Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([F:16])[CH2:12]1)=[O:10])(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>ClCCl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([F:16])[CH2:12]1)=[O:10]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[(R)-2-((S)-3-Fluoro-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (43 mg, 0.127 mmol) was dissolved in dichloromethane (1.6 ml) and cooled in an ice bath. Trifluoroacetic acid (0.8 ml) was slowly added and the reaction was stirred at room temperature for 3 h then evaporated and dried under high vacuum to afford (R)-2-amino-1-((S)-3-fluoro-pyrrolidin-1-yl)-propan-1-one trifluoroacetate which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[CH:12]=[N:13][NH:14][C:6]=12.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>O>[C:15]([O:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[CH:12]=[N:13][NH:14][C:6]=12)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(NCCO)c2[nH]ncc2n1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CO
Product: Cc1cc(NCCOC(=O)c2ccccc2)c2[nH]ncc2n1

Procedure:
The title compound was prepared from 7-(2-hydroxyethyl-amino)-5-methyl-1H-pyrazolo[4,3-b]pyridine (2 g) and benzoyl chloride by the general method of Example 4 without the addition of methanol. The crude reaction mixture was poured into a large excess of water and extracted with ethyl acetate (×3). The combined organic layers were washed with water (×2), dried with anhydrous sodium sulphate, filtered and evaporated to dryness. The resulting intermediate dibenzoylated compound was recrystallized from carbon tetrachloride/60°-80° C. petrol to give a pale yellow solid, m.p. 136°-138° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:13]([C:15]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:13]([C:15]1([C:18]([O:20][CH3:26])=[O:19])[CH2:16][CH2:17]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc(C(=O)C2(C(=O)O)CC2)cc1CNC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1(C(=O)c2ccc(OC)c(CNC(=O)OC(C)(C)C)c2)CC1
Reaction time: 0.5 h

Procedure:
Under a solution of 1.069 g of 1-(3-{[(t-butoxycarbonyl)amino]methyl}-4-methoxybenzoyl)-1-cyclopropanecarboxylic acid in 10 ml of methanol was added 8 ml of trimethylsilyldiazomethane (2N solution in hexane). After stirring for 30 minutes, the solution was treated with acetic acid until its color faded, and then concentrated. The residue was purified by silica gel column chromatography, to give 0.974 g of the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:23])([F:25])[F:24])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH2:34][OH:35])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCO)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), 2-aminoethanol (6.37 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). It was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 18 min, product retention=17.9 min (20 mL/min, 220 nM) to provide (R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (25 mg, 0.047 mmol, 68.2% yield): LCMS=475.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.25 (1 H, t, J=5.94 Hz), 8.09-8.19 (2 H, m), 7.58-7.84 (7 H, m), 5.14 (1 H, s), 3.60-3.67 (2 H, m), 3.34-3.44 (2 H, m); HPLC peak RT=8.2 min (Method A).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[C:17](Cl)(=[O:28])[O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][C:17]([NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:28])=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CNC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a solution of methyl 2-aminoacetate hydrochloride (0.137 g, 1.09 mmol) and DIPEA (0.52 mL, 2.98 mmol) in DCM (5 mL) at 0° C. was added a solution of 4-nitrophenyl carbonochloridate (0.20 g, 0.992 mmol) in DCM (2 mL) dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. After this time, the reaction was quenched with water, and the organic layer was separated. The aqueous phase was extracted with DCM, and the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (0.213 g, 84% yield) as a white solid. LCMS, [M+Na]+=277.1. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=9.1 Hz, 2H), 7.32 (d, J=9.1 Hz, 2H), 5.62 (br. s, 1H), 4.07 (d, J=5.5 Hz, 2H), 3.80 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:19]([OH:21])=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.[CH3:32][NH:33][CH3:34].CCN=C=NCCCN(C)C.Cl>O.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:19](=[O:21])[N:33]([CH3:34])[CH3:32])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)N(C)C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
THF (5 ml) charged in to a R B flask followed by the addition of piperidine-1,4,4-tricarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.5 g) and 1-hydroxybenzotriazole (0.38 g). Allowed to stir the reaction mixture at 25-300 C for 30 mins. Dimethylamine (0.75 mL) followed by EDC HCl (0.38 g) was added in to the above reaction mixture at 25-300 C. Allowed the reaction mixture to stir at 25-300 C for 1-2 hrs. Reaction is followed by TLC. The reaction mixture concentrated under vacuum using rota vapour and the product slurry obtained is suspended in D M Water (5 mL). The product extracted in to ethyl acetate (2×5 mL). The combined product layer dried with sodium sulphate and concentrated under vacuum to yield crude product which in turn purified by a column chromatography to yield pure 4-dimethylcarbamoyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:26]O>>[C:1]1([S:7][C:8]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:9]=2[C:10]([O:12][CH3:26])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Sc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(F)(F)F)ccc1Sc1ccccc1

