Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([C:7]([N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][N:21]3[CH2:20][CH2:19][N:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][CH3:10])[CH2:23][CH2:22]3)[CH2:26][CH2:27]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccccc1N1CCN(CC2CCNCC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CC2CCN(C(=O)C3CCCCC3)CC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
Cyclohexanecarbonyl chloride (0.506 g, 3.5 mmol) was added to a solution of 1-(2-methoxyphenyl)-4-piperidin-4-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 1 and triethylamine (2 equivalents, 1 mL) in CH2Cl2 (30 mL) and the solution stirred under N2 at 0° C. for 16 hours. The mixture was concentrated under vacuum, water (50 mL) added and the product extracted into ethyl acetate (3×25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (0.765 g, 55% yield). An ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (1.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[CH3:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C.O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[CH3:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(O)c2F)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2C)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]phenol (137 mg, 0.38 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (170 mg, 0.5 mmol, 1.4 eq). The resulting mixture was stirred for 30 min at room temperature, then ethyl 2-bromoacetate (77 mg, 0.46 mmol, 1.2 eq) was added. The mixture was stirred at room temperature for 2.5 h and then diluted in water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as an oil (120 mg, 70%).
Reaction SMILES: CO.S(=O)(=O)(O)O.[CH3:8][O:9][C:10]1[C:15]2[O:16][CH2:17][CH2:18][O:19][C:14]=2[C:13]([C:20]([OH:22])=[O:21])=[CH:12][C:11]=1[S:23](=[O:26])(=[O:25])[NH2:24].[C:27](=O)([O-])[O-].[Na+].[Na+]>O>[CH3:27][O:21][C:20]([C:13]1[C:14]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[C:10]([O:9][CH3:8])=[C:11]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:12]=1)=[O:22]
Reactant: COc1c(S(N)(=O)=O)cc(C(=O)O)c2c1OCCO2
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(S(N)(=O)=O)c(OC)c2c1OCCO2
Yield: 96.5 %

Procedure:
396 g of methanol were introduced into a balloon flask provided with a condenser and then 51 g of sulfuric acid and 114.5 g of 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were added while cooling. The mixture was heated under reflux and then poured into 485 cm3 of water and 40 g of sodium carbonate. The precipitate was dried off, washed and dried. 110.5 g of methyl-8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate were obtained (M.P.: 202°-203° C.; yield: 92%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH2:17])[CH:15]=[CH2:16]>CO>[N+:11]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=[O:9])[CH:6]=[N:7][C:2]=1[NH:17][CH2:14][CH:15]=[CH2:16])([O-:13])=[O:12]
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: C=CCN
Solvent: CO
Product: C=CCNc1ncc(C(=O)O)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-5-nitro-3-pyridinecarboxylic acid (4.72 g, 23.30 mmol) in methanol (70 mL) at room temperature was added allyl amine (5.25 mL, 70.0 mmol) and the mixture was stirred overnight. The reaction was then concentrated in vacuo and the residue taken up into water (100 mL). The solution was brought to pH 3 by addition of 1 M HCl aqueous solution. The resulting suspension was extracted with EtOAc (50 mL). The aqueous phase was back-extracted with additional EtOAc (2×50 mL). The organic phases were combined, dried with MgSO4, and filtered. The solution was concentrated in vacuo providing 5-nitro-6-(2-propenylamino)-3-pyridinecarboxylic acid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[F:75][CH2:76][CH2:77][NH2:78]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:78][CH2:77][CH2:76][F:75])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCCF
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCCF)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2-fluoroethylamine hydrochloride (8.09 mg, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (11.1 mg, 33%). LC-MS m/z 619 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13]I.[H-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH2:11][CH3:12])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C#N)c1cccc(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(C)(C#N)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110 %

Procedure:
A solution of 2-(3-chlorophenyl)butanenitrile (4.69 g, 26 mmol) and MeI (2.0 mL, 31 mmol) in DMSO (15 mL) was added dropwise to a stirred solution of NaH (60% dispersion in mineral oil (1.3 g, 31 mmol)) in DMSO (35 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes at 0° C. and then brought to room temperature and stirred for 15 hours. The reaction mixture was quenched with water carefully and then diluted with EtOAc. The organic layer was separated, washed with water (2×) and brine, dried (MgSO4), and concentrated in vacuo to give the desired compound as a light yellow oil (5.54 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][C:7]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[C:6]([F:28])[CH:5]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCCC1>[Cl:3][C:4]1[C:9]([N:10]([S:30]([CH3:29])(=[O:32])=[O:31])[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][C:7]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[C:6]([F:28])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(NS(C)(=O)=O)c(Cl)cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N(S(C)(=O)=O)S(C)(=O)=O)c(Cl)cc2F)c1=O
Temperature: 0 °C

