Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-:27].[K+]>C(O)(C)(C)C>[CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([NH2:24])=[O:27])=[N:21][CH:22]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: [OH-]
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C#N)nc2)CCN(C)C1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 12.8 %

Procedure:
To a solution of 5-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-pyridine-2-carbonitrile (1.5 g, 4.3 mmol) in tert-butanol (30 mL) was added crushed KOH (728 mg, 13 mmol) and the reaction mixture was stirred at 80° C. for 1 h. The progress of reaction was monitored by LCMS. The reaction mixture was concentrated. The residue was diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (2×100 mL), dried over anhydrous sodium sulfate and concentrated. The crude material was purified by reverse phase HPLC to yield 5-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-pyridine-2-carboxylic acid amide (200 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.45 (d, 1H), 8.12 (t, 1H), 7.78 (s, 2H), 7.05 (m, 2H), 6.94 (t, 1H), 5.57 (bs, 1H), 5.03 (m, 1H), 4.13 (s, 2H), 3.63 (m, 2H), 2.79 (m, 2H), 2.78 (bs 1H), 2.66 (d, 1H), 2.53 (d, 3H), 2.42 (s, 3H). Separation by chiral HPLC provided enantiomers 144a and 144b.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.[C:27]([Si:31]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39]Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>>[Si:31]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]2=[N:3][C:2]=3[NH2:1])=[C:15]([CH3:21])[CH:16]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Reactant: CC(C)(C)[Si](C)(C)OCCOCCCl
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCOCCO[Si](C)(C)C(C)(C)C)cc3C)cc12

Procedure:
2-(4-(2-(2-(Tert-butyldimethylsilyloxy)ethoxy)ethoxy)-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared following an analogous procedure to the preparation described for Example 145/Step 1, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) with tert-butyl(2-(2-chloroethoxy)ethoxy)dimethylsilane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:7](=[O:20])[N:6]=[CH:5]2.[CH:21]1([NH:24][C:25](=[O:42])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)[CH2:23][CH2:22]1>>[CH:21]1([NH:24][C:25](=[O:42])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:7](=[O:20])[N:6]=[CH:5]4)[CH:27]=2)[CH2:22][CH2:23]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=c1ncc2cc(Br)ccc2n1CCN1CCOCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnc(=O)n2CCN2CCOCC2)c1

Procedure:
The title compound was prepared as pale yellow solid, using 6-Bromo-1-(2-morpholinoethyl)quinazolin-2(1H)-one and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, by a method analogous to that described in Example 3 above. MS m/e 433 (M+H)+.
Reaction SMILES: C([O:5][C:6]([CH:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([C:31]3[O:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[CH:35]=3)=[O:30])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:9]([CH3:11])[CH3:10])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:6]([CH:8]([NH:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([C:31]3[O:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[CH:35]=3)=[O:30])=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)(=[O:14])=[O:15])[CH:9]([CH3:11])[CH3:10])([OH:7])=[O:5]
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)c3cc4ccccc4o3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)c3cc4ccccc4o3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 76 %

Procedure:
Benzofuran-2-carboxylic acid 4′-(1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl)-biphenyl-4-yl ester (325 mg) was dissolved in dichloromethane (15 mL) and added with TFA. The solution was stirred at room temperature for 7 hrs. Solvent was removed by rotovap and crude product purified by column chromatography (5-20% MeOH/ EtOAc) to yield Benzofuran-2-carboxylic acid 4′-(1-carboxy-2-methyl-propylsulfamoyl)-biphenyl-4-yl ester in 76% yield (241 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.S([O-])(O)=O.[Na+].[NH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[NH2:27])[N:23]=[CH:22][NH:21][C:20]2=[O:28]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]2[NH:16][C:17]3=[CH:18][C:19]4[C:20](=[O:28])[NH:21][CH:22]=[N:23][C:24]=4[CH:25]=[C:26]3[N:27]=2)=[CH:5][CH:4]=1
Reactant: Nc1cc2nc[nH]c(=O)c2cc1N
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc3cc4nc[nH]c(=O)c4cc3[nH]2)cc1
Yield: 82 %

