Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[C@H:14]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[C:22]([NH:28][C:29]3[N:34]=[C:33]([N:35](CC)[CH2:36][C:37]4C=CC(OC)=CC=4)[C:32]4=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:31]4[N:30]=3)[C:21]=2[Cl:52])[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[Cl:52][C:21]1[C:22]([NH:28][C:29]2[N:34]=[C:33]([NH:35][CH2:36][CH3:37])[C:32]3=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:31]3[N:30]=2)=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:20]=1[N:11]1[CH2:12][CH2:13][C@H:14]([NH:15][C:16](=[O:19])[O:17][CH3:18])[C@@H:9]([OH:8])[CH2:10]1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O[Si](C)(C)C(C)(C)C)C3)c2Cl)nn2c(C#N)cnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@H](NC(=O)OC)[C@@H](O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 133.3 %

Procedure:
methyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-m ethoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (140 mg, 0.188 mmol) was dissolved into Tetrahydrofuran (2 mL). TBAF 1M in THF (0.244 mL, 0.244 mmol) was added. The mixture was stirred at r.t. overnight. The mixture was concentrated to dryness, then diluted with EtOAc (50 ml) and washed with sat. NaHCO3. The water layer was extracted with 20 ml EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to dryness to give 128 mg of product, which was used further without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3([CH3:21])[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[C:14]3=[O:20])[CH:11]=2)[NH:6][C:5]=1[C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=1.CC1C=C(C2NC3C(C=2CCN[CH2:50][CH2:51][CH2:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([NH:60][S:61]([CH3:64])(=[O:63])=[O:62])=[CH:56][CH:55]=2)=CC(C(N2CCOCC2)=O)=CC=3)C=C(C)C=1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+].[NH4+].[OH-]>CO>[CH3:28][C:26]1[CH:27]=[C:22]([C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3][CH2:2][NH:1][CH2:50][CH2:51][CH2:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([NH:60][S:61]([CH3:64])(=[O:63])=[O:62])=[CH:56][CH:55]=2)=[CH:11][C:10]([C:13]2([CH3:21])[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[C:14]2=[O:20])=[CH:9][CH:8]=3)[CH:23]=[C:24]([CH3:29])[CH:25]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1
Reactant: CCN1CCC(C)(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCN)c3c2)C1=O
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Product: CCN1CCC(C)(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCNCCCCc4ccc(NS(C)(=O)=O)cc4)c3c2)C1=O
Reaction time: 0.29 h

Procedure:
A mixture of 37.0 mg (0.095 mmol) of (±)-3-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-ethyl-3-methylpyrrolidin-2-one (from Step 5), 25.3 mg (0.105 mmol) of 4-[4-(methanesulfonamido)phenyl]butyraldehyde (EXAMPLE 4), and 57.0 mg (0.475 mmol) of anhydrous magnesium sulfate was purged with nitrogen and cooled in an ice-methanol bath at about −10° to −5° C. as 0.300 mL of dry CDCl3 was added gradually by syringe. The mixture was stirred under nitrogen at this temperature for 15-20 minutes. The septum was removed just long enough to add 4.5 mg (0.12 mmol) of sodium borohydride, and the solution was repurged with nitrogen. The mixture was stirred at −10° to −5° C. as 0.200 mL of dry methanol was added gradually, and stirring was continued at this temperature. After 25 minutes, the mixture was partitioned between 5 mL of ethyl acetate and 5 mL of water. The ethyl acetate layer was washed with brine, then dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC on Analtech tapered silica gel GF plates (developed in 92.5:7.5:0.75 CH2Cl2-MeOH-concd. NH4OH). Isolation of the product band (by extraction with the same solvent) gave 32.3 mg (55%) of a pale yellow, stiff foam; homogeneous by TLC in 92.5:7.5:0.75 CH2Cl2-MeOH-concd. NH4OH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e=615.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[I-].[K+].Br[CH:14]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:21][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16]>O1CCCC1.C(O)(=O)C.O.CN(C)P(N(C)C)(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:14]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[CH:23][CH:24]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)C(Br)c1ccc(OCOc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(OCOc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a solution of 2.74 g of p-chlorophenol in 25 ml of tetrahydrofuran is added 0.85 g of 60% sodium hydride-oil dispersion. After stirring under argon at room temperature for 1 hour, 3.52 g of potassium iodide and 1 ml of hexamethylphosphoramide is added. To the mixture is added dropwise, a solution of 8.18 g of methyl bromo{p-[(p-chlorophenoxy)methoxy]phenyl}acetate in 45 ml of tetrahydrofuran. The mixture is refluxed for 18 hours. The mixture is poured into 500 ml of ice and water containing 2 ml of acetic acid. The mixture is extracted with ether and the ether extracts are washed with sodium chloride solution, sodium bicarbonate solution and with sodium chloride solution. The extract is dried (MgSO4) and the solvent removed under reduced pressure to give the product (9.5 g) as a viscous oil. Chromatography over silica gel with dichloromethane as eluent gives 7.6 g of gum which is crystallized from methanol to give 5.8 g of the product as white crystals. Recrystallization from methanol gives white crystals, mp 64°-65° C.
Reaction SMILES: [N:1]1([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]([O:11][C:12](C)(C)[CH3:13])=[O:10])[CH2:3][CH2:2]1.Cl>CCO>[N:1]1([CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[CH2:2][CH2:3][CH:4]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)COC1CCN(C2CCNCC2)CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)COC1CCN(C2CCNCC2)CC1
Reaction time: 8 h