Procedure:
To a suspension of 0.05g of sodium hydride(purity:60%) and 5 ml of tetrahydrofuran, 0.5g of 3-(4-chloro-2-fluoro-5-methanesulfonylaminophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione was added at a temperature of 0° C. Then 0.11 ml of methanesulfonyl chloride was added dropwise to the resultant suspension. After stirring for 7 hburs, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract of the ethyl acetate layer was washed with a saturated sodium chloride agueous solution and dried over anhydrous sodium sulfate. Then ethyl acetate was distilled off to obtain a crude product. The obtained product was washed with diethyl ether to obtain 0.50g of the objective product as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH2:30][C:31]([O:33]CC3C=CC(OC)=CC=3)=[O:32])[CH:27]=[CH:28][CH:29]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:43])[N:10]1[CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[OH:50].FC(F)(F)C(O)=O>C(Cl)CCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:43])[N:10]1[CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[OH:50]
Reactant: COc1ccc(COC(=O)Cc2cccc(CCNC(=O)C3c4ccccc4C(=O)N(C4CCCCC4O)C3c3ccc(Cl)cc3Cl)c2)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1cccc(CCNC(=O)C2c3ccccc3C(=O)N(C3CCCCC3O)C2c2ccc(Cl)cc2Cl)c1
Reaction time: 4 h
Yield: 41.2 %

Procedure:
To a mixture of 990 mg of 4-methoxybenzyl (3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenyl)acetate and 10 ml of ethylene chloride was added 10 ml of trifluoroacetic acid at room temperature, followed by stirring for 4 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 20 mL of methanol, and 20 mL of a saturated aqueous sodium hydrogen carbonate solution was added thereto at room temperature, followed by stirring for 30 minutes. The organic solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and neutralized with 1 M hydrochloric acid. The product was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 339 mg of (3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenyl)acetic acid as a colorless solid.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[CH3:29][N:30](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:29]#[N:30])=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: CN(C)C=O
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Temperature: 80 °C

Procedure:
A mixture of compound 31b (200 mg, 0.450 mmol), zinc cyanide (106 mg, 0.910 mmol), Pd(PPh3)4 (105 mg, 0.910 mmol) in DMF (5 mL) was heated to 80° C. for 4 h. The reaction was cooled to rt, filtered through a diatomaceous earth cartridge (2.5 g), and the filter cake was rinsed with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was recrystallized with hot EtOAc, collected by filtration, and dried to give compound 55a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C21H18N6O2: 387.2 [M+H]. found 387.2
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:22]2[C:30]3[C:25](=[C:26]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)[C:19](O)=O)=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:19]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:4]=2)[N:22]2[C:30]3[C:25](=[C:26]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)=[CH:14][CH:13]=1
Reactant: NC(=NO)c1ccccc1
Reactant: CS(=O)(=O)Nc1cccc2c1ccn2C(C(=O)O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc2c1ccn2C(c1ccc(Cl)cc1)c1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N′-Hydroxybenzenecarboximidamide (49 mg, 0.36 mmol) was added to a stirred solution of compound 6a (90 mg, 0.24 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol), 1-hydroxybenzotriazole (44 mg, 0.29 mmol) and N,N,-diisopropylethylamine (50 μL, 0.29 mmol) in DMF (2.4 mL). The reaction was allowed to stir at rt for 2 h, at which time, the reaction was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated to a crude oil that was dissolved in toluene (2.0 mL). The resulting mixture was heated to 100° C. for 1 h, at which time, the reaction was concentrated in vacuo, and the resulting crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 63. m/z (ES) 479 (MH)+; IP=C rating.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:11]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:14]>C(Cl)Cl.C(O)C.[Pd]>[NH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3](=[O:14])[N:2]([CH3:1])[CH2:10]2
Reactant: CN1Cc2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CN1Cc2cccc(N)c2C1=O
Yield: 88.5 %

Procedure:
A solution of 2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (6.09 g, 31 mmol) in DCM:ethanol (8:2) was hydrogenated under 40 psi of H2 in the presence of 5% Pd/C (500 mg) until cessation of H2 uptake. The reaction mixture was filtered, and the filtrate dried (Na2SO4) and concentrated in vacuo to afford 4.45 g of 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (XXXVIII, yield: 73%). 1H NMR (CDCl3, 400 MHz): δ 3.11 (s, 3H), 4.27 (s, 2H), 5.19 (bs, 2H), 5.5 (d, 1H, J=7.8 Hz), 6.71 (d, 1H, J=7.2 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)(=[O:16])=[O:15])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH3:13]
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(OC)cc2)CC1

Procedure:
1-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (2.42 g, 6.8 mmol) dissolved in methanol (100 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.29 g (58%); white solid; mp 209 ° C.; MS: 328 (M+H)+.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[OH:4].C1(=O)[NH:22]C(=O)C2=CC=CC=C12.[K]>CN(C)C=O.O>[NH2:22][CH2:2][CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[OH:4]
Reactant: OC(CBr)C1=CC2(CCCC2)c2ccccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: NCC(O)C1=CC2(CCCC2)c2ccccc21

