Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[O-].[Na+].[CH:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)=O>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7](/[CH:8]=[CH:22]/[C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a mixture of 50.3 g of diethyl (4-nitrobenzyl)phosphonate and 500 mL of methanol was added dropwise a solution of sodium methylate in methanol (ca. 5 mol/L, 73.7 mL) under ice-cooling, followed by stirring for 30 minutes under ice-cooling. To the reaction mixture was added dropwise a mixture of 30.6 g of methyl 4-formylbenzoate and 300 mL of methanol for 1 hour under ice-cooling, followed by stirring at room temperature for 15 hours after the addition dropwise. The precipitate was collected by filtration to obtain 48.8 g of methyl 4-[(E)-2-(4-nitrophenyl)vinyl]benzoate as a yellow solid. EI: 283
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([CH:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:4].[C:19](#[N:22])[CH:20]=[CH2:21]>O1CCCC1>[C:19]([CH2:20][CH2:21][C:5]1([C:3](=[O:4])[N:2]([CH3:18])[CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)#[N:22]
Reactant: C=CC#N
Reactant: CN(C)C(=O)C1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Product: CN(C)C(=O)C1(CCC#N)c2ccccc2-c2ccccc21
Reaction time: 0.25 h

Procedure:
A 28 g. of portion of 9-(N,N-dimethylcarbamoyl)fluorene was added to a 3-liter flask, and 1 liter of tetrahydrofuran was added. The mixture was heated to 45°, and 10 ml. of Triton B was added. The mixture was stirred at constant temperature for 15 minutes, and then 8 g. of acrylonitrile was added in one portion. The mixture was then stirred at reflux temperature for 3 hours, and was cooled and concentrated under vacuum to obtain 51.8 g. of oil. The product was isolated as described in Example 1 and was recrystallized from hexane to obtain 15 g. of first-crop purified product, m.p. 109°-110°. Infrared analysis showed a characteristic carbonyl band at 1610 cm-1, and a characteristic nitrile band at 2220 cm-1.
Reaction SMILES: C[Al](C)C.CCCCCC.[Cl-].[NH4+:12].[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([O:26]CC)=O)[O:23][C:19]=2[C:18]([F:29])=[C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16]=1[CH3:36])#[N:14].Cl>O.ClCCl>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([NH2:12])=[O:26])[O:23][C:19]=2[C:18]([F:29])=[C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16]=1[CH3:36])#[N:14]
Reactant: [NH4+]
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(N)=O)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
At room temperature, trimethylaluminium (4.49 ml, 4.63 mmol, 1.03 M hexane solution was added to an anhydrous dichloromethane (6 ml) suspension of ammonium chloride (247 mg, 4.62 mmol), followed by stirring at room temperature for 20 minutes. A dichloromethane (4 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (500 mg, 1.54 mmol) was added, followed by stirring for 4 hours and by heating under reflux in an oil bath at 45° C. for 48 hours. With cooling with ice, 1 N hydrochloric acid (10 ml) was added to the reaction liquid, then water (20 ml) was added, followed by extraction with chloroform (100 ml×2). The organic layer was washed with saturated brine (100 ml), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified in slurry with diethyl ether to obtain the entitled compound (368 mg, 80.8%) as a pale yellow solid.
Reaction SMILES: [ClH:1].Cl.Cl.Cl.[Cl:5][C:6]1[CH:40]=[CH:39][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([C:34]([O:36]CC)=[O:35])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:22][CH2:21]3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.[OH-].[Na+]>C(O)C>[ClH:5].[ClH:1].[ClH:5].[ClH:5].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH:27]([C:34]([OH:36])=[O:35])[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:25]3)[CH2:13][CH2:12]2)=[CH:39][CH:40]=1
Reactant: CCOC(=O)C(CN1CCN(CCCN2CCN(Cc3ccc(Cl)cc3)CC2)CC1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(CN1CCN(CCCN2CCN(Cc3ccc(Cl)cc3)CC2)CC1)c1ccccc1
Yield: 172 %

