Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.CON(C)[C:15](=[O:17])[CH3:16]>C1COCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:15](=[O:17])[CH3:16]
Reactant: CON(C)C(C)=O
Reactant: Clc1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1sccc1Cl
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
To a solution of 3-chlorothiophene (4.80 g, 40.48 mmol) in THF (50 mL) was added BuLi (2.5N in hexane, 17.9 mL) at −30° C. After addition, the mixture was stirred for 30 min at −10° C., and then cooled to −45° C. N-methoxy-N-methyl acetamide (55.0 g, 48.8 mmol) was added and allowed to warm to room temperature during 40 min and maintained for an additional 20 min. Brine (80 mL) was added to quench the reaction, extracted with EA (60 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated to afford 24-1 (˜80% pure) as a yellow oil (6.80 g) which used for the next step directly.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:40])[CH2:9][CH2:10][N:11]([CH3:39])[C:12](=[O:38])[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=2)[C:16]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:15]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:41]([NH:48][S:49]([CH2:52][CH2:53][CH2:54][Cl:55])(=[O:51])=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:41]([N:48]([S:49]([CH2:52][CH2:53][CH2:54][Cl:55])(=[O:51])=[O:50])[C:23]([C:20]1[CH:21]=[C:22]2[C:17]([C:16]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:15]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:14]2[CH2:13][C:12]([N:11]([CH3:39])[CH2:10][CH2:9][N:8]([CH3:40])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:38])=[CH:18][CH:19]=1)=[O:24])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Reactant: O=S(=O)(CCCCl)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CCN(C)C(=O)OC(C)(C)C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)N(Cc3ccccc3)S(=O)(=O)CCCCl)cc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of the crude 1-{2-[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]-2-oxoethyl}-3-cyclohexyl-2-phenyl-1H-indole-6-carboxylic acid in DCM (0.04 M) was treated with DMAP (2.5 eq), N-benzyl-3-chloropropane-1-sulfonamide (1.5 eq) and EDAC.HCl (1.5 eq). The reaction was left stirring at 40° C. overnight. Further DMAP (2.5 eq), N-benzyl-3-chloropropane-1-sulfonamide (1.5 eq) and EDAC.HCl (1.5 eq) were added and the reaction left to stir at 40° C. for another night. The mixture was diluted with DCM and washed with an aqueous solution of HCl (1N), a saturated aqueous solution of NaHCO3 and brine before being dried over Na2SO4, filtered and concentrated in vacuo. The crude was then used in the next step without any further purification. (ES+) m/z 777 (M+H)+
Reaction SMILES: [Cl:1]Cl.[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]>CO>[Cl:1][C:5]1[C:4]([OH:3])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: ClCl
Reactant: O=C(O)c1cccc(O)c1
Solvent: CO
Product: O=C(O)c1cccc(O)c1Cl
Temperature: 25 °C

Procedure:
Chlorine gas (10.3 g; 147 mmol) was slowly bubbled through a cold solution of 20 g (145 mmol) of 3-hydroxy benzoic acid in 100 mL of methanol, under nitrogen, while maintaining the temperature below −60° C. After approximately thirty minutes, the chlorine gas was flushed out with nitrogen and the reaction mixture was allowed to warm to room temperature and diluted with 100 mL of water. The desired titled compound was isolated by recrystallization to provide a white solid. This solid was purified by recrystallization from 50 mL of water followed by recrystallization from 130 mL of benzene containing 10 mL of acetone to provide the desired titled compound.
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[Cl:14][CH2:15][C:16](Cl)=[O:17]>CCOCC>[Cl:14][CH2:15][C:16]([N:3]1[CH2:4][CH2:5][CH2:6][O:2]1)=[O:17]
Reactant: C1CNOC1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(CCl)N1CCCO1
Reaction time: 4 h

Procedure:
To a stirred slurry of finely powdered isooxazolidine hydrochloride (H. King, J. Chem. Soc. 433,1942) (11.0 g) in dry ether (200 ml) at 0° C. was added triethylamine (28.0 ml) and a solution of chloroacetyl chloride (8.0 ml) in ether (50 ml). The reaction mixture was stirred for a further 4 hours, whilst the temperature rose to room temperature. The precipitate triethylamine hydrochloride was filtered off through diatomaceous earth and the filter bed washed well with ether. The combined ether solutions were evaporated to give N-chloroacetyl isooxazolidine as an oil (11.5 g) NMR (CDCl3) 2.38[quintet, 2H, CH2 ], 3.78[t,2H, NCH2 ], 4.05[t,2H, OCH2 ]and 4.22 [s,2H, ClCH2CO].
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CN1CCCC1.CCOCC>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: C1CCNC1
Agent: CN1CCCC1
Solvent: CCOCC
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(N3CCCC3)c(F)c21
Reaction time: 1 h

