Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:18][S:19]([O:1][CH2:2][CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CC1CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC1COS(C)(=O)=O
Reaction time: 8 h
Yield: 99 %

Procedure:
To a reaction solution of ethyl 2-(hydroxymethyl)cyclopropanecarboxylate (4-1) (577 mg; 4.0 mmol) with Et3N (1.1 mL; 8.0 mmol) and DMAP (49 mg; 0.4 mmol) in 12 mL of CH2Cl2 at 0° C. was added methanesulfonyl chloride (0.4 mL; 4.8 mmol). The resulting mixture of brown color suspension was stirred at 0° C. to room temperature under N2 for overnight. The reaction mixture was quenched with NaHCO3, then partitioned between CH2Cl2 (200 mL) and saturated NaHCO3 solution (50 mL); brine (50 mL). The organic layer was dried (Na2SO4), then filtered through silica gel pad, eluted with hexane:EtOAc/1:1. The filtrate was concentrated by vacuum to give 880 mg of ethyl 2-{[(methylsulfonyl)oxy]methyl}cyclopropanecarboxylate as a yellow oil (99% yield). 1H NMR (400 MHz, chloroform-D) δ ppm 0.91-1.02 (m, 1H) 1.26 (q, J=6.99 Hz, 3H) 1.29-1.36 (m, 1H) 1.63-1.74 (m, 1H) 1.79-1.92 (m, 1H) 3.02 (s, 3H) 3.99-4.24 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][NH:13][C@@H:14]([CH2:22][CH2:23][CH3:24])[CH2:15][N:16]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17]1>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:13]([C@@H:14]([CH2:22][CH2:23][CH3:24])[CH2:15][N:16]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17]2)[CH3:12])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCC[C@@H](CN1CC[C@H](O)C1)NC
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: CCC[C@@H](CN1CC[C@H](O)C1)N(C)C(=O)c1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 2 %

Procedure:
4-Cyanobenzoyl chloride (0.800 g, 4.83 mmol) was added to a solution of (S)-1-((S)-2-(methylamino)pentyl)pyrrolidin-3-ol (Compound J7) (1 g, 5.37 mmol) and TEA (1.496 mL, 10.74 mmol) in DCM (25 mL) at 0° C. The reaction was stirred for 30 min and was then allowed to attain rt. After 1.5 h the reaction was quenched with K2CO3 (1 M aq., 25 mL) and the aqueous phase was extracted with DCM. The organic phases were pooled, dried (MgSO4), filtered and evaporated. The residue was dissolved in EtOAc and poured on an SCX-2 column (10 g). The column was washed with EtOAc and MeOH, The product was eluted with NH3 saturated MeOH. The crude product (1.200 g, 70.9%) was obtained as a yellow oil. A fraction of the crude material was purified by preparative HPLC to yield 31 mg of the title product with a purity of 99.5%. 1H NMR (400 MHz, CD3OD) δ 0.85-1.09, 1.14-1.75, 2.03-2.23, 2.29-2.61, 2.66-2.76, 2.82-3.00, 4.24-4.39, 5.49, 7.57-7.65, 7.80-7.85. HRMS (M+H)+: calculated 316.2025. found 316.2038.
Reaction SMILES: C([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])(OC(C)(C)C)=O>CN(C)C=O>[NH2:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Solvent: CN(C)C=O
Product: NC(=O)CC[C@H](N)C(=O)O
Reaction time: 8 h