Procedure:
A suspension of 340 mg of 1-[4-(4-chlorobenzyl)-1-piperazinyl]-3-[4-(2-ethoxycarbonyl-2-phenylethyl)-1-piperazinyl]propane tetrahydrochloride in 10 ml of ethanol was treated with 1 ml of aqueous 5M sodium hydroxide and heated under reflux for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure. The residue was mixed with lN hydrochloric acid (3 ml) and the resulting mixture extracted with ether (2×10 ml). The extract was discarded and the pH of aqueous phase adjusted to 5.5 with 1N hydrochloric acid. Aqueous saturated sodium chloride solution (10 ml) was added and the mixture extracted with butanol (2×10 ml). The butanol extract was filtered and treated with excess ethereal hydrogen chloride. The white precipitate was collected and recrystallized from aqueous ethanol to yield 1-[4-(4-chlorobenzyl)-1-piperazinyl]-3-[4-(2-carboxy-2-phenylethyl)-1-piperazinyl]propane tetrahydrochloride (140 mg, 40% yield) as a white crystalline solid (m.p. 230°-245° C. decomp.).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=O)[CH3:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2].N1C=CC=C[CH:42]=1.CC(OC(C)=O)=O>C1(C)C=CC=CC=1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]([CH3:42])=[CH2:34])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C(C)c1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reaction time: 0.67 h

Procedure:
To a solution of Ph3PMeI (378 mg, 0.935 mmol) in toluene (3 mL) was added KN(TMS)2 (0.5 M, 1.8 mL) dropwise. After stirring for 40 min, (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-acetylbenzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (intermediate AY) (360 mg, 0.626 mmol) in toluene (5 mL) was added. After stirring overnight, the reaction was quenched with a saturated solution of NaHCO3. The mixture was extracted 3× with AcOEt. The combined organic extracts were washed 1× with brine prior to drying over Na2SO4. Concentration of the solution gave an oily residue, which was redissolved in 3 mL of CH2Cl2, and then 0.2 mL of pyridine (2.47 mmol), 0.23 mL of Ac2O (2.44 mmol) and DMAP (catalytic quantity) were added. The mixture was stirred for 2 h at room temperature. Additional CH2Cl2 (20 mL) was added, the mixture was washed 2× with 1N HCl and 1× with brine prior to drying over Na2SO4. Concentration of the solution and purification of the crude product by silical gel column gave intermediate AZ (286 mg).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH:5]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)(=[O:22])=[O:21].O>O1CCCC1>[Cl:30][C:25]1[CH:24]=[C:23]([S:20]([N:6]2[CH:5]([CH2:4][C:3]([OH:31])=[O:2])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=3)[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)(=[O:21])=[O:22])[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: COC(=O)CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a stirred solution of [5-(3,4-dichloro-benzenesulfonyl)-8-fluoro-5,6-dihydro-phenanthridin-6-yl]-acetic acid methyl ester (0.48 g, 1 mmol) in a 1:1 mixture of tetrahydrofuran and water (30 mL) lithium hydroxide monohydrate (105 mg, 2.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, then concentrated. The residue was dissolved in a mixture of ethyl acetate (25 mL) and water (25 mL) and acidified with 1N hydrochloride solution. The aqueous phase was separated and extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to yield 0.46 g (98%) of the title compound as white crystals.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[C:13][Si](C)(C)C)[CH:7]=1)([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[CH:13])[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cccc(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccc(C(=O)OC(C)C)c1
Reaction time: 0.08 h
Yield: 76.2 %

Procedure:
A solution of 3-trimethylsilanylethynyl-benzoic acid isopropyl ester (Intermediate 136, 0.6 g, 2.3 mmol) in anhydrous tetrahydrofuran (3 mL) was treated with a 1M solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran (4.6 mL, 4.6 mmol) and the resulting reaction mixture was stirred in an ice bath for 5 min. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil that was purified by flash column chromatography using 5%-30% ethyl acetate in hexane as the eluent to afford the title compound as a solid (0.33 g, 76%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:28][CH:27]=[C:26]([CH2:29][OH:30])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[CH:16]1([C:14]2[N:13]([CH3:19])[C:12]3[CH:20]=[C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:26]5[CH:25]=[C:24]([C:23]([F:32])([F:22])[F:31])[S:28][CH:27]=5)=[CH:3][C:4]4=[O:21])[CH:9]=[CH:10][C:11]=3[N:15]=2)[CH2:18][CH2:17]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Reactant: OCc1csc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)c4)cc3=O)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
A mixture of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (800 mg), (5-(trifluoromethyl)-3-thienyl)methanol (972 mg), cesium carbonate (2.61 g) and DMF (8 ml) was stirred at 80° C. overnight. The mixture was poured into water and extracted with EtOAc-THF. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH-water to give the title compound (258 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[NH2:44]>C(O)C>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([NH:44][C:7]2[N:8]=[CH:9][C:10]3=[C:2]([CH3:1])[N:3]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:5]3[N:6]=2)[CH:45]=[CH:46][C:47]=1[O:48][CH3:49]
Reactant: COc1ccc(N)cc1OC
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccccc4)n3n2)cc1OC
Yield: 36.6 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), 3,4-dimethoxyaniline (26.5 mg, 0.17 mmol) and ethanol (2.5 mL) to afford N-[3,4-bis(methyloxy)phenyl]-5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (22.5 mg) as a yellow solid. MS m/z 362 (M+1).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4]([C:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[NH:8][N:7]=1)=[O:5]>O1CCCC1.CO>[NH2:11][C:9]1[NH:8][N:7]=[C:6]([C:4]([N:3]([O:2][CH3:1])[CH3:14])=[O:5])[CH:10]=1
Reactant: CON(C)C(=O)c1cc([N+](=O)[O-])[nH]n1
Solvent: C1CCOC1
Solvent: CO
Product: CON(C)C(=O)c1cc(N)[nH]n1
Reaction time: 18 h
Yield: 95.5 %

