Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH2:16][Br:17])=[CH:10][CH:11]=3)[CH:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:5]=2[CH:4]=1.[C:28]1([P:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C)C=O>C(OCC)C>[C:41]1([PH+:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1.[Br:1][CH2:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH2:16][Br:17])=[CH:10][CH:11]=3)[CH:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:5]=2[CH:4]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: COCCOCCOCCC1c2cc(CBr)ccc2-c2ccc(CBr)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1

Procedure:
In a 1 L three-hole flask equipped with a stirrer, a thermometer and a reflux condenser, 24.9 g (0.05 mol) of 2,7-bis(bromomethyl)-9-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}fluorene, 39.3 g (0.15 mol) of triphenylphosphine, and 300 ml of dimethylformamide were introduced and reacted for 12 hours at reflux temperature. After reaction, the temperature was decreased to room temperature, and the reactant was dropped down slowly in 1.5 L of ethylether solvent under agitation, to obtain a white solid. After filtering, such extracted solid was washed several times with ethylether, and then dried sufficiently in a vacuum oven at 40° C. As a result, 48.5 g (yield: 95%) of a white solid was obtained. [1H=NMR (CDCl3), δ 1.22-1.41(m, 2H, CH2), 2.16-2.42(br, s, 3H, OCH3), 3.41-3.71(m, 10H, OCH2 CH2), 4.18(t, 1H, CH), 5.58-5.81(d, 4H, CH2Br), 6.81-7.22(m, 6H, fluoreyl aromatic), 7.27-7.84(m, 30H, aromatic)].
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:24]=[CH:25][CH:26]=1)=[CH2:20])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:22]=2)[CH3:20])[C:9]=1[OH:8])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=C(c1cccc(-c2ccccn2)c1)c1cccc(C(C)(C)C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(c1cccc(-c2ccccn2)c1)c1cccc(C(C)(C)C)c1O
Yield: 84.7 %

Procedure:
A solution of 5 (1.12 g, 2.67 mmol) in methanol (40 mL) and ethyl acetate (80 mL) was treated with 20% palladium on activated carbon (0.2 g, 0% wet) and hydrogenated in a Parr shaker at 10 psi for 3.5 hr. The catalyst was filtered off and washed with ethyl acetate. The solvent was removed on a rotary evaporator and the crude product was purified by chromatography on silica (80 g) with 2% ethyl acetate in hexane (1 L), then 4% (2 L) to yield pure A2 (0.75 g, 85%).
Reaction SMILES: Cl.[C:2]([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH2:8]/[C:7]/1=[CH:25]\[C:26]1[CH:30]=[CH:29][N:28]([CH2:31][C:32]([OH:34])=O)[N:27]=1)(=[O:4])[CH3:3].ClC(OCC(C)C)=O.[NH3:43].C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[C:2]([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:13]([CH:15]2[CH2:16][CH2:17]2)=[O:14])[CH2:8]/[C:7]/1=[CH:25]\[C:26]1[CH:30]=[CH:29][N:28]([CH2:31][C:32](=[O:34])[NH2:43])[N:27]=1)(=[O:4])[CH3:3]
Reactant: N
Reactant: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(CC(N)=O)n1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-{[1-(carboxymethyl)-1H-pyrazol-3-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidine hydrochloride (190 mg) in dichloromethane (15 ml) were added isobutyl chloroformate (0.06 ml) and triethylamine (0.18 ml) under ice-cooling, and the resulting mixture was stirred at the same temperature for 30 minutes. To this reaction mixture was added 28% aqueous ammonia solution (0.03 ml), and the resulting mixture was stirred at room temperature for 45 minutes. After stirring, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of methanol and dichloromethane (1:19) as the eluent to afford the title compound (80 mg, yield: 42%) as a yellow oil.