Procedure:
To the product of Step (F) above there is added with mixing 4 molar excess of the p-nitrophenyl ester of Boc-L-glutamine [Gln (ONp), Peninsula, supra.] dissolved in 15-20 ml. of dimethylformamide containing 1.5 M urea. The resulting mixture is shaken overnight, filtered, washed with dimethylformamide-ethanol mixture and dried.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[CH:8]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:9][CH2:10][C:5]2=[CH:4][CH:3]=1.Br[CH2:18][C:19](=O)[CH3:20].C(=O)([O-])O.[Na+]>C(O)C>[CH3:20][C:19]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]3[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[C:6]=3[N:7]2[CH:18]=1
Reactant: CC(=O)NCCC1CCc2ccc(N)nc21
Reactant: CC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)NCCC1CCc2ccc3nc(C)cn3c21
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
A suspension of N-[2-(2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)ethyl]acetamide (17.6 mg, 0.0803 mmol), bromoacetone (16.5 mg, 0.120 mmol) and sodium hydrogen carbonate (10.1 mg, 0.12 mmol) in ethanol (1 mL) was heated under reflux for 4 hr. The solvent was evaporated under reduced pressure, and N,N-dimethylformamide (1 mL) was added. The mixture was irradiated with 150 W microwave and stirred at 160° C. for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (methanol/ethyl acetate=17/83 and NH; methanol/ethyl acetate=5/95) to give the title compound (2.0 mg, yield 10%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.O>[CH2:20]([O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[Br:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.5 %

Procedure:
2-Bromo-4-(trifluoromethoxy)phenol (Preparation 8; 5 g, 20 mmol) was dissolved in N,N-dimethylformamide (60 ml), and potassium carbonate (5.4 g, 40 mmol) was added, followed by benzyl bromide (3.5 ml, 30 mmol), and the reaction was stirred at ambient temperature for 15 hours. The reaction was diluted with water (150 ml) and extracted into ethyl acetate (3×60 ml). The combined organic fractions were washed with water (100 ml), brine (100 ml), dried (MgSO4) and evaporated in vacuo. Purification on silica, eluting with 2% and 5% ethyl acetate in hexane gave the title compound as a clear oil (6.7 g, 96%). 1H NMR (250 MHz, CDCl3) δ 5.47 (2H, s), 7.23 (1H, d, J=9 Hz), 7.43 (1H, dd J=8.2, 2.9 Hz), and 7.75 (6H, m).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([O:13]CC)=O.O.[NH2:17][NH2:18]>>[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([NH:17][NH2:18])=[O:13]
Reactant: CCOC(=O)c1cnc2n(c1=O)CCC2
Reactant: NN
Solvent: O
Product: NNC(=O)c1cnc2n(c1=O)CCC2
Reaction time: 1 h
Yield: 77.5 %

Procedure:
2.08 g of ethyl 4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate is added to 10 ml of 98% by weight of hydrazine hydrate and the mixture is allowed to stand for 1 hour at room temperature and the obtained crystals are filtered and washed with water. 1.5 g (77.5%) of 4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carbohydrazide is obtained, melting at 180° to 181° C.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: CCc1cc2c(NCCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:12][O:13][C:14](=[O:32])[C@@H:15]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].F[C:34]1[CH:47]=[CH:46][C:37]([C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:39])=[CH:36][CH:35]=1>O>[CH3:12][O:13][C:14](=[O:32])[C@H:15]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:43]2[CH:44]=[CH:45][C:40]([C:38](=[O:39])[C:37]3[CH:46]=[CH:47][CH:34]=[CH:35][CH:36]=3)=[CH:41][CH:42]=2)=[CH:27][CH:26]=1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](Cc1ccc(Oc2ccc(C(=O)c3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 23.6 %

Procedure:
To a solution of N,N-Dimethylformamide (DMF) (3.16 mL) and potassium carbonate (0.222 g, 1.605 mmol) was added Boc-D-Tyrosine-Methyl ester (0.158 g, 0.535 mmol) and 4-Fluorobenzophenone (0.160 g, 0.802 mmol) at 100° C. under an atmosphere of nitrogen for 42 hours. The mixture was poured into 30 mL water solution and extracted with ethyl acetate (EtOAc) (4×10 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (0.060 g, 24%): 1H NMR (400 MHz, CDCL3): δ 1.42 (s, 9H), 2.99-3.17 (m, 2H), 3.71-3.74 (m, 3H), 4.53-4.61 (m, 1H), 4.96-5.16 (m, 1H), 6.75 (d, 1H, J=8.4 Hz), 6.97-7.03 (m, 4H), 7.16 (d, 2H, J=8.4 Hz), 7.46-7.50 (m, 2H), 7.56-7.58 (m, 1H), 7.77-7.83 (m, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:20]=2)=[CH:8][CH:7]=1>C(O)C.CO.[Pt](=O)=O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[CH:20]=2)=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccc(-c2cn3ccccc3n2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CO
Product: ClCCCOc1ccc(-c2cn3c(n2)CCCC3)cc1
Reaction time: 4 h
Yield: 96.4 %

