Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].[C:9]([CH2:11][C@@H:12]([OH:21])[CH2:13][C:14](OCCCC)=[O:15])#[N:10].C([N-]C(C)C)(C)C.[Li+].Cl>O1CCCC1.C(OCC)(=O)C>[C:9]([CH2:11][C@@H:12]([OH:21])[CH2:13][C:14](=[O:15])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])#[N:10]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCCCOC(=O)C[C@H](O)CC#N
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CC#N
Reaction time: 1.5 h

Procedure:
To a stirred -50° C. solution of tertiary-butyl acetate (60 mL, 0.44 mol), (R)-4-cyano-3-hydroxybutyric acid, n-butyl ester (20 g, 0.11 mol) and 150 mL tetrahydrofuran is added lithium diisopropylamide (300 mL of 1.5 M) in tetrahydrofuran over 15 minutes and the mixture is stirred at -45° C. to -50° C. for 90 minutes. To this solution is added 700 mL of 5% aqueous hydrochloric acid solution along with 300 mL of ethyl acetate. The aqueous layer is separated and the remaining top layer washed with aqueous sodium chloride solution. The organic layer is then concentrated in vacuo to afford crude (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate which is not isolated, and is carried on to (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl -1,3-dioxane-4-acetate as described in Example 2. TLC: Rf =0.15 (1:1 ethyl acetate: hexanes) on a Kieselgel 60 F254 0.254 mm silica thin layer plate.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH3:9][C:10]1[N:11]=[CH:12][N:13]([C@@H:15]([CH3:18])[CH2:16][OH:17])[CH:14]=1>C(Cl)Cl>[Si:5]([O:17][CH2:16][C@@H:15]([N:13]1[CH:14]=[C:10]([CH3:9])[N:11]=[CH:12]1)[CH3:18])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: Cc1cn([C@@H](C)CO)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Product: Cc1cn([C@@H](C)CO[Si](C)(C)C(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.6 %

