Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH2:18]([Sn](CC=C)(CC=C)CC=C)[CH:19]=[CH2:20].B(F)(F)F.CCOCC.[F-].[K+]>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8]([CH2:20][CH:19]=[CH2:18])([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: C=CC[Sn](CC=C)(CC=C)CC=C
Reactant: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Agent: FB(F)F
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC1(O)CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirred solution of 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1 g, 4.11 mmol) in THF (10 mL), tetraallyltin (1.08 mL, 4.52 mmol) in dry THF was added, then cooled to 0° C. before borontrifluoride etherate (0.520 mL, 4.11 mmol) was added drop wise. The mixture was stirred at 0° C. for 1 h and then at room temperature for an additional 2 hours. Potassium fluoride (360 mg in 5 mL water) and celite (1 g) was added and the reaction mixture was stirred for an hour. The reaction mixture was filtered and concentrated to dryness and the residue was dissolved in DCM (200 mL), washed with water (100 mL) and brine 100 mL), dried over MgSO4 and evaporated to dryness. The residue obtained on removal of solvent was purified by silica gel column chromatography using 50% EtOAc in hexanes to obtain 4-allyl-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.94 g, 80%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])[CH2:18][CH2:17]3)[C:8]2=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([O:34][C:35](N1CCC(C2C=CC=CC=2O)CC1)=[O:36])([CH3:33])([CH3:32])[CH3:31].ClCCCCN1CCN(C2CCCCC2)[C:56]1=[O:66].CC(=C)C.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C(N(CC)CC)C>[C:56]([OH:66])(=[O:28])[C:35]([OH:36])=[O:34].[CH:1]1([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:18][CH2:17]3)[C:8]2=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1N(CCCCN2CCC(c3ccccc3O)CC2)CCN1C1CCCCC1
Reactant: O=C1N(CCCCCl)CCN1C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2O)CC1
Agent: C=C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Oc1ccccc1C1CCN(CCCCN2CCN(C3CCCCC3)C2=O)CC1
Product: O=C(O)C(=O)O
Temperature: -20 °C
Reaction time: 3 h

Procedure:
A solution of 3-cyclohexyl-1-[4-[4-(2-hydroxyphenyl)-1-piperidinyl]butan-1-yl]-2-imidazolidinone (1 g, prepared from 4-(2-hydroxyphenyl)piperidine (described in Example 5) and 1a by the method described in Example 4) in dry methylene chloride (10 ml) was cooled to −20° C. Isobutylene (5 ml, condensed at −25° C.) was added under a nitrogen atmosphere followed by addition of trifluoromethanesulfonic acid (0.4 ml). The mixture was stirred for 3 h at −20° C. followed by addition of triethylamine (2 mL). After warming to room temperature the reaction mixture was concentrated in vacuo followed by addition of 2 M ammonia and extraction with methylene chloride. The organic phase was dried over magnesium sulfate and concentrated in vacuo leaving an oil which was purified by flash chromatography (silica gel, eluent: ethyl acetate/MeOH/triethylamine 97:2:1). The resulting colorless oil was dissolved in a mixture of ethyl acetate and acetone. Addition of oxalic acid gave the title compound, 10a, as a crystalline material. Yield: 0.8 g, mp: 147-53° C. 1H NMR (DMSO-d6): δ 0.95-2.10 (m, 18H), 1.35 (s, 9H), 2.85-3.15 (m, 7H), 3.25 (s, 4H), 3.35-3.60 (m, 3H), 6.90-7.25 (m, 4H).
Reaction SMILES: [S:1]=[C:2](C(S)C(OCC)=O)[CH3:3].[NH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH2:12].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2].C(OC(C)C)(C)C>ClCCl>[S:1]=[C:2]([NH:12][NH:11][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:3]
Reactant: CCOC(=O)NN
Reactant: CCOC(=O)C(S)C(C)=S
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CCOC(=O)NNC(C)=S
Yield: 79 %