Reaction SMILES: C1COCC1.[C:6]1([CH3:16])[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[Mg]Br.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C>CCCCCC.CCOC(C)=O>[CH3:16][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Brc1ccccn1
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C)c(-c2ccccn2)c(C)c1
Reaction time: 24 h
Yield: 76 %

Procedure:
Using a THF solution of mesitylmagnesium bromide (0.974 mL, 0.77 M, 0.75 mmol), 2-bromopyridine (158.0 mg, 1.0 mmol), FeF3.3H2O (5.01 mg, 0.03 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (38.4 mg, 0.09 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 90° C. for 24 hours in the same manner as in Example 2. After performing silica gel column chromatography (EtOAc=10 and 20% in hexane), the above compound was obtained as a yellow liquid (0.150 g, yield=76%, purity=>99% (GC analysis)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17](=[O:45])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:44])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])=[CH:30][C:29]=3[C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])[CH:19]=2)[NH:11]1.[Br:46]Br.O>C(O)(=O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[C:13]([Br:46])=[C:12]([NH:16][C:17](=[O:45])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:44])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])=[CH:30][C:29]=3[C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])[CH:19]=2)[NH:11]1
Reactant: BrBr
Reactant: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3cc(=O)n(-c4c(Cl)cc(Cl)cc4Cl)[nH]3)c2)c(C(C)(C)CC)c1
Solvent: O
Solvent: CC(=O)O
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3Br)c2)c(C(C)(C)CC)c1

Procedure:
In 200 ml of acetic acid, 33 g of 1-(2,4,6-trichlorophenyl)-3-[3-(2,4-di-tert-amylphenoxyacetamido)benzamido]-5-pyrazolone was dissolved. 7.5 g of bromine was dropwise added to the solution with stirring. After the completion of the reaction, the reaction mixture was added to water, and the thus obtained crystals recovered by filtration and washed were recrystallized, after drying, from 150 ml of a mixture of ethyl acetate and ligroin (1:10 by volume) to obtain 26 g of 1-(2,4,6-trichlorophenyl-3-[3-(2,4-di-tert-amylphenoxyacetamido)benzamido]-4-bromo-5-pyrazolone having a melting point of 139° to 141° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=1)[CH2:3][NH:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)[CH:6]=1.[C:28]1([CH2:34]CC#N)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][NH:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)[C:6]=1[CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N#CCCc1ccccc1
Reactant: N[C@H](CNc1cc(-c2ccc3cnccc3c2)no1)Cc1ccc(Cl)cc1
Solvent: CC#N
Product: N[C@H](CNc1onc(-c2ccc3cnccc3c2)c1Cc1ccccc1)Cc1ccccc1

Procedure:
This compound was synthesized in an analogous manner to N-((S)-2-amino-3-(4-chlorophenyl)propyl)-3-(isoquinolin-6-yl)isoxazol-5-amine starting with commercial available 3-phenylpropionitrile (commercially available from Acros Organics Order Number 17399) instead of acetonitrile. MS m/z: 435 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 9.43 (br s, 1H), 8.50 (br s, 1H), 8.23 (d, J=8.6, 1H), 8.06 (s, 1H), 7.89 (d, J=9.0, 1H), 7.87 (d, J=9.8, 1H), 7.15-7.42 (m, 10H), 3.89 (s, 2H), 3.70 (m, 1H), 3.57-3.62 (m, 2H), 3.02 (d, J=7.04 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([O:13][C:14](=[O:30])[CH2:15][N:16]([C:18](=[O:29])[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21])[CH3:17])[C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6].Cl[C:33]1[C:42]2[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=2)[N:36]=[C:35]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[OH:50])[N:34]=1.C(N(CC)CC)C>C(Cl)Cl.O>[OH:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[C:35]1[N:34]=[C:33]([N:10]2[CH2:11][CH2:12][N:7]([C:5]([CH:4]([O:13][C:14](=[O:30])[CH2:15][N:16]([C:18](=[O:29])[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH3:21])[CH3:17])[CH2:3][CH:2]([CH3:31])[CH3:1])=[O:6])[CH2:8][CH2:9]2)[C:42]2[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=2)[N:36]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)CC(OC(=O)CN(C)C(=O)CN(C)C(=O)OC(C)(C)C)C(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(N3CCN(C(=O)C(CC(C)C)OC(=O)CN(C)C(=O)CN(C)C(=O)OC(C)(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The