Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17](F)[F:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1C=CC=CC=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[F:18]/[CH:17]=[CH:16]/[C:13]1[CH:14]=[CH:15][C:10]([C@H:7]2[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1
Reactant: CCC[C@H]1CC[C@H](c2ccc(C=C(F)F)cc2)CC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](c2ccc(/C=C/F)cc2)CC1
Temperature: 0 °C

Procedure:
To trans-4-propyl-[4-(2,2-difluoro-1-ethenyl)phenyl]cyclohexane (23.4 g, 0.089 mol) were gradually added benzene (50 ml) and a 70 wt. % toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride (50 ml) at a reaction temperature of -5° C. or lower with stirring, followed by gradually raising the reaction temperature up to 0° C. over 20 minutes, pouring the reaction solution in ice water (500 ml), extracting the resulting product with toluene (300 ml), twice washing with 6N-HCl (300 ml), further washing with water till the aqueous layer became neutral, drying the toluene solution over anhydrous magnesium sulfate, filtering off the drying agent, distilling off toluene, dissolving the residue in heptane, purifying according to silica gel chromatography, vacuum-distilling (130° C., 1.2 mmHg), five times recrystallizing from a mixed solvent of heptane and ethanol (1:1) and drying to obtain the objective substance (2.66 g, 0.011 mol). This compound exhibited a CN point of 24° C. and an NI point of 70° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[Cl:20][C:21]1[N:22]=[C:23](N)[NH:24][C:25]=1[Cl:26]>>[Cl:26][C:25]1[N:24]=[CH:23][N:22]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]5[O:15][CH2:16][CH2:17][O:18][C:11]=5[CH:10]=4)[C:5]([F:19])=[CH:4][N:3]=3)=[CH:10][CH:11]=2)[C:21]=1[Cl:20]
Reactant: Nc1nc(Cl)c(Cl)[nH]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(Nc2ccc(-n3cnc(Cl)c3Cl)cc2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 4,5-dichloro-1H-imidazoleamine gave N2-[4-(4,5-dichloro-1H-imidazol-1-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.10 (s, 1H), 9.85 (s, 1H), 8.20 (d, 1H, J=4.2 Hz), 8.01 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.36 (d, 1H, J=9 Hz), 7.25 (d, 1H, J=3 Hz), 7.14 (dd, 1H, J=2.1 and 9 Hz), 6.85 (d, 1H, J=8.7 Hz); LCMS: ret. time: 23.59 min.; purity: 95%; MS (m/e): 474 (MH+).
Reaction SMILES: Cl[CH:2](Cl)[C:3]([OH:5])=[O:4].[H-].[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][C:13](C(C)(C)C)([OH:24])[CH:14]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:17])[CH:15]=1.O>O1CCOCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[O:24][CH:2]([C:3]([OH:5])=[O:4])[O:17][C:16]([C:14]([CH3:16])([CH3:15])[CH3:13])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]=2[CH:15]=1
Reactant: CC(C)(C)C1(O)C=CC(Cl)=CC1C(O)c1ccccc1
Reactant: O=C(O)C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C1(c2ccccc2)OC(C(=O)O)Oc2ccc(Cl)cc21
Temperature: 80 °C

Procedure:
A solution of 5.82 ml of dichloroacetic acid in 100 ml of dioxane was added dropwise with stirring to a mixture of 12.8 g of sodium hydride in a 50% oil suspension, 100 ml of anhydrous dioxane and 600 mg of dibenzo-18-couronne-6 kept at room temperature and a solution of 14.1 g of 5-chloro-2-tert.-butyl-2-hydroxy-α-phenyl-benzene-methanol in 100 ml of dioxane was added dropwise at room temperature. The mixture was heated at 80° C. for 6 hours and was then cooled to room temperature which was kept on an ice bath. 400 ml of water were added and the aqueous phase was extracted with 600 ml of ether. The ether extract was extracted 3 times with 100 ml of 0.1 N sodium hydroxide solution and the aqueous phase was acidified with 2 N hydrochloric acid and was extracted 3 times with 150 ml of ether. The organic extracts were washed 3 times with 100 ml of water and were extracted with a saturated sodium bicarbonate solution and then 3 times with 100 ml of water. The combined aqueous phases were washed 3 times with ether and was acidified with 2 N hydrochloric acid. The aqueous phase was extracted 4 times with 150 ml of ether and the ether phases were washed 3 times with water, dried over magnesium sulfate, treated with activated carbon and evaporated to dryness to obtain 9.1 g of raw 6-chloro-4-tert.-butyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two racemates diastereoisomers).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1>C(O)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[CH:6][C:7]2[NH:10][C:11]3[C:12]([C:8]=2[CH:9]=1)=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:17]
Reactant: COC(=O)c1ccc(Nc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2[nH]c3ccccc3c2c1
Yield: 123.9 %