Procedure:
To a Parr bottle charged with a mixture of platinum (IV) oxide (30 mg) in ethanol (3 mL) was added a solution of the product of Step A (90 mg) in methanol (6 ml). The mixture was hydrogenated at 40 psi for 4 hours and filtered through a Celite pad which was rinsed with several additional milliliters of methanol and ethanol. The filtrate was collected and evaporated in vacuo to yield the title compound (88 mg) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH:7]=O)[CH2:4][O:3]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:17]([NH:24][OH:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:9][C:2]1([CH3:1])[O:6][C@@H:5](/[CH:7]=[N+:24](\[O-:25])/[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4][O:3]1
Reactant: ONCc1ccccc1
Reactant: CC1(C)OC[C@H](C=O)O1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OC[C@H](/C=[N+](\[O-])Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 54.6 %

Procedure:
1.50 g (11.53 mmol) (R)-2,2-Dimethyl-1.3-dioxolane-4-carboxaldehyde (Fluorochem, Hadfield, UK) was dissolved in 60 ml of DCM and treated with 1.64 g (11.53 mmol) sodium sulfate. The reaction mixture was flushed with argon and treated with a solution of 1.42 g (11.53 mmol) N-benzyl-hydroxylamine (prepared from the commercially available hydrochloride salt) in 20 ml of CH2Cl2. The reaction mixture was stirred under argon at RT for 16.5 h and then filtered. Silicagel was added to the filtrate is and preabsorbed, before being purified by chromatography on silicagel (gradient: Heptane/EtOAc 0%-100% in 30 min). Fr. 20-80 were collected and evaporated to dryness and dried under vacuum overnight to give 1.48 g of a white solid (˜100% pure by HPLC, Rt=1.43); ESI-MS: 236.2 [M+H]+(LC-MS 1))
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:6][C@H:5]([NH:7][C:8](=[O:20])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[N:19]=[CH:18][CH:17]=[N:16]2)[C@@H:4]([NH:21]S(C(C)(C)C)(=O)=O)[CH2:3]1.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[NH2:21][C@H:4]1[CH2:3][C:2]([F:29])([F:1])[CH2:6][C@@H:5]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:16]=[CH:17][CH:18]=[N:19]1
Reactant: CC(C)(C)S(=O)(=O)N[C@H]1CC(F)(F)C[C@@H]1NC(=O)c1ccccc1-n1nccn1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: N[C@H]1CC(F)(F)C[C@@H]1NC(=O)c1ccccc1-n1nccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-[(1S,2S)-4,4-difluoro-2-(2-methylpropane-2-sulfonamido)cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (1.7 g, 3.98 mmol) in DCM (100 ml) at 0° C. was added anisole (CAS number 100-66-3; 7.82 ml, 71.6 mmol) followed by the drop wise addition of trifluoromethanesulfonic acid in DCM (0.2M, 1.55 ml, 17.5 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 18 hours. The reaction mixture was quenched with sodium hydroxide (0.2M) until pH 11 obtained then extracted with DCM. The organics were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by SCX chromatography (2M ammonia in methanol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[F:13][C:14]([F:30])([F:29])[C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)=[CH:17][CH:16]=1>CO>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:9])[CH2:10][N:23]2[CH2:24][CH2:25][CH2:26][CH:21]([CH2:20][O:19][C:18]3[CH:27]=[CH:28][C:15]([C:14]([F:13])([F:29])[F:30])=[CH:16][CH:17]=3)[CH2:22]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(OCC2CO2)cc1
Reactant: FC(F)(F)c1ccc(OCC2CCCNC2)cc1
Solvent: CO
Product: OC(COc1ccc(Cl)cc1)CN1CCCC(COc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
2-(4-Chloro-phenoxymethyl)-oxirane (50 mg) and of 3-(4-Trifluoromethyl-phenoxymethyl)-piperidine (70 mg, 1.0 equivalent) in 4 mL of methanol were heated in a sealed tube at 100° C. for 16 hours, cooled to room temperature, transferred to a round-bottomed flask, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 95 mg of 1-(4-Chloro-phenoxy)-3-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-propan-2-ol was obtained (79%). Data for this mixture of amino alcohol diastereomers: MS 444 (M++1).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C=O)C.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:22]#[C:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(C#Cc2ccccc2)cn1
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (31 mg, 44.7 μmol, 0.05 equiv.) was dissolved in 2 ml DMF. (230 mg, 894 μmol) 5-Bromo-pyridine-2-carboxylic acid tert-butylamide (Example 1, step 1) and phenylacetylene (183 mg, 196 μl, 1.79 mmol, 2 equiv.) were added at room temperature. Triethylamine (272 mg, 374 μl, 2.68 mmol, 3 equiv.), triphenylphosphine (7 mg, 26.8 μmol, 0.03 equiv.) and copper(I)iodide (5 mg, 26.8 μmol, 0.03 equiv.) were added and the mixture was stirred for 2 hours at 70° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 5-phenylethynyl-pyridine-2-carboxylic acid tert-butylamide (174 mg, 70% yield) was obtained as a light yellow solid, MS: m/e=279.1 (M+H+).
Reaction SMILES: C([NH:4][C:5]1([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9][N:8](C(OCC)=O)[CH2:7][C:6]1([CH3:17])[CH3:16])(=O)C.[OH-].[Na+].O>C(O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2([NH2:4])[CH2:10][CH2:9][NH:8][CH2:7][C:6]2([CH3:16])[CH3:17])=[CH:19][CH:20]=1
Reactant: CCOC(=O)N1CCC(NC(C)=O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CNCCC1(N)c1ccc(Cl)cc1
Yield: 92.7 %