Procedure:
A 200 mg portion of 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was dissolved in 1 ml of 1-methylpyrrolidine with warming. A 130 mg portion of pyrrolidine was added dropwise, the reaction was allowed to stand one hour and then diluted with ether. The solid was collected, washed with ether and hexane, dried and recrystallized from a mixture of dichloromethane-acetone, giving 140 mg of the desired product as white crystals, mp >320° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[C:17]1([CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-]>CO>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][CH2:24][CH:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: [BH4-]
Solvent: CO
Product: Clc1ccc(CN2CCC(CNCC(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 49 %

Procedure:
Reductive amination of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (120 mg) with 2,2-diphenylacetaldehyde (0.66 equiv.) and polymer-supported borohydride in methanol at 25° C. for 16 h, followed by general workup and column chromatography (SiO2) afforded 1-(4-chlorobenzyl)-4-{N-(2,2-diphenylethyl)aminomethyl}piperidine (70 mg, 49%): The purity was determined by RPLC (98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN([C:23]([O:27][N:28]1N=NC2[C:29]1=CC=CC=2)=[N+](C)C)C.CCN(CC)CC>CN(C=O)C.O>[CH3:23][O:27][N:28]([CH3:29])[C:12](=[O:14])[CH2:11]/[CH:10]=[CH:9]/[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1ccc(/C=C/CC(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(/C=C/CC(=O)N(C)OC)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.3 %

Procedure:
To the mixture of carboxylic acid (557) (5.7 g, 29.5 mmol) in DMF (150 mL) was added 0-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (9.5 g, 29.5 mol). After stifling for 5 minutes, N,O-dimethylhydroxylamine. HCl (2.9 g, 29.5 mmol) was added, followed by Et3N (8.2 mL, 58.9 mmol). The reaction mixture was stirred at room temperature for 3 hours, diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (40% EtOAc in hexanes) to provide (E)-N-methoxy-4-(4-methoxyphenyl)-N-methylbut-3-enamide (558) (2.1 g, 29.6%) as a yellow solid.
Reaction SMILES: [C:1]([C:4](=[C:10](OCC)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C(O)(=O)C.[CH:19]([NH2:21])=[NH:20].[O-]CC.[Na+]>C(O)C>[CH3:2][C:1]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:10]([CH3:11])[N:21]=[CH:19][N:20]=1
Reactant: N=CN
Reactant: CCOC(=O)C(C(C)=O)=C(C)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)ncnc1C
Temperature: 90 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
Ethyl 2-acetyl-3-ethoxybut-2-enoate (10.7 g, 0.0537 mol), formamidine acetate (5.6 g, 0.054 mol) and sodium ethoxide (2.7 M in ethanol, 20.0 mL) were mixed in ethanol (30 mL) and the mixture was stirred at 90° C. for 4 h. The reaction mixture was cooled, quenched with water and concentrated. The crude material was purified by flash chromatography on silical gel, eluting with 10%, 50% ethyl acetate/hexane to afford the desired product (7.4 g, 76%) as a yellow oil. MS (EI) 181.1 (M+1). 1H NMR (300 MHz, CDCl3) δ (ppm) 8.97 (s, 1H), 4.44 (q, 2H), 2.56 (s, 6H), 1.42 (t, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH:11]([CH3:12])[C:10](=[O:13])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:31]([N:9]2[C:10](=[O:13])[CH:11]([CH3:12])[N:8]2[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:32])(=[O:28])=[O:29])=[CH:25][CH:26]=1
Reactant: CC1C(=O)NN1C(c1ccccc1)c1ccccc1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: CC1C(=O)N(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)N1C(c1ccccc1)c1ccccc1
Yield: 88 %

