Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:22]=O)[CH:18]=3)[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:22][NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:18]=3)[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCC(=O)O
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3n2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC(=O)O)ccc3n2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-(4-tert-butyl-cyclohexyloxy)-quinoline-6-carbaldehyde (30.6 mg, 0.0983 mmol) and Beta-alanine (8.75 mg, 0.0983 mmol) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 h. The yellow solution was cooled to rt and sodium cyanoborohydride (7.41 mg, 0.118 mmol) was added and was heated to reflux for 1 h. After cooled down to rt, citric acid was added and concentrated down. The solid was suspended in water and filtrate, and the collected solid was washed thoroughly with water. HPLC purification of the solid give the product (7.5 mg, 15%). LCMS Rt=1.60 min m/z=385.49 [M+1]. 1H NMR (400 MHz, MeOD) δ=8.14 (d, J=8.8 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.72 (d, J=10.7 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 5.29-5.09 (m, 1H), 4.40 (s, 2H), 3.36 (t, J=5.8 Hz, 2H), 2.79 (t, J=6.7 Hz, 2H), 2.30 (d, J=10.9 Hz, 2H), 1.94 (d, J=12.9 Hz, 2H), 1.55-1.06 (m, 5H), 0.94 (s, 9H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH:5]1[CH:10]=[C:9]2[CH:11]=[CH:12][C:13]3[C:18]([C:19](=[O:20])[C:8]2=[CH:7][CH:6]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3.[Cl-].[NH4+]>CCOCC>[CH2:8]([C:19]1([OH:20])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:12]=[CH:11][C:9]2[CH:10]=[CH:5][CH:6]=[CH:1][C:2]1=2)[CH3:7]
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC1(O)c2ccccc2C=Cc2ccccc21
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To 150 mmol of ethyl magnesium bromide in 150 ml of ether are added 10 g (48.5 mmol) of dibenzosuberenone in 250 ml of ether at 0° C. After 3 hours at about 10° C., the mixture is cooled in an ice bath and 40 ml of saturated aqueous ammonium chloride are added slowly. Extractions of the aqueous phase with ether affords 10.75 g of a yellow oily residue. Purification by flash chromatography yields 8.5 g (74%) of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH3:19]>>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:14][CH2:2][CH2:3][CH3:4])([CH2:16][CH2:17][CH2:18][CH3:19])[C:4]=2[CH:3]=1
Reactant: CCCCBr
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(Br)cc21

Procedure:
2-bromo-9,9-dibutylfluorene was synthesized from 2-bromofluorene and 1-bromobutane following the general procedures outlined in Part A of Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH:24]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[N:31]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1ccn(Cc2cccnc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2ccn(Cc3cccnc3)n2)cc1Cl
Reaction time: 2 h
Yield: 45.9 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 115 mg, 0.33 mmol), 1-pyridin-3-ylmethyl-1H-pyrazol-3-ylamine (72 mg, 0.41 mmol) and N,N-diisopropylethylamine (232 μL, 1.33 mmol) were combined in methylene chloride (1.7 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (139 mg, 0.37 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/chloroform to 5% methanol/chloroform) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(1-pyridin-3-ylmethyl-1H-pyrazol-3-yl)-acetamide (76 mg, 46%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C23H24ClN5O4S [M+] 501.12, found 502 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.64 (m, 4 H, 2×CH2), 1.85 (m, 4 H, 2×CH2), 3.28 (s, 3 H, SO2CH3), 4.87 (m, 1 H, OCH), 5.26 (s, 2 H, NCH3), 6.78 (d, J=2.3 Hz, 1 H, Ar), 7.30 (dd, J=7.9, J=4.9 Hz, 1 H, Ar), 7.40 (d, J=2.3 Hz, 1 H, Ar), 7.51 (m, 1 H, Ar), 7.55 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.65 (d, Jm=1.6 Hz, 1 H, Ar), 8.18 (d, Jo=8.2 Hz, 1 H, Ar), 8.56 (m, 2H, Ar), 9.17 (s, 1 H, NH).
