Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.[C:12]1([CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:20]2[CH2:21][CH2:22][CH2:23][CH:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19]2)=[O:8])=[CH:9][CH:10]=1
Reactant: c1ccc(C2CCCNC2)cc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Br)cc1)N1CCCC(c2ccccc2)C1

Procedure:
The above compound could be made in the following manner, analogous to Example 60. 1 eq. of p-Bromobenzoic acid could be combined with 1 eq. 3-Phenylpiperidine HCl, 1.1 equivalents EDC, 1.1 equivalents HOBt and 2.2 equivalents Hunig's Base in DMF (concentration of 1 mL of DMF/mmol acid) would be stirred at room temperature overnight. The solution would then be diluted with water and extracted with ethyl acetate. The organic layers would then be combined and washed with water, aqueous saturated sodium bicarbonate solution, 1N HCl and brine. The organic layers would be dried with sodium sulfate, filtered and concentrated. Purification would be done with flash chromatography to afford product.
Reaction SMILES: [CH3:1][N:2]([CH3:47])[CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7]>C(O)(=O)C.CO.[Pd]>[CH3:47][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:43][CH2:42][C@@H:41]([CH:44]([CH3:45])[CH3:46])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:28])([CH3:29])[C:17]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)NCCN(C)C)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Yield: 22.1 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (27 mg, 0.042 mmol) and Pd/C (14.30 mg, 0.013 mmol) in acetic acid (4 mL) and MeOH (4 mL) was reacted in Parr shaker for 18 hours under 40 psi. The reaction mixture was filtered through celite to remove Pd/C. The filtrates were concentrated under reduced pressure. The residue was dissolved in methanol and then purified by prep HPLC to provide the title compound as a white solid (6 mg, 22%). LCMS: m/e 645.62 (M+H)+, 2.87 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 7.98 (d, J=8.24 Hz, 2H), 7.27 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.88 Hz, 1H), 3.94 (s, 3H), 3.74 (t, J=5.95 Hz, 2H), 3.43-3.32 (m, 2H), 2.95 (s, 6H), 2.59-2.48 (m, 1H), 2.42-2.31 (m, 1H), 2.28-1.10 (m, 22H), 1.07 (d, J=3.97 Hz, 6H), 1.05 (s, 3H), 1.00 (s, 3H), 0.99 (s, 3H), 0.91 (d, J=6.71 Hz, 3H), 0.82 (d, J=6.71 Hz, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27]C=C)([CH3:20])[C@@H:18]([O:30]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1.[F:38][C:39]([F:61])([C:57]([F:60])([F:59])[F:58])[CH2:40][CH2:41][CH2:42][CH:43]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56])[C:44]([O:46]CC)=[O:45]>>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH:43]([CH2:42][CH2:41][CH2:40][C:39]([F:38])([F:61])[C:57]([F:58])([F:59])[F:60])[C:44]([OH:46])=[O:45])([CH3:20])[C@@H:18]([OH:30])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: C[C@]12C[C@H](CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraene prepared in Example 20 and ethyl 2-(4,4,5,5,5-pentafluoro-pentyl)-9-decenoate prepared separately, the same procedure as shown in Example 20 was repeated to give 11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][OH:20])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([CH3:3])[CH3:2].IC[C@@H]1C[C@@H]1C1CCN(C2N=CC(C(C)C)=CN=2)CC1.[CH3:41][S:42]([C:45]1[CH:52]=[CH:51][C:48]([CH2:49]O)=[CH:47][CH:46]=1)(=[O:44])=[O:43]>>[CH:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][O:20][CH2:49][C:48]3[CH:47]=[CH:46][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:52][CH:51]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cnc(N2CCC([C@H]3C[C@H]3CO)CC2)nc1
Reactant: CS(=O)(=O)c1ccc(CO)cc1
Agent: CC(C)c1cnc(N2CCC([C@H]3C[C@H]3CI)CC2)nc1
Product: CC(C)c1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(S(C)(=O)=O)cc3)CC2)nc1