Procedure:
A mixture of dicylcohexylphosphino-2′,3′-dimethoxy biphenyl (17 mg, 0.04 mmol), palladium(II) acetate (5 mg, 0.02 mmol) in toluene (20 mL) was degassed with argon gas for 15 min. To the resulting mixture was added aniline (136 mg, 1.4 mmol), K3PO4 (636 mg, 3.0 mmol), and 4-bromobenzoic acid methyl ester (300 mg, 1.4 mmol) and stirring was continued at reflux temperature overnight. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 15% ethyl acetate in hexane as eluent) to afford 200 mg (63.4% Yield) of 4-phenylamino-benzoic acid methyl ester. A stirred solution of 4-phenylamino-benzoic acid methyl ester (98 mg, 0.43 mmol), Palladium acetate (193 mg, 0.86 mmol) in acetic acid (2 mL) was heated at 110° C. for 15 hr. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate and washed with sodium bicarbonate solution. The organic layer collected was dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 10% ethyl acetate in hexane as eluent) to afford 120 mg (60.3% Yield) of 9H-carbazole-3-carboxylic acid methyl ester. LiOH.H2O (680 mg, 16.2 mmol) was added to a stirred solution of 9H-carbazole-3-carboxylic acid methyl ester (120 mg, 0.53 mmol) in the mixture of methanol (1 mL), THF (3 mL) and H2O (1 mL). The reaction mixture was stirred at 60° C. for 3 hrs. The reaction mixture was concentrated. The residue was diluted with water, acidified with aqueous 10% aqueous HCl solution, filtered the solid to afford 104 mg (92.85% Yields) of 9H-carbazole-3-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: C1COCCN1
Reactant: Clc1cncc(Cl)n1
Solvent: CC#N
Product: Clc1cncc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
To a solution of 2,6-dichloropyrazine (1.0 equiv.) in acetonitrile (0.3 M) was added morpholine (3.5 equiv.) and the reaction was stirred at room temperature for 20 h. The resulting precipitate was filtered off and the filtrate was concentrated under vacuo. The crude material was partitioned between water and ethyl acetate, the organic phase was dried with sodium sulfate, filtered and concentrated to afford 4-(6-chloropyrazin-2-yl)morpholine in 75% yield. LCMS m/z (M+H)=200.0, Rt=0.61 min.
Reaction SMILES: [S-][C:2]#[N:3].[K+].F.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>>[C:14]1([C:2]#[N:3])[C:15]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc2ccccc2c1
Reactant: N#C[S-]
Agent: F
Agent: [K+]
Product: N#Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
At a temperature and in the manner as described in Example 1, 39 g of potassium thiocyanate (0.4 mol) are introduced into 0.3 l of 98% hydrofluoric acid, 42 g of naphthalene (0.33 mol) are added and the mixture is agitated for 2 days at room temperature. After work-up, 54 g of crude α-thionaphthoic acid amide (0.32 mol) having a melting point of 119° C are obtained. A sample recrystallized from xylene has a melting point of 122° - 125° C. By alkaline splitting of the product, pure α-naphthonitrile may be obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]O)[CH:28]=2)=[C:22]([CH3:35])[CH:21]=1)[CH3:15].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:1][C:2]3[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=3)[CH:28]=2)=[C:22]([CH3:35])[CH:21]=1)[CH3:15]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(/C=C/C(=O)OC)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.8 %

Procedure:
A solution of methyl (2E)-3-(4-hydroxyphenyl)acrylate (0.713 g, 4.00 mmol), [4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methanol (1.20 g, 4.00 mmol) and tributylphosphine (1.29 g, 6.40 mmol) in toluene (65 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (1.61 g, 6.40 mmol) was added in small portions, and the mixture was stirred at room temperature for 24 hr. Hexane (35 mL) was added to the reaction mixture. The precipitated insoluble material was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-25:75), and recrystallized from ethyl acetate-hexane to give the title compound (1.58 g, yield 86%) as colorless crystals.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC>[CH2:20]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCBr
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOc1ccccc1C=O
Temperature: 100 °C

