Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[H-].[Na+].CS(O[C@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C@H:14]([C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][O:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=3)=[O:42])[CH2:34][CH2:33]2)=[O:31])[CH2:13]1)(=O)=O.[Cl-].[Na+]>CN(C)C=O>[C:1]([S:3][C@@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C@H:14]([C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH2:38][CH2:39][O:40][C:41]([O:43][CH2:44][C:45]3[CH:46]=[CH:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=3)=[O:42])[CH2:36][CH2:37]2)=[O:31])[CH2:13]1)(=[O:4])[CH3:2]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(O)=S
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
51 μl of thioacetic acid were added, whilst ice-cooling, to a suspension of 26 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 1.4 ml of dry N,N-dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 340 mg of (2S,4R)-4-methanesulfonyloxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step 90(c)(i) above] in 2 ml of dry N,N-dimethylformamide was then added to the mixture, and the mixture was stirred at between 8° C. and 90° C. for 4 hours. At the end of this time, the temperature of the reaction mixture was allowed to reduce to room temperature, after which the mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was worked up and purified according to the procedure described in step 90(b)(i) above, to give 166 mg of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound thus obtained were identical with those of the compound prepared as described in step 90(b)(ii) above.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].B.C1COCC1.C1COCC1.O.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
15 g (70 mmol) of 3-bromo-4-methylbenzoic acid are placed in 150 ml of anhydrous THF in a round-bottomed flask and under a stream of nitrogen. 84 ml of 1M borane/THF are added dropwise and the reaction medium is stirred overnight at room temperature. A THF/water (50/50) solution is added slowly at 0° C. and the mixture is then poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. 14.4 g (100%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[O-][CH2:15][CH3:16].[Na+]>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>[C:15]1([CH:16]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(c1ccc(Cl)cc1)C(F)(F)F
Reactant: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)C(=Cc1ccccc1)c1ccc(Cl)cc1
Yield: 68 %

Procedure:
4'-Chloro-2,2,2-trifluoroacetophenone (R. Fuchs, J. Org. Chem. 22, 993-994 (1957)) is reacted with benzyl-triphenylphosphonium chloride in the presence of an ethanolic solution of sodium ethoxide. The product is crystallized from hexane. 1-Phenyl-3,3,3-trifluoro-2-(4-chlorophenyl)-propene is obtained with a yield of 68%; m.p.: 63-66° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([C:8]([Cl:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Br:13]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([C:8]([Cl:11])=[CH:9][C:10]=1[Br:13])[C:5]([OH:7])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cl)c(C(=O)O)c1Cl
Solvent: CC#N
Product: Nc1c(Br)cc(Cl)c(C(=O)O)c1Cl
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 73.1 %

Procedure:
A mixture of 3-amino-2,6-dichlorobenzoic acid (5 g, 24 mmol, Step b) in acetonitrile (50 mL) was treated with N-bromosuccinimide (5.1 g, 29 mmol) and the reaction mixture was stirred at 90° C. for 45 minutes. Acetonitrile was removed in vaccuo and the residue was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was separated and the aqueous layer was again extracted with ethyl acetate (2×100 mL). The combined organics were dried over anhydrous sodium sulfate and concentrated to afford 3-amino-4-bromo-2,6-dichloro-benzoic acid (5 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:3]=1.[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>>[ClH:1].[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: NCC(O)CO
Reactant: COc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Product: COc1ccc(-c2cc(NCC(O)CO)c3ccccc3n2)cc1
Product: Cl

Procedure:
The title compound, m.p. 216-218° C. and MS: m/e=324 (M+), was prepared from 4-chloro-2-(4-methoxy-phenyl)-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][OH:8].N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:8][CH2:7][C@H:2]2[CH2:3][O:4][CH2:5][CH2:6][O:1]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1COCCO1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Temperature: 0 °C
Reaction time: 15.5 h
Yield: 73 %

