Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14]([C:17]1[CH:18]=[C:19]([O:26][CH3:27])[C:20]([OH:25])=[C:21]([CH:24]=1)[CH:22]=O)[CH:15]=[CH2:16]>>[CH2:14]([C:17]1[CH:18]=[C:19]([O:26][CH3:27])[C:20]([OH:25])=[C:21]([CH:24]=1)[CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1)[CH:15]=[CH2:16]
Reactant: C=CCc1cc(C=O)c(O)c(OC)c1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: C=CCc1cc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c(O)c(OC)c1

Procedure:
6-[4-(5-Allyl-2-hydroxy-3-methoxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-allyl-2-hydroxy-3-methoxybenzaldehyde (available from Acros Organics, Geel, Belgium). 1H NMR (400 MHz, CDCl3) δ 2.58-2.63 (m, 4H), 3.27-3.29 (m, 2H), 3.58-3.65 (m, 4H), 3.71 (s, 2H), 3.91 (s, 3H), 5.03-5.08 (m, 2H), 5.39 (s, 1H), 5.88-5.95 (m, 1H), 6.43 (s, 1H), 6.65 (s, 1H), 7.84 (s, 1H), 10.40 (br s, 1H), 12.80 (br s, 1H). Mass spectrum (ES) MH+=357.
Reaction SMILES: O[C:2]([CH3:36])([CH3:35])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][C:2]([CH3:35])([CH3:36])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCC(C)(C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C)(C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 63.1 %

Procedure:
N-(2-Hydroxy-2-methylpropyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (307 mg, 0.594 mmol) synthesized in Example (36a) was dissolved in tetrahydrofuran (10 mL), and anhydrous methanesulfonic acid (160 mg, 0.918 mmol) and triethylamine (0.25 mL, 1.79 mmol) were added, followed by stirring at room temperature for 4 days under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and the solution was separated with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-70%) to afford the desired product (187 mg, yield 63%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:28].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:28])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
A solution of (R)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate (5.00 g, 14.95 mmol) in dry DMF (50 mL) was added dropwise to a suspension of sodium hydride 60% in mineral oil (0.7176 g, 17.94 mmol) in dry DMF (10 mL). The mixture was stirred at 0° C. for 1 hour and allowed to stir at room temperature for 2 hours. Then the mixture was cooled to 0° C. and treated dropwise with iodomethane (1.024 mL, 16.45 mmol). The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature over 18 hours. Water (40 mL) was added, and the mixture was extracted into EtOAc (3×50 mL). The organic layers were combined, washed with water (3×20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 20% EtOAc/hexane (1.25 L) to provide (R)-benzyl 3-(tert-butoxycarbonyl(methyl)amino)piperidine-1-carboxylate (4.10 g, 79% yield) as an oil. LCMS (APCI+) m/z 349 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][C:17]([OH:19])=[O:18])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.[CH3:20]C1C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:13][CH2:12][C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:14][CH2:15]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC12CCC(c3cccc(O)c3)(CC1)OC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CC12CCC(c3cccc(O)c3)(CC1)OC2
Temperature: 60 °C
Reaction time: 18 h
Yield: 925.1 %

Procedure:
A mixture of 2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetic acid (910 mg, 3.47 mmol) and p-TsOH (66 mg, 0.347 mmol) in MeOH (10 mL) was stirred at 60° C. for 18 h. The reaction was concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 50% EtOAc:hexanes) to afford the title compound (887 mg, 93% yield) as a clear oil. LCMS, [M+H]+=277.3. 1H NMR (500 MHz, CDCl3) δ 7.13 (t, J=7.9 Hz, 1H), 6.93-6.84 (m, 2H), 6.69-6.63 (m, 1H), 6.13 (s, 1H), 3.94 (s, 2H), 3.67 (s, 3H), 2.18 (s, 2H), 2.06-1.94 (m, 4H), 1.86-1.72 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[CH:14]=[CH:13]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CN(C=O)C>[C:12]1(=[O:17])[N:1]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)[C:15](=[O:16])[CH:14]=[CH:13]1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(N2C(=O)C=CC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
According to the method of M. P. Cava, A. A. Deana, K. Muth and M. J. Mitchell (Org. Synth., Coll. Vol. 5, 944 (1973)), 40 ml of a solution of 10 g (66.2 mmols) of 4-aminophenylacetic acid in DMF was added to 15 ml of a solution of 7.14 g (72.8 mmols) of maleic anhydride in DMF at room temperature in argon atmosphere. The reaction mixture was stirred at room temperature for 3 hours and then diluted with 250 ml of ether-benzene (1:1). The resulting precipitate was filtered off, with which 2.87 g (35 mmols) of sodium acetate and 70 ml of acetic anhydride were admixed. The mixture was stirred at 100° C. for 1 hour in argon atmosphere and concentrated in a vacuum. The residue was diluted with 300 ml of ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride aqueous solution, dried over Na2SO4, concentrated and thereafter subjected to silica gel column chromatography (90:10:5 chloroform-ethyl acetate-acetic acid to 50:50:5 chloroform-ethyl acetate-acetic acid), giving 8.72 g (yield 57%) of (4-maleimidophenyl)acetic acid in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[H-].[Na+].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20]
Reactant: Fc1cccc(CCl)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccc(F)c1
Yield: 39.2 %

