Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:10](Br)=[CH:9][C:8]([F:12])=[C:7]([N+:13]([O-])=O)[C:6]=1Br>C(O)C.[Pd]>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:12])=[C:7]([NH2:13])[CH:6]=1
Reactant: O=[N+]([O-])c1c(F)cc(Br)c(OCCCl)c1Br
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(OCCCl)ccc1F
Reaction time: 120 h
Yield: 90.2 %

Procedure:
A solution of 1-(2-chloroethoxy)-2,6-dibromo-4-fluoro-3-nitrobenzene (73.2 g, 0.19 mol) in ethanol (1.1 L) containing 7.3 g of 10% palladium on carbon was hydrogenated at 40 psi for 5 days. The catalyst was filtered and the solvent was removed. The residue was dissolved in diethyl ether (300 ml) and washed with saturated aqueous sodium carbonate (200 ml). The organic layer was separated and washed with water, dried over anhydrous magnesium sulfate and filtered. The solvent was removed to afford an oil which solidified to afford 32.5 g (90.0%) of product as a dark solid: mp 42-43° C.; MS EI m/e 189/191 (M+); 1H NMR (CDCl3) δ3.40-3.60 (2H, bs, NH2), 3.77 (2H, d, J=6 Hz), 4.14 (2H, d, J=6 Hz), 6.19-6.23 (1 H, m), 6.36 (1H, dd, J=7, 3 Hz), 6.88 (1H, dd, J=11, 9 Hz).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O.[CH2:19]([N:26]([CH2:30][Si](C)(C)C)[CH2:27]OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([N:26]1[CH2:30][CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]([N+:1]([O-:3])=[O:2])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (E)-(2-nitrovinyl)benzene (110 g, 0.738 mol) and TFA (8.42 g, 0.073 mol) in DCM (500 mL) was added N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)-methanamine (351.4 g, 1.476 mol) in DCM (500 mL) drop-wise at 0° C. for a period of 30 min. Then the reaction mixture was stirred at room temperature for 48 h. After completion of the reaction, the mixture was concentrated in vacuo, dissolved in water, and extracted into EtOAc (×2, 1.0 L). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified via flash chromatography (20-80% petroleum ether/EtOAc) to afford (3S and R, 4R and S)-1-benzyl-3-nitro-4-phenylpyrrolidine. MS ESI calc'd. For C17H18N2O2 [M+1]+ 283. found 283.
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[C:6]1[C:11]([F:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][N:14]=2)[N:9]=[C:8](F)[C:7]=1[F:23])([CH3:4])([CH3:3])[CH3:2].[CH3:26][CH:27]([CH3:37])[C@:28]([CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1)([OH:30])[CH3:29].C1COCC1.N1([Si:48]([CH3:51])([CH3:50])[CH3:49])C=CN=C1>CCOC(C)=O>[Si:5]([C:6]1[C:7]([F:23])=[C:8]([N:35]2[CH2:34][CH2:33][NH:32][C@H:31]([C@:28]([O:30][Si:48]([CH3:51])([CH3:50])[CH3:49])([CH:27]([CH3:37])[CH3:26])[CH3:29])[CH2:36]2)[N:9]=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][N:14]=2)[C:11]=1[F:12])([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:24])[CH3:25]
Reactant: C[Si](C)(C)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(-c2n[nH]c3ncccc23)c1F
Reactant: CC(C)[C@@](C)(O)C1CNCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[C@@](C)(O[Si](C)(C)C)[C@@H]1CN(c2nc(-c3n[nH]c4ncccc34)c(F)c([Si](C)(C)C(C)(C)C)c2F)CCN1
Temperature: 95 °C
Reaction time: 8 h
Yield: 378.5 %