Procedure:
In a 500-mL round-bottom flask, (S)-2-(4-methyl-1H-imidazol-1-yl)propan-1-ol (12.0 g) and TEA (12 mL) were dissolved in DCM at room temperature. To this solution, TBSCl (21.3 g, 0.141 mol) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was washed with H2O, the organic phase was separated, and the aqueous was extracted with DCM. The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified on a silica gel column eluted with 1/30˜1/9 MeOH/DCM, affording a sample (1.20 g), which was further purified by prep-HPLC, to afford the title compound (0.557 g). 1H NMR (CDCl3): δ 7.41 (d, 1H), 6.67-6.65 (m, 1H), 4.16-4.10 (m, 1H), 3.73-3.62 (m, 2H), 2.20 (d, 3H), 1.44 (d, 3H), 0.86 (s, 9H), −0.04 (s, 6H); LCMS: 255 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].N12CCCN=C1C[CH2:17][CH2:16][CH2:15][CH2:14]2.BrC(CC)C>CN(C=O)C>[CH:15]([O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7])([CH2:16][CH3:17])[CH3:14]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CCC(C)Br
Product: CCC(C)ON1C(=O)c2ccccc2C1=O
Temperature: 55 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
N-hydroxylphthalimide (18.4 mmol, 3.0 g) was dissolved in anhydrous DMF (20 mL) under nitrogen. To the stirring solution, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (27.6 mmol, 4.13 mL) was injected followed by 2-bromobutane (22.1 mmol, 2.41 mL) and the reaction was warmed to 55° C. After stirring for 18 hour, the reaction was cooled to room temperature and concentrated to a red oil. The reaction was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with saturated aqueous sodium bicarbonate solution, distilled water, brine and dried over magnesium sulfate. The solvent was removed under vacuum providing 3.57 g (89%) of a yellow solid. Rf: 0.8 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.80 (2H,m), 7.73 (2H,m), 4.31 (1H,m), 1.81 (1H,m), 1.64 (1H,m), 1.32 (3H,d), 1.03 (3H,t).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH2:30][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][N:33]2[CH3:37])[C:27]([OH:29])=O)=[CH:22][CH:21]=1)=[O:17])=O)(C)(C)C.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:69][C:70]1[CH:75]=[CH:74][C:73]([NH2:76])=[CH:72][CH:71]=1.Cl.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH2:30][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][N:33]2[CH3:37])[C:27]([NH:76][C:73]2[CH:74]=[CH:75][C:70]([Br:69])=[CH:71][CH:72]=2)=[O:29])=[CH:22][CH:21]=1)=[O:17]
Reactant: Nc1ccc(Br)cc1
Reactant: CN1CCCC1CCC(C(=O)O)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CN1CCCC1CCC(C(=O)Nc1ccc(Br)cc1)c1ccc(/C=C/C(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-4-(1-methyl-pyrrolidin-2-yl)-butyric acid (2.54 g, 5 mmol), Et3N (1.21 g, 10 mmol), and HATU (3.80 g, 10 mmol) in CH2Cl2 (30 mL) was added 4-bromo-phenylamine (1.29 g, 7.5 mmol). This mixture was stirred overnight at room temperature and then evaporated. The mixture redissolved in 20 mL of EtOAc and washed with 2N HCl (20 mL×3), brine, 5% NaHCO3 (20 mL×3), brine, dried with Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel using hexane/EtOAc to give a white solid. 1.25 M HCl/MeOH (4 mL) was added to the product. The solution was stirred for 4 h at ambient temperature. After reaction, the solution was neutralized with solid NaHCO3. The final product was obtained by preparative HPLC. MS: calc'd 561 (MH+), exp 561 (MH+). 1H NMR (d6-DMSO, 400 MHz), 10.25 (d, 1H, J=8.8 Hz), 9.40 (s, 1H), 7.60-7.56 (m, 4H), 7.53 (d, 1H, J=15.6 Hz), 7.49-7.45 (m, 4H), 7.34 (d, 1H, J=8.0 Hz), 6.93 (d, 1H, J=7.6 Hz), 6.88 (d, 1H, J=15.6 Hz), 6.75 (d, 1H, J=7.6 Hz), 6.58 (t, 1H, J=8.0 Hz), 4.95 (s, 2H), 3.71 (broad s, 1H), 3.07 (broad s, 1H), 2.31 (broad s, 4H), 1.99 (broad s, 2H), 1.69-1.46 (broad m, 5H).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28](O)=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1.CC1N(CC(C2C=CC(F)=CC=2)OC2C=CC(CCC3C=CC(F)=CC=3)=C(C=2)C(OC)=O)C=CN=1>>[N:1]1([CH2:6][CH:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[O:8][C:28]2[CH:29]=[CH:30][C:21]([CH2:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:33][CH:32]=3)=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1cc(O)ccc1CCc1ccc(F)cc1
Reactant: OC(Cn1ccnc1)c1nccs1
Agent: COC(=O)c1cc(OC(Cn2ccnc2C)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Product: COC(=O)c1cc(OC(Cn2ccnc2)c2nccs2)ccc1CCc1ccc(F)cc1