Procedure:
Using the procedure outlined in intermediate 8 (step B) the product from step C was reacted with 4-(methylsulfonyl)benzyl alcohol to yield the title compound. MS (ESI) m/z 444 [M+H]+. GPR119 Human EC50: 0.26 nM
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:13])=[C:9]([CH2:11][OH:12])[CH:10]=1.N1C=CN=C1.Cl[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>ClCCl>[C:23]([Si:20]([O:12][CH2:11][C:9]1[CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=[CH:7][C:8]=1[CH3:13])([CH3:22])[CH3:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COCOc1ccc(C)c(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COCOc1ccc(C)c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
[5-(methoxymethoxy)-2-methyl-phenyl]methanol (Intermediate 173, 1.9 g, 10 mmol) was dissolved in dichloromethane (10 ml) to give a colourless solution. 1H-imidazole (1.137 g, 16.7 mmol) and chloro(1,1-dimethylethyl)dimethylsilane (2.095 g, 13.9 mmol) were added. The reaction mixture immediately became a white suspension and was stirred at room temperature for 30 minutes. The reaction mixture was quenched with 10 ml of water and diluted with 10 ml of dichloromethane. Two phases were separated through a separating funnel. The organic phase was dried over Na2SO4 and evaporated under vacuum and the residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 50:50 as eluents affording the title compound (2.9 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](COC)=[CH:16][C:17](=[O:21])[O:18]2)=[CH:13][CH:12]=1>>[O:18]1[C:19]2[C:14](=[CH:13][CH:12]=[C:11]([NH:10][C:2]3[N:7]=[C:6]([NH:10][C:11]4[CH:20]=[C:19]5[C:14]([CH:15]=[CH:16][C:17](=[O:21])[O:18]5)=[CH:13][CH:12]=4)[C:5]([F:9])=[CH:4][N:3]=3)[CH:20]=2)[CH:15]=[CH:16][C:17]1=[O:21]
Reactant: COCc1cc(=O)oc2cc(N)ccc12
Reactant: Fc1cnc(Cl)nc1Cl
Product: O=c1ccc2ccc(Nc3ncc(F)c(Nc4ccc5ccc(=O)oc5c4)n3)cc2o1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-4-methoxymethylcoumarin were reacted to yield N2,N4-bis(coumarin-7-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.38 (s, 1H), 8.42 (d, 1H, J=3 Hz), 8.28 (m, 1H), 8.05–7.93 (m, 2H), 7.77–7.50 (m, 4H), 6.31 (s, 1H), 6.29 (s, 1H), 4.66 (s, 2H), 4.65 (s, 2H), 3.43 (s, 3H), 3,41 (s, 3H); LCMS: MS (m/e): 505 (MH+).
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28]([O:37][CH2:38][CH2:39][OH:40])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[CH2:12][N:13]([CH3:22])[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[Cl:10].C(N(CC)CC)C.[C:48]([Cl:51])(=[O:50])[CH3:49].Cl>C(Cl)Cl>[OH2:21].[ClH:3].[C:48]([O:40][CH2:39][CH2:38][O:37][C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:12][N:13]([CH3:22])[C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:30][CH2:29]1)(=[O:50])[CH3:49].[C:48]([O:40][CH2:39][CH2:38][O:37][C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:12][N:13]([CH3:22])[C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:30][CH2:29]1)(=[O:50])[CH3:49].[ClH:51]
Reactant: CN(CC(CCN1CCC(OCCO)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)OCCOC1(c2ccccc2)CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
A solution of 0.6 g of the compound obtained in EXAMPLE 1 and 0.3 ml of triethylamine in 20 ml of DCM is cooled to 0-5° C., 0.08 ml of acetyl chloride is added and the mixture is left stirring while the temperature is allowed to rise to RT. The reaction mixture is concentrated under vacuum and the residue is chromatographed on silica, eluting with DCM and then with a DCM/MeOH (97:3; v/v) mixture. The product obtained is dissolved in DCM, the mixture is acidified to pH 1 by adding ethereal hydrogen chloride and the precipitate formed is drained. 0.23 g of the expected product is obtained, m.p.=95° C. ##STR45##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O.[BH4-].[Na+].[NH4+].[Cl-]>CO.CCOC(C)=O.[Pd]>[NH2:13][C:3]1[CH:4]=[C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CS(=O)(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(N)c(N)c1
Reaction time: 1 h

