reaction time: 1 h

Procedure:
A mixture of 4-phenylethynyl-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 3 above (1.5 g, 4.6 mmol) and Lindlar catalyst (5%Pd on CaCO3 plus Pb;150 mg) in EtOH (25 mL) was stirred under an atmosphere of hydrogen at ambient pressure and temperatue for 1 h. The catalyst was removed by filtration and the filtrate solvent was removed in vacuo to give the title compound as a mixture containing 20% of the fully saturated (phenethyl) derivative (1.5 g; TLC Rf=0.5, 1:1 EtOAc:hexanes; HPLC RT=8.15 min, method A).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]([NH2:13])[N:7]=1)[CH2:2][CH2:3][CH3:4].N1C(N)=NC(N)=NC=1N.[C:23]1([CH3:29])[CH:28]=[CH:27]C=CC=1>>[CH2:27]([N:13]([CH2:29][CH2:23][CH2:28][CH3:27])[C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]=[C:10]([NH:12][CH2:1][CH2:2][CH2:3][CH3:4])[N:9]=1)[CH2:28][CH2:23][CH3:29]
Reactant: Cc1ccccc1
Reactant: CCCCNc1nc(N)nc(N)n1
Agent: Nc1nc(N)nc(N)n1
Product: CCCCNc1nc(NCCCC)nc(N(CCCC)CCCC)n1
Yield: 4.8 %

Procedure:
After 1-butanol and water were distilled off from the crude reaction product, toluene was added to the residue. result, 2-n-butylamino-4,6-diamino-1,3,5-triazine in a yield of 4.8% (based on the starting melamine) and 55.5% of the starting melamine were obtained. The toluene solution was analyzed through HPLC. As a result, it was confirmed that a total amount of the other reaction product was extracted.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[OH:14])[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1.[CH3:27][Si:28](Cl)([CH3:30])[CH3:29]>C1COCC1>[NH2:1][C@@H:2]([C@H:13]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[O:14][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9]
Reactant: CN(C[C@@H](N)[C@@H](O)C1CCCCC1)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(C[C@@H](N)[C@@H](O[Si](C)(C)C)C1CCCCC1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 93 %

Procedure:
To a solution of crude tert-butyl (2R,3S)-2-amino-3-cyclohexyl-3-hydroxypropyl(methyl)carbamate (300 mg, 1.05 mmol) in anhydrous THF was added pyridine (846 μL, 10.50 mmol) and TMSCl (663 μL, 5.25 mmol). The mixture was heated to 60° C. and maintained for 20 min, then quenched with satd aq NaHCO3 (5 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over NaSO4 and concentrated to afford tert-butyl (2R,3S)-2-amino-3-cyclohexyl-3-(trimethylsilyloxy)propyl(methyl)carbamate (350 mg, yield 93.1%). 1H NMR (400 MHz, MeOD): 0.13 (s, 9H), 0.80-1.40 (m, 6H), 1.40 (s, 9H), 1.50-2.10 (m, 5H), 2.90 (s, 3H), 3.15-3.50 (m, 4H). MS (E/Z): 359.0 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:19])[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[C:10]([CH2:17][CH3:18])[CH:9]=3)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[CH2:17]([C:10]1[CH:9]=[C:8]2[C:13]([S:14][C:15]3[CH:16]=[C:3]([C:1]4[NH:22][N:21]=[N:20][N:2]=4)[CH:4]=[CH:5][C:6]=3[C:7]2=[O:19])=[CH:12][CH:11]=1)[CH3:18]
Reactant: CCc1ccc2sc3cc(C#N)ccc3c(=O)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCc1ccc2sc3cc(-c4nnn[nH]4)ccc3c(=O)c2c1