Procedure:
Following the procedure of Example 2 and using 1-(diphenylmethyl)-4-methyl-1,2-diazetidin-3-one (prepared according to Example 1B.) and p-chlorophenylsulfonylisocyanate there is obtained 1.7 g (88%) of the title compound having a melting point of 124°-129° C.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:12]([CH2:17][CH2:18]CC#N)=[N:13][CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:22].[Na+].[CH2:24]([OH:26])[CH3:25]>>[C:1]1([S:7]([NH:10][C:11]2[C:12]([CH2:17][CH2:18][CH2:25][C:24]([OH:22])=[O:26])=[N:13][CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: [OH-]
Reactant: N#CCCCc1ncccc1NS(=O)(=O)c1ccccc1
Agent: [Na+]
Product: O=C(O)CCCc1ncccc1NS(=O)(=O)c1ccccc1

Procedure:
A solution of 3-benzenesulphonamido-2-(3-cyanopropyl)pyridine (5.22 g) in ethanol (100 ml) and 15% w/v sodium hydroxide solution (50 ml) was refluxed for 6 hours. The pH of the solution was adjusted to pH=4 when a white solid precipitated from the solution. The solid was collected by filtration and recrystallised from ethanol to give the title compound (3.34 g) as white needles. m.p. 156°-157° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].C([O-])([O-])=O.[K+].[K+].II>CC(O)(C)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]2[NH:13][CH2:12][CH2:11][N:14]=2)=[CH:5][CH:4]=1
Reactant: NCCN
Reactant: CSc1ccc(C=O)cc1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CSc1ccc(C2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(methylthio)benzaldehyde (1-Im-1, 10 g, 1.0 eq) in 1000 mL of t-BuOH, ethylene diamine (1.1 eq) was added. The mixture was stirred at rt under Ar for 30 min, then K2CO3 (3.0 eq) and I2 (1.25 eq) were added to the mixture. This mixture was stirred at 70° C. for 3 h, then was quenched with aqueous Na2SO3 until the color of iodine disappeared, then extracted with CHCl3. The organic layer was washed with NaHCO3 and brine and dried with Na2SO4. The solvent was removed to give 2-(4-(methylthio)phenyl)-4,5-dihydro-1H-imidazole (compound 2-Im-1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)n1cnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a stirred solution of 4-phenyl imidazole (245.1 mg, 1.7 mmol,), Et3N (258.0 mg, 2.6 mmol), and DMAP (20.1 mg, 170.0 μmol) in DCM (5 mL) was slowly added ethyl chloroformate (276.7 mg, 2.6 mmol) at room temperature. The reaction was allowed to stir overnight at room temperature. The solution was poured into water and the organic layer was washed with water, brine and dried (Na2SO4). The crude residue was purified by column chromatography (30% EtOAc/hexanes) to afford a colorless solid (301.0 mg, 80% yield). 1H NMR: 1.47 (t, 3H, J=6.9 Hz), 4.50 (q, 2H, J=7.0 Hz), 7.30 (t, 1H, J=7.0 Hz), 7.41 (t, 2H, J=7.5 Hz), 7.69 (s, 1H), 7.80 (d, 2H, J=7.9 Hz), 8.2 (s, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=2)[N:12]=1.[ClH:20].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][CH:45]1[CH2:52][CH:51]2[N:53]([CH3:54])[CH:47]([CH2:48][CH2:49][CH2:50]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[ClH:20].[CH3:54][N:53]1[CH:47]2[CH2:48][CH2:49][CH2:50][CH:51]1[CH2:52][CH:45]([NH:44][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])=[N:12][C:11]=13)=[O:19])[CH2:46]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3ccccc3O)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccccc4O)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.2 %