Procedure:
In a manner analogous to that described in Example 20, from 4-methoxy-benzaldehyde, sodium hydrogen sulphite and 6,7-diamino-3,4-dihydroquinazolin-4-one (see Example 2), after boiling with methanol, there was obtained the title compound in a yield of 82% of theory; m.p. >300° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4](SC2C=CC=CC=2)[N:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][NH2:36]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([NH:36][CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCCO2
Reactant: NCc1ccccn1
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(NCc2ccccn2)c(C#N)c1-c1ccc2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
100 mg (0.26 mmol) of 2-amino-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(phenyl-sulfanyl)-3,5-pyridinedicarbonitrile and 56 mg (0.52 mmol) of 2-picolylamine in 8 ml of DMF are heated at 100° C. After 3 hours, another 224 mg (2.08 mmol) of 2-picolylamine are added, and the mixture is heated at 100° C. for another 4 hours. After dilution with water, the mixture is extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The evaporation residue is purified by preparative HPLC on reversed-phase silica gel.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C@@H:4]2[C:3]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C(O)C>CCOCC.O1CCCC1.CCOCC>[CH3:1][N:2]1[CH2:6][CH:5]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]2=[CH:3]1
Reactant: CN1C[C@@H]2c3ccccc3Cc3ccccc3[C@@H]2C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CN1C=C2c3ccccc3Cc3ccccc3C2C1
Reaction time: 0.25 h
Yield: 38 %

Procedure:
0.7 g cis-2-methyl-3,3a,8,12b-tetrahydro-dibenzo[1,2;5,6]cyclohepta[3,4-c]pyrrol-1(2H)-one is dissolved in 25 ml dry ether/tetrahydrofuran (1:1). This solution is slowly added at 0° C. to a suspension of 0.35 g LiAlH4 in 20 ml ether/t.h.f. (1:1). After stirring for 15 minutes, water is added and the mixture is then filtered. The filtrate is subsequently evaporated to dryness under vacuum. This gives an oily residue, weighing about 0.7 g. Addition of 8 ml ethanol to this residue results in the formation of a precipitate, which is filtered off. [The crystalline product thus obtained is recrystallized, giving 0.25 g 2-methyl-2,3,3a,8-tetrahydro-dibenzo[1,2;5,6]cyclohepta[3,4-c]pyrrole of melting point 128°-131° C. (=enamine according to formula III)].
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)C>[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[O:23])=[CH:15][CH:14]=1
Reactant: OCCCCCOc1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCCCOc1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
To a suspension of 33 g (0.15 mmol) of pyridinium chlorochromate in 450 ml of methylene chloride is added 21.4 g (0.1 mmol) of 5-(4-chlorophenoxy)-1-pentanol. The mixture is maintained with stirring for 3 hours, diluted with 900 ml of ethyl ether and stirred for an additional 1 hour.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[OH:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.[ClH:17]>CO>[ClH:17].[OH:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:2][CH2:1][OH:3])[CH2:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: C1CO1
Reactant: Oc1cccc(C2CCCNC2)c1
Agent: Cl
Solvent: CO
Product: OCCN1CCCC(c2cccc(O)c2)C1
Temperature: -30 °C
Yield: 41 %

Procedure:
Ethylenoxide (0.36 ml, 7.0 mmol) was added to a stirred solution of 3-(3-hydroxyphenyl)piperidine (1.0 g, 5.6 mmol) in methanol (150 ml), maintaining the temperature at -30° C., whereafter the reaction mixture was allowed to reach room temperature. (The reaction was followed by TLC). More ethylenoxide (0.5 ml, 9.8 mmol) was added in portions until the reaction was complete (two weeks). An excess of ethereal hydrogen chloride was added and the solvent was evaporated. The oily residue was passed through a silica column with 10% methanol in chloroform. After evaporation the hydrochloride was recrystallized from ethanol/ether to yield 0.6 g (41%) of 2-[3-(3-hydroxyphenyl)-piperidino]ethanol hydrochloride, m.p. 116.5°-120° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([Br:13])[N:7]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:13][C:8]1[N:7]=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][C:9]=1[F:12]
Reactant: CC(=O)OCc1ccc(F)c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCc1ccc(F)c(Br)n1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 107.9 %

