Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1Cl.[F:17][C:18]([F:26])([F:25])[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[N:22]1[CH2:23][CH2:24][CH:19]([C:18]([F:26])([F:25])[F:17])[CH2:20][CH2:21]1
Reactant: CNc1cc(Cl)c(C(=O)OC)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to 26a from methyl-2-chloro-4-methylamino-5-nitro-benzoate (1.37 g, 5.6 mmol), 4-trifluoromethylpiperidine×HCl (1.27 g, 6.7 mmol), DIPEA (3.8 mL, 22 mmol) and dioxane (50 mL).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1.O>[CH2:19]([O:18][C:16]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@H]1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A solution of (S)-piperidine-3-carboxylic acid (XXXI) (10.0 g, 77.4 mmol) in a mixture of 80 ml of THF and 50 ml of water was cooled to 0° C. and sodium bicarbonate (13.0 g, 15.5 mmol) and benzyl chloroformate (15.8 g, 92.9 mmol) were added simultaneously. The reaction mixture was stirred at 0° C. for 6 hours and concentrated under reduced pressure. The aqueous layer was extracted with ethyl ether to remove excess of benzyl chloroformate, then it was acidified with 1 M HCl solution to pH 6 followed by extraction with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to provide (S)-piperidine-1,3-dicarboxylic acid 1-benzyl ester (XXXII) (10.0 g, 49%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[S:22][CH3:21])[CH2:34][CH2:33]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=S)Oc1ccccc1
Reactant: CSc1ccccc1N1CCNCC1
Product: COc1nc(C)c(C)nc1NC(=S)N1CCN(c2ccccc2SC)CC1
Yield: 61.4 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH:9]=1)[CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH:9]=1)[CH2:7][Br:36]
Reactant: COCCOCOc1ccc(I)cc1CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOCOc1ccc(I)cc1CBr
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-iodo-2-(2-methoxy-ethoxymethoxy)-benzyl alcohol (7.5 g, 22 mmol) in 60 mL of THF at 15° C. is added triphenylphosphine (6.35 g, 24 mmol) followed by N-bromosuccinimide (4.3 g, 24 mmol). The solution is stirred for 5 minutes. The solution is allowed to warm to ambient temperature. After 20 minutes, the solution is concentrated. The crude product is purified by column chromatography eluting with EtOAc:CH2Cl2 :hexane (3:1:6).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[N:17]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.Cl.ClCCl.CO>CO>[Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[N:4][C:5]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:28][CH:27]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: Clc1ncc(Br)c(NCCc2c[nH]cn2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Brc1cnc(Nc2ccc(CN3CCCC3)cc2)nc1NCCc1c[nH]cn1
Yield: 4.6 %

Procedure:
A mixture of 5-bromo-4-(2-(1H-imidazol-4-yl)-ethylamino)-2-chloro-pyrimidine (60 mg), 4-pyrrolidin-1-ylmethyl-phenylamine (35 mg) and hydrochloric acid (37% in water, 40 μL) in methanol (2 mL) was refluxed overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic phase dried (Na2SO4) and evaporated, which gave, after chromatography on silica using dichloromethane/methanol, the title compound (4 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:9]2[NH:8][CH:7]=1)=[O:5])C.C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[C:4]([C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:15]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)=[C:9]2[NH:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1c[nH]c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2c1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1c[nH]c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2c1=O
Yield: 31.4 %

Procedure:
A mixture of 4,7-dihydro-6-ethoxycarbonyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-7-oxopyrazolo[1,5-a]pyrimidine (946 mg) in sulfuric acid (40% in water, 5 ml) was refluxed for 2 hours. After cooling, the pH of the reaction mixture was adjusted to 5 with an aqueous saturated sodium bicarbonate solution. The crude crystalline was obtained and washed with hot ethanol to give 4,7-dihydro-6-carboxy-2-(4-fluorophenyl)-3-(pyridin-4-yl)-7-oxopyrazolo[1,5-a]pyrimidine (275 mg).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:16]=[CH:15][C:8]([C:9](N(OC)C)=[O:10])=[C:7]([Cl:17])[CH:6]=1.[Cl-].[NH4+]>O1CCCC1>[Br:4][C:5]1[CH:16]=[CH:15][C:8]([C:9](=[O:10])[CH3:1])=[C:7]([Cl:17])[CH:6]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 37.1 %