Procedure:
Using 0.15 g of 3-fluorobenzyl chloride, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.11 g of 2-(3-fluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (79)).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>CN(C)C=O>[Cl:9][CH2:10][C:11]([NH:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)nn1
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Amino-6-chloropyridazine (10.4 g) was dissolved in N,N-dimethylformamide (200 ml), chloroacetyl chloride (7.48 ml) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue. Solids deposited were collected by filtration and washed with ethyl acetate and water to obtain the title compound (9.39 g).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[NH:6][N:5]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:5]=[C:4]([I:3])[C:12]=12
Reactant: CCOC(=O)CBr
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(I)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
Sodium hydride (60%, 0.138 g, 3.45 mmol) was added to a suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.750 g, 2.87 mmol) in N,N-dimethylformamide (9 mL), and the mixture was stirred at ambient temperature for 1 hour until a homogeneous solution was obtained. Ethyl bromoacetate (0.447 mL, 4.03 mmol) was added, and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 14 hours. The solvent was removed under reduced pressure and the resulting solid was triturated sequentially with water (25 mL) and then ether/petroleum ether (4:1, 50 mL) to yield ethyl 2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate (0.791 g, 2.28 mmol) as a brown solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.21 (s, 1H), 5.17 (s, 2H), 4.15 (qt, 2H), 1.20 (t, 3H); RP-HPLC (25 to 100% CH3CN in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt 6.87 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[O:7]=[C:8]([CH3:19])[CH2:9][CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>O1CCCC1>[OH:7][C:8]([CH3:19])([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1)[CH2:9][CH2:10][P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17]
Reactant: Cn1cncn1
Reactant: CCOP(=O)(CCC(C)=O)OCC
Solvent: C1CCOC1
Product: CCOP(=O)(CCC(C)(O)c1ncnn1C)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To a solution of 1-methyl-1,2,4-triazole (3.0 g, 36.1 mmol) in tetrahydrofurane (60 ml) was added n-buthyllithium (43.3 mmol, 1.2 eq) at -78° C. under nitrogen. The mixture was stirred for 1 hour, then diethyl 3-oxo-butylphosphonate (8.3 g, 39.7 mmol, 1.1 eq) was added. The mixture was stirred for 2 hours and quenched with aq. NH4Cl (ca. 15 ml). The mixture was warmed to room temperature and extracted with CH2Cl2 (5×100 ml). The extract was dried over MgSO4, concentrated in vacuo, and purified by a silica gel column chromatography (200 g, AcOEt-EtOH) to give (2.99 g, 28% yield) of diethyl 3-hydroxy-3-methyl-3-(1-methyl-1,2,4-triazol-5-yl)propyl-phosphonate.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:12][C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH2:29]([NH2:32])[CH2:30][CH3:31].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[N+:9]([C:8]1[CH:7]=[CH:6][C:5]([S:12][C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[CH:4][C:3]=1[CH2:1][NH:32][CH2:29][CH2:30][CH3:31])([O-:11])=[O:10]
Reactant: O=Cc1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CCCNCc1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]