Procedure:
A solution of 100 mg (0.33 mmol) tert. butyl ([1,4′]bipiperidinyl-4-yloxy)-acetate in 1 mL EtOH was combined with 2 mL ethanolic HCl with heating, the mixture was refluxed for a further 2 h and left overnight at RT. The precipitate formed was suction filtered and dried.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)[CH:6]=[CH:5][C:4]=1[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]3[C:29](=[O:32])[O:30][CH2:31][C:27]=3[CH:26]=2)[CH2:19][CH2:18]1)=[O:16])=[CH2:2].[CH2:35](Cl)Cl>CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]1([C:3]2[CH:8]=[C:7]([N:9]3[CH:13]=[N:12][N:11]=[N:10]3)[CH:6]=[CH:5][C:4]=2[CH2:14][C:15]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]3[CH:34]=[CH:33][C:28]4[C:29](=[O:32])[O:30][CH2:31][C:27]=4[CH:26]=3)[CH2:21][CH2:22]2)=[O:16])[CH2:35][CH2:2]1
Reactant: ClCCl
Reactant: C=Cc1cc(-n2cnnn2)ccc1CC(=O)N1CCN(CCc2ccc3c(c2)COC3=O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: O=C1OCc2cc(CCN3CCN(C(=O)Cc4ccc(-n5cnnn5)cc4C4CC4)CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-[2-(4-{[2-ethenyl-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (40 mg, 0.08 mmol) in 5 mL of DCM was added a solution of CH2N2 in 2 mL Et2O and Pd(OAc)2 (10 mg) at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was filtrated and purified by prep-TLC to afford 5-[2-(4-{[2-cyclopropyl-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 9.0 (s, 1H), 7.76˜7.78 (m, 1H), 7.26˜7.4 (in, 5H), 5.22 (s, 2H), 3.88 (s, 2H), 3.49˜3.66 (m, 4H), 2.83˜2.93 (m, 2H), 2.6˜2.62 (m, 2H), 2.38˜2.48 (m, 4H), 2.0 (s, 1H), 0.94˜0.98 (m, 2H), 0.66˜0.68 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)Cl.[Pd](Cl)Cl>[C:11]1([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: OB(O)C1=CCCCC1
Reactant: O=C(O)c1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cccc(C2=CCCCC2)n1
Yield: 55.5 %

Procedure:
Under an atmosphere of nitrogen, a solution of 6-bromo-pyridine-2-carboxylic acid (CAN 1190-87-4, 3 g, 6.4 mol), cyclohexenylboronic acid (CAN 21190-87-4, 0.89 g, 7.1 mmol), 1,1′-bis(diphenyl-phosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 95464-05-4, 8 mg, 0.13 mmol), potassium carbonate (1.78 g, 12.9 mmol) in H2O (30 mL) was heated to 100° C. overnight. The reaction mixture was extracted with ethyl acetate (50 mL). The pH of the aqueous layer was adjusted to 5 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by prep-HPLC to yield the title compound (0.8 g, 3.94 mmol, 61.2%) as yellow oil; MS (EI): m/e=204.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([CH2:7][CH2:8][CH:9]=[CH2:10])[C:3]([NH:5][NH2:6])=O.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:19][NH:20][C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=NC>CO>[F:1][C:2]([C:3]1[N:20]([CH3:19])[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:6][N:5]=1)([F:11])[CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: CN=C(NC)c1ccccc1
Reactant: C=CCCC(F)(F)C(=O)NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCCC(F)(F)c1nnc(-c2ccccc2)n1C
Yield: 10.2 %