Procedure:
Methyl 5-[2-(imidazol-1-yl)-1-(thiazol-2-yl)ethoxy]-2-(4-fluorophenethyl)benzoate was prepared from 2-(imidazol-1-yl)-1-(thiazol-2-yl)ethanol and methyl 2-(4-fluorophenethyl)-5-hydroxybenzoate by the Mitsunobu methodology used for the preparation of methyl 5-[2-(2-methylimidazol-1-yl)-1-(4-fluorophenyl)ethoxy]-2-(4-fluorophenethyl)benzoate in Example 45.
Reaction SMILES: [N:1]1([C:16]([O:18][CH:19]2[CH:26]3[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:28][CH:20]2[CH2:21]4)[CH2:25]3)=[O:17])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.Cl[C:30]1[N:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOCC>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([N:8]2[CH2:7][C:4]3([CH2:5][CH2:6][N:1]([C:16]([O:18][CH:19]4[CH:20]5[CH2:28][CH:24]6[CH2:23][CH:22]([CH2:27][CH:26]4[CH2:25]6)[CH2:21]5)=[O:17])[CH2:2][CH2:3]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[N:35][CH:34]=1)#[N:37]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=C(OC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: N#Cc1ccc(N2Cc3ccccc3C3(CCN(C(=O)OC4C5CC6CC(C5)CC4C6)CC3)C2)nc1
Temperature: 150 °C
Yield: 36.5 %

Procedure:
Crude 2-adamantyl 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (21 mg, 0.054 mmol), 6-chloro-3-pyridine carbonitrile (11 mg, 1.5 equiv.) and DIEA (20 μL, 2 equiv.) were dissolved in dry DMF (1.5 mL). The mixture was heated in microwave oven for 20 min at 150° C. The mixture was diluted with ether (10 mL), washed with 3% aq HCl (2×4 mL), concentrated and purified by preparative HPLC to afford 2-adamantyl 2-(5-cyanopyridin-2-yl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (9.5 mg, 37%). LC-MS Method 1 tR=2.48 min, m/z=483; 1H NMR. (CDCl3) δ=8.67 (br s, 1H), 8.50 (d, 1H), 7.76 (m, 1H), 7.41 (dd, 1H), 7.30 (m, 1H), 7.21 (d, 1H), 6.78 (m, 1H), 4.89 (s, 1H), 4.73 (s, 2H), 4.13 (d, 4H), 3.31 (t, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH3:12][N:13]([C:37]1[CH:38]=[N:39][N:40]([CH3:62])[C:41]=1[NH:42][C:43]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:14](=O)[CH2:15][NH:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].[Na+]>O>[CH3:12][N:13]([CH2:14][CH2:15][NH:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:37]1[CH:38]=[N:39][N:40]([CH3:62])[C:41]=1[NH:42][C:43]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CN(C(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCNC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.8 %

Procedure:
Lithium aluminum hydride (455 mg) was added slowly to tetrahydrofuran (40 ml) at 0° C. and the mixture was stirred for 20 minutes. N-Methyl-N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-2-(tritylamino)acetamide (2 g) was added to the mixture at 0° C., and the whole mixture was stirred for 2 hours with warming to room temperature and refluxed for 2 hours. Sodium fluoride (2.51 g) and water (862 mg) were added to the mixture, and the whole mixture was stirred at room temperature for 30 minutes. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure to give crude residue, which was chromatographed (silica gel; ethyl acetate:dichloromethane=1:10) to give N4,1-dimethyl-N5-trityl-N4-[2-(tritylamino)ethyl]-1H-pyrazole-4,5-diamine (740 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25].C(=O)(O)[O-].[Na+].NC1C(C#N)=C(C2CCCCC2)C(C#N)=C(SCC2N=C(C3C=CC(Cl)=CC=3)SC=2)N=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:18][CH2:20][C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[C:5]([C:16]#[N:17])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:7]=1[C:8]#[N:9]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1C1CCCCC1
Agent: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CSc2nc(N)c(C#N)c(C3CCCCC3)c2C#N)c1