Procedure:
A 500 ml glass pressure vessel was charged with tert-butyl-dimethyl-[2,3,5-trifluoro-6-(1H-pyrazolo[3,4-b]pyridin-3-yl)-4-pyridyl]silane (26.80 g, 73.53 mmol), (2R)-3-methyl-2-piperazin-2-yl-butan-2-ol (19 g, 110.3 mmol), THF (53 mL) and imidazol-1-yl-trimethyl-silane (51.57 g, 53.72 mL, 367.7 mmol). An identical experiment was run in parallel. The containers was sealed and the mixture was heated and stirred at 95° C. overnight. Lc/Ms after this time showed a mixture consisting of 73% of the desired (S,R)-diastereoisomer and 18% of the (R,R)-diastereoisomer. Both reaction mixtures were cooled, combined and diluted with EtOAc (500 ml). The solution was washed with saturated sodium bicarbonate (2×200 ml). The combined aqueous layers are extracted 3 times with ethyl acetate (200 ml). The combined organics were washed with brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo to give 163.874 g of viscous brown oil. The diastereoisomers were separated on silica gel, eluting with 10-95% ethyl acetate in petroleum ether containing 2% triethylamine). This gave the required (S,R)-diastereoisomer as an orange foam (60.1 g, 69%); 1H NMR (CDCl3) 0.001 (9H, s), 0.32 (6H, s), 0.76-0.84 (9H, m), 1.11 (4H, m), 1.45 (4H, m), 1.72 (1H, m), 1.90 (1H, s), 2.61 (1H, m), 2.74 (2H, m), 2.97 (1H, m), 3.11 (1H, m), 3.64 (1H, m), 3.82 (1H, m), 3.96 (1H, m), 7.09 (1H, m), 8.48 (1H, m), 8.74 (1H, m), 11.31 (1H, brs); 19F NMR (decoupled) −113.45, −108.39; MS ES(+) 589.3 (M+1). The (R,R)-diastereoisomer was isolated as an orange foam (22%); 1H NMR (CDCl3) 0.001 (9H, s), 0.33 (6H, s), 0.72-0.88 (10H, m), 1.07 (3H, m), 1.45 (5H, m), 1.86 (1H, m), 2.54 (1H, m), 2.74 (2H, m), 2.94 (1H, m), 3.07 (1H, m), 3.63 (1H, m), 3.73 (1H, m), 3.96 (1H, m), 7.04 (1H, m), 8.46 (1H, m), 8.69 (1H, m), 11.35 (1H, brs); 19F NMR (decoupled) −113.78, −108.4; MS ES(+) 589.3 (M+1).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH3:29])([CH3:28])[CH2:20]1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[CH3:28][C:21]1([CH3:29])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:10]([NH2:9])=[S:11])[CH2:20]1
Reactant: CC1(C)CN(c2ccccc2NC(=S)NC(=O)c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CN(c2ccccc2NC(N)=S)c2ccccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 2f (60 mg, 0.149 mmol) in MeOH was added 1N NaOH (0.2 mL, 0.2 mmol). The reaction mixture was stirred at 50° C. for 2 h. The solvent was evaporated under reduced pressure and co-evaporated with toluene to afford 2g (35 mg, 80%). MS (ES) m/z 298 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[C:6]([CH:14]=1)[C:7](N(CC)CC)=[O:8].[Li+].CC([N-]C(C)C)C>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>[Br:1][C:2]1[CH:14]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:15][C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][C:21]=1[C:7]2=[O:8]
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: O=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 9.2 %

Procedure:
A solution of 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethylbenzamide (457.5 g, 1.23 mol) in THF (3 L) was cooled to −74 to −78° C. and treated with a solution of LDA (2M in heptane/THF/ethyl benzene, 2.25 L, 4.5 mol. After the addition was complete, the solution was stirred for 30 min at −78° C. The cold bath was removed and then the reaction was quenched with saturated aqueous NH4Cl (1 L), maintaining the temperature below 10° C. The mixture was added to an addition funnel and the layers were separated. The aqueous layer was extracted with EtOAc (3×2.5 L). The combined organic layers were dried over sodium sulfate, filtered and passed through a pad of silica gel. The filtrate was evaporated, and the residue was triturated with DCM to give 35 g of 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one. The mother liquor was evaporated and the solid thus obtained was purified by recrystallization using dichloromethane/hexanes to give 90 g of 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]2[CH3:21])=[N:6][CH:7]=1.[Br:22][C:23]1[C:31]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[Cl:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:22][C:23]1[C:31]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][C:26]([C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]3[CH3:21])=[N:6][CH:7]=2)=[O:28])=[CH:25][C:24]=1[Cl:37]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)cn1
Reactant: O=C(O)c1cc(Cl)c(Br)c(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(NC(=O)c2cc(Cl)c(Br)c(OC(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (R)-tert-butyl 4-(5-aminopyridin-2-yl)-3-methylpiperazine-1-carboxylate (59.9 mg, 0.21 mmol) and 4-bromo-3-chloro-5-(trifluoromethoxy)benzoic acid (65.5 mg, 0.21 mmol; Preparation 50) in DMA (0.5 mL) at RT was added HATU (86 mg, 0.23 mmol) followed by DIPEA (0.11 mL, 0.62 mmol). The reaction mixture was stirred at RT for 1 h, partitioned between EtOAc (10 mL) and water (2 mL). The organic layer was washed with water (2 mL), dried over sodium sulfate, filtered and concentrated to give the title intermediate as a dark purplish oil. (m/z): [M+H]+ calcd for C23H25BrClF3N4O4 593.07; 595.07. found 595.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([I:13])=[CH:5]2.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[C:6]([I:13])=[CH:5]2
Reactant: COc1ccc(CN)cc1
Reactant: Clc1nc2ccc(Br)cc2cc1I
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2I)cc1
Temperature: 130 °C

