Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.C([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=O)[CH2:14]Br)[N:8]=1)(=O)C.[NH2:17][C:18](=[N:20][C:21]([NH2:23])=[S:22])[NH2:19]>CO>[NH2:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[N:23]=[C:21]([N:20]=[C:18]([NH2:19])[NH2:17])[S:22][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)NCc1cccc(C(=O)CBr)n1
Reactant: NC(=S)N=C(N)N
Agent: Br
Solvent: CO
Product: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Yield: 42.4 %

Procedure:
A mixture of 2-(acetylaminomethyl)-6-bromoacetyl-pyridine hydrobromide (3.34 g) and diaminomethylenethiourea (1.01 g) in methanol (50 ml) was refluxed for 10 hours with stirring. The resulting precipitate was collected, dissolved in water (50 ml) and the solution was made basic with aqueous potassium carbonate. The separated product was collected and washed with water to give 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.90 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:20][CH:21]([OH:30])[CH2:22][S:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O.O>[CH2:1]([O:8][C:9]1[C:14]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:20][CH:21]([OH:30])[CH2:22][S:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCSCC(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCSCC(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
0.675 g (1.63 mmol) of methyl 7-(2-benzyloxy-3-cyclopentylphenyl)-6-hydroxy-4-thiaheptanoate (Example 1) is dissolved in 10 ml of methanol/water 9:1, and 0.7 g (17.5 mmol) of NaOH dissolved in a little water is added. The mixture is left to stir at room temperature overnight, then the solvent is removed by distillation in vacuo, and the residue is acidified with cold 1N hydrochloric acid. Three extractions with diethyl ether are carried out, and the organic phases are washed twice with saturated brine and dried over sodium sulfate, and the solvent is removed by distillation in vacuo. 444 mg (66% of theory) of 7-(2-benzyloxy-3-cyclopentylphenyl)-6-hydroxy-4-thiaheptanoic acid are obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=O.[OH-].[K+].[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=1.Cl>C(O)C>[OH:10][C:9]1[CH:8]=[C:7]([OH:11])[CH:6]=[CH:5][C:4]=1[CH:2]=[CH:1][C:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)=[O:23]
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)C=Cc2ccc(O)cc2O)cc1
Temperature: 0 °C

Procedure:
A mixture of 3.04 g (0.02 mole) of 2,4-dihydroxyacetophenone, 10 ml of 60% strength aqueous potassium hydroxide and 10 ml of ethanol is cooled to 0° C. 2.72 g (0.02 mole) of anisaldehyde are added with stirring and the reaction mixture is heated to 50° C. for 4 hours. The mixture is then poured into a 10% solution of hydrochloric acid. The precipitate formed is filtered off, washed three times with water and is dried. It is then taken up with ethyl acetate, is treated with animal charcoal and is filtered rapidly through silica with a 9/1 mixture of pentane and ethyl acetate. A yellow product is obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOCC>[OH-].[Na+]>[C:9]1([CH2:15][C:16]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: C[C@@H](O)[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reaction time: 16 h

Procedure:
L-Threonine (35.7 g) is dissolved in 1N sodium hydroxide (1 liter) and chilled to -5° to -10° C. To the cold, mechanically stirred solution is added dropwise phenylacetyl chloride (46.3 g). The reaction mixture is stirred for about 16 hours as the temperature rises to 26° C. The mixture is washed with ether, acidified to pH 2 with hydrochloric acid, and extracted with ethyl acetate (two times). The combined extracts are dried over sodium sulfate and concentrated under reduced pressure until crystalline solids form. Ether is added to the mixture and the crystals are collected (34.8 g); melting point 161°-163° C.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[N-:9]=[N+:10]=[N-:11].[Na+]>CC(C)=O>[N:9]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])=[N+:10]=[N-:11]
Reactant: CC(C)(C)C(=O)CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)CN=[N+]=[N-]
Temperature: 25 °C