Procedure:
A mixture of salicylaldehyde (10.15 mmoles), undecylbromide (10.3 mmoles) and potassium carbonate (11.7 mmoles) in dimethylformamide (10 ml) is heated to 100° C. for 1 hour and then is cooled. The reaction mixture is taken up in hexane and is washed with 5 percent sodium hydroxide and brine. After treatment with anhydrous magnesium sulfate and charcoal, the volatiles are removed under vacuum and the residue is purified by flash chromatography to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([C@@H:12]([NH2:14])[CH3:13])=[N:7]2.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([C@@H:12]([NH:14][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)[CH3:13])=[N:7]2
Reactant: C[C@H](N)c1nc2cccc(Cl)c2cc1-c1cccc(F)c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(Cl)c2cc1-c1cccc(F)c1

Procedure:
Prepared according to Procedure H using (1S)-1-(5-chloro-3-(3-fluorophenyl)-quinolin-2-yl)ethanamine (0.050 g, 0.166 mmol), 6-chloropurine (0.031 g, 0.20 mmol, 1.2 eq) and DIEA (0.33 mmol, 2.0 eq) in n-butanol (3 mL). N—((S)-1-(5-chloro-3-(3-fluorophenyl)quinolin-2-yl)ethyl)-9H-purin-6-amine [PI3Kδ C50=5 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 9.22 (s, 1 H), 8.63 (s, 1 H), 8.44-8.47 (m, 3 H), 8.42 (s, 1 H), 8.34 (s, 1 H), 7.87-7.94 (m, 2 H), 7.56 (t, 1 H), 1.79 (d, 3H), Mass Spectrum (ESI) m/e=419 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:30]=[CH:29][C:14]2[O:15][C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[C@@H:18]3[C@H:23]([NH2:24])[CH2:22][CH2:21][CH2:20][N:19]3[C:13]=2[CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:55]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56][C:57](O)=[O:58]>C(Cl)Cl>[CH3:66][C:63]([O:62][C:60](=[O:61])[NH:55][CH2:56][C:57]([NH:24][C@H:23]1[C@@H:18]2[N:19]([C:13]3[CH:12]=[C:11]([Cl:10])[CH:30]=[CH:29][C:14]=3[O:15][C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=32)[CH2:20][CH2:21][CH2:22]1)=[O:58])([CH3:64])[CH3:65]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reaction time: 3 h
Yield: 104.1 %

Procedure:
DIPEA was added (pH=9) to trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) in 1 mL of CH2Cl2 with HATU (12.5 mg, 0.03 mmol) and Boc-Gly-OH (10.3 mg, 0.03 mmol). The resulting mixture was stirred for 3 h, washed with 5% aqueous sodium bicarbonate and H2O, dried (Na2SO4) and evaporated to give [[[(trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)amino]carbonyl]methyl]carbamic Acid 1,1-dimethylethyl Ester (14.3 mg, 100%). Data: (m/z)=405 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C[O:14][B:15](OC)[O:16]C.[C:20]12([OH:31])[CH2:28][CH:24]([C:25]1([CH3:27])[CH3:26])[CH2:23][CH2:22][C:21]2([OH:30])[CH3:29]>>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([B:15]([OH:16])[OH:14])[CH:7]=[CH:6][CH:5]=1.[C:20]12([OH:31])[CH2:28][CH:24]([C:25]1([CH3:27])[CH3:26])[CH2:23][CH2:22][C:21]2([OH:30])[CH3:29]
Reactant: COB(OC)OC
Reactant: Brc1cccc(C2OCCO2)c1
Agent: CC1(O)CCC2CC1(O)C2(C)C
Product: OB(O)c1cccc(C2OCCO2)c1