Procedure:
6.40 g (32.00 mmol) of N-methoxy-N-methyl-5-nitro-1H-pyrazole-3-carboxamide are dissolved in 500 ml of tetrahydrofuran/methanol mixture (50:50). The solution is purged under argon and 220 mg of palladium on charcoal (10%) are added. The solution is then degassed with hydrogen and stirred under a hydrogen atmosphere for 18 h. After degassing with argon, the solution is filtered on Celite and the solvent is concentrated to yield 5.2 g of 5-amino-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide in the form of a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=CC=CC=2)[CH:3]=[CH:2]1.Br[C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:24])[CH:21]=3)[NH:16][C:15]=2[C:14]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[C:13]2[NH:31][C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=3[C:12]=12>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:13]1[C:14]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[C:15]3[NH:16][C:17]4[CH:18]=[CH:19][C:20]([Cl:24])=[CH:21][C:22]=4[C:23]3=[C:11]([N:1]3[CH2:9][CH2:4][CH2:3][CH2:2]3)[C:12]2=1
Reactant: CN(C)CCOc1c2[nH]c3ccc(Cl)cc3c2c(Br)c2c1[nH]c1ccc(Cl)cc12
Reactant: c1ccc2[nH]ccc2c1
Product: CN(C)CCOc1c2[nH]c3ccc(Cl)cc3c2c(N2CCCC2)c2c1[nH]c1ccc(Cl)cc12

Procedure:
The title compound was prepared in a manner analogous to Example 126 except the starting indole is 2-(12-bromo-2,10-dichloro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine. 1H-NMR (400 MHz, CDCl3) δ ppm 10.14 (br s, 2H), 8.11 (s, 2H), 7.37-7.28 (m, 4H), 4.34 (t, J=4.4 Hz, 2H), 3.67-3.55 (m, 4H), 2.72 (t, J=4.4 Hz, 2H), 2.53 (s, 6H), 2.45-2.33 (m, 4H); MS (ESI) m/z 479.1 (M−H)−; MS (ESI) m/z 481.1 (M+H)+
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10][C:11]1[S:12][C:13](Br)=[N:14][N:15]=1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C(O)C.O.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(Cl)Cl.C(OCC)(=O)C>[Br:10][C:11]1[S:12][C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:14][N:15]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1nnc(Br)s1
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: O
Solvent: ClCCl
Solvent: CCO
Product: Brc1nnc(-c2ccccc2)s1
Yield: 37.9 %