Procedure:
To a solution of 2,2-difluoro-5-hexenohydrazide (275 mg) in MeOH (8 ml) were added K2CO3 (232 mg) and N,N′-dimethylbenzenecarboximidamide hydrochloride (309 mmol). The solution was heated at reflux for 3 days. Volatiles were evaporated in vacuo and the crude was purified by column chromatography (DCM:MeOH=95 to 5) to give 45 mg of the title compound. MS (m/z): 264[MH]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][N:26]([CH3:35])[CH2:27][CH2:28][N:29]1[C:33]([SH:34])=[N:32][N:31]=[N:30]1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:34][C:33]3[N:29]([CH2:28][CH2:27][N:26]([CH3:35])[CH3:25])[N:30]=[N:31][N:32]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: CN(C)CCn1nnnc1S
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3nnnn3CCN(C)C)s2)c(C(=O)C2CCCC2)c1
Yield: 25 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-{5-[1-(2-dimethylamino-ethyl)-1H-tetrazol-5-ylsulfanyl]-thiazol-2-yl}-urea (125 mg, 25%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 1-(2-dimethylamino-ethyl)-1H-tetrazole-5-thiol (346 mg, 2 mmol) following the general procedure Y
Reaction SMILES: COCN[C:5]([C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:10][CH:11]=1)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(C2SC=C(C(C3C=C(OC)C(OC)=C(OC)C=3)=O)N=2)C=CC=CC=1>C1COCC1>[C:12]1([C:9]2[S:10][CH:11]=[C:7]([CH:5]=[O:6])[N:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COCNC(=O)c1csc(-c2ccccc2)n1
Agent: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1csc(-c2ccccc2)n1
Yield: 45.8 %

Procedure:
At −78° C., to a solution of 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (1 equiv) in THF was added LiAlH4 (1 equiv, 1 N in THF) and stirring for 1h at −20° C. The reaction mixture was placed on an ice bath and quenched by 20% H2SO4 solution, extracted with ethyl acetate and dried over MgSO4. The solvent was removed under reduced pressure and purified by column chromatography to yield 42b (45.8%). NMR (300 MHz, CDCl3) δ 10.1 (s, 1H), 8.17 (s, 1H), 8.02-8.00 (m, 2H), 7.50-7.48 (m, 3H). MS (ESI) m/z 244.1 (M+Na+MeOH)+.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH3:18]>>[Cl:10][C:11]1[CH:16]=[C:15]([N+:6]([O-:9])=[O:7])[C:14]([F:17])=[CH:13][C:12]=1[CH3:18]
Reactant: Cc1cc(F)ccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1Cl
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To concentrated sulfuric acid (23.81 g), cooled to 0° C., under a nitrogen atmosphere, was added concentrated nitric acid (27.5 g) dropwise. 2-Chloro-5-fluorotoluene (9 g) was added dropwise and the reaction was stirred for 2 hours. The reaction was poured into ice and extracted with ethyl acetate. The organic phase was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography [eluting with ethyl acetate/heptane (1:2)] to yield the title compound (9.4 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([NH:15][CH:16]([CH:30]([CH3:32])[CH3:31])[CH:17]([O:22][Si](C(C)(C)C)(C)C)[C:18]([F:21])([F:20])[F:19])=[O:14])[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:7][CH:6]=1)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[C:1]([NH:4][C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([NH:15][CH:16]([CH:30]([CH3:31])[CH3:32])[CH:17]([OH:22])[C:18]([F:20])([F:21])[F:19])=[O:14])[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cnc(-c2ccccc2)n(CC(=O)NC(C(C)C)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)Nc1cnc(-c2ccccc2)n(CC(=O)NC(C(C)C)C(O)C(F)(F)F)c1=O
Reaction time: 0.08 h
Yield: 87.9 %