Procedure:
A solution of ethyl 4-acetamido-4-(4-chlorophenyl)-3,3-dimethylpiperidine-1-carboxylate (2.04 g, 5.78 mmol) in ethanol (25 mL) was treated with 5 N NaOH (aq) (23.13 mL, 116 mmol), and the mixture was heated at reflux for two days. During the reflux, a colorless, soapy solid predipitated. Water was added until a clear solution was observed. The ethanol was removed under reduced pressure, and the aqueous mixture was extracted 4× with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in-vacuo to yield the title compound (1.28 g, 5.36 mmol, 93% yield) as a colorless powder. MS (ESI+)=239, (M+H)+.
Reaction SMILES: [Cl:1]NC(=O)CCC(N)=O.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:15][C:16]=1[Cl:1]
Reactant: NC(=O)CCC(=O)NCl
Reactant: CC(=O)Cc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Cc1ccc(N)c(Cl)c1
Reaction time: 1 h

Procedure:
N-Chlorosuccinamide (1.79 g, 13.4 mmol) is added to a stirred solution of 1-(4-amino-phenyl)-propan-2-one (2.0 g, 13.4 mmol) in chloroform at 0° C. After 1 hour the reaction is complete. The solvent is removed to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:6]=1[S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.O>[NH2:11][C:10]1[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[C:6]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1NCCO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)S(=O)(=O)c1cccc(N)c1NCCO
Temperature: 60 °C