Procedure:
N-(4-amino-3-nitrophenyl)methanesulfonamide (1.5 g, 6.5 mmol) was dissolved in MeOH/EtOAc(1:1, 160 mL). To the above solution were slowly added 10% Pd/C (110 mg) and NaBH4 (418 mg, 11.0 mmol). The reaction mixture was stirred for 1 h, after which TLC showed absence of starting material. After addition of NH4Cl (400 mg), the reaction mixture was filtered through CELITE. The filtrate was concentrated and the product was used without further purification.
Reaction SMILES: O.[SH-].[Na+:3].C([S:11]([C:14]1[N:19]=[C:18]([N:20]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[S:21]([N:24]2[CH2:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:17]=[C:16]([NH:36][C@H:37]([CH3:40])[CH2:38][OH:39])[N:15]=1)(=O)=O)C1C=CC=CC=1>CS(C)=O>[N:24]1([S:21]([N:20]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:18]2[CH:17]=[C:16]([NH:36][C@H:37]([CH3:40])[CH2:38][OH:39])[N:15]=[C:14]([S-:11])[N:19]=2)(=[O:22])=[O:23])[CH2:27][CH2:26][CH2:25]1.[Na+:3]
Reactant: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCC2)nc(S(=O)(=O)Cc2ccccc2)n1
Agent: [Na+]
Agent: [SH-]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCC2)nc([S-])n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Sodium hydrosulfide hydrate (1.18 g) was added to a solution of the subtitle product of step iv) (8.0 g) in DMSO (67 ml) and the green solution stirred for 2 h. A further aliquot of sodium hydrosulfide hydrate (0.79 g) was added and stirred for 1 h. This aliquot addition was repeated twice more before heating the solution at 50° C. for 30 min. The resulting reaction solution was used directly in the following step. The subtitle compound was also kept as a stock solution for further reaction with alkyl halides, described in Examples 41-42.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[CH2:9][N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7]1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:19]([N:8]1[CH2:9][C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[C@@H:6]([CH:4]=[O:5])[CH2:7]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CON(C)C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of (3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carboxylic acid methoxy-methyl-amide 3.24 g (9 mmol) dissolved in THF (60 mL) was added 9 mL (9 mmol) of lithiumaluminiumhydride (1.0M in THF) dropwise at 0° C. and stirred for one hour. The reaction was quenched by aq. ammonium chloride solution and extracted with ethylacetate twice. The combined organic layers were dired on anhydrous sodium sulfate and concentrated in vaccuo. The residue was purified by silica gel column chromatography eluted by a mixture of heptane and ethyl acetate (3:2) yielding 2.7 g (99%) of the title compound as a light yellow oil. ES-MS m/e: 302.1 (M+H+).
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].CN(C)C=O.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(OCC)C.O>[F:15][C:12]([F:13])([F:14])[C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:1]=1)[O:11][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a stirred solution containing 11.5 g (0.05 mole) of 3,5-ditrifluoromethylphenol, 3.3 g (0.05 mole) of 85% potassium hydroxide, 200 ml of N,N-dimethylformamide and 10 ml of water, 0.055 mole of ethyl 4-bromobutyrate was added in one portion. The stirred reaction mixture was heated at 80°-90° C. for 24 hours. After cooling to 25° C., 500 ml of water and 500 ml of ethyl ether were added; and stirring was continued for 15 minutes. The separated ether layer was washed with water until neutral to litmus and dried over sodium sulfate. The ether was removed in vacuo at a maximum temperature of 80°-90° C. at 1-2 mm of Hg. A product with a ND25 =1.4281 was obtained with a 95% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[B:30](OC(C)C)([O:35]C(C)C)[O:31]C(C)C>CC(OC)(C)C>[CH3:14][C:12]1[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([B:30]([OH:35])[OH:31])[CH:7]=[CH:6][CH:5]=2)[CH:13]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(B(O)O)c2)c1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 2-(3-bromo-phenyl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.90) (1.23 g, 3.13 mmol) in TBME (80 mL) at −78° C. was added n-BuLi (1.6 M in hexane, 3.2 mL, 5.0 mmol) keeping the internal temperature below −60° C. (ca. 3 min), stirring was continued at −78° C. for 25 min, then triisopropyl borate (1.5 mL, 6.27 mmol) was added quickly, causing the internal temperature to rise to −60° C., stirring was continued at −78° C. for 20 min. The mixture was quenched by addition of 1M NaH2PO4.2H2O-solution, the cooling bath was removed and the mixture was allowed to warm to 0° C. and stirred at 0° C. for 10 min. Diluted with EtOAc and brine, extracted three times with EtOAc, dried the combined organic layers over Na2SO4. Removal of the solvent in vacuum left the title compound as a light brown foam (1.20 g, 70.5%, purity: 65.8%), which was used without further purification. MS (ISP) 358.2 [(M+H)+].
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](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6]2.Cl.[CH2:22]([N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)N)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C(O)C.CCCCCCC>[CH2:22]([N:29]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:13]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Reactant: NN(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCCCCCC
Product: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)n(Cc2ccccc2)c2ccccc12
Temperature: 10 °C
Yield: 80 %