amine was taken up in 1 mL CH2Cl2 and treated with 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (53 mg, 0.19 mmol) and 49 μL of triethylamine, and stirred at room temperature for 3 h. The reaction mixture was diluted with 10 mL of CH2Cl2 and 10 mL of water. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid 1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carbonyl}-3-methyl-butyl ester. LC/MS: m/z 677.4 (M+H)+ at 3.25 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][C@H:2]1[C:6]([OH:8])=[O:7].[OH-].[Na+].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:18][C:19]([N:1]1[CH2:5][CH:4]=[CH:3][C@H:2]1[C:6]([OH:8])=[O:7])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1C=CCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C=CCN1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (S)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (15 g, 133 mmol) and sodium hydroxide (10.6 g, 265 mmol) in THF (150 mL) cooled at 0° C. was added benzylchloroformate (32.0 mL, 166 mmol). The mixture was allowed to reach RT overnight. The reaction mixture was concentrated, water was added and the aqueous layer was extracted with Et2O (2×200 mL), acidified (6N HCl) and extracted with AcOEt (2×200 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was used in the next step without purification. MS (UPLC/MS): 248 [M+H]+; tR (HPLC conditions b): 1.66 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:33]1(C)[C:37]2(CS(O)(=O)=O)[C:38](C[CH:34]1[CH2:35]C2)=[O:39].O1C=CCCC1>ClCCl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH:38]2[CH2:37][CH2:33][CH2:34][CH2:35][O:39]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1c(CCCCCCCCCCCO)cc(OCc2ccccc2)c2ccccc21
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C1=COCCC1
Solvent: ClCCl
Product: [O-][n+]1c(CCCCCCCCCCCOC2CCCCO2)cc(OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
In this example, 5 m moles of 4-benzyloxy-2-(11-hydroxyundecyl)-quinoline-N-oxide is dissolved in dichloromethane, and a catalytic amount of D-camphorsulfonic acid and 6 m moles of 2,3-dihydropyran are added thereto. The mixture is stirred at room temperature for 3 hours. Then, the reaction solution is washed with an aqueous sodium hydrogen carbonate solution and then with water, and dried over anhydrous sodium sulfate. The solvent is removed therefrom by distillation, and the residue is purified by silica gel column procedure, whereby the cationed compound is obtained as a colorless oily substance (yield: 82.3%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[N:4]([CH3:6])[CH3:5].[H-].[Na+].C(O[C:13](=O)[CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C>C1COCC1>[CH3:5][N:4]([CH3:6])[C:3]1[N:7]=[C:13]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:1][N:2]=1
Reactant: CCOC(=O)CSc1ccccc1
Reactant: CN(C)C(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1noc(CSc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a stirred suspension of 14 g (0.129 mol, 1.4 eq) of 3-hydroxy-1,1-dimethyl-guanidine in 300 mL dry THF at 0° C. was added portionwise 6.191 g (0.155 mol, 1.2 eq) of NaH (60% in oil). The resulting heavy suspension was stirred at RT for 1 hour 30 minutes. Then, 28.126 g (0.129 mol) phenylsulfanyl-acetic acid ethyl ester were slowly added. The reaction mixture was stirred at RT for 2 hours and then at 65° C. for 1 hour. The reaction was quenched by addition of a saturated aqueous solution of NH4Cl and the product extracted with EtOAc. The combined organic phase was dried on Na2SO4, filtered and evaporated. Column chromatography on silica gel (EtOAc/heptane, 1:9 to 1:2) yielded 19.370 g (64%) dimethyl-(5-phenylsulfanylmethyl-[1,2,4]oxadiazol-3-yl)-amine as a colorless oil, MS: 236 (MH+).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)(=[O:3])[CH3:2].[C:16]([OH:22])([C:18]([F:21])([F:20])[F:19])=[O:17]>C(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:16]([OH:22])=[O:17].[NH:7]1[CH2:8][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6]1