Procedure:
A mixture of N-[3-(3-formyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide (0.0027 mol), propylamine (0.003 mol) and NaBH(OAc)3 (0.0041 mol) in DCE (60 mL) was reacted overnight at room temperature. Then a 10% NaOH solution was added and the mixture was extracted with CH2Cl2. The extract was dried (MgSO4) and then purified by column chromatography over silica gel (eluent: 1:0 to 7:1 CH2Cl2:CH3OH). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](=[N:11]O)[CH2:6]2.N>CO>[CH3:1][N:2]1[C@@H:7]2[CH2:6][CH:5]([NH2:11])[CH2:4][C@H:3]1[CH2:10][CH2:9][CH2:8]2
Reactant: CN1C2CCCC1CC(=NO)C2
Agent: N
Solvent: CO
Product: CN1[C@@H]2CCC[C@H]1CC(N)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
A solution of 9-methyl-9-azabicyclo[3.3.1]nonan-3-one oxime (10 g, 0.06 moles) in methanol (70 ml) and 0.88 ammonia; (36 ml; 10.0 equivs) was hydrogenated at 50° C. and 50 psi (344.8 kPa)/H2 for 16 hrs using 5% Rhodium on carbon paste (1 g dry weight). The reaction mixture was cooled to room temperature and filtered to remove catalyst. The catalyst bed was washed with methanol and the methanolic solution was then evaporated under reduced pressure to give the title compound as an oil (8.6 g, 93% weight recovery) which solidified to a waxy solid on standing (8.6 g, 93%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].CN1CCCC1=O.[NH2:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22]>C(N(CC)CC)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: NC(CO)CO
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1NC(CO)CO
Temperature: 60 °C
Yield: 11 %

Procedure:
2 g of 2-fluoro-5-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.4 g of 2-amino-1,3-propanediol, and 1.57 g of triethylamine. The reaction medium was heated at 60° C. for 10 hours and, after cooling to room temperature, was poured into a water/ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 0.32 g of 2-(4-nitro-2-methylphenylamino)propane-1,3-diol (13) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19](O)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:23][NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:23][N:24]([CH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:19]([C:12]1[C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:10][CH:11]=1)=[O:20]
Reactant: O=C(O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Reactant: CNCC1CCOCC1
Agent: Cl
Product: CN(CC1CCOCC1)C(=O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F

Procedure:
In a manner similar to Reference Example 1 (c) 2-(3-chlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (50 mg) and N-methyl-N-(tetrahydro-pyran-4-yl methyl)amine hydrochloride (39 mg) afforded, after Biotage chromatography over silica gel, eluting with 1% MeOH/CH2Cl2, the title compound (33 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:11][CH:10]=1
Reactant: OCCCCCCCCCCCBr
Reactant: Oc1ccc(-c2cccc(F)c2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: OCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Yield: 87.6 %

Procedure:
First, 5.0 g of 2,3-difluoro-4'-hydroxybiphenyl, 7.3 g of 11-bromo-1-undecanol, 6.7 g of potassium carbonate, and 150 ml of methyl ethyl ketone were placed in a 200 ml flask. The mixture was stirred under reflux for 20 hours. The reaction mixture was poured into water and an organic layer was extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was recrystallized from acetone to obtain 8 g of 2,3-difluoro-4'-(11-hydroxyundecyl)oxybiphenyl (Y: 88%). The compound thus obtained had a purity of 98.8% by GC.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Br:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[I:17](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[C:1]([NH:4][C:5]1[C:6]([I:17])=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Br:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Br)c(NC(C)=O)cc1O
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(Br)c(NC(C)=O)c(I)c1O
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Methyl 4-acetylamino-5-bromosalicylate (I-249) (576 mg, 2.0 mmol) was dissolved in a mixed liquid of methylene chloride (20 ml) and methanol (10 ml), then benzyltrimethylammonium dichloroiodate (835 mg, 2.4 mmol) and sodium bicarbonate (1.1 g, 13.0 mmol) were added, followed by stirring at room temperature for 30 hours. The reaction liquid was filtered, the filtrate was concentrated under reduced pressure, then saturated ammonium chloride water was added to the residue, followed by extraction twice with chloroform, then the organic layer was washed with saturated sodium thiosulfate water, and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with chloroform/methanol (50:1) gave the entitled compound (889 mg, quant.) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]([C:24]1[CH:33]=[C:32]([C:34]([NH:36][NH2:37])=[O:35])[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])[C:21]([CH3:23])=[O:22].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>C(O)(C)C>[NH:20]([C:24]1[CH:33]=[C:32]([C:34]([NH:36][N:37]=[C:17]([C:14]2[C:15]([OH:16])=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[S:12][CH:13]=2)[CH3:19])=[O:35])[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])[C:21]([CH3:23])=[O:22]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1NC(C)=O
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1NC(C)=O
Yield: 82.7 %