Procedure:
3-Cyano-7-ethylthioxanthone (5.3 g), sodium azide (1.55 g), and ammonium chloride (1.26 g) in dimethylformamide were heated at 120° C. for 3 hours, cooled, and poured into dilute hydrochloric acid. The solid precipitate was filtered off and recrystallised twice from acetic acid to yield 7-ethyl-3-(5-tetrazolyl)thioxanthone m.p. 247° C. with decomposition.
Reaction SMILES: [CH2:1]([O:4][CH3:5])[C:2]#[CH:3].C(N(CC)CC)C.Br[C:14]1[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH3:5][O:4][CH2:1][C:2]#[C:3][C:14]1[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=1
Reactant: C#CCOC
Reactant: COC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC#Cc1ccc(C(=O)OC)nc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Bis(triphenylphosphine)palladium (II) chloride (82.4 mg), copper iodide (22.3 mg), methyl propargyl ether (828 μL) and triethylamine (1.9 mL) were added to a solution of methyl 5-bromo-pyridine-2-carboxylate (423 mg) in tetrahydrofuran (10.6 mL), and the mixture was stirred at room temperature for 19 hours and 50 minutes. The reaction solution was concentrated under reduced pressure and water was added to the residue. After extraction with ethyl acetate, the organic layer was washed with brine and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (88.1 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1.C(N(C(C)C)CC)(C)C.[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34](Cl)=[O:35]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=2)=[CH:15][C:16]=1[F:21])=[O:35]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCCn1nc(-c2ccc(O)c(F)c2)c2cccc(Cl)c21
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCn1nc(-c2ccc(OC(=O)CC(C)(C)C)c(F)c2)c2cccc(Cl)c21
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 4-(7-chloro-1-propyl-1H-indazole-3-yl)-2-fluorophenol (0.10 g, 0.33 mmol) in dichloromethane (20 mL) at −78° C. was added diisopropylethylamine (0.70 mL, 0.41 mmol), 3,3-dimethylbutanoyl chloride (0.05 mL, 0.35 mmol) and catalytic amount of 4-(dimethylamino)pyridine. The reaction was stirred at this temperature for 30 minutes. The mixture was diluted with dichloromethane and the organic layer washed with 1n hydrochloric acid solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate evaporated in vacuo to yield crude title compound. The oil was purified by silica gel column chromatography eluting with hexane/ethyl acetate (5/1) to provide the title compound as a white solid (0.11 g, 0.27 mmol, 83%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:13][CH:14](O)[CH3:15]>CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:14]([CH3:15])[CH3:13])=[O:6]
Reactant: CC(C)O
Reactant: O=C(O)CCCBr
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)OC(=O)CCCBr
Temperature: 25 °C

Procedure:
A solution of 4-bromobutyric acid (50 g) in 2-propanol (200 mL) containing 1 mL of H2SO4 was refluxed for 3 h, then cooled to ambient temperature, diluted with ether (500 mL), washed with saturated NaHCO3 (3×300 mL), and brine (300 mL). The organic extract was dried (MgSO4), filtered and concentrated in vacuo to give isopropyl 4-bromo-butyrate (52 g) as an oil. This ester was dissolved in MeCN (380 mL). Ph3P (100 g) was added and the solution was heated at reflux for 72 h, after which TLC analysis (20% water/MeCN, C-18 RP TLC plates) showed complete reaction. The mixture was cooled and concentrated and the residue was slurried with toluene (400 mL) for 1 h. The solid was collected by filtration and was washed with toluene (100 mL) and then dried in vacuo at 50° C. to provide (3-(isopropoxycarbonyl)propyl)triphenylphosphonium bromide (100.6 g). 1H NMR (CDCl3): δ1.19-1.22 (d, 6H), 1.85-1.97 (mn, 2H), 2.85 (t, 2H), 3.95-4.10 (m, 2H), 4.89-5.03 (m, 1H), 7.65-7.94 (m, 15H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9]([S:12]([CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:27][C:28]([F:38])([F:37])[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>CCCCCCC>[CH3:18][CH:16]([CH3:17])[CH2:15][S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:34]([C:33]3[CH:35]=[CH:36][C:30]([O:29][C:28]([F:27])([F:37])[F:38])=[CH:31][CH:32]=3)[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)(=[O:13])=[O:14]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)CC(C)C)CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Yield: 77.2 %

Procedure:
This material was prepared in analogy to example 1 step D) 4-(2-methoxy-ethyl)-1-(2-methyl-propane-1-sulfonyl)-piperidine-4-carboxylic acid ethyl ester (0.134 g), dimethylaluminium chloride in heptane (1.0 molar, 1.2 ml) and 4-(trifluoromethoxy)-aniline (0.106 g) to give the desired 8-(2-methyl-propane-1-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.134 g) as an off-white solid. MS (ESI): 435.15 (MH+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])O.[K+].O>ClCCl>[CH2:29]([O:28][C:26]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:24])[CH2:10][CH2:9]1)=[O:27])[CH3:30]
Reactant: Cc1cccc([N+](=O)[O-])c1NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCC(Nc2c(C)cccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
1-Benzyl-4-[(2-methyl-6-nitrophenyl)amino]piperidine (45.2 mg) was dissolved in dichloromethane (0.9 ml), added with ethyl chloroformate (27 μl) and potassium hydrogencarbonate (28 mg) and stirred at room temperature for 30 minutes. The reaction mixture was added with water (2 ml) and extracted twice with ethyl acetate (2 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=2:1) to obtain 38.3 mg of the title compound. Yield: 90%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[N:23]([CH2:27][O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:22](=[O:36])[CH2:21]2)=[CH:11][C:12]2[CH2:13][CH2:14][CH:15]([OH:19])[CH2:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:29]([O:28][CH2:27][N:23]1[C:22](=[O:36])[CH2:21][N:20]([C:10]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:18][C:17]3[CH2:16][C:15](=[O:19])[CH2:14][CH2:13][C:12]=3[CH:11]=2)[S:24]1(=[O:25])=[O:26])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CN(c2cc3c(cc2OCc2ccccc2)CC(O)CC3)S(=O)(=O)N1COCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCc2cc(N3CC(=O)N(COCc4ccccc4)S3(=O)=O)c(OCc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-(3-benzyloxy-6-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-benzyloxymethyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one (87.6 mg, 0.17 mmol) in DCM (3 mL) is added to a suspension of Dess-Martin reagent (80 mg, 0.19 mmol) in DCM (1 mL). The mixture is stirred at RT for 30 min and filtered through Celite. The filtrate is concentrated and purified by chromatography to give the title compound as an oil: 1H NMR (CDCl3) δ 2.54 (t, J=7 Hz, 2H), 3.01 (t, J=7 Hz, 2H), 3.55 (s, 2H), 4.44 (s, 2H), 4.57 (s, 2H), 5.03 (s, 2H), 5.8 (s, 2H), 6.82 (s, 1H), 7.28-7.36 (m, 11H); (M+NH4)+=524.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][NH2:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH2:13]=O>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[CH2:13][NH:12][CH2:11][CH2:10]2)[CH3:2]
Reactant: C=O
Reactant: CCOc1cccc(CCN)c1
Product: CCOc1ccc2c(c1)CCNC2
Temperature: 110 °C