Procedure:
A mixture of 110 g of 2-(1-thioxoethyl)thioglycolic acid, ethyl ester, 65.2 g of ethyl hydrazinocarboxylate and 500 ml of dichloromethane was heated at reflux for 3 hours, then concentrated in vacuo. The oily residue was concentrated further under high vacuum, giving a yellow oil. This oil was dissolved in 500 ml of dichloromethane and passed through a bed of hydrous magnesium silicate, washing with additional dichloromethane. The resulting light yellow oil was crystallized from diisopropyl ether giving a 79% yield of the desired compound as ivory crystals, mp 54.0-57.5° C. Proton nuclear magnetic resonance (δ ppm], CDCl3) 90MHz: 1.30 (t, 3H, J =7.4Hz, CH3CH2); 2.55 (s, 3H, CH3CS); 4.25 (q, 2H, CH2CH3); 8.75 (bs, 1H, NH); 10.35 (bs, NH).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[NH2:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:24]=[N:25][N:26]([CH2:28][C@H:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31])[CH:27]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1>O1CCOCC1.O>[F:10][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:15][C:16]2[CH:17]=[C:18]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][C@H:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31])[CH:27]=3)[CH:19]=[C:20]([CH3:22])[CH:21]=2)[N:7]=1)[CH3:9]
Reactant: COC(=O)[C@@H](O)Cn1cc(-c2cc(C)cc(N)c2)cn1
Reactant: CC(F)c1ccnc(Cl)n1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@@H](O)Cn1cc(-c2cc(C)cc(Nc3nccc(C(C)F)n3)c2)cn1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
2-Chloro-4-(1-fluoroethyl)pyrimidine (58 mg, 0.36 mmol) and acetic acid (0.022 mL, 0.38 mmol) were added to an oven-dried flask containing methyl (2S)-3-[4-(3-amino-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanoate (100 mg, 0.36 mmol) in dioxane (1.2 mL). The mixture was stirred for 3 hours at 120° C. then cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (2 to 100% EtOAc/hexanes) to afford methyl (2S)-3-[4-(3-{[4-(1-fluoroethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanoate. MS ESI calcd. for C20H23FN5O3 [M+H]+ 400. found 400.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH2:9])[CH:2]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([S:23]([CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])(=[O:25])=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH:9][C:37]([C:36]2[CH:35]=[CH:34][C:33]([C:29]3[O:30][C:31]([CH3:32])=[C:27]([CH2:26][S:23]([CH:20]4[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:16])[CH2:18][CH2:19]4)(=[O:24])=[O:25])[N:28]=3)=[CH:41][CH:40]=2)=[O:38])[CH:2]=1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NCCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 97.8 %

Procedure:
To a solution of 2-(pyridin-3-yl)ethanamine (940 mg, 7.70 mmol, 5.00 equiv), 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoic acid (700 mg, 1.51 mmol, 1.00 equiv), HOBt (250 mg, 1.85 mmol, 1.20 equiv), EDCI (350 mg, 1.83 mmol, 1.20 equiv) in N,N-dimethylformamide (20 mL) at 30° C. was added triethylamine (460 mg, 4.55 mmol, 3.00 equiv) dropwise with stirring. The reaction mixture was stirred at 30° C. overnight and then quenched by the addition of 30 mL of water/ice. The precipitate was collected by filtration, washed with water and dried in a vacuum oven to give 840 mg (98%) of tert-butyl 4-((2-(4-((2-(pyridin-3-yl)ethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate as a yellow solid. LC-MS: (ES, m/z): 569 [M+H]+, 469, 361, 320, 169, 126. 1HNMR (400 MHz, DMSO-d6, ppm) δ 8.73 (s, 1H), 8.50-8.45 (d, 2H), 7.99-7.94 (d, 5H), 7.74 (s, 1H), 7.38 (s, 1H), 4.54 (s, 3H), 4.07 (s, 3H), 3.54 (s, 3H), 2.90 (m, 6H), 2.50-2.45 (s, 6H), 2.11 (s, 3H), 1.48-1.41 (s, 16H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10](=[O:27])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23](OC)=[O:24])=[O:20])[CH:14]=1.[Cl-].[NH4+:29].N>>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10](=[O:27])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]([NH2:29])=[O:24])=[O:20])[CH:14]=1
Reactant: COC(=O)CNC(=O)c1cccc(C=CC(=O)c2c(O)cc(C)[nH]c2=O)c1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(C(=O)NCC(N)=O)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture of 0.37 g of 4-hydroxy-3-[3-[3-[(methoxycarbonylmethyl)aminocarbonyl]phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone, 18 mg of ammonium chloride and 4 ml of aqueous concentrated ammonia was stirred at room temperature for 1 hour. Two ml of aqueous concentrated ammonia was added, and this was further stirred for 30 minutes, and concentrated under reduced pressure. The residue was washed with tetrahydrofuran, and the resulting crude crystals were recrystallized from dimethylformamide to obtain 0.11 g of 4-hydroxy-3-[3-[3-[(aminocarbonylmethyl)aminocarbonyl]phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (91a)] as a yellow crystal.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:25]([O:29][C:30](=[O:35])[CH2:31][CH2:32][CH2:33][NH2:34])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[C:25]([O:29][C:30](=[O:35])[CH2:31][CH2:32][CH2:33][NH:34][CH2:22][C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]3)[CH:13]=2)[CH:18]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C