Procedure:
To a suspension of 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (54.8 mg, 0.2 mmol) and methyl 2-acetamino-4-hydrazinocarbonylbenzoate (50.2 mg, 0.2 mmol) in isopropyl alcohol (2 mL), tosylic acid monohydrate (11.4 mg, 0.06 mmol) was added, and the mixture was heated with reflux for 12 hours. The precipitated solid was filtered to obtain 84 mg of the desired product as a pale yellow solid (yield 83%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]([C:13]2[S:17][C:16]([C:18]3[NH:22][C:21]([C@@H:23]4[CH2:27][CH2:26][CH2:25][N:24]4C(OC(C)(C)C)=O)=[N:20][CH:19]=3)=[N:15][CH:14]=2)=[CH:11][N:10]=[C:9]1[C:35]1[NH:39][C:38]([C@@H:40]2[CH2:44][CH2:43][CH2:42][N:41]2C(OC(C)(C)C)=O)=[N:37][CH:36]=1>ClCCl>[NH:41]1[CH2:42][CH2:43][CH2:44][C@H:40]1[C:38]1[NH:39][C:35]([C:9]2[S:8][C:12]([C:13]3[S:17][C:16]([C:18]4[NH:22][C:21]([C@@H:23]5[CH2:27][CH2:26][CH2:25][NH:24]5)=[N:20][CH:19]=4)=[N:15][CH:14]=3)=[CH:11][N:10]=2)=[CH:36][N:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ncc(-c3cnc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)s3)s2)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1nc([C@@H]2CCCN2)[nH]c1-c1ncc(-c2cnc(-c3cnc([C@@H]4CCCN4)[nH]3)s2)s1
Reaction time: 2 h
Yield: 58.6 %

Procedure:
TFA (2 mL, 26.0 mmol) was added to a stirred solution of di-tert-butyl (2S,2′S)-2,2′-(5,5′-bi-1,3-thiazole-2,2′-diylbis(1H-imidazole-5,2-diyl))di(1-pyrrolidinecarboxylate) (450 mg, 0.704 mmol) in dichloromethane (15 mL) at room temperature. The reaction mixture was stirred for 2 h, additional TFA (2 mL, 26.0 mmol) was added and the mixture was stirred for an additional 2 h. The reaction was concentrated in vacuo and the residue was dissolved in methanol and filtered through a Strata XC MCX cartridge. The cartridge was washed with methanol and then the compound was released from the cartridge by washing with a solution of 2M ammonia in methanol. The filtrate was evaporated under reduced pressure to give 2,2′-bis(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-5,5′-bi-1,3-thiazole (181 mg) as an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C)C=O>[Si:18]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1-c1cccc(C=O)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
4′-Hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde 3d (7.20 g, 31.80 mmol, prepared by a method disclosed in Chinese patent application CN101616913), tert-butyldimethylsilyl chloride (5.27 g, 34.90 mmol), and imidazole (2.60 g, 38.10 mmol) were dissolved in 60 mL of N,N-dimethylformamide. The reaction solution was heated to 60° C. and stirred for 12 hours. The resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound 4′-((tert-butyldimethylsilyl)oxy)-2′,6′-dimethylbiphenyl-3-carbaldehyde 3e (10 g, yield 92.0%) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:20]=[CH:19][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][O:10][CH:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:8]3)=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(CN2CCOC(c3ccccc3)C2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(CN3CCOC(c4ccccc4)C3)cc2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
91 mg of 4-(4-Bromo-benzyl)-2-phenyl-morpholine was combined with 56 mg of 4-Methylphenyl boronic acid, 16 mg of tetrakis(triphenylphosphine)palladium(0), 0.92 mL of 2M sodium carbonate solution, 2.5 mL toluene and 1.23 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with 4 mL DCM and 130 mg of MP-TsOH resin (4.2 mmol/g loading) was added and the mixture agitated at room temperature overnight. The solution is filtered and the resin is then washed with 2M N3 in methanol to liberate product. The resin is washed several times with methylene chloride, concentrated in vacuo and purified by reverse phase HPLC. 18.5 mg of product was obtained as oil. ES MS m/z 344, 20% yield