Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20](=O)[CH2:21][CH3:22]>CCOCC.O>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:19][C:20]2[CH:22]=[CH:21][C:20]([CH:19]3[C:21]4[CH:22]=[CH:5][CH:7]=[CH:8][C:20]=4[CH2:19][CH2:22][C:21]4[CH:10]=[CH:11][CH:12]=[CH:19][C:20]3=4)=[CH:22][CH:21]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCC(C)=O
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(Cc2ccc(C3c4ccccc4CCc4ccccc43)cc2)C1
Temperature: 50 °C
Yield: 77 %

Procedure:
A mixture of the above iodide (1.80 g, 0.0044 mol), (R)-3-piperidinecarboxylic acid ethyl ester (0.69 g, 0.0044 mol) and anhydrous potassium carbonate (1.82 g, 0.0132 mol) in 2-butanone (30 ml) was heated to 50° C. for 6 h. After cooling, the mixture was diluted with ether (50 ml) and water (50 ml) and the phases were separated. The organic phase was washed with water (30 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the oily residue (2.1 g) was purified by gradient column chromatography on silica gel (40 g) using benzene and ethyl acetate as eluents. The benzene/ethyl acetate (9:1) fraction afforded 1.50 g (77%) of (R)-1-(4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-benzyl)-3-piperidinecarboxylic acid ethyl ester.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C=O)C.CN(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O>[CH3:27][S:28]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:2][CH2:3]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: CN(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril (1.0 g) was added to a mixture of 10 ml of DMF and 0.85 ml of trimethylamine and the mixture was stirred at room temperature while slowly adding dropwise 5 ml of DMF solution containing 440 mg of methanesulfonyl chloride. After completion of addition, the reaction mixture was stirred at the same temperature as above for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol to give 0.17 g of 6-(4-methanesulfonyl-1-piperazinyl)-3,4-dihydrocarbostyril, m.p. 241.5°-243° C., colorless granules.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:5]=[C:6]([Cl:22])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15](OCC)[O:16]CC.C(O)(=O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:5]=[C:6]([Cl:22])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]=[O:16]
Reactant: CCOC(COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 98.8 %

Procedure:
First, 1.81 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene was added to a mixture of 10 ml of acetic acid and 1 ml of concentrated hydrochloric acid with stirring under ice cooling. After further stirring for 15 minutes, the reaction mixture was poured into water and extracted twice with diethyl ether. The diethyl ether layers were combined and washed with water, aqueous sodium hydrogencarbonate solution and then saturated sodium chloride solution. The combined diethyl ether layer was dried over magnesium sulfate, and the diethyl ether was distilled out, which afforded 1.51 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-butyloxyacetaldehyde (yield, 94%).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:10]([O-:12])=O)[C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[NH2:17].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:10](=[O:12])[CH:3]([O:2][CH3:1])[C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCCOC(=O)C(OC)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCOC(=O)C(OC)C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 28.6 %

Procedure:
Mono-n-propyl methoxymalonate (13.07 grams, 0.07 mole), prepared in Part B, 3,5-dichloroaniline (12.02 grams, 0.07 mole) and 1,3-dicyclohexylcarbodiimide (15.31 grams, 0.07 mole) were reacted in a manner similar to that described in Example LVII to give 7.22 grams (0.02 mole) of n-propyl 3-[(3,5-dichlorophenyl)amino]-2-methoxy-3-oxopropanoate having a melting point of 89° C.-93° C. An analytical sample recrystallized from hexane had a melting point of 89° C.-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]3[N:16]=[CH:17][C:18](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1)#[CH:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]3[N:16]=[CH:17][C:18]([C:21]#[C:20][C:22]4[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: CCc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Product: CCc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(N)nc3)cnn12