Procedure:
To a solution of (6-bromo-5-fluoropyridin-2-yl)methyl acetate (240 mg) in methanol (2.50 mL) was added an aqueous solution of 1M potasium carbonate (1.64 mL) and the mixture was stirred at room temperature for 20.5 hr. After the solvent was distilled off under reduced pressure, water was added, followed by exraction with chloroform. The organic phase was separated out and the solvent was distilled off under reduced pressure to afford (6-bromo-5-fluoropyridin-2-yl)methanol (215 mg) as the residue.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>ClCCl>[ClH:32].[CH3:31][S:28]([NH:27][CH2:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:29])=[O:30]
Reactant: CCOC(=O)C1(Cc2cccc(CNS(C)(=O)=O)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1(Cc2cccc(CNS(C)(=O)=O)c2)CCNCC1
Reaction time: 2.5 h

Procedure:
A solution of ethyl N-tert-butoxycarbonyl-4-[3-(methane-sulfonylaminomethyl)benzyl]piperidine-4-carboxylate (270 mg) in dichloromethane (40 mL) at 0° C. was saturated with hydrogen chloride gas. The resultant solution was sealed with a rubber septum and stirred at room temp. for 2.5 h. The product solution was concentrated under vacuum to provide the title compound
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+:35].O>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH2:27][CH2:28][C:29]([O-:31])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[Na+:35]
Reactant: CCOC(=O)CCn1ccc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3ccn4CCC(=O)[O-])no2)cc1C#N
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-[4-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]propanoate (D63) (81 mg, 0.18 mmol) was dissolved in ethanol by warming to 50° C. Added 2N sodium hydroxide (0.25 ml, 0.5 mmol) followed by water (2 ml), warmed to 50° C. to give a clear solution then left standing at RT for 30 minutes. LC/MS showed a single product. The ethanol was evaporated off to obtain a precipitate which was filtered off and dried. Mass of title compound as a pale brown solid obtained was 60 mg δH (400 MHz, d6-DMSO) 1.39 (6H, d), 2.32 (2H, t), 4.39 (2H, t), 4.96-5.00 (1H, m), 7.01 (1H, d), 7.31 (1H, t), 7.56-7.61 (2H, m), 7.74 (1H, d), 7.91 (1H, d), 8.45 (1H, dd), 8.55 (1H, d). MS (ES) C23H20N4O4 requires 416; found 417 (MH+).
Reaction SMILES: Br.C(OC(=O)[NH:11][C:12]([C:28]1[NH:29][CH:30]=[C:31]([CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][CH3:36])[N:32]=1)([CH3:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:37][C:34]([CH3:38])([CH2:35][CH3:36])[CH2:33][C:31]1[N:32]=[C:28]([C:12]([NH2:11])([CH3:27])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[NH:29][CH:30]=1
Reactant: CCC(C)(C)Cc1c[nH]c(C(C)(Cc2ccc(-c3ccc(F)cn3)cc2)NC(=O)OCc2ccccc2)n1
Agent: Br
Solvent: ClCCl
Product: CCC(C)(C)Cc1c[nH]c(C(C)(N)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrogen bromide (37 wt % in acetic acid) (1 mL) was added to a solution of benzyl{1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]-2-[4-(5-fluoropyridin-2-yl)phenyl]-1-methylethyl}carbamate (Example 58) (10 mg, 0.02 mmol) in methylene chloride (0.5 mL). After stirring at ambient temperature for 1 h, volatiles were removed in vacuo, azeotroping with toluene. The residue was diluted with 1 N aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound. (M+H) found: 381.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH:7]([O:16][C:17]1[C:22]([Br:23])=[CH:21][C:20]([C:24]2[C:33]3[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[S:36][C:32]=3[C:31]([Br:41])=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[CH:29]3)=[CH:19][C:18]=1[Br:42])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)(C)(C)C.O>FC(F)(F)C(O)=O>[Br:23][C:22]1[CH:21]=[C:20]([C:24]2[C:33]3[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[S:36][C:32]=3[C:31]([Br:41])=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[CH:29]3)[CH:19]=[C:18]([Br:42])[C:17]=1[O:16][CH:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]([OH:43])=[O:5]
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(F)cc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)C(Cc1ccc(F)cc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 55 °C