Procedure:
Methyl magnesium bromide (44 mL, 61.6 mmol, 1.4 M in tetrahydrofuran) was added to tetrahydrofuran (50 mL) at −78° C. (4-Bromo-2-chloro-N-methoxy-N-methyl-benzamide (3.52 g, 12.7 mmol) (from step 6-I) in tetrahydrofuran (30 mL) was added. The mixture was stirred at −78° C. for 45 minutes and then at room temperature for 1.5 hours. The reaction mixture was poured into ice water and saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate (3 times) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was recrystallized from ethyl acetate/hexanes to give 1-(4-bromo-2-chloro-phenyl)-ethanone as a white solid (1.1 g, 37%).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[CH:27][CH2:28][CH3:29])[CH2:23][CH2:22]2)C=CC=CC=1.CC(C)([O-])C.[K+]>C1COCC1>[CH2:1]([CH:4]1[CH2:9][CH2:8][C:7](=[CH:19][CH2:20][CH:21]2[CH2:22][CH2:23][C:24](=[CH:27][CH2:28][CH3:29])[CH2:25][CH2:26]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC=C1CCC(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CCCC1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC=C1CCC(CC=C2CCC(CCC)CC2)CC1
Temperature: -10 °C

Procedure:
57.0 g of 4-propylcyclohexanone and 25.0 g of triphenyl[2-(4-propylidenecyclohexyl)ethyl]phosphonium bromide were introduced into 150 ml of THF under nitrogen, and the mixture was cooled to -10° C. A solution of 5.61 g of potassium tert-butoxide in 100 ml of THF was then added dropwise with stirring, and the mixture was stirred at RT for a further 2 h. Conventional work-up gave 4-[2-(4-propylcyclohexylidene)ethyl]propylidenecyclohexane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33]([N:35]([CH2:39][C:40]2[CH:41]=[C:42]([CH:51]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:53]=2)[O:43][CH2:44][C@@H:45]2[CH2:47][C@H:46]2[C:48]([OH:50])=[O:49])[CH:36]2[CH2:38][CH2:37]2)=[O:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:59]([O-:73])([O:61][CH2:62][C@H:63]([O:69][N+:70]([O-:72])=[O:71])[CH2:64][CH2:65][CH2:66][CH2:67]O)=[O:60].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:70]([O:69][C@@H:63]([CH2:62][O:61][N+:59]([O-:73])=[O:60])[CH2:64][CH2:65][CH2:66][CH2:67][O:49][C:48]([C@@H:46]1[CH2:47][C@H:45]1[CH2:44][O:43][C:42]1[CH:41]=[C:40]([CH:53]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:51]=1)[CH2:39][N:35]([CH:36]1[CH2:37][CH2:38]1)[C:33]([C@@H:10]1[C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]1)=[O:34])=[O:50])([O-:72])=[O:71]
Reactant: O=[N+]([O-])OC[C@@H](CCCCO)O[N+](=O)[O-]
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1R,2R)-2-{[3-{[[((3R,4S)-1-(tert-butoxycarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidin-3-yl)carbonyl](cyclopropyl)-amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylic acid (1 eq.) from Example 4/Step 1 in DCM (0.17 M) was added (2R)-6-hydroxyhexane-1,2-diyl dinitrate (1.5 eq., prepared according to the procedure described in WO2005070868/Example 2, incorporated by reference), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq.), and 4-dimethylaminopyridine (1.5 eq.). The reaction was stirred at rt for 18 h and then concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 40% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH3:1][CH:2]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:3][CH3:4]
Reactant: CCC(C)c1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)c1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(1-methylpropyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][CH:11]=[N:12][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=1)[CH3:8]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cccnc1Cl
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: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1cccnc1-c1ccc(C(F)(F)F)cc1
Yield: 109.7 %

Procedure:
Ethyl 2-chloro-nicotinate (1.86 g, 10.0 mmol) was dissolved in 10 ml of dimethoxyethane. Tetrakis(triphenylphosphine)palladium (347 mg, 0.3 mmol) was added and the reaction vessel purged by alternating vacuum and nitrogen gas three times. A solution of 4-trifluoromethylphenylboronic acid (2.09 g, 11.0 mmol) in 20 ml of dimethoxyethane was added to the reaction mixture followed by 10 ml of a 2M sodium carbonate solution. The reaction mixture was heated at 90 C. for 1.5 h before being cooled and extracted with 150 ml of ether. The organic layer was washed with 50 ml of 2N NaOH, 2×50 ml water, and brine before being dried (magnesium sulfate), filtered and concentrated under vacuum to afford 3.24 g of a brown oil. This material was purified by silica gel chromatography eluting with 5 to 10% ethyl acetate in hexanes to afford 2.34 g of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18](=[O:40])[C@H:19]([CH2:36][CH2:37][S:38][CH3:39])[NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:16][O:17][C:18](=[O:40])[C@H:19]([CH2:36][CH2:37][S:38][CH3:39])[NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:13]([C@@H:12]2[CH2:11][S:10][CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])=[CH:24][C:23]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)[C@@H]2CSCN2C(=O)OC(C)(C)C)cc1-c1ccccc1