Procedure:
The title compound was prepared 5-(4-chloro-phenyl)-7-ethyl-3-iodo-pyrazolo[1,5-a]pyrimidine (96 mg, 0.25 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (30 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (41 mg, 44%). MS (ISP) 374.3 [(M+H)+]; mp 205-206° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[F:5][C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15])=[O:11])=[CH:8][CH:7]=1.[Na]>C(O)C>[OH:20][C:19]1[C:13]([NH:12][C:10](=[O:11])[C:9]2[CH:24]=[CH:25][C:6]([F:5])=[CH:7][CH:8]=2)=[C:14]([OH:15])[N:4]=[C:2]([SH:3])[N:1]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: O=C(Nc1c(O)nc(S)nc1O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
Thiourea (0.72 g, 9.4 mmol) and diethyl 2-(4-fluorobenzamido)malonate (example 1, 2.0 g, 6.7 mmol) were added to a solution of sodium (0.16 g, 6.7 mmol) in ethanol (50 ml). The reaction mixture was refluxed for 3 hours and then cooled down to room temperature. The precipitate was filtered off and washed with ethanol. The product was dissolved in a minimal volume of water and acidified to pH 4-5 with 5M HCl. The precipitate was collected, washed with water and dried, furnishing the title compound as a white solid (0.78 g, 41%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:33])[C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:20][C:25](=[O:24])[CH2:26][C:27](=[O:33])[C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: CCOC(=O)CC(=O)c1ccsc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1ccsc1
Yield: 81.3 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (144 mg, 0.51 mmol) and 3-oxo-3-thiophen-3-yl-propionic acid ethyl ester (FR 7191887) (151 mg, 0.76 mmol) according to the general procedure K. Obtained as a yellow foam (181 mg).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:13]3)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([Cl:35])[CH:34]=1.CS(C)=O>O>[Cl:28][C:29]1[CH:30]=[C:31]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:24])([F:23])[F:25])(=[O:21])=[O:20])=[CH:13]4)=[CH:4][CH:3]=2)[CH:32]=[C:33]([Cl:35])[CH:34]=1
Reactant: O=S(=O)(Nc1ccc2c(OCc3ccc(Br)cc3)cccc2c1)C(F)(F)F
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(Nc1ccc2c(OCc3ccc(-c4cc(Cl)cc(Cl)c4)cc3)cccc2c1)C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 1 and 3,5-dichloro phenyl boronic acid according to the procedure of Example 2, m.p. 138-140 DMSO: δ 12.1(s, 1H), 7.0-8.3(m, 13H, arom), 5.38 (s, 2H). CHN 53.84, 3.20, 2.62 (0.5 M H2O) Found 53.97, 3.02, 2.40.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14](B(O)O)[CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1.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.C(O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[NH2:8])[CH:11]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Nc1ccncc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(Cl)cc1-c1cnccc1N

Procedure:
3-iodopyridin-4-amine (2.2 g, 10 mmol), (5-chloro-2-methoxyphenyl)boronic acid (1.86 g, 10 mmol) and, and K2CO3 (4.2 g, 30 mmol) were mixed in 50 mL of toluene, 5 mL of deionized water and 5 mL of ethanol. To the solution was bubbled with nitrogen for 15 min. Pd(PPh3)4 (0.23 g, 0.2 mmol) was then added. The mixture was refluxed overnight under nitrogen. After cooling, the aqueous layer was removed and the organic layer was then concentrated. The residue was then purified by column chromatography using ethyl acetate as the eluent. 2.0 g (85%) of product was collected as the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][O:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][S:10][C:11]=2[CH:16]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Product: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1

Procedure:
In analogy to example 2.1, 3-(4-chloro-phenyl)-benzo[d]isothiazol-6-ol and 1,4-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole as white solid, mp: 68-69° C., MS: 395 (M, 1Br, 1 Cl).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH:24]1([NH:30][C:31]2[CH2:35][S:34][C:33](=[O:36])[N:32]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:35]2/[C:31]([NH:30][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[N:32][C:33](=[O:36])[S:34]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(NC2CCCCC2)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NC2CCCCC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (673 mg) in 2-propanol (15 mL) were added 4-(cyclohexylamino)thiazol-2(5H)-one (590 mg) and piperidinium acetate (294 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (582 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH:12]=[C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[CH:20]=2)[N:15]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:14]1[CH3:33].C1(CNC=C2C(=O)C3C(=CC(OC)=C(OC)C=3)N(C(OCC)=O)C2C)C2C(=CC=CC=2)C=CC=1.C1(C(NC=C2C(=O)C3C(=CC(OC)=C(OC)C=3)N(C(OCC)=O)C2C)CC)C2C(=CC=CC=2)C=CC=1.C1(C(CC)CNC=C2C(=O)C3C(=CC(OC)=C(OC)C=3)N(C(OCC)=O)C2C)C2C(=CC=CC=2)C=CC=1>>[C:2]1([NH:11][CH:12]=[C:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[CH:20]=3)[N:15]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:14]2[CH3:33])[C:1]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNc2ccc3ccccc3c2)C1C
Agent: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNC(CC)c2cccc3ccccc23)C1C
Agent: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNCC(CC)c2cccc3ccccc23)C1C
Agent: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNCc2cccc3ccccc23)C1C
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNc2cccc3ccccc23)C1C