Procedure:
A suspension of 2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11 -yl)-phenoxy]-3-(4-fluoro-phenyl)-propionic acid tert-butyl ester (0.232 g 0.295 mmol) in trifluoroacetic acid (5 mL) was heated at 55° C. for 11 hours. After cooling to room temperature the reaction mixture was poured into water (60 mL) and extracted with ether. The combined ether extracts were washed with water and brine, concentrated, and dried in vacuo at 60° C. to provide the title compound as an off white solid (0.187 g, 98%): NMR (CDCl3); δ8.36 (d, J=7 Hz, 1 H), 7.82 (d, J=7 Hz, 1 H), 7.68 (ddd, J=8, 6, 2 Hz, 1 H), 7.58 (dd, J=8, 2 Hz, 2 H), 7.55-7.48 (m, 2 H), 7.45-7.35 (m, 3 H), 7.15 (dt, J=7, 1, 1H), 7.03 (tt J=10, 3, 1, 2H), 6.71 (d, J=8 Hz, 1 H), 5.44 (t, J=6 Hz, 1 H), 3.56 (d, J=7 Hz, 2 H); MS (+FAB): [M+], 3 bromine isotope pattern, 726 (15%), 728 ( 30%) 730 (35%) 732 (15%); Anal. Calc. for C31H18Br3FO3S: C, 51.06, H, 2.49, N, 0.00. Found: C, 50.80, H, 2.46, N, 0.10.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]>O>[OH2:3].[OH2:3].[OH2:3].[C:6]([CH:4]([CH:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[C:6]([CH:4]([CH:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
3.91 g (9.5 mmol) of the above product was added to a solution of L(+)-tartaric acid (3.54 g, 23.6 mmol) in water (60 ml) and the solids were dissolved by heating to reflux. The hot solution was treated with decolorizing carbon, filtered and allowed to cool. The separated crystals were collected, washed with water and acetonitrile and dried to give the ditartrate-trihydrate of the title compound, mp. 185°-190° C., yield of the salt formation: 66.9%.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:19])[F:20])=[CH:10][CH:9]=2)[S:28]([CH3:27])(=[O:30])=[O:29])[CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)COc1ccc(NCc2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 4.2 g. portion of 3-[4-(2,2,2-trifluoroethoxy)phenylaminomethyl]pyridine was dissolved in 15 ml. of dichloromethane, and to it were added 2.7 g. of potassium carbonate and 1.6 ml. of methanesulfonyl chloride. The mixture was stirred at ambient temperature for 3 days, and it was then diluted with dichloromethane, extracted with 25 ml. of water, dried over magnesium sulfate and evaporated to an oil. The residue was taken up in diethyl ether, and the insoluble portion was separated. The product slowly crystallized upon standing, and the solids were triturated with petroleum ether and washed with diethyl ether and petroleum ether to obtain 3.7 g. of the desired product, m.p. 69°-70°.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]#[N:22])=[N:6][N:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[CH:8]=1)(=O)[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].O1CCC[CH2:31]1>C1(C)C=CC=CC=1.CCOCC>[C:21]([C:5]1[C:4]([C:1]([CH3:31])=[CH2:2])=[CH:8][N:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:6]=1)#[N:22]
Reactant: C1CCOC1
Reactant: CC(=O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=C(C)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-acetyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.75 g) in tetrahydrofuran (5 ml) cooled to −40° C. under an atmosphere of nitrogen was added μ-chloro-μ-methylene-[bis(cyclopentadienyl)titanium]dimethylaluminium (5.18 ml of a 0.5M solution in toluene) and the mixture was stirred for 15 minutes then allowed to warm to room temperature. After 2 hours at room temperature 0.1M aqueous sodium sulphate solution was added dropwise until effervescence ceased. The reaction mixture was diluted with ether (50 ml), washed with aqueous sodium sulphate solution, dried and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane: hexane (1:1). Combination and evaporation of suitable fractions provided the title compound as a tan solid m.p. 63-64° C.
Reaction SMILES: C([O:4][C:5](=[O:44])[CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C@H:14]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C@H:13]1[CH2:31][O:32][C:33](=[S:43])[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)C=C.[OH-].[Li+].Cl>C1COCC1.O>[Cl:42][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:33]([O:32][CH2:31][C@@H:13]1[C@@H:14]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:15][C@@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C@H:12]1[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][C:5]([OH:44])=[O:4])=[S:43]
Reactant: C=CCOC(=O)CCC/C=C\C[C@H]1[C@H](COC(=S)NCc2cccc(Cl)c2)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC/C=C\C[C@H]1[C@H](COC(=S)NCc2cccc(Cl)c2)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1
Yield: 72.6 %