Procedure:
140 mg (0.54 mmol) of the compound from Example 33A, 137 mg (0.60 mmol) of methyl 3-(bromomethyl)benzoate and 182 mg (2.17 mmol) of sodium bicarbonate in 2.0 ml of dry DMF are reacted analogously to the preparation of the compound of Example 29.
Reaction SMILES: Cl[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]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[O:19]C)[N:3]=1.C(OC(N1CCCCC(N)C1)=O)(C)(C)C.C(OC([N:43]1[CH2:49][CH2:48][CH2:47][CH:46]([NH2:50])[CH2:45][CH2:44]1)=O)(C)(C)C>>[NH:43]1[CH2:49][CH2:48][CH2:47][CH:46]([NH:50][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[OH:19])[N:3]=2)[CH2:45][CH2:44]1
Reactant: COc1ccc(F)cc1-c1nc(Cl)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Agent: CC(C)(C)OC(=O)N1CCCCC(N)C1
Product: Oc1ccc(F)cc1-c1nc(NC2CCCNCC2)c2ccccc2n1

Procedure:
The title compound was prepared using a method analogous to that described in Synthesis 52, replacing 4-chloro-2-(2-methoxyphenyl)quinazoline with 4-chloro-2-(5-fluoro-2-methoxyphenyl)quinazoline in Synthesis 52-A and tert-butyl-3-aminoazepane-1-carboxylate with tert-butyl-4-aminoazepane-1-carboxylate in Synthesis 52-B.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([NH:8][NH2:9])=[O:7])[N:3]=[CH:2]1.[CH:10](OCC)(OCC)OCC.C1(OC2C=CC=CC=2)C=CC=CC=1.C>CO.C(O)C>[C:6]1(=[O:7])[NH:8][N:9]=[CH:10][N:3]2[CH:2]=[N:1][CH:5]=[C:4]12
Reactant: CCOC(OCC)OCC
Reactant: NNC(=O)c1c[nH]cn1
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: O=c1[nH]ncn2cncc12
Temperature: 240 °C

Procedure:
A mixture of 6.30 gm. of imidazole-4-carboxylic acid hydrazide [Jones et al., J.A.C.S. 71, 2444 (1949)], 63 ml. of triethyl orthoformate and 500 ml. of ethanol is stirred and refluxed for 81/2 hours. The mixture is concentrated in vacuo to a solid. A 100 ml. portion of diphenyl ether is added and the mixture is heated at 240° C. for 15 minutes. The mixture is cooled to room temperature, petroleum ether is added and a solid is collected. This solid is boiled with 150 ml. of methanol. The insoluble portion is collected by filtration and saved. The filtrate is evaporated to give a solid which is heated with 100 ml. of diphenyl ether at reflux for 15 minutes. Cooling to room temperature and the addition of petroleum ether produces a solid. This solid is combined with the above solid, boiled with 600 ml. of methanol and treated with charcoal. The mixture is filtered. The filtrate is boiled down to 35 ml. and cooled giving a solid. This solid is boiled with 50 ml. of ethanol and the hot mixture is filtered. The solid is boiled with 200 ml. of methanol and the insoluble solid is collected by filtration and saved. The filtrate is boiled down to 75 ml. and cooled giving a second solid. These two solids are combined giving the desire product, m.p. 294°-305° C.
Reaction SMILES: [C:1]([NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\CC.[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1C1C=CC(O)=C(C(O)=O)C=1>>[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[C:33]1[CH:32]=[CH:31][C:30]([OH:35])=[C:29]([C:28]([NH:27][CH2:26][CH2:25][NH:24][C:1](=[O:23])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20])=[O:36])[CH:34]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)c1ccccc1O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NCCNC(=O)c1cc(-c2ccc(F)cc2F)ccc1O

Procedure:
2′,4′-Difluoro-4-hydroxy-N-(2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethyl)biphenyl-3-carboxamide was prepared in a similar fashion as N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide, using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid and EPA starting materials. for C35H42F2N2O3=576.72. found: [M+H]+=577.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14][O:15]CC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44]Br)=[C:40]([F:46])[CH:39]=1>>[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:40]([F:46])[CH:39]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Product: COC(=O)c1ccc(COCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 26, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c) and 4-bromomethyl-3-fluorobenzoic acid methyl ester (commercially available) to give the compound as light yellow solid (34%). MS (Turbo Spray): m/z=557.4 [M+H].
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].O.ClS(C1C=CC=CC=1C(O)=O)(=O)=[O:17]>C1(C)C=CC=CC=1>[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])([OH:17])(=[O:4])=[O:3]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1cccc(S(=O)(=O)O)c1
Temperature: 100 °C
Yield: 95.4 %