Procedure:
A solution of 6-(4-tert-butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (45 mg, 0.15 mmol, 4-amino-butyric acid tert-butyl ester HCl salt (115 mg, 0.59 mmol), and triethylamine (81 μL, 0.58 mmol) in 1,2-dichloroethane (1.5 mL) was treated with sodium triacetoxyborohydride (65 mg, 0.29 mmol). After stirring at room temperature over night, the mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate. The organic phase was dried over MgSO4, filtered and concentrated and residue was purified by silica gel column eluted with ethyl acetate in hexane from 0 to 100% to give colorless oil (33 mg, yield: 50%). ESI-MS: 454.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ=7.65-7.70 (m, 3H), 7.38-7.40 (dd, 1H), 7.10-7.14 (m, 2H), 4.22-4.28 (m, 1H), 3.90 (s, 2H), 2.67 (t, 2H), 2.28 (t, 4H), 1.89 (d, 2H), 1.81 (t, 2H), 1.40 (m, 1H), 1.42 (s, 9H), 1.30 (m, 4H), 0.9 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:13].CCCC[O:18][N:19]=O.[O-:21]CC.[K+]>>[OH:18][N:19]=[C:7]1[CH2:8][CH2:9][C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]1=[O:21].[OH:18][N:19]=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:13]
Reactant: CC[O-]
Reactant: CCCCON=O
Reactant: COC1CCc2ccccc2C1=O
Agent: [K+]
Product: COc1ccc2c(c1)C(=O)C(=NO)CC2
Product: O=C1C(=NO)CCc2ccccc21

Procedure:
4-(p-methoxyphenyl)butanoic acid (Compound 13, R1 =H, R2 =CH3) is treated with polyphosphoric acid (PPA) to form 7-methoxytetralone via Friedel-Crafts acylation (Compound 1, R1 =H, R2 =CH3 on C7. ##STR19## The tetralone (Compound 1) is then reacted with N-butylnitrite and potassium ethoxide to yield 2-hydroxyimino-7-methoxy-1-tetralone (Compound 2, R2 =CH3 on C7.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1)[CH3:2].[CH2:13]([O:20][CH2:21][N:22]1[N:26]=[N:25][C:24]([Sn](CCCC)(CCCC)CCCC)=[N:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.[Cu]I.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>[CH2:13]([O:20][CH2:21][N:22]1[N:26]=[N:25][C:24]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:12])=[N:23]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(COCc2ccccc2)n1
Reactant: CCOC(=O)c1cccc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(-c2nnn(COCc3ccccc3)n2)c1
Temperature: 25 °C