Procedure:
A glass microwave reaction vessel was charged with 6-bromo-2-chloro-3-iodoquinoline (0.918 g, 2.492 mmol) and 4-methoxybenzylamine (2.279 mL, 17.44 mmol) in N-methyl-2-pyrrolidinone (3.56 mL). The reaction mixture was stirred and heated in a microwave reactor at 130° C. for 20 min. The solution was poured into water and extracted with diethyl ether. The combined organic extracts were washed with saturated ammonium chloride, water, saturated sodium chloride, and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to give the crude material 6-bromo-3-iodo-N-(4-methoxybenzyl)quinolin-2-amine as a tan solid which was used without further purification.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10][S:11][C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[N:13]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl>[N:1]1[CH:2]=[C:3]([CH2:10][S:11]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[N:13]=2)=[O:29])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2[nH]c(SCc3cnc4ccccn34)nc2c1
Solvent: ClCCl
Product: O=S(Cc1cnc2ccccn12)c1nc2ccccc2[nH]1
Yield: 21.9 %

Procedure:
A suspension of 150 mg (0.54 mmole) of 2-[(imidazo[1,2-a]pyridin-3-ylmethyl)thio]-1H-benzimidazole (see Example 1) in 4.0 ml of dichloromethane was cooled in an ice bath. A solution of 120 mg (0.59 mmole) of ca. 85% m-chloroperbenzoic acid in the minimum amount of dichloromethane needed to form a solution was then added dropwise with stirring. The reaction was quenched with a few drops of dimethylsulfide. The mixture was washed with saturated aqueous sodium bicarbonate. The organic phase was concentrated in vacuo and chromatographed on silica gel (using ethanol-dichloromethane-triethylamine as eluent) to yield 35 mg of the title compound. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([C:22]1[C:27]([Br:28])=[CH:26][N:25]=[C:24]([O:29][CH3:30])[CH:23]=1)[OH:21])([O-:13])=[O:12].C(N(CC)CC)C>ClCCl>[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([C:22]1[C:27]([Br:28])=[CH:26][N:25]=[C:24]([O:29][CH3:30])[CH:23]=1)=[O:21])([O-:13])=[O:12]
Reactant: COc1cc(C(O)c2ccccc2[N+](=O)[O-])c(Br)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(C(=O)c2ccccc2[N+](=O)[O-])c(Br)cn1
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
Anhydrous dimethylsulphoxide (1.2 ml) in anhydrous dichloromethane (20 ml) was added dropwise to a stirred, cooled (-75° C.) solution of oxalyl chloride (0.7 ml) in anhydrous dichloromethane (100 ml) under a nitrogen atmosphere. After 5 minutes a solution of (2-nitrophenyl)-(5-bromo-2-methoxypyridin-4-yl)methanol (2.5 g) in anhydrous dichloromethane (70 ml) was added dropwise keeping the temperature of the reaction mixture below -72° C. After a further 15 minutes triethylamine (5.3 ml) was added dropwise and the reaction mixture stirred at -75° C. for 10 minutes then the cooling bath was removed and the mixture allowed to warm to room temperature. Water (50 ml) was added, the organic layer separated, washed with water then dried (sodium sulphate) and evaporated to dryness. The product was dissolved in dichloromethane, treated with activated charcoal, filtered, evaporated to dryness, then recrystallised from dichloromethane/petroleum ether (60-80) to afford the title compound as a pale yellow solid (2.4 g). mp 128°-131° C. Rf =0.9 in 10% diethyl ether/dichloromethane on silica plates; 1 H NMR (360 MHz, CDCl3) δ 3.91 (3H, s), 6.69 (1H, s), 7.59 (1H, dd, J=1.5 and 7 Hz), 7.74 (1H, dt, J=1.5 and 7 Hz), 7.79 (1H, ddd, J=1.5 and 7 Hz), 8.13 (1H, dd, J=1.5 and 7 Hz), 8.38 (1H, s); IR (KBr) 1705 and 1695 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH2:17][CH2:16]2.[OH-].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([F:12])=[CH:21][CH:20]=3)[CH2:16][CH2:17]2)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Reactant: Fc1ccc2c(c1)CCN2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc(Cl)nc(Cl)c1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g (9.5 mmol) 2,6-dichloro-pyridine-4-carboxylic acid chloride in 50 mL DCM were cooled in the ice/EtOH bath and combined with 1.3 g (9.6 mmol) 5-fluoro-2,3-dihydro-1H-indole. In addition 9.6 mL (9.6 mmol) of a 1N aqueous sodium hydroxide solution were added dropwise and the mixture was stirred for 2 h while being cooled and for 1 h at RT. Then 50 mL of a saturated sodium hydrogen carbonate solution were added and the mixture was stirred for a further 10 min. The organic phase was separated off, extracted with 1N aqueous hydrochloric acid solution and with water, dried on sodium sulphate and evaporated down.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5].C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:30]=1[C:31](Cl)=[O:32]>CN(C=O)C>[CH2:17]([NH:16][C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH2:3][CH2:2][NH:1][C:31](=[O:32])[C:30]3[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:29]=3[F:28])[CH:20]=[CH:19][C:9]=2[N:10]=1)=[O:15])[CH3:18]
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Reactant: O=C(Cl)c1cc(F)ccc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCNC(=O)c3cc(F)ccc3F)cc2s1
Yield: 22 %