Procedure:
The desired compound was prepared by coupling of N-tert-butoxycarbonyl-(R)-(−) thiazolidine-4-carboxylic acid, prepared as in Example 164A with [4-amino-2-phenylbenzoyl]methionine methyl ester (compound 8) according to the method of Example 163D.
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9]C)=[CH:7][C:5]([NH2:6])=[C:4]([O:11][CH3:12])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23]C)C(O)=O>>[Br:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]2[N:6]=[C:12]([C:16]3[CH:20]=[CH:21][C:22]([OH:23])=[C:14]([F:13])[CH:15]=3)[O:11][C:4]=2[CH:3]=1
Reactant: COc1cc(Br)c(OC)cc1N
Reactant: COc1ccc(C(=O)O)cc1F
Product: Oc1ccc(-c2nc3cc(O)c(Br)cc3o2)cc1F

Procedure:
The title compound was prepared in substantially the same manner as described in Example 16, from 4-bromo-2,5-dimethoxyaniline, and 3-fluoro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 224-226° C.; MS m/e 322 (M−H)+.
Reaction SMILES: [NH:1]=[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=2)[C:9]2[C:4](=[CH:5][C:6]([N:25]([CH3:27])[CH3:26])=[CH:7][CH:8]=2)[O:3]1.N[C:29]1OC2C(C(C3C=C(OC)C(OC)=C(Br)C=3)C=1C#N)=CC=CC=2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[O:3][C:4]2[C:9]([C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)([CH3:29])[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2
Reactant: COc1cc(C2C(C#N)=C(N)Oc3ccccc32)cc(Br)c1OC
Reactant: COc1cc(-c2c(C#N)c(=N)oc3cc(N(C)C)ccc23)cc(Br)c1OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C2(C)C(C#N)=C(N)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Reaction time: 0.25 h
Yield: 79 %

Procedure:
2-Imino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-chromene: 4 Å Molecular sieves (20 mg) was added to 2-amino-3-cyano-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromene (20 mg, 0.05 mmol) in dichloromethane (1 mL). The solution was stirred for 15 min. Then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10 mg, 0.05 mmol, 1 eq.) was added and stirred continuously at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with sodium bicarbonate saturated solution (20 mL), brine (20 mL), dried over sodium sulfate and concentrated to yield 17 mg (79%) of the desired compound. 1H NMR (DMSO-d6): 8.33 (s, 1H), 7.28 (d, J=1.9 Hz, 1H), 7.21 (d, J=1.9 Hz, 1H), 6.87 (d, J=9.1 Hz, 1H), 6.56 (dd, J=2.5, 9.1 Hz, 1H), 6.40 (d, J=2.5 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.03 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH-].[Na+].[CH2:13]([OH:18])[CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC=CC=1>O>[CH2:13]([O:18][C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 125.1 %

Procedure:
17.0 g (0.11 mol, 1.0 eq.) of 4-chlor-2,3-dimethylpyridine-N-oxide, 8.6 g (0.225 mol, 2.0 eq.) of caustic soda, and 19.0 g (0.22 mol, 2.0 eq.) of 1-pentanol were added to 68 mL of toluene, and the mixture as heated to reflux for 5 hours, and then cooled to room temperature. 15 mL of water was added to the reaction liquid, and the mixture was concentrated, to obtain a residue in the form of a black paste. Subsequently, the residue was dissolved in 500 mL of water, and then the aqueous solution was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, to obtain 28.8 g of 4-pentyloxy-2,3-dimethylpyridine-N-oxide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].Cl>N1C=CC=CC=1>[F:9][C:5]1[CH:4]=[C:3]([F:10])[C:2]([NH:1][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:6]=1[OH:8]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(O)c(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cc(O)c(F)cc1F
Reaction time: 0.5 h
Yield: 91 %