Procedure:
Crude 2-bromo-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (7.3 g; prepared as described in Example 3) in dimethylformamide (100 g) is stirred at 40° C. for 4 hours with potassium phthalimide (5.0 g), then diluted with water and extracted three times with chloroform. The combined extracts are dried and evaporated to dryness. The crude 2-phthalimido-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol is added to ethanol (100 ml) containing hydrazine hydrate (1.5 g). The reaction mixture is stirred under reflux for 4 hours, concentrated hydrochloric acid (2 ml) is added, and the mixture is heated for 15 minutes. The solution is cooled, filtered from the solid precipitate and concentrated to a small volume. The concentrate is made alkaline with 2 N sodium hydroxide solution and repeatedly extracted with diethyl ether. Evaporation of the ether and crystallization of the residual product from cyclohexane gives 2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, m.p. 76°-78° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH:15]=1)[CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:23]([O:16][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][C:12]=1[CH:13]=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1cc(Oc2ccccc2)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc(Oc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Phenoxy-2-hydroxybenzaldehyde (20 g, 94 mmol) and potassium carbonate (26.1 g, 188 mmol) are taken up in DMF (250 mL) and treated with benzyl bromide (16.1 g, 94 mmol). The mixture is stirred at room temperature overnight. The mixture is diluted with ethyl acetate and washed three times with saturated aqueous ammonium chloride, dried over magnesium sulfate and evaporated to give 2-benzyloxy-5-phenoxybenzaldehyde as a colorless solid. This is used without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@H:5]([CH3:18])[CH2:4][N:3]1[C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22].[CH2:28]([CH2:30][NH2:31])[OH:29].[Cl-].[NH4+]>CN1CCCC1=O>[CH3:1][C@H:2]1[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:31][CH2:30][CH2:28][OH:29])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@H:5]([CH3:18])[CH2:4][N:3]1[C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:22])[F:23]
Reactant: NCCO
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(NCCO)cc1
Temperature: 120 °C
Yield: 37.6 %

Procedure:
To a solution of (R)-[(2S,5R)-2-methyl-5-methyl-5-methyl-4-(4-fluorophenylsulphonyl)-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (Example 6, 350 mg, 0.85 mmol) in 1-methyl-2-pyrrolidone (2 ml) was added ethanolamine (114 mg, 1.87 mmol) and the mixture heated at 120° C. for 24 hours. The mixture was cooled to ambient temperature, poured onto saturated ammonium chloride solution (30 ml), the mixture extracted with diethyl ether (2×30 ml), the combined ether extracts washed with brine, dried and evaporated. The residue was chromatographed on silica with EtOAc as eluent to give the title compound as a solid (143 mg, 0.32 mmol). NMR: 0.95 (d, 3H), 1.55 (d, 3H), 1.6 (s, 3H), 3.1 (m, 2H), 3.3 (dt, 2H), 3.4 (d, 1H), 3.8 (dt, 2H), 4.2 (s, 1H), 4.6 (m, 2H), 6.6 (d, 2H), 7.5 (d, 2H); m/z 411.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]1([CH3:26])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:23]2[CH2:24][CH2:25][N:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:26])[CH2:21][CH2:22]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccccc1N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
A mixture of 7.88 g (0.0356 m) of p-nitrobenzenesulfonylchloride, 6.27 g (0.0356 m) of 1-(o-tolyl)piperazine, 4.96 ml (0.0356 m) of triethylamine, and 100 ml of tetrahydrofuran is stirred at room temperature for 18 hours. The solvent is then removed in vacuo and the residue is extracted with methylene chloride/aqueous sodium bicarbonate and brine. The organic layer is filtered through sodium sulfate and taken to dryness. Crystallization from methylene chloride/Skellysolve® B hexanes gives 9.51 g of 1-[(p-nitrophenyl)sulfonyl]-4-(o-methylphenyl)piperazine of melting point 176°-177.5° C. and 1.33 g of a second crop (84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][NH2:48])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][NH:48][C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[CH2:26][CH:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]2[S:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:11])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C(O)CNC(=O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)CC2c3ccccc3-c3ccccc3N2S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
The title compound was prepared from {2-[5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetylamino}-acetic acid and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester according to the method described in Example 1e.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([O:12]C)=O)[CH2:3]1.O.[NH2:15][NH2:16]>CO>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:15][NH2:16])=[O:12])[CH2:3]1
Reactant: COC(=O)CN1C[C@@H](C)O[C@@H](C)C1
Reactant: NN
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(CC(=O)NN)C[C@H](C)O1
Temperature: 70 °C
Yield: 66.3 %

Procedure:
Methyl [(2R,6S)-2,6-dimethyl-4-morpholinyl]acetate (5.05 g, 27.0 mmol, see Journal of Fluorine Chemistry (1998) 193-201 for literature preparation) was dissolved in methanol (20 ml) and hydrazine hydrate (2.013 ml, 27.0 mmol) added. The reaction mixture was heated to 70° C. for 18 h. The solvent was partially concentrated in vacuo to remove the methanol and extracted with ethyl acetate (3×20 ml). The combined organic layers were dried and concentrated to afford the title compound as a yellow solid (3.35 g).