Procedure:
To a solution of 1-bromo-3,3-dimethylbutan-2-one (50 g, 279 mmol) in acetone (400 mL) is added NaN3 (22 g, 335 mmol) at 0° C. The reaction mixture is warmed to room temperature for 7 h. The reaction mixture is filtered and the filtrate is concentrated. The residue is diluted with EtOAc and washed with water and brine. The organic layer is dried (Na2SO4) and concentrated to afford the title crude compound which is used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[C:12]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])=[N:13][O:14][C:15]=2[CH:16]([CH3:18])[CH3:17])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:27]([O:38][CH3:39])(=[O:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32]([O-])=[O:33])=[CH:30][CH:29]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[C:12]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])=[N:13][O:14][C:15]=2[CH:16]([CH3:18])[CH3:17])[CH:6]=[CH:5][C:3]=1[NH:4][C:32]([C:31]1[CH:35]=[CH:36][C:28]([C:27]([O:38][CH3:39])=[O:37])=[CH:29][CH:30]=1)=[O:33]
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(N)c(Cl)c1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-chloro-4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}aniline (85 mg, 206 μmol), monomethyl terephthalate (37.2 mg, 206 μmol), 1-hydroxybenzotriazole (5.6 mg, 41 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39.6 mg, 206 μmol) in dichloromethane (1 mL) was stirred at ambient temperature for 24 h. The reaction was partitioned with ethyl acetate and water. The organic layer was washed sequentially with saturated aqueous sodium hydrogensulfate and brine, then was dried over anhydrous sodium sulfate, filtered, and condensed to a residue which was chromatographed on silica gel eluting with 30% ethyl acetate/hexanes. Yield=65 mg, (55%) of methyl 4-{[(2-chloro-4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}phenyl)amino]carbonyl}-benzoate.
Reaction SMILES: [OH:1][CH:2]([CH2:9][OH:10])[CH2:3][NH:4][C:5](=[O:8])[CH2:6][Cl:7].[CH2:11]([O:14][CH:15](OCC=C)OCC=C)[CH:12]=[CH2:13].[Cl-].[NH4+]>ClC(Cl)C>[CH2:11]([O:14][CH:15]1[O:1][CH:2]([CH2:3][NH:4][C:5](=[O:8])[CH2:6][Cl:7])[CH2:9][O:10]1)[CH:12]=[CH2:13]
Reactant: C=CCOC(OCC=C)OCC=C
Reactant: O=C(CCl)NCC(O)CO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Product: C=CCOC1OCC(CNC(=O)CCl)O1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
Six and seven-tenths g (0.04 mole) of N-(2,3-dihydroxypropyl)chloroacetamide, 7.3 g (0.04 mole) of triallylorthoformate, 0.2 g of ammonium chloride, and 50 ml of dichloroethane were combined in a reaction flask and distilled to a head temperature of 82° C. The distillate was cooled to room temperature, stirred with potassium carbonate and filtered over Florisil. The filtrate was evaporated to yield 3.2 g of 2-allyloxy-4-(chloroacetylamino)methyl-1,3-dioxolane, a yellow oil. Structure was confirmed by NMR. nD30 =1.4888.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([S:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:14])=[O:13])[CH:6]=1)(=[O:4])=[O:3].[C:29]([C:33]1[O:37][N:36]=[C:35]([OH:38])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:29]([C:33]1[O:37][N:36]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][C:7]=2[S:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:14])=[O:13])[C:35](=[O:38])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CCCCCCCCCCCCCCS(=O)(=O)c1cc(S(C)(=O)=O)ccc1Cl
Reactant: CC(C)(C)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCS(=O)(=O)c1cc(S(C)(=O)=O)ccc1-n1oc(C(C)(C)C)cc1=O
Reaction time: 4 h
Yield: 50.7 %

Procedure:
After mixing 32 g of 4-methanesulfonyl-2-tetradecylsulfonylchlorobenzene, 20 g of 5-t-butyl-3-hydroxyisoxazole, 20 g of potassium carbonate, and 140 ml of dimethyl sulfoxide, the reaction was performed for 4 hours at 80° C. After the reaction was over, the reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic phase obtained was purified by silca gel column chromatography to provide 20.0 g of the aforesaid compound with a yield of 50.8%. The melting point thereof was 97° C. to 98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.[F:29][C:30]([F:37])([F:36])[CH2:31][S:32](Cl)(=[O:34])=[O:33]>>[F:29][C:30]([F:37])([F:36])[CH2:31][S:32]([NH:26][CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Product: COc1ccc2cc(-c3nc(C(C)(C)CNS(=O)(=O)CC(F)(F)F)[nH]c3-c3ccncc3)ccc2c1
Yield: 43 %

Procedure:
The title compound (12 mg, 43%) was prepared starting from the product of Example 2 and 2,2,2-trifluoroethanesulfonyl chloride using the method described in Example 4; MS(ES) m/e 519 [M+H]+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1C
Product: Cc1ccc(-c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3ccccc23)cc1C

Procedure:
The product of Example 163A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.74 (s, 1H), 8.39-8.42 (m, 1H), 7.89-8.02 (m, 2H), 7.74-7.77 (m, 1H), 7.25-7.39 (m, 3H), 7.12-7.18 (m, 3H), 3.77 (s, 2H), 2.32 (s, 3H), 2.31 (s, 3H); MS (APCI+) M/Z 420 (M+H)+.
Reaction SMILES: C(OC(=O)[N:10]([CH2:32][C:33]([CH3:39])([CH3:38])[CH2:34][CH2:35][C:36]#[N:37])[CH2:11][C@@H:12]([OH:31])[C@@H:13]([NH:21][C:22]([O:24][CH:25]1[CH2:30][O:29][CH2:28][O:27][CH2:26]1)=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[O:27]1[CH2:26][CH:25]([O:24][C:22](=[O:23])[NH:21][C@@H:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:12]([OH:31])[CH2:11][NH:10][CH2:32][C:33]([CH3:39])([CH3:38])[CH2:34][CH2:35][C:36]#[N:37])[CH2:30][O:29][CH2:28]1
Reactant: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1
Reaction time: 16 h