Reaction SMILES: [C:1]1([C:7]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[C:1]1([C:7]2([CH2:12][O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1(c2ccccc2)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
To a solution of (1-phenyl-cyclopentyl)-methanol (11.5 g, 64.34 mmol) in DCM (100 ml) was added TEA (17.5 ml, 130.68 mmol) and followed by methanesulfonyl chloride (MsCl) (8.9 g, 78.4 mmol) was added drop wise at 0° C. and the reaction mixture was stirred at RT for 16 h. After completion of the reaction, it was quenched with water and concentrated. Then the crude product was dissolved in DCM, extracted with DCM and the organic layer was washed with water, and brine and then dried over Na2SO4. The combined organic layer was concentrated to get crude methanesulfonic acid 1-phenyl-cyclopentylmethyl ester (10 g, crude) as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Si:20]([O:27][CH2:28][CH:29]([OH:40])[C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C(OCC)(=O)C>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:40][CH:29]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][CH:35]=2)[CH2:28][O:27][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CC(C)(C)c1ccc(C(O)CO[Si](C)(C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C(CO[Si](C)(C)C(C)(C)C)Oc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 2-tert-butyl-4,5-dichloro-3(2H)-pyridazinone (0.5 g, 2.27 mmol) in DMF (10 ml) were added anhydrous cesium carbonate (0.74 g, 2.27 mmol) and 1-tert-butyldimethylsilyloxy 2-hydroxy 2-(4-tertbutylphenyl)ethane (0.7 g, 2.27 mmol). The mixture is stirred for 2 hours at 70° C. and then cooled to room temperature and ethyl acetate is added to it. The solution is then washed with water, dried and concentrated and the residue subjected to purification by flash chromatography (silica gel; ethyl acetate/hexanes) to give the above compound.
Reaction SMILES: [CH2:1]1[N:9]2[CH:4]([NH:5][S:6](=[O:16])(=[O:15])[C:7]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[CH3:17][S:18]([NH:21][C:22]1([C:25]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)(=[O:20])=[O:19].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:16]=[S:6]1(=[O:15])[C:7]2[CH:13]=[C:12]([O:14][C:28]3[CH:27]=[CH:26][C:25]([C:22]4([NH:21][S:18]([CH3:17])(=[O:19])=[O:20])[CH2:24][CH2:23]4)=[CH:30][CH:29]=3)[CH:11]=[CH:10][C:8]=2[N:9]2[CH2:1][CH2:2][CH2:3][CH:4]2[NH:5]1
Reactant: O=S1(=O)NC2CCCN2c2ccc(O)cc21
Reactant: CS(=O)(=O)NC1(c2ccc(B(O)O)cc2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC1(c2ccc(Oc3ccc4c(c3)S(=O)(=O)NC3CCCN43)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension composed of 290 mg (1.21 mmol) of 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-ol 5,5-dioxide, 465 mg (1.82 mmol) of the compound obtained in Step D, 330 mg (1.82 mmol) of copper(II) acetate, 294 μl (3.64 mmol) of pyridine and about 3.5 g of 4 Å molecular sieve in 35 ml of CH2Cl2 is stirred for 5 hours at ambient temperature. The reaction mixture is filtered and rinsed with CH2Cl2/MeOH (1/1). The filtrate is concentrated and then directly applied to a silica column, eluting with a mixture of CH2Cl2/acetone 96/4. The fractions containing the expected compound are collected and evaporated and the residue is taken up in a small amount of ethyl ether. After filtering off the solid, the title compound is collected in the form of a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:7]2=[O:14].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:32])([F:20])[F:33])=[CH:27][CH:26]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:14])[N:6]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[CH:5]=[CH:4]2
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(5-amino-6-methoxy-1-oxoisoquinolin-2(1H)-yl)propanamide (98.34 mg, 0.0003764 mol), 2-(4-(trifluoromethyl)phenyl)acetic acid (115.2 mg, 0.0005646 mol), N,N-diisopropylethylamine (163.9 μL, 0.0009409 mol), N,N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (357.8 mg, 0.0009409 mol) and N,N-dimethylformamide (2 mL, 0.02 mol) was stirred at room temperature overnight. the solvent was removed under reduced pressure and the residue purified by reverse phase preparative HPLC to afford the product as a light yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8][OH:9])[CH2:3]1.C(N(CC)CC)C.[Cl:17][C:18]1[C:23]([CH2:24][CH:25]=O)=[C:22](Cl)[N:21]=[CH:20][N:19]=1>CC(O)C>[Cl:17][C:18]1[C:23]2[CH:24]=[CH:25][N:1]([C@H:2]3[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8][OH:9])[CH2:3]3)[C:22]=2[N:21]=[CH:20][N:19]=1
Reactant: O=CCc1c(Cl)ncnc1Cl
Reactant: N[C@@H]1C[C@@H](CO)[C@@H](O)C1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: OC[C@@H]1C[C@@H](n2ccc3c(Cl)ncnc32)C[C@@H]1O