Procedure:
Phenylboronic acid (2.0 g, 16.4 mmol) and 2,5-dibromo-1,3,4-thiadiazole (4.0 g, 16.4 mmol) are refluxed for 24 hours in a mixture of sodium carbonate (15.64 g), toluene (60 ml), ethanol (30 ml) and water (30 ml) and tetrakis(triphenylphosphine)palladium(0) (10 mol %) as catalyst. Aqueous work-up and column chromatography (SiO2, CH2Cl2 /ethyl acetate 9:1) give 1.5 g (38% of theory) of 2-bromo-5-phenyl-1,3,4-thiadiazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([F:10])[CH:3]=1.[Li]CCCC.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1
Reactant: CSc1cc(F)cc(F)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of 1,3-difluoro-5-(methylthio)benzene (0.800 g, 4.99 mmol) in dry THF (25 mL) under nitrogen at −78° C., n-BuLi in THF (1.6 M; 3.28 mL, 5.24 mmol) was added slowly while keeping the internal temperature below −65° C. The reaction mixture was stirred at −78° C. for 2 h. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.07 g, 5.74 mmol) was then added. The reaction mixture was allowed to warm to room temperature for 2 h, and then quenched with aq. NaHCO3 and extracted with EtOAc. The organic extracts were washed with brine, dried, filtered and concentrated under reduced pressure to yield the crude sub-title compound (1.42 g, 99%) as a viscous liquid.
Reaction SMILES: C([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH2:20])=[N:14][O:15][C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=1)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:20][C:13](=[N:14][O:15][C:16]([O:18][CH3:19])=[O:17])[C:10]1[CH:9]=[CH:8][C:7]([C:6]([OH:21])=[O:5])=[CH:12][CH:11]=1
Reactant: COC(=O)ON=C(N)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)ON=C(N)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 4.0 ml of trifluoroacetic acid was dissolved 1.0 g of 4-(amino-methoxycarbonyloxyiminomethyl)benzoic acid t-butyl ester. The solution was stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure. The concentrate was subjected to azeotropic distillation with toluene to afford 0.80 g of the titled compound as a colorless amorphous powdery product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[CH3:13][NH:14][CH3:15].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([N:14]([CH3:15])[CH3:13])=[O:8]
Reactant: CNC
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
5-Bromo-2-fluorobenzoic acid (500 mg, 2.23 mmol) was dissolved in DMF (5.0 mL), and dimethylamine hydrochloride (223 mg, 2.72 mmol), WSC.HCl (511 mg, 2.66 mmol), HOBt.H2O (410 mg, 2.68 mmol), and potassium carbonate (367 mg, 2.66 mmol) were added thereto, and the mixture was stirred at room temperature for 3 hours. To the mixture, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50) to give 5-bromo-2-fluoro-N,N-dimethylbenzamide (550 mg, 2.23 mmol, yield: 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:57])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C@@H:32]([CH3:50])[C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40]([O:42]CC3C=CC=CC=3)=[O:41])=[O:34])[N:28]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:57])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C@@H:32]([CH3:50])[C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40]([OH:42])=[O:41])=[O:34])[N:28]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@@H](C)C(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@@H](C)C(=O)N3CCC[C@H]3C(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 24 h

Procedure:
To a solution of 2.177 g 4-[(S)-2-({5-[(S)-2-((S)-2-Benzyloxycarbonyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-4-tert-butoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester in 50 ml ethyl acetate were added under argon 0.5 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (1 bar) for 24 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 1.784 g colorless foam.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH:24]3[CH2:26][CH2:25]3)[CH3:23])[CH:16]=2)=[CH:9][CH:8]=1)C.[OH-].[K+]>C(O)C.O1CCCC1>[CH:24]1([N:22]([CH2:21][C:17]2[CH:16]=[C:15]([C:14]#[C:13][C:10]3[CH:11]=[CH:12][C:7]([CH:6]=[C:5]([CH3:27])[C:4]([OH:28])=[O:3])=[CH:8][CH:9]=3)[CH:20]=[CH:19][CH:18]=2)[CH3:23])[CH2:25][CH2:26]1
Reactant: CCOC(=O)C(C)=Cc1ccc(C#Cc2cccc(CN(C)C3CC3)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=Cc1ccc(C#Cc2cccc(CN(C)C3CC3)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A solution of 3-(4-{3-[(cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-2-methyl-acrylic acid ethyl ester (Intermediate 94, 0.15 g, 0.4 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 3M solution of potassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature for overnight. The reaction mixture was concentrated, neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to a solid. The solid was subjected to flash column chromatography using 5% methanol in ethyl acetate as the eluent to afford the title product as an amorphous solid (0.115 g, 83%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.[F:30][C:31]([F:47])([F:46])[O:32][C:33]1[CH:45]=[CH:44][C:36]([O:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[F:47][C:31]([F:30])([F:46])[O:32][C:33]1[CH:45]=[CH:44][C:36]([O:37][CH:38]2[CH2:39][CH2:40][N:41]([CH2:28][C:25]3[CH:24]=[CH:23][C:22]([C:19]4[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=4)=[CH:27][CH:26]=3)[CH2:42][CH2:43]2)=[CH:35][CH:34]=1
Reactant: O=Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: Oc1ccc(-c2ccc(CN3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
Sodium triacetoxyborohydride (1.69 g) was added to a 1,2-dichloroethane solution (11 ml) of 4′-hydroxybiphenyl-4-carbaldehyde (1.13 g) and 4-(4-trifluoromethoxyphenoxy)piperidine (1.78 g) and stirred at room temperature overnight. A potassium carbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→0:10) to afford the title compound as a yellow powder (1.73 g).