Procedure:
A stirred mixture of 2-(3-ethoxy-phenyl)-ethylamine (7.0 g, 42 mmol) and 37% aqueous formaldehyde solution (3.5 mL) was heated at 110° C. for 30 minutes. The stirring was stopped and the upper water layer was removed by pipette. To the resulting mixture water (5.25 mL) and concentrated HCl (10.5 mL) were added followed by heating 100° C. for 30 minutes. After allowing to cool to room temperature the mixture was evaporated to dryness and recrystallised from acetone yielding the subtitled compound as a cream solid (2.73 g). MH+ 178. 1H NMR δ (DMSO) 1.27-1.35 (3H, t), 2.88-3.03 (2H, t), 3.18-3.40 (2H, br, t), 3.95-4.08 (2H, q), 4.10-4.22 (2H, m), 6.74-6.85 (2H, m), 7.05-7.15 (1H, m), 9.33-9.55 (2H, br.s).
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([Cl:46])[C:40]([CH2:44]Br)=[C:41]([Cl:43])[CH:42]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([Cl:46])[C:40]([CH2:44][CH:15]2[CH2:16][CH2:17][N:13]([C@H:10]3[CH2:9][CH2:8][C@@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19])[CH2:12][CH2:11]3)[C:14]2=[O:18])=[C:41]([Cl:43])[CH:42]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCC2=O)CC1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve 2 g (6.7 mmol) cis-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (Preparation 69) in 40 mL of dry THF and cool to −78° C. Add 4 mL 2M LDA dropwise and continue stirring at −78° C. for 30 minutes. Allow the mixture to warm to −40° C. for 0.5 hour then re-cool to −78° C. Add a solution of 2.3 g (6.6 mmol) of the 5-benzyloxy-2-bromomethyl-1,3-dichloro-benzene (Preparation 70) in 20 mL dry THF dropwise, remove the cooling bath and stir the reaction at ambient temperature for 72 hours. Dilute the mixture with 100 mL saturated aqueous NaHCO3 and 50 mL EtOAc. Separate the layers, dry the organic layer with MgSO4 and concentrate under vacuum to an oil. Purify by chromatography using 80/20 Hex/EtOAc to recover 2.3 g (59%) of the title compound as an oil.
Reaction SMILES: BrC=C([C:5]1[CH:15]=[CH:14][C:8]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:7][CH:6]=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:32][N:33]1[CH2:46][CH2:45][C:36]2[NH:37][C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][C:43]=3[C:35]=2[CH2:34]1>CN(C=O)C.[Cu]I>[CH3:32][N:33]1[CH2:46][CH2:45][C:36]2[N:37]([C:8]3([CH:7]=[CH:6][CH:5]=[CH:15][CH2:14]3)[C:9]([N:11]([CH3:12])[CH3:13])=[O:10])[C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][C:43]=3[C:35]=2[CH2:34]1
Reactant: CC(=CBr)c1ccc(C(=O)N(C)C)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2C2(C(=O)N(C)C)C=CC=CC2)CCN(C)C1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
4-(1-Bromoprop-1-en-2-yl)-N,N-dimethylbenzamide (264 mg, 1 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude compound was purified on silica gel (100-200 mesh) using 0-7% MeOH:DCM as eluent. Yield: 60 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.30 (m, 2H), 7.20 (s, 2H), 7.10 (d, 1H), 6.95 (d, 1H), 6.86 (s, 1H), 6.80 (s, 1H), 4.58 (m, 1H), 4.30 (m, 1H), 3.60 (m, 1H), 3.10 (m, 1H), 3.0 (s, 3H), 2.92 (s, 3H), 2.80 (m, 2H), 2.50 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H),