Procedure:
100 g of 2-(phenylthio)-5-trifluoromethyl-benzoic acid, 750 ml of absolute methanol and 100 ml of sulphuric acid are heated under reflux for 24 hours. The solution is concentrated under reduced pressure and treated with water and benzene. After equilibration, the organic phase is washed successively with saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The benzene phase is subsequently dried over sodium sulphate, filtered and evaporated. There is obtained methyl 2-(phenylthio)-5-trifluoromethyl-benzoate as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]=O>C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.[Co+2].C(O)(=O)C>[C:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)(=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=O
Reactant: CC(C(=O)O)c1cccc(Cc2ccccc2)c1
Agent: [Co+2]
Agent: O=C([O-])c1ccc2ccccc2c1
Solvent: CC(=O)O
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1

Procedure:
To a 300 ml reaction vessel with a stirrer were fed 25 g of α-(3-benzylphenyl)propionic acid obtained in Experiment 5, 0.08 g of cobalt naphthenate and 100 ml of acetic acid as a solvent, and 150 ml/min of pure oxygen was fed into the vessel for 16 hours at a reaction temperature of 120 ° C. After the reaction, the solvent was removed by reduced-pressure distillation to obtain a solid substance. The solid substance was washed five times with 500 ml of water and it was dissolved in 500 ml of ether and washed three times again with water. After that, the ether was removed by reduced-pressure distillation and the product was finally recrystallized with a benzene/petroleum ether mixture to obtain 13.2 g of α-(3-benzoylphenyl)propionic acid (ketoprofen). The properties such as melting point and spectrum of the final product were the same as those of an authentic sample.
Reaction SMILES: [CH2:1]([C@H:8]([NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[C:9](=[O:17])[N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:1]([C@H:8]([NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[C:9]([N:10]1[CH2:15][CH2:14][C:13](=[N:32][OH:33])[CH2:12][CH2:11]1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(C(=O)[C@H](Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(=NO)CC1)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-1H-indole-2-carboxylic acid [1(S)-benzyl-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl]-amide (406 mg, 0.96 mmol) , hydroxylamine hydrochloride (80 mg, 1.15 mmol), and potassium carbonate, (159 mg, 1.15 mmol) in ethanol (6 mL) and water (1 mL) was stirred at 25° C. for 18 h and concentrated. The residue was dissolved in ethyl acetate and the resulting solution washed with water and dried (411 mg, 98%): HPLC (60/40) 5.13 minutes (97%); TSPMS 439/441 (MH+, 100%);
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)=O.[CH:21]1([C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27])[CH2:23][CH2:22]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:21]1([C:24]([C:25]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)=[C:3]3[C:4]4[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]3=[N:1][C:26]=2[CH3:27])=[O:29])[CH2:23][CH2:22]1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)c(Cl)c1)CCCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccc(Cl)c(Cl)c2)c1C(=O)C1CC1)CCCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a stirred solution of 60 mg (0.18 mmol) (2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-(3,4-dichloro-phenyl)-methanone in 2 ml acetic acid was added 31 mg (0.24 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 18 mg (23%) cyclopropyl-[(4-(3,4-dichloro-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno [2,3-b]pyridin-3-yl)]-methanone as a light brown solid. ES-MS m/e (%): 416 (M+H+, 100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:28]=[CH:27][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([Br:26])=[CH:21][CH:20]=4)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH:55]2[CH2:57][O:56]2)=[CH:49][CH:48]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[Br:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([C:15]([N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:57][C@H:55]([OH:56])[CH2:54][O:53][C:50]4[CH:51]=[CH:52][C:47]([OH:46])=[CH:48][CH:49]=4)=[CH:28][CH:27]=3)[CH2:14][CH2:13]1)=[O:16])=[CH:25]2
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)c3cc4cc(Br)ccc4[nH]3)CC2)cc1
Product: O=C(c1cc2cc(Br)ccc2[nH]1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 38.8 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(5-bromo-1H-indol-2-yl)methanone (0.160 g, 0.363 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.15 g, 0.37 mmol) according to Procedure G to give the title compound (0.119 g, 0.141 mmol).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[O:9])[CH2:3]1.[Br:22][C:23]1[CH:24]=[C:25]([C:29](O)=[O:30])[O:26][C:27]=1[Br:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:23]1[CH:24]=[C:25]([C:29]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([C:10]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)[N:11]=3)=[O:9])[CH2:3][C@@H:2]2[CH3:1])=[O:30])[O:26][C:27]=1[Br:28]
Reactant: Cc1cccc(-n2cnc(C(=O)N3CCN[C@@H](C)C3)n2)c1
Reactant: O=C(O)c1cc(Br)c(Br)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(-n2cnc(C(=O)N3CCN(C(=O)c4cc(Br)c(Br)o4)[C@@H](C)C3)n2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 86 mg (0.30 mmol) ((S)-3-methyl-piperazin-1-yl)-(1-m-tolyl-1H-[1,2,4]triazol-3-yl)-methanone, 84 mg (0.30 mmol) 4,5-dibromo-2-furoic acid, 0.11 g (0.33 mmol) TBTU and 80 μL (0.45 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]([CH3:22])([CH:19]([CH3:21])[CH3:20])[C:13](=[O:18])[CH2:14]C([O-])=O)=[O:10])=[CH:4][CH:3]=1.CC(O)C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[CH3:22][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH:19]([CH3:21])[CH3:20])[C:13](=[O:18])[CH3:14]
Reactant: CC(C)C(C)(NC(=O)Cc1ccc(Cl)cc1)C(=O)CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)C(C)(NC(=O)Cc1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Yield: 95.7 %