Procedure:
300 g of 3-(chlorosulfonyl)benzoic acid containing 38.8% of water (corresponding to 183.6 g (0.83 mol) of 100% chlorosulfonylbenzoic acid) are admixed with 100 g of water and heated to 100° C. for 1 hour. Then 500 g of toluene are added dropwise over 1 hour and a total of 164 ml of water distilled off azeotropically with toluene. The reaction mixture is cooled and the precipitated product filtered off with suction. After drying at 100° C./100 torr (13.16 kPa) 163.5 g of 3-sulfobenzoic acid are obtained, the purity determined by titration being 98.2%; this corresponds to a yield of 95.4%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH2:15][N:14]([C:18]4[S:19][C:20]5[C:21](=[O:29])[NH:22][C:23]([CH3:28])([CH3:27])[CH2:24][C:25]=5[N:26]=4)[C:13]=3[CH:30]=2)[CH:3]=1.C(OC=C)(=O)C.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:27][C:23]1([CH3:28])[NH:22][C:21](=[O:29])[C:20]2[S:19][C:18]([N:14]3[C:13]4[CH:30]=[C:9]([C:4]5[CH:3]=[CH:2][N:7]=[C:6]([CH3:8])[N:5]=5)[CH:10]=[CH:11][C:12]=4[O:17][CH2:16][CH2:15]3)=[N:26][C:25]=2[CH2:24]1
Reactant: Cc1nc(Cl)cc(-c2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C=COC(C)=O
Solvent: CN(C)C=O
Product: Cc1nccc(-c2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)n1
Temperature: 140 °C
Yield: 36.8 %

Procedure:
To a solution of Example 456 (100 mg, 0.227 mmol) in DMF (4 mL) was added vinyl acetate (0.11 mL, 1.13 mmol), triethylamine (0.06 mL, 0.454 mmol), 1,3-bis-(diphenylphosphino)propane (10 mg, 0.023 mmol) and palladium acetate (2.5 mg, 0.011 mmol). The mixture was heated to 140° C. under microwave irradiation for 1 h. The resulting suspension was partitioned between DCM (50 mL) and water (50 mL); the organic fraction was washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative HPLC (Method 6) to yield the title compound (34 mg, 35%) as an off-white solid. δH (CDCl3) 8.72 (1H, d, J 2.1 Hz), 8.65 (1H, d, J 5.4 Hz), 7.84 (1H, dd, J 8.6 and 2.1 Hz), 7.44 (1H, d, J 5.4 Hz), 7.07 (1H, d, J 8.6 Hz), 5.24 (1H, br. s), 4.47-4.28 (2H, m), 4.30-4.11 (2H, m), 2.90 (2H, s), 2.78 (3H, s), 1.41 (6H, s). LCMS (ES+) 408.0 (M+H)+, RT 2.83 minutes (Method 1).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:7]([OH:9])=O)[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:47]([O:54][C:55]1[C:64]([CH3:65])=[CH:63][C:58]([C:59]([NH:61][NH2:62])=[O:60])=[CH:57][C:56]=1[CH2:66][CH3:67])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)Cl.CN(C=O)C>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([C:7]([NH:62][NH:61][C:59](=[O:60])[C:58]2[CH:63]=[C:64]([CH3:65])[C:55]([O:54][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:56]([CH2:66][CH3:67])[CH:57]=2)=[O:9])[CH:10]=[C:11]([CH3:13])[N:12]=1)[CH3:15]
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NNC(=O)c2cc(C)nc(N(CC)CC)c2)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
To a solution of 2-diethylamino-6-methyl-isonicotinic acid (1.50 g, 6.13 mmol) and DIPEA (2.38 g, 18.4 mmol) in DCM (25 mL), TBTU (2.16 g, 6.74 mmol) is added. The mixture is stirred at rt for 10 min before a solution of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide (3.32 g, 6.13 mmol) in DMF (10 mL) is added. The mixture is stirred at rt for 1 h before it is diluted with DCM and washed with sat. aq. NaHCO3-solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with a gradient of EA in heptane to give 4-benzyloxy-3-ethyl-5-methyl-benzoic acid N′-(2-diethylamino-6-methyl-pyridine-4-carbonyl)-hydrazide (2.1 g) as a gum; LC-MS: tR=0.88 min, [M+1]+=not detectable. This material (2.10 g, 4.42 mmol) is dissolved in THF (40 mL) and Burgess reagent (1.16 g, 4.87 mmol) is added. The mixture is stirred at 110° C. for 5 min under microwave irradiation. The mixture is cooled to rt, diluted with diethyl ether and washed with water. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give {4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-6-methyl-pyridin-2-yl}-diethyl-amine (1.03 g) as a pale yellow gum; LC-MS: tR=0.99 min, [M+1]+=457.27.
Reaction SMILES: [F:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[S:9][C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])=[N:7][C:6]=2[CH:17]=1.S(Cl)([Cl:23])(=O)=O>>[Cl:23][C:4]1[C:5]2[S:9][C:8]([C:10]3[C:11]([NH2:16])=[N:12][NH:13][C:14]=3[CH3:15])=[N:7][C:6]=2[CH:17]=[C:2]([F:1])[C:3]=1[O:18][CH3:19]
Reactant: COc1cc2sc(-c3c(C)n[nH]c3N)nc2cc1F
Reactant: O=S(=O)(Cl)Cl
Product: COc1c(F)cc2nc(-c3c(N)n[nH]c3C)sc2c1Cl
Temperature: 25 °C
Yield: 62 %