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A solution of (1S,2S,4R)-4-amino-2-(hydroxymethyl)cyclopentanol (250 mg, 1.90 mmol) and triethylamine (380 mg, 3.80 mmol) in 2-propanol (30 mL) was treated with 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (330 mg, 1.71 mmol) at 80° C. The reaction was monitored by HPLC and all aldehyde was found to have been consumed after 19 h. The reaction mixture was cooled to ambient temperature. Approximately 80% of the solvent was removed under reduced pressure and the resulting brown solution was added with stirring to water (30 mL). The resulting clear solution was cooled in an ice-water bath resulting in product crystallization. The resulting slurry was stirred at less than 5° C. for thirty minutes and filtered. The filter cake was washed with cold water (10 mL) and dried in a vacuum oven at 40° C. for 14 h to obtain the title compound as a brown solid (311 mg, 68% yield). 1H NMR (500 MHz, CDCl3) δ 8.54 (s, 1H), 7.68 (d, J=3.7 Hz, 1H), 6.66 (d, J=3.6 Hz, 1H), 5.54 (m, 1H), 4.52 (m, 1H), 3.82 (dd, J=10.7, 7.2 Hz, 1H), 3.68 (dd, J=10.8, 6.5 Hz, 1H), 2.64 (m, 1H), 2.32 (m, 2H), 2.24 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[N:16]1([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)[CH:20]=[CH:19][N:18]=[CH:17]1>>[N:16]1([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][N:28]([C:29]3[CH:30]=[CH:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=3)[C:13]([CH:10]3[C:11]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=4)[CH2:7][CH2:8][CH2:9]3)=[O:15])=[CH:25][CH:26]=2)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(NCc2ccc(-n3ccnc3)cc2)cc1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(-n3ccnc3)cc1)c1ccc(C(C)C)cc1)CCC2
Yield: 30.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.39 g) and {[4-(imidazol-1-yl)phenyl]methyl}(4-isopropylphenyl)amine (0.55 g) as starting materials, N-{[4-(imidazol-1-yl)phenyl]methyl}-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide ½ hydrate (0.28 g) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:24]1([C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)O)[OH:25].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[CH3:22][S:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:23][C:31]3[CH:30]=[CH:29][CH:28]=[CH:26][C:24]=3[O:25]2)=[CH:20][CH:19]=1
Reactant: Oc1ccccc1O
Reactant: CSc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CSc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Yield: 87.3 %

Procedure:
A solution of 4-(4-methylsulfanyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 28) (335 mg, 1.0 mmol), catechol (440 mg, 4.00 mmol) and p-TsOH.H2O (380 mg, 2.00 mmol) in xylene (10 mL) was heated at reflux under a Dean-Stark trap for 45 hours. Standard work-up and purification gave 4-[2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a white solid (286 mg, 87%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:30][B:31](OC(C)C)[O:32]C(C)C)(C)C.P(=O)(O)(O)O>C1(C)C=CC=CC=1.O1CCCC1>[CH:18]([Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([B:31]([OH:32])[OH:30])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])[CH3:19]
Reactant: CC(C)[Si](OC(=O)N1CCN(c2ccc(Br)cc2)CC1)(C(C)C)C(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[Si](OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of triisopropylsilyl 4-(4-bromophenyl)-1-piperazinecarboxylate (4.5 g, 10.2 mmoles) in toluene (17 mL) and tetrahydrofuran (17 mL) was degassed by bubbling nitrogen at room temperature via a fritted gas dispenser for 10 minutes and then cooled to −78° C. for the addition of butyllithium (4.9 mL as a 2.5 M solution in hexanes, 12.3 mmoles). The solution turned yellow and after 30 minutes, triisopropylborate (3 mL, 13.3 mmoles) was added and the solution was warmed to 0° C. over 2.5 h prior to quenching with sat. aq. ammonium chloride (22 mL). To the flask was added 0.825 mL of phosphoric acid (14.8 M, 12.3 mmoles). The solution was stirred for 30 minutes. The phases were separated and the organic phase was dried over sodium sulfate. Right after filtering off the drying agent, the organic phase was washed with wet tetrahydrofuran (approx 2% water). The solution was concentrated to approx 15 mL. While concentrating, three 0.5 mL-portions of water were added to prevent boroxine formation. At this point, hexane was added and the resulting precipitate was filtered to yield 4-(4-{[(triisopropylsilyl)oxy]carbonyl}-1-piperazinyl)phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[CH3:27][S:28]([CH2:31][CH2:32][NH2:33])(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:33][CH2:32][CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-(methylsulfonyl)ethanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-(methylsulfonyl)ethyl)terephthalamide. MS (Q1) 492 (M)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9]C)=O.[NH2:11][NH2:12]>CO>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:11][NH2:12])=[O:9]
Reactant: COC(=O)c1cnccn1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1cnccn1