Reactant: CC(=O)OC1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC1CNC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 3-acetoxyazetidine-1-carboxylate (Intermediate 95, 0.914 g) in DCM (5 mL) was added TFA (5 mL) and the mixture was stirred at room temperature for 30 minutes. The resultant mixture was concentrated in vacuo and azeotroped with toluene and diethyl ether to give acetic acid azetidin-3-yl ester trifluoroacetate salt (1.40 g) as a clear oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[CH2:22][C:23]([NH2:25])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.P(Cl)(Cl)(OC)=O.C(OCC)(=O)C>C(Cl)Cl.CCCCCCC>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=1)[CH2:22][C:23]#[N:25])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCC(CC(N)=O)c1ccc(C(F)(F)F)cc1)(c1ccccc1)c1ccccc1
Agent: COP(=O)(Cl)Cl
Solvent: CCCCCCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCC(CC#N)c1ccc(C(F)(F)F)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
5-(tert-Butyldiphenylsilanyloxy)-3-(4-trifluoromethylphenyl)pentanoic acid amide (640 mg) was dissolved in methylene chloride (13 mL), and 1,8-diazabicyclo[5,4,0]undec-7-ene (862 μL) and methyl dichlorophosphate (301 μL) were added at 0° C. After stirring at room temperature for 1.5 hours, the reaction was terminated with a saturated sodium bicarbonate aqueous solution. The organic layer was washed with brine and then dried over magnesium sulfate. Concentration under reduced pressure gave an oil. The oil was allowed to pass through a silica gel pad (mobile phase:ethyl acetate:heptane=1:2) to obtain the title compound (600 mg).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])=[CH:22][CH:21]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[S:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(Cl)cc2)s1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)sc3-c3ccc(Cl)cc3)cn2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.77 min; [M+H]+=457.15.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[CH:17]=2)[S:10][C:11]=1Br.IC>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[CH:17]=2)[S:10][C:11]=1[CH3:2]
Reactant: [Li]CCCC
Reactant: Cc1cc(-c2cc(Br)c(Br)s2)sc1C
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(Br)c(C)s2)sc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
n-BuLi (2.5M in hexane) (10 mL, 25 mmol) was added dropwise to a solution of 4,5-dibromo-4′,5′-dimethyl-2,2′-bithiophene (3.37 g, 9.57 mmol) in 100 mL of THF at −78° C. After 90 minutes upon addition, excess iodomethane (3.6 g, 25 mmol) was added dropwise by syringe, and the mixture was stirred for 30 min, then warmed to RT and stirred for another 3 hours. Solvents were evaporated and the residue was poured into water. The mixture was extracted with hexanes, dried over MgSO4, and the solvent was evaporated to give off-yellow solid (2.71 g, 9.43 mmol, 99% yield) of 4-bromo-4′,5,5′-trimethyl-2,2′-bithiophene. 1H NMR (600 MHz, CDCl3) δ 6.85 (s, 1H), 6.82-6.76 (m, 1H), 2.37 (s, 3H), 2.33 (s, 3H), 2.11 (s, 3H)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:10]([NH:12][C@H:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:14][C:15]([OH:17])=[O:16])=[O:11])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].O>CN(C=O)C.C1(B(O)O)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C@@H:13]([NH:12][C:10]([C:4]1[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1)=[O:11])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: COc1ncc(C(=O)N[C@@H](CC(=O)O)c2ccccc2Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(C(=O)N[C@@H](CC(=O)O)c2ccccc2Cl)cc1-c1ccccc1