Procedure:
Synthesis of compounds 16 and 21 are as previously described above. As detailed below, with reference to Scheme 3 and examples 20 and 21, below, the synthesis of compound 26 is described. (+)-pinanediol (1R)-1-acylamino-1-(3-formylphenyl)methylboronates 25, 26 were obtained starting from commercial 2-(3-bromo-phenyl)-[1,3]dioxolane (22a), following the same procedure. Metallation of 22a with buthyllithium at −78° C., followed by reaction with trimethylborate and transesterification with (+)-pinanediol, afforded the desired (+)-pinanediol (3-[1,3]dioxolan-2-yl-phenyl)boronate (+)-23a together with variable amount of (+)-pinanediol (3-dimethoxymethyl)phenylboronate (+)-23b, this latter probably formed by transacetalization with the in situ formed methanol. To avoid this problem, 22a was converted to 22b (88%) and subsequently boronated to (+)-23b (75%).
Reaction SMILES: [CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2].[F:46][C:47]([F:71])([C:67]([F:70])([F:69])[F:68])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH:53]([CH2:59][CH2:60]CCCCC=C)[C:54]([O:56]CC)=[O:55]>>[CH2:1]([C:3]1([C:39]2[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:60][CH2:59][CH:53]([CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][C:47]([F:46])([F:71])[C:67]([F:70])([F:69])[F:68])[C:54]([OH:56])=[O:55])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-9-decenoate prepared in Example 7, the same procedure as shown in Example 13 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)undecanoic acid.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[C:1]1([CH:7]([C:11]2[CH:12]=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:8]([N:14]([CH3:13])[C@H:15]2[CH2:34][N:19]3[C:20]4[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]3[CH2:17][CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: CCC(C(=O)Cl)c1ccccc1
Product: CN(C(=O)C(c1ccccc1)c1ccccc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from 2-phenylbutanoyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 405.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1)#[N:2].[C:11]([O-])(=[O:13])[CH3:12].[Na+].C(OC(=O)C)(=O)C>[Ni]>[C:11]([NH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1)(=[O:13])[CH3:12]
Reactant: COc1cccc(C#N)n1
Reactant: CC(=O)[O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1cccc(CNC(C)=O)n1
Reaction time: 5.5 h

Procedure:
A mixture of 1.0 g (7.46 mmole) of 2-cyano-6-methoxypyridine, 0.37 g (4.48 mmole) of sodium acetate, 25 ml of acetic anhydride and about 1.0 g of Raney nickel was hydrogenated on a Parr apparatus for about 5.5 hours. The mixture was filtered, and then evaporated with warming in vacuo to provide 2-acetamidomethyl-6-methoxypyridine. The structural assignment was supported by infrared spectral analysis.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][O:7][C:6]=2[N:13]=1.[C:20]([O:24][C:25](=[O:45])[NH:26][C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O>[C:20]([O:24][C:25](=[O:45])[NH:26][C:27]1([C:30]2[CH:31]=[CH:32][C:33]([C:2]3[C:3]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:4][C:5]4[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][O:7][C:6]=4[N:13]=3)=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CC4)cc3)c(-c3ccccc3)cc21
Temperature: 80 °C
Yield: 101.8 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (40 mg, 0.125 mmol) and tert-butyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate (54 mg, 0.150 mmol) in 1,4-dioxane (1 ml), followed by a solution of sodium carbonate (40 mg, 0.3 mmol) in water (0.25 ml) to give a white suspension. This was degassed by bubbling nitrogen for 10 minutes, followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (9 mg, 0.013 mmol). The reaction mixture was heated to 80° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with brine (4 ml) and extracted into ethyl acetate (3×4 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as a white solid (60 mg, quantitative yield). 1H-NMR (500 MHz, CDCl3) δ 7.14-7.26 (6H, m), 7.08-7.14 (2H, m), 6.93 (2H, d), 4.99-5.27 (1H, br m), 4.80 (2H, s), 3.31 (3H, s), 1.35 (9H, br s), 1.25 (2H, br s), 1.03 (2H, br s). LCMS (Method D): RT=1.44 min, M+H+=472.20.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[C@@H]2C3[CH:46]=[CH:47][S:48]C=3CC[C@H]2CCC)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:19]3[CH:46]=[CH:47][S:48][C:20]=3[CH2:22][CH2:21][C@H:26]2[CH2:25][CH2:24][CH3:23])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(Br)nc1CC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.50, 7.35–7.31, 7.11, 6.91, 5.21, 4.59, 2.82, 2.64, 2.48, 2.05, 1.82, 1.43–1.35, 1.25, 1.18, 0.94; HRMS (FAB) calcd for C25H29Cl2N3S+H 474.1537, found 474.1526.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[Br:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:30]2
Reactant: Brc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4ccc(Br)cc4C3)c(F)cc2c1=O
Yield: 16.5 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 119 mg of 5-bromoisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 44 mg of the target compound.