Procedure:
4-(5-Fluoro-6-methoxybenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine (596 mg; 2.14 mmol) was mixed with 4 mL of sulfuryl chloride. The reaction was stirred at room temperature for several hours and then the reaction was quenched by the addition of water. The resulting precipitate was isolated by filtration to yield 417 mg (62%) of the title compound. MS (m/z, ES+): 364.2 (M+1, 100%).
Reaction SMILES: C(Cl)(Cl)Cl.C(O)C.[F:8][C:9]1[CH:39]=[CH:38][C:12]([C:13](=[O:37])[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:22]=[C:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:24]4[CH:29]=[C:28]([CH3:30])[S:27][C:25]=4[N:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[BH4-].[Na+]>O>[F:8][C:9]1[CH:39]=[CH:38][C:12]([CH:13]([OH:37])[CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]3[N:22]=[C:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:24]4[CH:29]=[C:28]([CH3:30])[S:27][C:25]=4[N:26]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: Cc1cc2c(-c3ccccc3)nc(N3CCN(CC(=O)c4ccc(F)cc4)CC3)nc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(-c3ccccc3)nc(N3CCN(CC(O)c4ccc(F)cc4)CC3)nc2s1
Yield: 94.4 %

Procedure:
Into a mixture of 10 ml of chloroform and 10 ml of ethanol is dissolved 1.34 g of 2-(4-(4-fluorophenacyl)-piperazinyl)-6-methyl-4-phenyl-thieno[2,3-d]pyrimidine, and then 0.23 g of sodium borohydride is added at room temperature. After reaction for one hour, 60 ml of chloroform and 100 ml of water are added and two layers are separated. The chloroform layer is washed with 100 ml of water and then with saturated aqueous solution of sodium chloride, and dried over anhydrous sodum sulfate. Chloroform is distilled off and 1.27 g of the desired crystal is obtained from methanol. The product has a melting point of 180°-181.5° C.