Procedure:
To a cooled (0° C.) solution of (S)-(1,4-dioxan-2-yl)methanol (Kim, H. Y., et al., Bioorg. Med. Chem. Lett. (2005), 15:3207-11) (2.02 g, 17.1 mmol) and pyridine (14 mL, 173 mmol) in dichloromethane (11 mL) was added p-toluenesulfonyl chloride (3.85 g, 20.2 mmol). The reaction was stirred at 0° C. for 20 min and at ambient temperature for an additional 15.5 h. The solution was diluted with dichloromethane (100 mL) and was washed sequentially with hydrochloric acid (100 mL, 2 M), water (50 mL) and brine (50 mL). The organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with hexanes/ethyl acetate (2:1 to 3:2) to afford (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (3.40 g, 73%) as a colorless solid: mp 53-54° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ7.79 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.02 (dd, J=10.8, 5.4 Hz, 1H), 3.95 (dd, J=10.5, 4.5 Hz, 1H), 3.82-3.50 (m, 6H), 3.35 (dd, J=11.6, 9.8 Hz, 1H), 2.45 (s, 3H); MS (ES+) m/z 295.0 (M+23).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[F:25]>>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][C:19]=1[F:25]
Reactant: Nc1ccc(O)cc1F
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1F
Yield: 83.6 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 182 using Compound 83 (250 mg, 1.08 mmol) and 4-amino-3-fluoro-phenol (276 mg, 2.17 mmol) to provide 185 (290 mg, 83% yield) as a solid. LC-MS (M+H=322, obsd.=322).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[Br:13]Br.C(=O)([O-])[O-].[K+].[K+].O>CO>[Br:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:1][CH3:2])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCc1ccccc1C(=O)OC
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1ccc(Br)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The above methyl 2-ethylbenzoate was mixed with molecular sieve 13× (powder, 70 g), and while stirring the mixture, bromine (5.2 ml) was added dropwise thereto at 80° C. The mixture was further stirred at the same temperature for 1.5 hours. The mixture was cooled to room temperature, and added thereto were potassium carbonate (7.4 g), water (70 ml) and methanol (350 ml), and the mixture was stirred for 8 hours. Insoluble materials were filtered off, and suspended in a mixed solution of methanol (500 ml)-water (500 ml), and the mixture was stirred at room temperature overnight. Insoluble materials were filtered off and the filtrate was combined with the previously obtained filtrate, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure, to give methyl 5-bromo-2-ethylbenzoate (2.44 g). APCI-Mass m/Z 260/262 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:9]([O:11]CC)=[O:10])=[C:4]([F:20])[CH:3]=1>CO.C1COCC1.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:14]([CH3:19])[C:15]([F:16])([F:18])[F:17])[C:9]([OH:11])=[O:10])=[C:4]([F:20])[CH:3]=1
Reactant: CCOC(=O)C(c1ccc(Cl)cc1F)[C@@H](C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](C(C(=O)O)c1ccc(Cl)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.26 g (13.6 mmol) of ethyl (3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) were dissolved in a mixture of 22 ml of methanol, 22 ml of THF and 11 ml of water, and 10.9 g of 50% strength aqueous sodium hydroxide solution were added at 0° C. The reaction mixture was stirred at RT overnight. Most of the organic solvents were then removed under reduced pressure. The mixture that remained was diluted with water and extracted with diethyl ether. After phase separation, the organic phase was discarded and the aqueous phase was acidified with semiconcentrated hydrochloric acid (pH about 2) and extracted repeatedly with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulphate and concentrated under reduced pressure. This gave 3.38 g (76.7% of theory) of the target product as a mixture of diastereomers which could be used without further purification for subsequent reactions.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]=2[C:6](=[O:16])[C:5]2[C:17](=[O:24])[C:18]3[C:23]([C:4]1=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:2].[BH4-].[Na+]>>[CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]=2[C:6](=[O:16])[C:5]2[CH:17]([OH:24])[C:18]3[C:23]([C:4]1=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:2]
Reactant: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(=O)c1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Product: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ethanolic solution of 5-ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (500 mg, 1,58 mmol) was added sodium borohydride (62 mg, 1.64 mmol) in portions followed by stirring at room temperature for 1 hour. After removing ethanol, the reaction mixture was diluted with water and extracted with chloroform twice. The combined organic layers were washed with saturated sodium chloride solution and dried with sodium sulfate followed by evaporating to remove chloroform. The title compound was obtained by crystallizing the residue from acetone-diethyl ether mixture. 1H-NMR(CDCl3)δ 1.35(6H,d,CH(CH3)2), 1.72(3H,t,NCH2CH3), 3.11(1H,septet,CH), 4.79(2H,q,NCH2), 5.86(1H,s,H-11), 7.52-7.63(3H,m,Ar-H), 7.85(1H,dd,H-9)
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[CH:6][CH:5]=1.[C-]#[N:20].[K+].O.O1CCOCC1>C(Cl)Cl>[N:12]1[O:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][C:2]#[N:20])=[CH:5][CH:6]=2)=[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=12
Reactant: BrCCc1ccc(-c2onc3ccccc23)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: N#CCc1ccc(-c2onc3ccccc23)cc1