Procedure:
A mixture of 2-(2-hydroxyphenyl)benzoxazole-4-carboxylic acid (96 mg, 0.37 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (143 mg, 0.75 mmol), 1-hydroxybenzotriazole (102 mg, 0.75 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (85 mg, 0.37 mmol) in DMF (5 mL) was stirred at room temperature for 10 min. then triethylamine (0.15 mL, 1.12 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (2×50 mL) and brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford the desired product (70 mg, 48%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 10.54 (s, 1H), 8.21 (dd, J=7.8, 1.1 Hz, 1H), 8.09 (dd, J=8.1, 1.6 Hz, 1H), 7.80-7.77 (m, 1H), 7.75 (dd, J=8.1, 0.9 Hz, 1H), 7.57-7.50 (m, 2H), 7.17 (dd, J=8.6, 0.6 Hz, 1H), 7.10-7.05 (m, 1H), 4.70-4.60 (m, 1H), 3.25-3.15 (m, 2H), 2.73-2.69 (m, 2H), 2.56 (s, 3H), 2.15-1.95 (m, 2H), 1.65-1.45 (m, 4H), 1.25-1.10 (m, 2H); MS (ESI+) m/z 392 (M+H).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:40]([O:41]CC2C=CC=CC=2)[C@H:39]([O:49][C@@H:50]2[O:79][C@H:78]([CH3:80])[C@@H:69]([O:70]CC3C=CC=CC=3)[C@H:60]([O:61]CC3C=CC=CC=3)[C@H:51]2[O:52]CC2C=CC=CC=2)[C@@H:38]([CH2:81][O:82]CC2C=CC=CC=2)[O:37][C@@H:10]1[O:11][C@@H:12]1[CH2:16][N:15](C(OCC2C=CC=CC=2)=O)[C@H:14]([CH2:27][O:28]CC2C=CC=CC=2)[C@H:13]1[OH:36])C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-].[C]>[C@@H:50]1([O:49][C@@H:39]2[C@@H:38]([CH2:81][OH:82])[O:37][C@H:10]([O:11][C@@H:12]3[CH2:16][NH:15][C@H:14]([CH2:27][OH:28])[C@H:13]3[OH:36])[C@H:9]([OH:8])[C@H:40]2[OH:41])[O:79][C@H:78]([CH3:80])[C@@H:69]([OH:70])[C@H:60]([OH:61])[C@H:51]1[OH:52]
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@@H]3CN(C(=O)OCc4ccccc4)[C@H](COCc4ccccc4)[C@H]3O)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@@H]3CN[C@H](CO)[C@H]3O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
The compound (90 mg, 74.6 μmol) synthesized in Example 12 (12a) was dissolved in methanol (10 mL) and hydrochloric acid (140 μL) and 20% palladium hydroxide-carbon (90 mg) were added thereto, followed by stirring of the mixture at room temperature under a hydrogen atmosphere for 2 hours. After the celite filtration, ammonia water (5%) was added thereto until the pH became neutral. The solvent was distilled off under reduced pressure and the residue was purified by ion exchange resin (Dowex 50w×8) column (water—5% ammonia water). Further, it was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 1:1:1, V/V) to obtain the desired title compound (26 mg, 79%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13]([O:18][CH3:19])(=[O:17])[C:14]([CH3:16])=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH:15][C:14]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)([CH3:16])[C:13]([O:18][CH3:19])=[O:17]
Reactant: COc1ccc2ccccc2c1
Reactant: COC(=O)C(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)(O)c1ccc2cc(OC)ccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
A mixture of 2-methoxynaphthalene (20,0 g, 126 mmol) and methyl pyruvate (19,3 g, 190 mmol) in dichloromethane (100 mL) was added to a suspension of aluminium chloride (25,3 g, 190 mmol) in dichloromethane (100 mL) at 6° C. over 140 minutes. The solution was stirred for a further 15 minutes at this temperature and added to ice/water. Methyl 2-hydroxy-2-(6-methoxynaphth-2-yl)propionate (52% yield) and 2-methoxynaphthalene (34% recovery) were the primary components of the reaction mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.I[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:17]
Reactant: CCOC(=O)CI
Reactant: OCCc1ccc(F)cc1
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 78.1, 2-(4-fluoro-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(4-fluoro-phenyl)-ethoxy]-acetic acid ethyl ester as colorless liquid. 1H NMR (CDCl3): 1.28 (t, J=7.2 Hz, 3H), 2.92 (t, J=7.0 Hz, 2H), 3.73 (t, J=7.0 Hz, 2H), 4.07 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 6.97 (m, 2H), 7.21 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:30]([CH3:35])[C:31]([F:34])([F:33])[F:32])[C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][C:17]2([C:20]([O:22]C(C)(C)C)=[O:21])[CH2:19][CH2:18]2)=[O:11])=[CH:5][CH:4]=1)[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH:30]([CH3:35])[C:31]([F:32])([F:33])[F:34])[C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][C:17]2([C:20]([OH:22])=[O:21])[CH2:19][CH2:18]2)=[O:11])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C(C(=O)Nc2cccc(CC3(C(=O)OC(C)(C)C)CC3)c2)C(C)C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C(C(=O)Nc2cccc(CC3(C(=O)O)CC3)c2)C(C)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.52 g (3.11 mmol) of (+/−)-tert-butyl 1-(3-{[2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}benzyl)cyclopropanecarboxylate were dissolved in 3 ml of dichloromethane, and 12 ml of TFA were added at RT. The reaction mixture was stirred at RT for 2 h and then concentrated under reduced pressure, and the residue was dried under high vacuum overnight. This residue was triturated with acetonitrile, and the resulting solid was filtered off with suction, washed with a little acetonitrile and dried under high vacuum. This gave 1.16 g (86.2% of theory) of the target compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:38]([O:40][CH3:41])=[O:39].CCN(C(C)C)C(C)C>C1COCC1>[CH3:41][O:40][C:38](=[O:39])[N:31]([CH2:30][C:27]1[CH:26]=[N:25][C:24]([C:22]2[S:23][C:16]3[C:17](=[N:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[CH:9][C:10]=3[F:36])[CH:21]=2)=[CH:29][CH:28]=1)[CH2:32][CH2:33][O:34][CH3:35]
Reactant: COC(=O)Cl
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.3 %