Procedure:
A solution of (4-Cyano-2,2-dimethyl-butyl)-[(2R,3S)-3-([1,3]dioxan-5-yloxycarbonylamino)-2-hydroxy-4-phenyl-butyl]-carbamic acid benzyl ester (0.420 g, 0.76 mmol) in EtOAc at ambient temperature was treated with palladium on carbon (0.050 g) and stirred under a balloon of hydrogen. After stirring 16 h the mixture was filtered and solvent was removed in vacuo to give desired product as a colorless oil.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:28][CH2:27][CH2:26][O:25][CH3:24])=[O:3])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: COCCN
Product: COCCNC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-methoxyethylamine (29.6 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(2-methoxyethyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (31.2 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:13]1([CH2:2][CH2:3][O:4][C:5]2[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCN2CCCC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
A mixture of 2.29 g of 4-(2-bromoethoxy)benzaldehyde, 1.42 g of pyrrolidine and 2.07 g of potassium carbonate in 8 ml of N,N-dimethylformamide was stirred at 60° C. for 2 hours. After cooling, water was added and the whole was extracted with ethyl acetate. The ethyl acetate layer was extracted with aqueous hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was distilled to give 1.72 g of colorless oil, b.p. 170° C. (5 mmHg).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:18][C:17]1[CH:20]=[CH:21][C:14]([OH:13])=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: Oc1ccc(C=NNC(=S)NC2CC3C=CC2C3)cc1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 4-hydroxybenzaldehyde (68 mg, 0.56 mmol) similar to Example 3 and isolated as a yellow solid (47 mg, 29%). 1H NMR (CDCl3): 9.00 (s, 1H), 7.68 (s, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.43 (d, J=6.9 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 6.23-6.14 (m, 2H), 4.30-4.26 (m, 1H), 3.05 (s, 1H), 2.96 (s, 1H), 1.94-1.86 (m, 1H), 1.66 (d, J=9.0 Hz, 1H), 1.51 (d, J=9.0 Hz, 1H), 1.45-1.38 (m, 1H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[C:20](Cl)=[N:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1>C1COCC1>[Cl:10][C:11]1[C:20]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nc2ccccc2nc1Oc1ccccc1
Reaction time: 72 h

Procedure:
A solution of phenol (564 mg, 6 mmol) in THF (5 ml) was added to a suspension of sodium hydride (60% in mineral oil, 240 mg, 6 mmol) in THF (10 ml). After 10 min 2,3-dichloroquinoxaline (995 mg, 5 mmol) was added. The mixture was stirred for 3 days. The solvent was removed in vacuo, the residue was dissolved in EtOAc, washed with NaOH (1M), dried (Na2SO4) and evaporated in vacuo to give a yellow solid. Recrystallisation from diisopropylether gave the title compound as off-white needles: δH (DMSO d6) 8.01-7.98 (1H, m), 7.77-7.67 (3H, m), 7.53-7.48 (2H, m), 7.37-7.30 (3H, m); m/z (EI+, 70V) 257.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:18])=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:18])=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nc(C)c(C)s2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)sc1C
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(4,5-dimethylthiazol-2-yl)-2-naphthalenyl)ethynylbenzoate (Compound 17) (58.0 mg, 0.13 mmol) and 4 ml of EtOH at room temperature was added aqueous NaOH (1 ml, 1 M, 1 mmol). The resulting solution was warmed to 50° C. for 1 hour and concentrated in vacuo. The residue was suspended in a solution of CH2Cl2 and ether (5:1) and acidified to pH 5 with 1M aqueous HCl. The layers were separated and the organic layer was washed with brine, dried Na2SO4), filtered and the solvents removed under reduced pressure to give the title compound as a white solid. 1H NMR (d6-DMSO): δ 7.94 (2H, d, J=8.4 Hz), 7.86 (1H, d, J=1.6 Hz), 7.61 (2H, d, J=8.3 Hz), 7.50 (1H, dd, J=1.6, 8.0 Hz), 7.45 (1H, d, J=8.0 Hz), 6.51 (1H, t, J=4.9 Hz), 2.37 (3H, s), 2.36 (2H, d, J=4.6 Hz), 2.32 (3H, s), 1.26 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@H:8]2[CH2:12][C@@H:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.I[CH:18]([CH3:20])[CH3:19]>>[CH3:7][C:4]1[N:3]([C@H:8]2[CH2:12][C@@:11]([CH:18]([CH3:20])[CH3:19])([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9]2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H]1C=C[C@@H](n2c(C)ccc2C)C1
Reactant: CC(C)I
Product: COC(=O)[C@@]1(C(C)C)C=C[C@@H](n2c(C)ccc2C)C1