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 1 step c) (22 g, 159 mmol) in methanol (250 ml) was slowly added hydrazine monhydrate (36.6 ml, 710 mmol). The reaction mixture was stirred for 1.5 h. The precipitate produced was filtered, washed with diethyl ether and dried in the oven at 80° C. to give the required product (30 g). 1H NMR (250 MHz, DMSO) δ 4.66 (2H, broad peak), 8.66 (1H, m), 8.84 (1H, d, J=2.5 Hz), 9.13 (1H, d, J=2.5 Hz), 10.15 (1H, broad peak); MS (ES+) m/e 139 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
4-Hydroxybenzoic acid (1.1 g, 7.96 mmoL) and aniline (742 mg, 7.23 mmol) were dissolved in 20 mL of dry DMF. To the above solution EDCI (1.53 g, 7.23 mmol) was added in one portion and the resulting mixture was stirred at rt overnight under nitrogen. The reaction mixture was then partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was separated, washed consecutively with 1 N HCl, water, saturated sodium bicarbonate solution, water, and brine, and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified by column chromatography using 10% EtOAc in hexane to give 450 mg (29% yield) of 4-Hydroxy-N-phenyl-benzamide. MS (ES) m/z: 214.08 (M+1).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][CH2:6][C:7]([NH2:9])=[O:8].C(O)(=O)C.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:29][CH3:30])=[C:19]([C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=1>CO>[NH2:9][C:7](=[O:8])[CH2:6][NH:5]/[C:21](/[C:19]1[CH:20]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[O:29][CH3:30])=[CH:22]\[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: NCC(N)=O
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\NCC(N)=O)c1cc(Cl)ccc1OC
Temperature: 65 °C
Yield: 105.4 %

Procedure:
A 5-L reaction vessel was charged with methanol (3.3 L), sodium methoxide (102.4 g, 1.8 moles), and glycinamide hydrochloride (202 g, 1.8 moles). The mixture was heated at 65° C. for 1 hour before cooling to 50° C. and adding acetic acid (514.25 mmoles, 30.88 g, 29.47 mL) and ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (300 g, 1.03 mole). After heating to reflux for 16 hours, the reaction mixture was stirred as it was cooled to 10° C. After 30 min the resulting solid was collected by vacuum filtration, pulling dry to form a cake that was dried in a vacuum oven (20 mm Hg, 65° C.) for 14 hours to afford the title compound (339.4 g).
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][C:18]1[CH2:23][CH2:22][CH2:21][C:20]([CH3:25])([CH3:24])[C:19]=1/[CH:26]=[CH:27]/[C:28](/[CH3:37])=[CH:29]/[CH:30]=[CH:31]/[C:32](/[CH3:36])=[CH:33]/[CH:34]=O>>[CH3:36][C:32]([CH:31]=[CH:30][CH:29]=[C:28]([CH3:37])[CH:27]=[CH:26][C:19]1[C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][CH2:23][C:18]=1[CH3:17])=[CH:33][CH:34]=[C:3]([CH2:2][CH3:1])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Product: CCOC(=O)C(=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C)CC

Procedure:
In analogy to the procedure given in Example 1: Triethyl 2-phosphonobutyrate was reacted with retinal to give ethyl 5,9-dimethyl-2-ethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoate, which was converted by the procedure of Example 2 to 5,9-dimethyl-2-ethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoic acid, m.p.=164°-165° C.
Reaction SMILES: Br[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1.[CH3:14][NH:15][CH3:16]>ClCCl>[CH3:14][N:15]([CH3:16])[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1
Reactant: CNC
Reactant: Brc1nsc2nc3ccccc3n12
Solvent: ClCCl
Product: CN(C)c1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a cooled mixture of 3-bromo-1,2,4-thiadiazolo [4,5-a]benzimidazole (15.44 g, 0.0603 mole) in 100 mL dichloromethane, dimethylamine (40% solution in water) (5.44 g, 0.121 mole) was added dropwise. The reaction mixture was allowed to stir for 16 h at room temperature. It was then diluted with dichloromethane, washed with water, dried with sodium sulfate and evaporated under vacuum to give 10.47 g (80%) of 3-(dimethylamino)-1,2,4-thiadiazolo[4,5-a]benzimidazole as colourless crystals: mp 102-104° C.; 1H NMR (CDCl3)δ 7.74 (t, 2H), 7.41 (t, 1H), 7.27 (t, 1H), 3.06 (s, 6H) ppm. Anal. Calcd for C10H10N4S: C, 55.03;H, 4.62; N, 25.69. Found: C, 54.53;H, 4.90; N, 25.50.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30]O)([CH3:4])([CH3:3])[CH3:2].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:58]>CCOC(C)=O>[C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][Br:58])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A 100 mL round bottomed flask was charged with 3-{2-hydroxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid tert-butyl ester (1.0 g, 2.29 mmol), anhydrous THF (25 mL), and then triphenylphosphine (1.20 g, 4.57 mmol) and CBr4 (1.52 g, 4.57 mmol). The yellow mixture was stirred at ambient temperature under a nitrogen atmosphere for 1 h and was poured into EtOAc (100 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified using radial chromatography (EtOAc:hexanes 15:85 to 25:75) to give a colorless oil (0.95 g, 83%). MS (ES) m/e 501 (M+1).