Procedure:
3-(β-naphthylaminomethylene)-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester; 3-(α-naphthylmethylaminomethylene)-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester; 3-(β-naphylethylaminomethylene)-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester; 3-(α-naphthylpropylaminomethylene)-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester; and 3-(β-naphthylbutylaminomethylene)-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester.
Reaction SMILES: N(OC(C)(C)C)=O.[Cl:8][C:9]1[CH:15]=[C:14]([F:16])[C:13]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[CH:12][C:10]=1[NH2:11].[N-:28]=[N+:29]=[N-].[Na+]>FC(F)(F)C(O)=O>[Cl:8][C:9]1[CH:15]=[C:14]([F:16])[C:13]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:26])([F:27])[F:25])=[CH:19][N:18]=2)=[CH:12][C:10]=1[N:11]=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Agent: CC(C)(C)ON=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
With ice-cooling, initially 9.5 g (92 mmol) of tert-butyl nitrite were added dropwise to a solution of 20 g (62 mmol) of 2-chloro-5-(3-chloro-5-trifluoromethyl-2-pyridyl)-4-fluoroaniline in 40 ml of trifluoroacetic acid, and—with strong evolution of gas—6 g (92 mmol) of sodium azide were then added a little at a time. The mixture was stirred for 16 hours, and a further 15 ml of trifluoroacetic acid and 1.7 g (17 mmol) of tert-butyl nitrite were then added to the reaction mixture. Stirring was subsequently continued for another 30 minutes, and the mixture was then poured onto 0.3 l of ice-water. The resulting solid fraction was separated off and washed with 50 ml of water. For purification, the crude product was initially dissolved in 100 ml of toluene. The resulting toluene phase was then washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and finally concentrated. Yield: 90%;
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][CH:2]([F:5])[CH2:3][N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: FC(F)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(F)F
Temperature: 120 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
An amount of 27.6 g (0.269 mol) of 2,2-difluoro-1-chloroethane, 2.16 g (6.73 mmol) of tetra(n-butyl)ammonium bromide and 20 g (0.135 mol) of phthalimide are dissolved in 95 g of N,N-dimethylformamide and treated with 46.96 g (0.336 mol) of potassium carbonate. The reaction mixture is stirred in an autoclave under pressure at 120° C. for 16 h. After the end of the reaction, cooling is carried out to ambient temperature and the solvent is exhaustively removed under vacuum. The remaining residue is treated with 150 ml of water and the solid is filtered off. The filter residue is washed twice with water and the product is dried under vacuum. An amount of 28.5 g of 2-(2,2-difluoroethyl)-1H-isoindole-1,3(2H)-dione with a purity of 97.4% is obtained. This corresponds to a yield of 97.7% of theory.
Reaction SMILES: C1(C(=[N:14][CH:15]([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=[N:30][O:31][C:32]([C:33]4[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[O:35][N:34]=4)=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18]CC)=[O:17])C2C=CC=CC=2)C=CC=CC=1.Cl.[OH-].[Na+].[C:54]([OH:60])([C:56]([F:59])([F:58])[F:57])=[O:55]>C(OCC)C.CO.O>[NH2:14][CH:15]([CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:48](=[CH:49][CH:50]=1)[C:29]1=[N:30][O:31][C:32]([C:33]3[C:37]([C:38]([F:39])([F:40])[F:41])=[C:36]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[O:35][N:34]=3)=[C:28]1[CH2:27][CH2:26]2)[C:16]([OH:18])=[O:17].[C:54]([OH:60])([C:56]([F:59])([F:58])[F:57])=[O:55]
Reactant: CCOC(=O)C(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: NC(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of ethyl 2-(diphenylmethyleneamino)-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 91A, 34 mg, 0.050 mmol) and water (0.025 mL) in diethyl ether (1.5 mL) was added 6 N aqueous HCl (50 μL, 0.300 mmol). The mixture was stirred at room temperature for 30 min. The ether layer was removed and the residue was mixed with MeOH (0.5 mL) and 2 N aqueous sodium hydroxide (0.5 mL, 1.000 mmol). After being stirred at room temperature for 30 min, the mixture was acidified with TFA to get a clear solution. Purification using reverse phase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration and lyophilization gave 2-amino-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoic acid, TFA (10 mg, 0.015 mmol, 30.6% yield) as a white solid. The compound had an HPLC retention time=3.40 min. (condition C); LC/MS M+1=484.1; 1H NMR (400 MHz, MeOD) δ ppm 7.91 (1H, d, J=7.7 Hz), 7.78 (2H, d, J=8.1 Hz), 7.59-7.72 (3H, m), 7.33 (1H, s), 7.30 (1H, dd, J=8.0, 1.7 Hz), 4.00 (1H, t, J=6.3 Hz), 3.04-3.10 (4H, m), 2.74-2.95 (2H, m), 2.12-2.36 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4](SC2C=CC=CC=2)[N:3]=1.[CH:28]1([Mg]Br)[CH2:30][CH2:29]1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)C.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([CH:28]2[CH2:30][CH2:29]2)[N:3]=1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCO2
Reactant: Br[Mg]C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1c(N)nc(C2CC2)c(C#N)c1-c1ccc2c(c1)OCO2
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
Under an atmosphere of argon, 2-amino-4-(1,3-benzodioxol-5-yl)-6-(phenyl-sulfanyl)-3,5-dicyanopyridine [preparation analogously to J. M. Quintela, J. L. Soto, Anales de Quimica 79, 368–372 (1983)] (100 mg, 0.27 mmol) is dissolved in absolute THF (3 ml). 1,3-Bis(diphenylphosphino)propanedichloronickel(II) (4.4 mg, 0.008 mmol) is added, the color of the solution changing to pink. On slow dropwise addition of cyclopropylmagnesium bromide (1M solution in THF; 0.644 ml, 0.644 mmol), a clear change in color to brown-red can be observed. The solution is heated at 50° C. for 3 hours. After only about 5 minutes, the solution turns green. 1N hydrochloric acid (1 ml) is added and the mixture is then diluted with diethyl ether. Solid sodium carbonate and water are added. The phases are separated and the organic phase is dried over magnesium sulfate, filtered and concentrated. The mixture is separated by silica gel column chromatography (toluene:ethyl acetate=2:1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]([CH3:14])([CH3:13])[C:11]2[CH:10]=[C:9]([C:15]([NH2:17])=[O:16])[CH:8]=[CH:7][C:6]=2[CH2:5][C@H:4]1[O:18][CH3:19].C(N(CC)C(C)C)(C)C.[CH:29]([C@@H:31]1[CH2:35]OC(C)(C)[N:32]1C(OC(C)(C)C)=O)=[O:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.CO.CC(O)=O>[NH2:32][C@@H:31]([CH2:29][OH:30])[CH2:35][NH:2][C@@H:3]1[C:12]([CH3:14])([CH3:13])[C:11]2[CH:10]=[C:9]([C:15]([NH2:17])=[O:16])[CH:8]=[CH:7][C:6]=2[CH2:5][C@H:4]1[O:18][CH3:19]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1NC[C@@H](N)CO
Reaction time: 1 h
Yield: 118.2 %