Procedure:
To a solution of 2-(5-acetamido-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (0.86 g) in tetrahydrofuran (15 mL) at 0° C. was added tetrabutylammonium fluoride (1.95 mL, 1M in tetrahydrofuran) and the resulting solution was allowed to stir for 5 min. The mixture was poured into saturated aqueous ammonium chloride and the product extracted into ethyl acetate. The organic solution was washed (water), dried, and evaporated. The resulting white solid was collected and washed with ether:hexane to provide 2-(5-acetamido-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-hydroxypropyl)acetamide (0.6 g); NMR: 8.87 (s,1), 8.07 (d,1), 7.57 (m,5), 4.62 (d,1), 4.42 (d,1), 4.10 (m,1), 3.68 (t,1), 2.18 (s,3), 1.80 (m,1), 0.89 (d,3), 0.82 (d,3).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:28])([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br.[Br-].[K+].S([O-])([O-])=O.[Na+].[Na+].CBr>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:28])([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(P(=O)(c2ccc(OC)cc2)c2cccc3ccccc23)cc1
Agent: Br
Agent: CBr
Agent: O=S([O-])[O-]
Product: O=P(c1ccc(O)cc1)(c1ccc(O)cc1)c1cccc2ccccc12
Yield: 81.8 %

Procedure:
Bis(4-methoxyphenyl)(1-naphthyl)phosphine oxide (352 g, 0.906 mol), hydrobromic acid (1474 g, 48%, 8.74 mol), and potassium bromide (45 g, 0.378 mol) were heated at 110° C. for 96 h. The flask was fitted with a sodium sulfite scrubber for containment of methyl bromide. The mixture was worked up to give the product as a brown solid (267 g, 82% yield). 31P NMR (d6-DMSO): δ 35.19 (s, 5.2%), 30.96 (s, 74.4%), 27.16 (s, 19.3%). m.p. (DSC): 114.7° C.
Reaction SMILES: [CH:1]([NH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.S(=O)(=O)(O)O.[OH-].[NH4+]>O>[CH:1]1[NH:3][C:4](=[O:12])[CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=CNC(=O)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=c1cc2ccccc2c[nH]1
Reaction time: 4 h
Yield: 40 %

Procedure:
200 g. N-formyl-2-phenyl-acetamide are dissolved in an inert atmosphere (nitrogen) in 1250 ml. concentrated sulfuric acid, while stirring and cooling in a bath of cold water in order to maintain the temperature at about 20°-25°C., whereafter the reaction mixture is left to stand for 4 hours at ambient temperature. The sulfuric acid solution is then poured, with stirring, into about 4 liters of a mixture of ice and water, the temperature not exceeding 50°C. The reaction mixture is then filtered through "Hyflo Super-Cel" a very pure diatomaceous silica filter-aid sold by Johns-Manville Sales Corp. (HYFLO is a Trade Mark). The filtrate obtained is poured, while stirring mechanically and cooling in ice (temperature of the reaction medium about 20°C.), into 3.5 liters concentrated ammonium hydroxide solution. The yellow precipitate of 2H-3-isoquinolone obtained is filtered off, washed with water and dried. There are obtained 72 g. of product; m.p. 201°C.; yield 40% of theory.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=[O:14].[OH-].[K+].Cl>C(O)C>[Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn(-c2ccccc2)c1Br
Temperature: 0 °C
Yield: 64.2 %

Procedure:
A mixture of 15.5 g of 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester and 14 g of potassium hydroxide in 300 ml of 3A ethanol was refluxed for 3 hours. The solution was poured into ice water and acidified with concentrated hydrochloric acid. The precipitated solid was collected by filtration and recrystallized from ethanol/water to afford 9.0 g of 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid. Yield 64%. mp=218°-222° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[O:4][N:3]=1.[CH:16]([O-])([O-])[O:17][CH2:18][CH3:19]>>[CH2:18]([O:17][CH:16]=[N:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[O:4][N:3]=1)[CH3:19]
Reactant: CCOC([O-])[O-]
Reactant: Nc1noc(Cc2c(Cl)cccc2Cl)n1
Product: CCOC=Nc1noc(Cc2c(Cl)cccc2Cl)n1