Procedure:
A mixture of 11.1 g (0.039 mole) of 3-[4-(bromoethyl)phenyl]-2,1-benzisoxazole, 13.0 g (0.2 mole) of potassium cyanide, 55 ml of water and 80 ml of dioxane was heated at reflux under a nitrogen atmosphere for 2 hrs. The mixture was cooled, 200 ml of methylene chloride was added and the layers were separated. The organic layer was washed twice with water, dried over sodium sulfate and concentrated to give a gummy solid as residue. The residue was chromatographed on 150 g of silica gel and the product was eluted with 10% methanol in benzene to yield 4.4 g (48%) of solid, m.p. 118°-121° C. (after recrystallization from 2-propanol, charcoal).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.[Cu](C#N)[C:18]#[N:19]>CN(C)C=O.Cl.[Fe](Cl)Cl>[C:18]([C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)#[N:19]
Reactant: N#C[Cu]C#N
Reactant: Brc1ccsc1-c1sccc1-c1cccs1
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1ccsc1-c1sccc1-c1cccs1
Temperature: 25 °C

Procedure:
10 mmol of 3-bromoterthiophene was refluxed in anhydrous dimethylformamide (10 ml) containing 15 mmol of copper cyanide for 4 hours. After the dark mixture was allowed to cool to room temperature it was mixed with iron chloride (10 g) in hydrochloric acid solution (20 ml, 2.0M) and maintained at 60˜70° C. for 30 minutes. The organic extract was washed with hydrochloric acid solution (20 ml, 6M), distilled water, saturated sodium bicarbonate solution and aqueous sodium chloride solution to obtain a dark yellowish solid. The obtained solid was recrystallized from an organic solvent. The product has a melting point of 83° C. and a molecular weight of 272.9736 g/mol as measured using a mass spectrometer. The structure of the product was identified through 13C NMR, 1H NMR, and IR spectrometer.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][S:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1.C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1.[F:25][C:26]([F:42])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:27][NH:28][CH:29]1[CH2:34][CH2:33][CH:32]([CH3:35])[CH2:31][CH2:30]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][S:5][C:6]1[S:10][C:9]([NH:11][C:18]([N:28]([CH2:27][C:26]([F:42])([F:25])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:29]2[CH2:30][CH2:31][CH:32]([CH3:35])[CH2:33][CH2:34]2)=[O:19])=[N:8][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)CSc1cnc(N)s1
Reactant: CC1CCC(NCC(F)(F)c2ccccc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CSc1cnc(NC(=O)N(CC(F)(F)c2ccccc2)C2CCC(C)CC2)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of (2-amino-thiazol-5-ylsulfanyl)-acetic acid methyl ester (403 mg, 1.98 mmol) in CH2Cl2 (100 mL) was added CDI (480.2 mg, 2.96 mmol) and DMAP (25 mg, 0.20 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h, and then (2,2-difluoro-2-phenyl-ethyl)-(4-methyl-cyclohexyl)-amine (500 mg, 1.98 mmol) was added. The mixture was stirred for 16 h at room temperature. The solvent was removed at reduced pressure and the residue was purified by preparative HPLC to give {2-[3-(2,2-difluoro-2-phenyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)CCN(C)C.[CH2:21]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1>CCOCC.O.CCCCCC>[N:5]1[CH:6]=[CH:7][C:2]([C:29]2([OH:30])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]2=3)=[CH:3][CH:4]=1
Reactant: Brc1ccncc1
Reactant: O=C1c2ccccc2CCc2ccccc21
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: OC1(c2ccncc2)c2ccccc2CCc2ccccc21
Temperature: -75 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a stirred solution of 4-bromopyridine (37.9 g, 0.24 mol) in anhydrous ether (475 mL) at -75° C. under a nitrogen atmosphere was added n-butyllithium (160 mL of a 1.5 M hexane solution, 0.24 mol). Tetramethylethyenediamine (36.2 mL, 0.24 mol) was added and the solution was stirred at -75° C. for 1 hour. A solution of dibenzosuberone (50.l g, 0.24 mol) in anhydrous ether (250 mL) was added dropwise, the reaction mixture was stirred at -75° C. for 40 minutes, warmed to ambient temperature and stirred at that temperature for 1.5 hours. Water (650 mL) was added dropwise. The solid which crystallized was isolated by filtration to give 43.54 g of 10,11-dihydro-5-(4-pyridinyl)-5H-dibenzo[a,d]cyclohepten-5-ol, mp 174-177° C. Recrystallization from ethyl acetate-hexane gave material of mp 183-185° C.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[NH2:15])\[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.N1C=CC=CC=1.Cl[C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)(Cl)Cl>[F:14][C:11]([F:13])([F:12])[O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]2[N:15]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:1][N:2]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: N/C(=N/O)c1ccc(OC(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Yield: 109.5 %