Procedure:
To a solution of compound 339 (220 mg, 0.433 mmol) and methyl chloroformate (50.2 μl, 0.65 mmol) in THF (4 ml) was added DIPEA (227 μl, 1.30 mmol) and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, the residue was triturated with MeOH and the solid suspension was collected by filtration and purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap 25 g column) to afford compound 340 (123.1 mg, 0.218 mmol, 50.2% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.70 (s, 1H), 8.56-8.50 (m, 2H), 8.33 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.84-7.77 (m, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.2 Hz, 1H), 7.20 (dd, J=8.8, 1.2 Hz, 1H), 6.65 (d, J=5.6 Hz, 1H), 6.56 (d, J=2.8 Hz, 1H), 4.54 (s, 2H), 3.64 (s, 2H), 3.44 (s, 3H), 3.22 (s, 2H), 2.59-2.51 (m, 1H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H). MS (m/z): 566.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[N:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22][CH:21]=1>>[F:17][C:16]1([F:18])[CH2:15][O:14][C:13]([NH2:19])=[N:12][C@@:11]21[C:4]1[C:5](=[CH:6][CH:7]=[C:2]([C:24]3[CH:25]=[N:20][CH:21]=[N:22][CH:23]=3)[CH:3]=1)[O:8][CH2:9][CH2:10]2
Reactant: OB(O)c1cncnc1
Reactant: NC1=N[C@@]2(CCOc3ccc(Br)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(CCOc3ccc(-c4cncnc4)cc32)C(F)(F)CO1
Yield: 55 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (R)-6-bromo-5′,5′-difluoro-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.1) with pyrimidin-5-ylboronic acid yielded the title compound (55% yield) as a pale yellow solid. MS (ISP): m/z=333.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([CH3:17])[C:13]([NH:15][NH2:16])=O)=[C:10]([F:18])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=1>C(O)CCC>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]2[N:15]([C:13]([CH:12]([C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:18])[N:7]=[CH:6][CH:5]=[CH:4]4)[CH3:17])=[N:21][N:22]=2)[N:16]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C(=O)NN)c1c(F)cc2ncccc2c1F
Solvent: CCCCO
Product: CC(c1c(F)cc2ncccc2c1F)c1nnc2ccc(Cl)nn12

Procedure:
A solution of 2-(5,7-difluoro-quinolin-6-yl)-propionic acid hydrazide (2.404 g, 9.404 mmol) and 3,6-dichloropyridazine (2.138 g, 14.35 mmol) in butan-1-ol (60 mL) was stirred at 135° C. in a sealed tube overnight. Solvent was removed under reduced pressure, and the residue was purified by column chromatography to afford 1.476 g (45% for two steps) of the title compound as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.93 (dd, 1H), 8.36 (dd, 1H), 8.07 (d, 1H), 7.62 (dd, 1H), 7.43 (dd, 1H), 7.05 (d, 1H), 5.26 (q, 1H), 2.13 (d, 1H). LCMS (method A): [MH]+=346, tR=5.00 min.