Procedure:
To a solution of 2-[(2-hydroxyethyl)amino]-N,N-dimethyl-3-nitrobenzenesulfonamide (107 mg, 0.37 mmol) in methanol (2 mL) a solution of 85% sodium hydrosulfite (0.30 g, 1.5 mmol) in water (1.2 mL) was added. The obtained suspension was heated at 60° C. for 10 min. The volatiles were removed in vacuo, and the residue was partitioned between a saturated solution of sodium bicarbonate and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo affording 3-amino-2-[(2-hydroxyethyl)amino]-N,N-dimethylbenzenesulfonamide, 69 mg (72 %) as an oil: MS (ESI) m/z 260 [M+H].
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[O:22]([CH2:29][CH2:30][CH2:31]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:31][CH2:30][CH2:29][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCCOc2ccccc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g--see Preparation B), 3-phenoxypropylbromide (0.24 g), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. On cooling to room temperature water (40 ml) was added and the resulting mixture extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 7%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.23 g.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]=1/[CH:19]=[CH:20]/[CH:21]=[O:22]>O1CCCC1.CCCCCC>[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]=1/[CH:19]=[CH:20]/[CH:21]([OH:22])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: O=C/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
Methyl acetoacetate (9.56 g, 82.3 mmole) was added dropwise to a stirred suspension of sodium hydride (50% oil suspension) (3.95 g, 82.3 mmole) in anhydrous tetrahydrofuran at 0° C. under a nitrogen atmosphere. The resulting solution was stirred 15 minutes at 0° C. and then treated with a 1.6 M solution (51.5 ml, 82.3 mmole) of n-butyllithium in hexane over 5 minutes. The resulting yellow solution was stirred 15 minutes at 0° C. and then treated with a solution of (E)-2,4-dichloro-6-phenylmethoxycinnamaldehyde (25.3 g, 82.3 mmole) in anhydrous tetrahydrofuran (150 ml). The resulting orange solution was stirred 15 minutes at 0° C. and then quenched by dropwise addition of 12 N hydrochloric acid (ca. 20 ml). The reaction mixture was diluted with water (100 ml) and extracted with ether (3×300 ml). The organic extracts were combined, washed with brine (3×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo leaving the title compound as a yellow oil (34.8 g, 100%): pmr (CDCl3) δ2.75 (2H, d), 3.45 (2H, s), 3.72 (3H, s), 4.71 (H, m), 5.50 (2H, s), 7.37 (5H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[S:3]([C:6]1[CH:7]=[C:8]([C:15]([CH3:29])([CH3:28])[CH2:16][C:17]2([C:24]([F:27])([F:26])[F:25])[CH2:21][O:20]C(C)(C)[O:18]2)[C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)(=[O:5])=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(=O)(O)[O-].[Na+]>[CH3:30][N:2]([CH3:1])[S:3]([C:6]1[CH:7]=[C:8]([C:15]([CH3:28])([CH3:29])[CH2:16][C:17]([OH:18])([CH2:21][OH:20])[C:24]([F:25])([F:27])[F:26])[C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1cc2c(c(C(C)(C)CC3(C(F)(F)F)COC(C)(C)O3)c1)OCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)S(=O)(=O)c1cc2c(c(C(C)(C)CC(O)(CO)C(F)(F)F)c1)OCC2
Yield: 78.7 %

Procedure:
A mixture of 1.18 g (2.61 mmol) of 7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3]dioxolan-4-yl)-1,1-dimethyl-ethyl]-2,3-dihydrobenzofuran-5-sulfonic acid dimethylamide and 303 mg (1.59 mmol) of p-toluenesulfonic acid monohydrate in 20 mL of methanol was warmed at reflux for 3 days. The mixture was then cooled and diluted with 15 mL of saturated aqueous sodium bicarbonate and extracted with three 15 mL portions of ethyl acetate. The combined organic layers were washed with two 15 mL portions of saturated aqueous sodium bicarbonate, two 15 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ether to afford 845 mg (78% yield) of the title compound as a white solid.