Procedure:
A solution of ester 6 (614 mg, 0.97 mmol) and lithium hydroxide (62 mg, 1.5 mmol) in THF/H2O (1:1, 20 mL) was stirred at 23° C. for 72 h. The mixture was acidified with 1N HCl and extracted with EtOAc. The organic portion was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give 430 mg of the above titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[C:6]([C@H:9]2[CH2:11][O:10]2)[C:7]=1[F:8].[CH3:19][C:20]([NH2:31])([CH3:30])[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[CH3:30][C:20]([NH:31][CH2:11][C@H:9]([C:6]1[CH:5]=[C:4]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=[C:2]([F:1])[C:7]=1[F:8])[OH:10])([CH3:19])[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(N)CCCc1ccccc1
Reactant: CCOC(=O)CCc1cc(F)c(F)c([C@H]2CO2)c1
Solvent: CCO
Product: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)CNC(C)(C)CCCc2ccccc2)c1
Yield: 77.6 %

Procedure:
A solution of ethyl 3-{3,4-difluoro-5-[(2S)-2-oxiranyl]phenyl}propanoate (11.07 g, 43.2 mmol) and (1,1-dimethyl-4-phenylbutyl)amine (7.68 g, 43.4 mmol) in ethanol (50 mL) was heated at 70° C. for 36 h. The reaction was concentrated and purified by column chromatography (0-90% ethyl acetate:hexane) afforded the desired product (14.54 g, 78%). MS (m/z): 434.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:13]C)=[C:10]([Br:12])[CH:11]=1)[CH3:2].IC>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([OH:13])=[C:10]([Br:12])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cnc(OC)c(Br)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CI
Product: CCOC(=O)Cc1cnc(O)c(Br)c1
Temperature: 55 °C
Reaction time: 2.5 h

Procedure:
(5-Bromo-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester (5.02 mmol) was dissolved in CHCl3 (17 mL). Silver carbonate (1.58 g, 5.7 mmol) and iodomethane (0.82 mL, 13.14 mmol) were added, and the reaction was stirred at 55° C. for 2.5 hours. The mixture was filtered through Celite, and the filtrate was concentrated and purified by silica gel chromatography (0-60% EtOAc in hexanes) to give (5-bromo-6-hydroxy-pyridin-3-yl)-acetic acid ethyl ester.