Procedure:
18.9 g (130 mmol) of the resulting 5-amino-2,4-difluorophenol was dissolved in 45 ml of pyridine, 16.0 ml of pivaloyl chloride was added dropwise over 8 minutes under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. 1N hydrochloric acid was added to the reaction solution and the mixture was extracted with ether. The organic layer was washed once with a 1N aqueous solution of hydrochloric acid, water and an aqueous saturated solution of sodium chloride, respectively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was triturated with n-hexane to give 27.0 g (91%) of 2,4-difluoro-5-pivaloylaminophenol.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=O.[C:20]([NH:23][CH2:24][CH2:25][NH2:26])(=[O:22])[CH3:21]>C(O)(=O)C>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:26]([CH2:25][CH2:24][NH:23][C:20](=[O:22])[CH3:21])[CH:2]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: O=C(CCC1OCCO1)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)NCCN
Solvent: CC(=O)O
Product: CC(=O)NCCn1cccc1-c1ccc(C(F)(F)F)cc1
Yield: 78.1 %

Procedure:
3-(1,3-Dioxolan-2-yl)-4'-(trifluoromethyl)-propiophenone (6.4 g) was added under argon and while stirring to a solution of 4.8 g of N-acetylethylenediamine in 70 ml of acetic acid. The reaction mixture was refluxed overnight, the acetic acid was subsequently removed in a vacuum. The residue was taken up in 200 ml of methylene chloride and washed with a mixture of 100 ml of saturated sodium hydrogen carbonate solution and 70 ml of 2N sodium hydroxide solution. The aqueous phase was back-extracted twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 9.4 g of yellow-brown solid was chromatographed on 500 g of silica gel with ethyl acetate as the eluent. 5.4 g (78%) of N-[2-[2-[4-(trifluoromethyl)phenyl]-pyrrol-1-yl]ethyl]acetamide were isolated as a yellow amorphous solid. MS: m/e=296 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH2:19][OH:20])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]([O:33][C@@H:34]([CH2:40][C:41]1[CH:46]=[CH:45][C:44](O)=[CH:43][CH:42]=1)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:32]>>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([C:13]2[CH:14]=[C:15](/[CH:17]=[CH:18]/[CH2:19][O:20][C:44]3[CH:43]=[CH:42][C:41]([CH2:40][C@H:34]([O:33][CH2:31][CH3:32])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:46][CH:45]=3)[CH:16]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=3)[CH:12]=2)=[CH:22][CH:23]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1ccc(-c2cc(/C=C/CO)cc(-c3ccc(C(C)(C)C)cc3)c2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2cc(-c3ccc(C(C)(C)C)cc3)cc(-c3ccc(C(C)(C)C)cc3)c2)cc1)OCC
Yield: 79.3 %

Procedure:
The title compound (368 mg, 79%) was prepared from (E)-3-(4,4″di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-prop-2-en-1-ol (300 mg, 0.75 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (188 mg, 0.79 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:6]=O.[C:12]([CH2:14]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:13]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:12]#[N:13])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: COc1cc(C=O)ccc1C
Reactant: N#CC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1cc(C=CC#N)ccc1C
Yield: 77 %

Procedure:
Wittig reaction of 3-methoxy-4-methylbenzaldehyde with cyanomethyl triphenylphosphorane gave 3-(3-methoxy-4-methylphenyl)acrylonitrile in 77% yield which was further transformed to 3-(3-methoxy-4-methylphenyl)propan-1-amine using the above described procedures.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:18][CH:17]([NH:19][C:20](=[O:39])[CH2:21][NH:22][C:23](=[O:38])[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[CH2:16]1)=O)(C)(C)C>>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:21][NH:22][C:23](=[O:38])[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:35])([F:37])[F:36])[CH:25]=2)=[O:39])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CNC1

Procedure:
The title compound was prepared as colorless oil from TFA de-protection of 3-[2-(3,5-bis-trifluoromethyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butylester (as prepared in the previous step) using the procedure described in Step E of Example 1.
Reaction SMILES: [OH:1][CH2:2][C:3]([S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=[O:8])=[O:7])([CH3:5])[CH3:4].[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[CH:28]([NH:31][C:32]([O:1][CH2:2][C:3]([S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])(=[O:8])=[O:7])([CH3:5])[CH3:4])=[O:33])([CH3:30])[CH3:29]
Reactant: CC(C)(CO)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)N=C=O
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)OCC(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 1.0 g (2.56 mmol) of benzyl rac-α-[[(2-hydroxy-1,1-dimethylethyl)sulfonyl]methyl]hydrocinnamate and 0.97 g (10.24 mmol) of isopropyl isocyanate in 20 ml of dry toluene was heated to 100o for 4 hours. Subsequently, the reaction solution was evaporated under reduced pressure. The benzyl rac-α-[[[2-[(isopropylcarbamoyl)oxy]-1,1-dimethylethyl]sulfonyl]methyl]hydrocinnamate was obtained in quantitative yield as a yellowish oil, MS: 384 (M-benzyl)+.