Procedure:
A solution of ethyl-3-bromobenzoate (0.47 g, 2.05 mmol) and 2-(benzyloxymethyl)-5-(tributylstannyl)-2H-tetrazole in toluene (20 mL) was degassed under vacuum and argon. To this solution was added copper (I) iodide (20 mg, 0.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.10 mmol), and the mixture was again degassed under vacuum and argon. The flask and condenser were covered in foil to exclude light, and the reaction was heated at reflux temperature for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in-vacuo. The residue was purified over a 3.5×12 cm silica gel column, eluting with 5% then 10% then 15% ethyl acetate/hexanes to yield the title compound as a colorless oil which contained 5% of a tributyltin impurity. MS (ESI+)=339.22, (M+H)+. The oil was used as-is in the next step.
Reaction SMILES: [H-].[K+].[CH3:3][C:4]([CH3:6])=[O:5].[C:7](Cl)(=[O:11])[CH:8]([CH3:10])[CH3:9].O>O1CCCC1>[C:7]([O:5][C:4]([CH3:6])=[CH2:3])(=[O:11])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)=O
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)OC(=O)C(C)C
Temperature: -10 °C

Procedure:
Isopropenyl isobutyrate was prepared by the potassium hydride catalyzed condensation of acetone with isobutyryl chloride as follows. A suspension of potassium hydride (100 g, 2.5 mol.) in 1.5 liters of dry tetrahydrofuran was prepared. The suspension was cooled to -10° C. and 200 ml acetone was slowly added maintaining the temperature of the reaction mixture between 0° and -10° C. The resulting solution of acetone enolate was added to a solution of 266 g (2.5 mol.) of isobutyryl chloride in 3 liters of tetrahydrofuran over a 30-minute period. The temperature of the reaction flask was maintained between -30° and -50° C. during the addition. After 16 hours the reaction mixture was poured into water and the resulting mixture was extracted with ether. The ether extracts were combined, dried over sodium sulfate, and the solvent was removed. The residue was distilled through a thin film evaporator (114° to 125° C.) and the distillate was redistilled through a spinning band column. The fraction boiling at 40° to 46° C. (1.5 mm Hg) was collected to give a total of 21 g (7%) of pure isopropenyl isobutyrate. The isopropenyl isobutyrate was polymerized according to the method described in Example 2 to give the corresponding polymer.
Reaction SMILES: [I-].[C:2]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1)=[O:19])#[N:3].Cl.[NH3:36].[C:37]([OH:40])(=[O:39])[CH3:38].F[C:42](F)(F)[C:43]([OH:45])=[O:44]>>[C:37]([OH:40])(=[O:39])[CH3:38].[C:43]([O-:45])(=[O:44])[CH3:42].[C:2]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([NH:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([CH3:30])([CH3:31])[CH3:29])=[CH:26][CH:27]=1)=[O:19])(=[NH:36])[NH2:3]
Reactant: O=C(O)C(F)(F)F
Reactant: C[N+](C)(C)c1ccc(CNC(=O)c2cc3cc(F)ccc3n2Cc2cccc(C#N)c2)cc1
Reactant: N
Agent: Cl
Agent: [I-]
Solvent: CC(=O)O
Product: CC(=O)[O-]
Product: C[N+](C)(C)c1ccc(CNC(=O)c2cc3cc(F)ccc3n2Cc2cccc(C(=N)N)c2)cc1

Procedure:
This compound was prepared from [4-({[1-(3-cyano-benzyl)-5-fluoro-1H-indole-2-carbonyl]-amino}-methyl)-phenyl]-trimethyl-ammonium iodide, hydrogen chloride, and liquid ammonia analogously to example 19/3. Instead of trifluoroacetic acid acetic acid was used for chromatography. Yield: 74%. M.p. 172° C. (dec.). MS: 458.2 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[C:19]([NH2:22])(=[S:21])[CH3:20]>>[CH3:1][O:2][C:3]([C:4]1[N:22]=[C:19]([CH3:20])[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:18]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C(F)(F)F)cc1
Product: COC(=O)c1nc(C)sc1-c1ccc(C(F)(F)F)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.98 min; [M+H]+=302.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:14][CH2:13][C@H:12]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[N:39]=[C:40]([C@@H:43]5[CH2:47][CH2:46][CH2:45][N:44]5C(OC(C)(C)C)=O)[NH:41][CH:42]=4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[N:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:14][CH2:13][C@H:12]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[N:39]=[C:40]([C@@H:43]5[CH2:47][CH2:46][CH2:45][NH:44]5)[NH:41][CH:42]=4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[N:25]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5COC6(CCOCC6)N5C(=O)OCc5ccccc5)n4)cc3)cc2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1[C@H](c2nc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6CCCN6)n5)cc4)cc3)c[nH]2)COC12CCOCC2
Reaction time: 2 h
Yield: 47.6 %