Procedure:
To a suspension of trans-7-amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide hydrochloride (229.3 mg, 0.81 mmol) in a mixture of dichloromethane (2.0 mL) and methanol (0.3 mL) was added N,N-diisopropyl-ethylamine (0.10 g, 0.80 mmol) followed by tert-butyl (4S)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (0.18 g, 0.80 mmol). Sodium triacetoxyborohydride (0.20 g, 0.97 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated to dryness and dissolved in ethyl acetate (40 mL). The suspension was washed with saturated sodium bicarbonate (15 mL) and brine (15 mL), dried over sodium sulfate, filtered and concentrated to give a white foam. The white foam was treated with AcOH (1.0 mL) and 6N HCl (1.0 mL) at 70° C. for 1 h. The reaction mixture was concentrated, and evaporated with ethyl acetate (3×2 mL) to give the hydrochloride salt of the title compound as a dark greenish powder (304 mg, 96% yield). (m/z): [M+H]+ calcd for C17H27N3O3, 322.21; found, 322.2.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]3=[O:22])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:23].CSC.C(Cl)(=O)C>>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]3=[O:22])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:23]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2)CC1F
Solvent: CC(=O)Cl
Solvent: CSC
Product: O=C1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2)CC1F
Temperature: 40 °C
Reaction time: 96 h
Yield: 49 %

Procedure:
To the mixture of (R)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-alcohol (0.726 mmol), freshly fused zinc chloride (2.17 mmol), dimethyl sulphide (3.2 mmol), acetyl chloride (2.17 mmol) in tetrahydrofuaran (50 ml) was stirred at 40° C. for 4 days. To this reaction mixture extracted with the ethyl acetate water mixture and organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel afforded title compound in 49% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:7]=1)=[O:5])C.[OH-].[Li+]>CO.O>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2)c2ccccc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3ccccc32)cc1

Procedure:
Experimental conditions analogous to those described for Step 4 of Example 60, from 3.10 g (8.80 mmol) of 1-(4-methoxy-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester, 40 mL of 1:1 methanol-water mixture and 0.44 g (18.3 mmol) of lithium hydroxide with a work-up consisting only of thorough evaporation of solvents.