Procedure:
1 g of 3-amino-5-(2,6-dichlorobenzyl)-1,2,4-oxadiazole is heated in air at 150° C. for 3 hours with a few ml of ethyl orthoformate in an amount which is just sufficient to ensure slight agitation. The excess ethyl orthoformate is driven off under reduced pressure. The residue is crystallised from ether.
Reaction SMILES: [S:1]([O:5][CH2:6][C@H:7]1[O:9][CH2:8]1)([CH3:4])(=[O:3])=[O:2].[ClH:10]>>[S:1]([O:5][CH2:6][C@@H:7]([OH:9])[CH2:8][Cl:10])([CH3:4])(=[O:3])=[O:2]
Reactant: Cl
Reactant: CS(=O)(=O)OC[C@@H]1CO1
Product: CS(=O)(=O)OC[C@@H](O)CCl
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Concentrated HCl (20 ml) was added to (S)-3-mesyloxy-1,2-epoxypropane (5.0 g, 0.033 m) over 15-20 minutes. After stirring for an additional 30 minutes, the water was removed through the addition and subsequent evaporation of ethanol. Finally, residual ethanol was removed at room temperature and 0.1 mm to give (R)-3-mesyloxy-2-hydroxy-1-chloropropane, (5.4 g, 85%); 1H NMR (CDCl3) 4.35 (2H, d), 4.1 (1H, m), 3.65 (2H, d), 3.1 (3H, s), 2.9 (1H, broad s); [α]D22 =7.1° (c=5.78, CH3OH).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[N:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[N:27]2[CH2:32][CH2:31][CH:30]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:8]=[CH:9][CH:10]=[C:11]5[C:16]=4[N:15]=[CH:14][CH:13]=[CH:12]5)[CH2:2][CH2:3]3)[CH2:29][CH2:28]2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: c1cnc2c(N3CCC(N4CCN(c5cccc6cccnc56)CC4)CC3)cccc2c1

Procedure:
Using the synthetic methods described in previous examples, 8-(piperazin-1-yl)quinoline (Oruz et al., J. Med. Chem. 45:4128 (2002)) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired product as a light yellow solid; MP. 194-196° C.; MS (ES) m/z (relative intensity) 424 (M+H)+ (100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:5]=1[OH:11].[CH2:13](OB(C=C)OCCCC)[CH2:14]CC>C1COCC1.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:13]=[CH2:14])=[CH:6][C:5]=1[OH:11]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C=CB(OCCCC)OCCCC
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(C(=O)OC)c(O)c1

Procedure:
A solution of 2-hydroxy-4-iodo-benzoic acid methyl ester (8.01 g, 0.0288 mol) in THF (184 ml) and H2O (46 ml) is treated with vinyl-boronic acid di-butyl ester (9.53 ml, 0.0432 mol, 1.5 eq.), NaCO3 (21.37 g, 0.201 mol, 7 eq.), and dichloro-bis(triphenyl-phosphine)palladium (1.01 g, 1.44 mmol, 5 mol %). The solution is purged with N2 (g) for 5 minutes and then heated to reflux for 2 hour. The reaction is concentrated in vacuo, diluted with EtOAc, and sequentially washed with H2O and saturated aqueous NaCl. The organic phase is dried over MgSO4, filtered, and concentrated. The crude product is purified with silica gel column chromatography (5% ethyl acetate in hexanes) to afford 2-hydroxy-4-vinyl-benzoic acid methyl ester: ESMS m/z 179.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:38])[CH3:37])=[CH:31][CH:30]=2)[N:28]=1>>[C:36]([NH:35][C:32]1[CH:33]=[CH:34][C:29]([C:27]2[N:28]=[C:24]([NH:23][C:17](=[O:19])[C:16]3[CH:15]=[CH:14][C:13]([S:10](=[O:12])(=[O:11])[N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH3:22])=[CH:21][CH:20]=3)[S:25][CH:26]=2)=[CH:30][CH:31]=1)(=[O:38])[CH3:37]
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3nc(-c4ccc(NC(C)=O)cc4)cs3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with N-(4-(2-aminothiazol-4-yl)phenyl)acetamide (61 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 30-90% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(4-(4-acetamidophenyl)thiazol-2-yl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamide as a yellow solid. Yield: 68 mg (49%). 1H-NMR: 10.03 (s, 1H), 8.27 (d, J=9.0 Hz, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.68-7.63 (m, 4H), 7.60 (s, 1H), 7.01 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 3.75 (s, 3H), 3.16 (s, 3H).