Procedure:
(R)-3-(4-{4′-[2-((S)-1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-1H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-1,8-dioxa-4-aza-spiro[4.5]decane-4-carboxylic acid benzyl ester (0.04 gm, 0.05 mmol) was dissolved in DCM (2 mL), TFA (2 mL) was added and the mixture stirred for 2 hours. The solvent was evaporated, the residue redissolved in EtOAc (20 mL) and the organics washed with aqueous NaHCO3, water and brine. Drying the organic layer afforded (R)-3-{4-[4′-((S)-2-pyrrolidin-2-yl-1H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-1,8-dioxa-4-aza-spiro[4.5]decane-4-carboxylic acid benzyl ester (0.015 gm, 44%). LCMS 631.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][C:14]([C:17]([NH:19][C@@H:20]4[CH:25]5[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]5)[CH2:21]4)=[O:18])=[CH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:28]1[C:32]([C:33]([Cl:35])=[O:34])=[CH:31][CH:30]=[N:29]1>>[ClH:35].[N:22]12[CH2:23][CH2:24][CH:25]([CH2:26][CH2:27]1)[C@@H:20]([NH:19][C:17]([C:14]1[O:15][C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:33]([C:32]5[O:28][N:29]=[CH:30][CH:31]=5)=[O:34])[CH:7]=[CH:6][CH:5]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=1)=[O:18])[CH2:21]2
Reactant: O=C(Cl)c1ccno1
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Product: Cl
Product: O=C(Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1)c1ccno1

Procedure:
50 mg (0.14 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 114) and 36.4 mg (0.28 mmol) of 5-isoxazolecarbonyl chloride are reacted together by general method F. 39.6 mg (53.3% of theory) of the title compound are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: OCCCCCl
Reactant: O=C1CCNCC1
Product: O=C1CCN(CCCCO)CC1

Procedure:
1-(4-Hydroxybutyl)-4-piperidone is prepared from 4-piperidone and 4-chloro-1-butanol essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:20].B1([O-])OO1.O.O.O.O.[Na+]>CO>[N:1]1([CH2:7][CH2:8][S:9]([C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[O:20])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccc(SCCN2CCOCC2)cc1
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(S(=O)CCN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A cold (0° C.) solution of 1-[[(4-morpholinyl)ethyl]thio]-4-nitrobenzene in methanol is treated slowly with excess 30% sulfuric acid and then sodium perborate tetrahydrate (10 equivalents) is added. The mixture is stirred at 0° C. for 2 hrs and then at ambient temperature for 2 hrs. The methanol is removed in vacuo and the residue basified with 50% sodium hydroxide solution and filtered. The filter cake is washed with methylene chloride and the aqueous filtrate extracted with the methylene chloride washings. The combined extract is washed with water, dried, and concentrated to obtain the product.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:21])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].O.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:23][O:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:21])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(O)c1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Solvent: O
Solvent: CO
Product: COC(C)(C)c1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of 3-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-isoquinolin-1-one (83.8 mg, 0.30 mmol) in methanol (1 ml) is added toluene-4-sulfonic acid monohydrate (5.2 mg, 0.030 mmol). The reaction mixture is stirred for 5 days at ambient temperature. The reaction mixture, a white suspension, is evaporated and the residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 3-[4-(1-methoxy-1-methyl-ethyl)-phenyl]-2H-isoquinolin-1-one as white crystals; HPLC/MS 2.66 min (B), [M+H] 294;