Procedure:
To a solution of (E)-N′-hydroxy-4-(trifluoromethoxy)benzimidamide (3.0 g, 13.6 mmol) and pyridine (1.6 g, 20.4 mmol) in CHCl3 (20 mL), ethyl 2-chloro-2-oxoacetate (2.2 g, 16.4 mmol) was added slowly at 0° C. The mixture was stirred at reflux for 3 h, and then concentrated to give the crude product, which was purified by silica gel column chromatography (Petroleum ether:EtOAc=10:1) to give ethyl 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate as a white solid (4.5 g, 82%). MS (ES+) C12H9F3N2O4 requires: 302. found: 303[M+H]+.
Reaction SMILES: C(OC([N:8]1[CH:12]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]#[N:21])=[O:14])[CH2:11][CH2:10][CH:9]1[CH2:22][O:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:34])=[CH:26][CH:25]=1)=O)(C)(C)C.N1C=CC=CC=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[C:20]([C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:13]([C@H:12]1[NH:8][C@@H:9]([CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([NH:34][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:26][CH:25]=2)[CH2:10][CH2:11]1)=[O:14])#[N:21]
Reactant: CC(C)(C)OC(=O)N1C(COc2ccc(N)c3ccccc23)CCC1C(=O)N1CCCC1C#N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OC[C@H]2CC[C@@H](C(=O)N3CCC[C@H]3C#N)N2)c2ccccc12

Procedure:
The compound of Example 97A (32 mg, 0.07 mmol) was dissolved in CH2Cl2 (1 mL) and pyridine (0.5 mL) in a microwave reaction tube. Methanesulfonyl chloride (6.0 μL, 0.21 mmol) was added. It was reacted under microwave condition at 130° C. for 20 minutes. The mixture was filtered and purified by reverse phase HPLC to give the desired sulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C(=O)=O.CC(C)=O.[H-].[Na+].[CH3:21][N:22]([CH2:29][CH2:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>O1CCCC1>[CH3:21][N:22]([CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35](/[CH:36]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])=[CH:38][CH:39]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CN(CCOc1ccc(C=O)cc1)c1ccccn1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(OCCN(C)c2ccccn2)cc1
Reaction time: 0.17 h

Procedure:
A solution of trimethyl phosphonoacetate (5.5 mL) in dry tetrahydrofuran (25 mL) was added slowly to a cooled (cardice-acetone bath) suspension of sodium hydride (60% dispersion in oil, 1.34 g) in tetrahydrofuran (100 mL) under a nitrogen atmosphere such that the temperature of the reaction mixture remained between 0° C. and 10° C. during the addition. The resultant slurry was then cooled in an ice bath and stirred for 10 minutes prior to the addition of a solution of 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzaldehyde (8.3 g) (Eur. Patent. Appl., Publication No. 0306228) in tetrahydrofuran (100 mL). The mixture was stirred at room temperature for 20 hrs, then quenched with brine (10 mL) and concentrated in vacuo. The residue was suspended in brine (500 mL) and extracted with dichloromethane (3×300 mL), and the combined organic layers washed with water (1 L) and brine (1 L), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 1% methanol in dichloromethane as eluent to afford the title compound, mp 93°-5° C. (dichloromethane-hexane).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:21]O>CO>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:21])=[O:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(C(=O)O)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
In 630 g of methanol was dissolved 203 g of 4-tert-butylcyclohexanecarboxylic acid. The solution was combined with 0.54 g of conc. sulfuric acid and heated under reflux for 72 hours. The reaction solution was allowed to cool to room temperature, 18 g of 2.5 wt % sodium hydroxide/methanol mixture was added, and the solvent was distilled off in vacuum from the reaction solution. The crude oil was purified by vacuum distillation, obtaining 207 g of methyl 4-tert-butylcyclohexanecarboxylate as colorless liquid (yield 95%, isomer ratio 76:24).
Reaction SMILES: C[O:2][C:3](=[O:49])[C@@H:4]([NH:26][C:27](=[O:48])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[C:39]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:41][C:36]([CH2:35][O:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([NH:26][C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[CH:8][CH:7]=2)[C:3]([OH:49])=[O:2])=[O:48])=[CH:37][CH:38]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1)NC(=O)c1ccccc1OCc1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1)C(=O)O)c1ccccc1OCc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
(S)-2-[2-(biphenyl-4-ylmethoxy)-benzoylamino]-3-[4-(biphenyl-4-ylmethoxy)-phenyl]-propionic acid methyl ester (50 mg, 0.077 mmol) was dissolved in 5 mL of THF-MeOH (4-1), cooled to 0° C. and 1.1 equiv of 2 N LiOH added. After 30 minutes, 3.2 additional equiv of 2N LiOH was added and the reaction stirred for 30 minutes. The reaction was worked up according to Procedure C to give 29 mg of the title compound.