Procedure:
Generally, a suspension of equimolar amounts of 1-(6-methoxynaphthalen-2-yl)heptan-1-one and N-benzyl-N-phenylhydrazine hydrochloride (BPH) in ethanol is heated under reflux for five hours. Two portions of 0.1 equivalent of BPH in ethanol are added to the suspension at one hour intervals. Alternatively, the solution of BPH in ethanol is added to reaction mixture continuously. The resulting mixture is refluxed for an hour, diluted with heptane, and treated with water at 45° C. The organic and aqueous phases are separated, and the organic phase is washed with water and cooled to 10° C. to initiate crystallization. Upon cooling to −15° C., 80%-85% of crystalline 1-benzyl-2-(6-methoxy-naphthalen-2-yl)-3-pentyl-1H-indole is obtained.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:30])=[C:20]([CH:29]=1)[O:21][CH2:22][C:23]1[N:24]=[N:25][N:26]([CH3:28])[CH:27]=1>>[F:1][C:2]1[C:3]2[N:4]([C:12]([C:16]3[CH:17]=[CH:18][C:19]([F:30])=[C:20]([O:21][CH2:22][C:23]4[N:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:29]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9]
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: Cn1cc(COc2cc(Br)ccc2F)nn1
Product: Cn1cc(COc2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)nn1

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 4-(5-bromo-2-fluorophenoxymethyl)-1-methyl-1H-[1,2,3]triazole as described in Example 6 to give 2-{8-fluoro-3-[4-fluoro-3-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid: δH (400 MHz, d6-DMSO) 1.58 (6H, s), 4.07 (3H, s), 5.35 (2H, s), 5.55 (1H, s), 7.16-7.23 (2H, m), 7.37 (1H, dd, J 11 and 9), 7.65 (1H, dd, J 8 and 2), 7.76 (1H, s), 8.21 (1H, s), 8.43 (1H, d, J 7); m/z (ES+) 400 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[CH3:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: Cc1ccccc1CN
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1CNc1ccc2c(=O)[nH]nc(Cl)c2c1

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-methyl-benzylamine (0.080 mL, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (108 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-methyl-benzylamino)-2H-phthalazin-1-one: 36 mg (20.7%): m/z (M+H)=300. 1H-NMR (DMSO-d6) δ: 12.34 (s, 1H), 7.93 (d, 1H), 7.50 (m, 1H), 7.26 (m, 1H), 7.16 (m, 4H) 6.84 (s, 1H), 4.37 (d, 2H), 2.48 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[OH:5][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@:12]3([OH:27])[CH2:13][CH2:14][C@@H:15]2[CH:25]=O)[CH2:7]1.C([O-])(O)=O.[Na+]>O.O1CCOCC1>[CH3:1][N:2]([CH3:4])/[N:3]=[CH:25]/[C@H:15]1[CH2:14][CH2:13][C@:12]2([OH:27])[C@H:11]3[C@H:20]([CH2:19][CH2:18][C@:16]12[CH3:17])[C@:21]1([CH3:24])[C@@H:8]([CH2:7][C@@H:6]([OH:5])[CH2:23][CH2:22]1)[CH2:9][CH2:10]3
Reactant: CN(C)N
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)/N=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a solution of 0.80 g of NaH2PO4.H2O, 1.70 g of Na2HPO4.12H2O and 0.12 ml of N,N-dimethylhydrazine in 200 ml of water a solution of 0.64 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 20 ml of dioxane was added dropwise at room temperature. After 1.5 hrs the solution was alkalinized with an acqueous solution of NaHCO3 and extracted with ethyl acetate; the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash-chromatography (SiO2) using cyclohexane/chloroform/acetone 4/3/3 as eluant to give 0.37 g of the title compound (I-ai), as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13]>C(O)(C)(C)C>[CH3:16][O:15][C:11](=[O:14])[CH2:12][CH2:13][C:8]([C:9]#[N:10])([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14]
Reactant: N#CCc1ccc(F)cc1
Reactant: C=CC(=O)OC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(F)cc1
Yield: 72.2 %

Procedure:
A mixture of 25 g. (0.185 mole) of the known compound p-fluorophenylacetonitrile and 86 ml. of methyl acrylate in 90 ml. of t-butyl alcohol is heated to reflux. The heat is removed and 28.1 ml. of 40% methanolic Triton B in 42 ml. of t-butyl alcohol quickly added. After about 4 hours of heating at reflux the mixture is allowed to cool and taken up in water and benzene. The organic layer is washed successively with 2.5 N hydrochloric acid, water and brine and then evaporated to dryness. The residue is distilled under vacuum, first at 40 mm. of mercury to remove methyl acrylate and then at 0.25 to 0.30 mm. to give 41 g. (72.2% yield) of dimethyl-4-cyano-4-(4-fluorophenyl)pimelate having a boiling point of 179° to 181°C. The NMR spectrum of the compound confirms its expected structure.