Procedure:
Similar to the synthesis of Example 249, a mixture of 1-(6-(3-aminopropanoyl)-2-benzothiazolyl)-3-ethylurea, triethylamine and 2,5-difluorobenzoyl chloride in DMF was reacted to give the desired compound 0.019 g (22%). LC/MS 433.0 (M+1); LC retention time 2.94 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:23]2([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[Cl:37].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:23]3([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:9][N:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]3)[CH:3]=2)[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(Br)c2)C2(O)CCCCC2)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: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(-c3ccc(Cl)c(Cl)c3)c2)C2(O)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
A mixture of tert-butyl 4-[2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate (0.72 g, 1.55 mmol) and tetrakiS(triphenylphosphine)palladium (37 mg, 0.032 mmol, 10 mol %) in 1,2-dimethoxyethane (30 mL) was stirred for 10 min at room temperature. To this mixture was added sequentially 3,4-dichlorophenyl boronic acid (0.44 g, 2.32 mmol) and a 2M aqueous solution of sodium carbonate (0.8 mL, 1.6 mmol, 5 equivalent), and the mixture was heated at reflux until all starting material was consumed and precipitation of black palladium occurred (3 h). After cooling, water was added and the reaction mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude solid, which was purified via flash column chromatography (silica, gradient from 0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to yield 0.55 g (67%) of tert-butyl 4-[2-(3′,4′-dichloro-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate as a foam, which was used as such in the next step.
Reaction SMILES: [CH:1]1[C:6]([NH:7]N)=[CH:5][CH:4]=[C:3]([N:9]2[CH:13]=[N:12][N:11]=[CH:10]2)[CH:2]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.Cl>O1CCOCC1>[N:12]1[N:11]=[CH:10][N:9]([C:3]2[CH:2]=[C:1]3[C:6](=[CH:5][CH:4]=2)[NH:7][CH:19]=[C:18]3[CH2:17][CH2:16][CH2:15][OH:14])[CH:13]=1
Reactant: C1=COCCC1
Reactant: NNc1ccc(-n2cnnc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: OCCCc1c[nH]c2ccc(-n3cnnc3)cc12
Yield: 29.6 %