Temperature: 100 °C
Yield: 59.9 %

Procedure:
To a solution of 50 mg (0.13 mmol) of (S)-3-[(5-Chloro-6-methoxy-pyridine-3-carbonyl)-amino]-3-(2-chloro-phenyl)-propionic acid in 3 ml of DMF are added: 25 mg (0.21 mmol, 1,5 eq) phenylboronic acid, 60 mg Na2CO3 (0.56 mmol, 4.2 eq) and 10 mg (0.13 eq) DI-MICRO-CHLOROBIS[2-[(DIMETHYLAMINO)METHYL]PHENYL-C,N]DIPAL as catalyst. After the addition of 1 ml of water the resulting mixture is heated to 100° C. for 6 hours, the reaction is filtered via a pad of celite and the resulting solution subjected to preparative HPLC chromatography yielding 16 mg of product (Yield: 29%).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=2[CH2:15]O)=[CH:8][C:7]=1[O:23][CH3:24].C(Cl)(Cl)[Cl:26].O>N1C=CC=CC=1.C1C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=2[CH2:15][Cl:26])=[CH:8][C:7]=1[O:23][CH3:24]
Reactant: ClC(Cl)Cl
Reactant: COc1ccc(CO)c(Sc2ccc(Cl)c(OC)c2)c1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(CCl)c(Sc2ccc(Cl)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Thionyl chloride (40.5 g) is added dropwise at 10°-20° C. to a stirred solution of the alcohol from the preceding experiment (91 g) in pyridine (30 ml) and chloroform (30 ml) in the course of 1 hour. The mixture is stirred at room temperature for an additional hour, set aside for 48 hours, heated to 40° C. for 2 hours and decomposed with water. The product is isolated by extraction with benzene. The extract affords 86 g of crude oily 2-(4-chloro-3-methoxyphenylthio)-4-methoxybenzyl chloride which is used without purification in the next step.
Reaction SMILES: [CH3:1][N:2]([S:42]([CH3:45])(=[O:44])=[O:43])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([NH:33][C@@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH3:35])=[O:32])[CH:30]=1)[C:6]([NH:8][C@@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:10]([O:14]C1CCCCO1)[C:11]([OH:13])=O)=[O:7].[NH2:46][C:47]1[NH:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.C1C=CC2N(O)N=NC=2C=1.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:21]([C@H:9]([NH:8][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([N:2]([CH3:1])[S:42]([CH3:45])(=[O:44])=[O:43])[CH:30]=[C:29]([C:31]([NH:33][C@@H:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35])=[O:32])[CH:28]=1)[C@@H:10]([OH:14])[C:11]([NH:46][C:47]1[NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[CH:55][C:49]=2[N:48]=1)=[O:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: C[C@@H](NC(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](OC2CCCCO2)C(=O)O)cc(N(C)S(C)(=O)=O)c1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C(=O)Nc2nc3ccccc3[nH]2)cc(N(C)S(C)(=O)=O)c1)c1ccccc1
Reaction time: 8 h
Yield: 48 %

Procedure:
To a 2 mL solution of (2R,3S)-3-{[3-[methyl(methylsulfonyl)amino]-5-({[(1R)-1-phenylethyl]amino}carbonyl)benzoyl]amino}-4-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)butanoic acid obtained in Reference Example 27 64 mg (0.1 mmol), 2-aminobenzimidazole 27 mg (0.2 mmol), HOBt.H2O 31 mg (0.2 mmol) and 4-(dimethylamino)pyridine 2.4 mg (0.02 mmol) in N,N-dimethylformamide was added a polystyrene-supported carbodiimide (1.38 mmol/g) 181 mg (equivalent to carbodiimide 0.25 mmol) and the mixture was shaken overnight. After completion of the reaction, the mixture was filtered and the filtrate was extracted by adding ethyl acetate and 5% aqueous sodium carbonate solution. The organic layer was washed with an aqueous saturated sodium chloride solution and dried on the magnesium sulfate, filtered and concentrated. The concentrated residue was redissolved in chloroform 2 mL and thereto was added TFA 1 mL and the mixture was stirred at room temperature for 3 hours to remove the protecting group. After completion of the reaction, the mixture was concentrated and the concentrated residue was purified by HPLC fraction collector to give 32 mg (0.05 mmol) of the title compound (overall yields: 48%).