Procedure:
In a reactor were placed 2.5 g (0.007 mole) of 4-[(4-chlorophenyl)acetylamino]-4,5-dimethyl-3-oxohexanoate, 7 ml of 2-propanol, 8 ml of water and 0.7 ml of concentrated sulfuric acid. The mixture was refluxed for 5 hours with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was cooled at room temperature. 20 ml of water was added. The mixture was neutralized with a 23% aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration to obtain 2.37 g (0.0067 mole) of N-[1-methyl-1-(methylethyl)-2-oxopropyl]-(4-chlorophenyl)acetamide (yield=96.3%).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[N:31]=[C:30]([CH2:32][N:1]3[CH:2]([C:11]4[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=4[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]3=[O:7])[CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: O=Cc1cccc(-n2cccn2)n1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-n2cccn2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 6-(1H-pyrazol-1-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.80 min.; [M+H]+: 393.10 g/mol.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClCCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]3-oxopentanoate (0.60 g) in 1,2-dichloroethane (15 ml) was added rhodium(II) acetate (2 mg) under reflux. The mixture was refluxed for 30 minutes under nitrogen atmosphere and concentrated under reduced pressure to give 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The compound obtained above was dissolved in acetonitrile (15 ml) and N,N-diisopropyl-N-ethylamine (0.32 ml). Diphenyl phosphorochloridate (0.33 ml) was added thereto at -10~-5° C. in a nitrogen stream, followed by stirring at the same temperature for 30 minutes. To the solution were added N,N-diisopropyl-N-ethylamine (0.32 ml) and a solution of a mixture of (2S,4S)-4-mercapto-2-(1-methyl-1H-tetrazol-5-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine and (2S,4 S)-4-mercapto-2-(2-methyl-2H-tetrazol-5-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.55 g) in acetonitrile (2 ml) successively at -20° C. The mixture was stirred at the same temperature for 30 minutes and at 0°-10° C. for 3 hours. The mixture was poured into ethyl acetate (150 ml) and water (100 ml). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of acetone and dichloromethane (10:90,V/V) to give 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-2-{1(or 2)-methyl-1H(or 2H)-tetrazol-5-yl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (isomer A) (0.32 g).
Reaction SMILES: ClC1C(OC2C=CC(F)=CC=2F)=CN=C(S(C)(=O)=O)N=1.CN1C=C(B2OC(C)(C)C(C)(C)O2)C2CCCCC=2C1=O.[F:42][C:43]1[CH:71]=[C:70]([F:72])[CH:69]=[CH:68][C:44]=1[O:45][C:46]1[C:47]([C:56]2[C:65]3[CH2:64][CH2:63][CH2:62][CH2:61][C:60]=3[C:59](=[O:66])[N:58]([CH3:67])[CH:57]=2)=[N:48][C:49](S(C)(=O)=O)=[N:50][CH:51]=1.[CH2:73]([S:75]([NH2:78])(=[O:77])=[O:76])[CH3:74]>>[F:42][C:43]1[CH:71]=[C:70]([F:72])[CH:69]=[CH:68][C:44]=1[O:45][C:46]1[C:47]([C:56]2[C:65]3[CH2:64][CH2:63][CH2:62][CH2:61][C:60]=3[C:59](=[O:66])[N:58]([CH3:67])[CH:57]=2)=[N:48][C:49]([NH:78][S:75]([CH2:73][CH3:74])(=[O:77])=[O:76])=[N:50][CH:51]=1
Reactant: CCS(N)(=O)=O
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2c(c1=O)CCCC2
Agent: CS(=O)(=O)c1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Agent: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2c(c1=O)CCCC2
Product: CCS(=O)(=O)Nc1ncc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3c2CCCC3)n1