Procedure:
A solution of 4'-(1,2,4-triazol-4-yl)phenylhydrazine (25 g, 143 mmol) in dioxan (250 ml) was treated with dihydropyran (24 g, 286 mmol) followed by 1M hydrochloric acid (150 ml) and heated at reflux for 18 h. The reaction mixture was evaporated, treated with toluene then re-evaporated. Inorganic solids were removed by treating the residue with a mixture of methanol and acetonitrile. The mother liquors were purified by column chromatography on silica using dichloromethane/methanol (9:1→4:1) as the eluant. The compound was recrystallised from acetonitrile to afford the title compound as a colourless solid (10.24 g, 30%); mp 205°-207° C. (Found: C, 64.37; H, 5.76; N, 22.83. C13H14N4O requires C, 64.45; H, 5.82; N, 23.13%.) δ (360 MHz, d6 -DMSO) 1.81 (2H, q, J=7 Hz, CH2), 2.75 (2H, t, J=8 Hz, CH2), 3.46 (2H, dt, J1 =6, J2 =5 Hz, CH2), 4.43 (1H, t, J=5 Hz, OH), 7.26 (1H, d, J=2 Hz, Ar--H), 7.29 (1H, dd, J1 =9, J2 =2 Hz, Ar--H), 7.47 (1H, d, J=9 Hz, Ar--H), 7.77 (1H, d, J=2 Hz, Ar--H), 9.01 (2H, s, triazole-H), 11.05 (1H, br s, indole NH). MS, CI+, m/z=243 for (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[OH2:14]>>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[C:4]([C:5]([OH:14])=[O:6])[C:3]=1[C:8]([OH:7])=[O:9]
Reactant: O
Reactant: O=C1OC(=O)c2c(F)cc(F)cc21
Product: O=C(O)c1cc(F)cc(F)c1C(=O)O

Procedure:
reacting said 3,5-difluorophthalic anhydride with excess water to produce 3,5-difluorophthalic acid;
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[CH2:17]([O:19][C@H:20]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28](O)=[O:29])=[CH:24][CH:23]=1)[CH3:18].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=1)[C:28](=[O:29])[CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@H:20]([O:19][CH2:17][CH3:18])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(C(F)(F)F)cc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of N-butyl-N-[4-(trifluoromethyl)benzyl]amine (0.486 g, 2.10 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (80 mL) and the organic phase was washed with 5% HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 0.355 g (35%) of a colourless oil.
Reaction SMILES: S(=O)(=O)(O)O.O.C(C1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)#N.[C:22]([OH:25])(=[O:24])[CH3:23]>>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:23]([C:22]([OH:25])=[O:24])=[CH:10][CH:11]=2)=[CH:16][CH:17]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
A mixture of concentrated sulphuric acid (115 ml) and water (115 ml) was added dropwise to a stirred suspension of 4-cyano-4'-hydroxybiphenyl 39 (25.62 g, 131.4 mmol) in glacial acetic acid (400 ml). The mixture was heated under reflux for 48 hours, the cooled reaction mixture was then poured into water (600 ml) with stirring and the white precipitate filtered off. The aqueous filtrate was then washed with diethyl ether (4×70 ml); the combined extracts were then washed with water (50 ml), dried (MgSO4) filtered and evaporated to give a white solid, both crops of product were combined, dried thoroughly and recrystallised (glacial acetic acid) and dried in vacuo (P2O5, 0.30 mm Hg, 50° C., 5 hours).
Reaction SMILES: [CH2:1]([Si:7]([CH3:10])(C)[Cl:8])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C=CCCC=C.C[SiH](Cl)[Cl:19]>[Pt]>[CH2:1]([Si:7]([CH3:10])([Cl:8])[Cl:19])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCC[Si](C)(C)Cl
Reactant: C[SiH](Cl)Cl
Agent: [Pt]
Agent: C=CCCC=C
Product: C=CCCCC[Si](C)(Cl)Cl
Yield: 68 %

Procedure:
Procedure is similar to the one described above for 5-hexenyldimethylchlorosilane. 8.4 g (100 mmole) of 1,5-Hexadiene was refluxed with platinum catalyst (100ppm). To the mixture 5.7 g (50 mmole) of methyldichlorosilane was added dropwise over 30 min. period. The completion of the reaction was monitored by infrared spectroscopy. The product distilling at 65° C./0.22 mm was obtained in 68% yield.