Procedure:
reacting said methyl (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylate with 2-iodopropane to form methyl (1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxylate; and
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][C:16](O)=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[H][H]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CCC(=O)O)C1
Reactant: [H][H]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(CCCO)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
To a solution of commercially available 3-[1-(tert-butoxycarbonyl)-3-piperidinyl]propionic acid (2.57 g, 10.0 mmol) in 100 mL of anhydrous THF was added slowly a solution of BH3.THF complex in THF (1.0 M, 20 mL, 2.0 equiv) at room temperature under N2. The solution was stirred for 16 h at room temperature. Water was added carefully (hydrogen evolution!), and the resulting solution was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to give the alcohol (2.35 g, 97%) as a colorless oil. LC-MS (ESI) m/z 244 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1.[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:10])[C:12]([F:14])([F:13])[F:11])=[CH:7][N:8]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(C=O)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(C(O)C(F)(F)F)cn1
Yield: 93.5 %

Procedure:
According to Reference Example 8-12, by use of 6-methoxy-3-pyridinecarboxaldehyde (300 mg, 2.19 mmol), (trifluoromethyl)trimethylsilane (388 μL, 2.63 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 220 μL, 0.220 mmol) and tetrahydrofuran (6.0 mL), the mixture was stirred and reacted at room temperature for 3 hours. Then, purification by silica gel column chromatography (hexane/ethyl acetate=4/1) was performed to give 2-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound CT) (424 mg, yield: 93%).
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:20])=O>>[F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1F
Reactant: O=S(Cl)Cl
Product: CCCS(=O)(=O)Nc1cccc(C(=O)Cl)c1F

Procedure:
To 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (50, 1.17 g, 4.5 mmol) was added thionyl chloride (10.0 mL). The reaction was heated to reflux for 3 hours. The reaction was concentrated to give crude compound 51 that was used in the next step.
Reaction SMILES: [CH3:1][CH:2]1[CH:9]2[CH:5]([CH2:6][NH:7][CH2:8]2)[C:4]2[S:10][CH:11]=[CH:12][C:3]1=2.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:7]1[CH2:6][CH:5]2[CH:9]([CH:2]([CH3:1])[C:3]3[CH:12]=[CH:11][S:10][C:4]=32)[CH2:8]1)=[O:22])[CH3:25]
Reactant: CC1c2ccsc2C2CNCC12
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CC2c3sccc3C(C)C2C1
Temperature: 22 °C
Yield: 68 %

Procedure:
A 0° C. solution of the product from step h) (258 mg, 1.19 mmol) in CH2Cl2 (6 ml) was treated with triethylamine (497 μl, 3.57 mmol) and ethyl chloroformate (227 μl, 2.38 mmol) and the reaction was warmed to 22° C. Next, the reaction mixture was extracted with CH2Cl2 (50 ml) and brine (25 ml). The combined organic layers were dried (MgSO4) and the crude product was purified by silica-gel chromatography (hexanes:EtOAc-50:50) to give the subtitle compound (204 mg, 68%). MS calculated for C13H17NO2S+H 252, observed 252.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[F:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[F:21]>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[F:21])[O:22][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: Oc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2ccc(F)c(F)c2)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluoro-3-(trifluoromethyl)benzaldehyde and 3,4-difluorophenol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17]C(O)=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.C1C[O:34]CC1>>[C:1]([O:5][C:6](=[O:21])[NH:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][OH:34])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)Nn1ccc2cc(CC(=O)O)ccc21
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(C)OC(=O)Nn1ccc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68 %

Procedure:
To a −78° C. solution of 5-(carboxymethyl)-indole-1-carbamic acid tert-butyl ester (10.8 g, 39 mmol) in THF (180 mL) was added DIBAL (127 mL of a 1 M solution in THF, 127 mmol), and the reaction mixture was stirred for 2.5 h. The reaction was quenched with 1:1 1 N HCl/MeOH (100 mL), the reaction mixture was warmed to room temperature, diluted with CH2Cl2 (100 mL), and separated. The organic solution was washed with saturated Rochelle salt, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 EtOAc/hexanes) provided 5-hydroxymethylindole-1-carbamic acid tert-butyl ester as a yellow oil (6.5 g, 68%): 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=9 Hz, 1H), 7.59 (d, J=6 Hz, 1H), 7.54 (s, 1H), 7.28 (d, J=9 Hz, 1H), 6.58 (d, J=6 Hz, 1H), 4.73 (s, 2H), 1.97 (s, 9H).