Procedure:
The title compound of Example 149, step 3 was reacted with the title compound of Example 163, step 3 in a manner similar to Example 163, step 4 and the resulting 4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one was treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 163, step 5 to give the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 8.38 (s, 1H), 7.61 (s, 1H), 7.35-7.31 (m, 1H), 7.04-6.95 (m, 2H), 3.41 (s, 3H), 3.30-3.20 (m, 2H), 2.42-2.40 (m, 2H), 2.32-2.30 (m, 2H), 1.61-1.51 (m, 4H), 1.18 (t, J=7.2 Hz, 3H). LCMS: 477.1 (M+H)+
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([O:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:20][CH2:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[O:30][CH3:31])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].FC(F)(F)S(O[CH2:43][CH:44]([F:46])[F:45])(=O)=O>C(O)C>[F:45][CH:44]([F:46])[CH2:43][N:20]1[CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][O:23][C:16]2([CH2:15][CH2:14][N:13]([C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([O:30][CH3:31])[CH:7]=3)=[O:12])[CH2:18][CH2:17]2)[CH2:19]1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CNC(c2ccccc2)CO3)ccc1OC(C)C
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(=O)N2CCC3(CC2)CN(CC(F)F)C(c2ccccc2)CO3)ccc1OC(C)C
Temperature: 80 °C
Yield: 25.6 %

Procedure:
To a solution of (4-isopropoxy-3-methoxy-phenyl)-(9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)methanone (15 mg, 0.04 mmol) in ethanol (375 μL) was added NaHCO3 (12 mg, 0.14 mmol), followed by the addition of 2,2-difluoroethyl trifluoromethanesulfonate (11 mg, 0.05 mmol). The reaction mixture was heated at 80° C. for 16 hours. The reaction mixture was filtered and purified by Waters mass directed LC/MS: (1-99% ACN/H2O (5 mM HCl) to obtain [8-(2,2-difluoroethyl)-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methoxy-phenyl)methanone (5 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 7.45-7.36 (m, 5H), 6.98-6.83 (m, 3H), 5.25 (d, J=10.4 Hz, 1H), 4.57 (dt, J=12.2, 6.1 Hz, 1H), 3.85 (s, 3H), 3.60 (d, J=10.9 Hz, 1H), 3.47-3.12 (m, 6H), 2.86-2.60 (m, 3H), 1.88-1.50 (m, 5H), 1.38 (d, J=6.1 Hz, 6H); ESI-MS m/z calc. 488.5. Found 489.7 (M+1)+; Retention time: 2.17 minutes (3 min run).