Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](P(=O)=O)[C:3]=1[OH:11].[P:12](C1C(C)=CC=CC=1O)(=[O:14])=[O:13]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][P:12](=[O:14])=[O:13]
Reactant: Cc1cccc(O)c1P(=O)=O
Reactant: Cc1cccc(P(=O)=O)c1O
Product: Cc1ccccc1OP(=O)=O

Procedure:
The mixing ratio of 2-methyl-6-phosphophenol and its positional isomer, 2-phospho-3-methyl phenol, was 5:3. The mixing ratio was obtained from the integral values of the spectrum of the two compounds using 1H-NMR.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[O:25][CH3:26].[Cl-].[Na+]>CN(C=O)C.O>[CH3:26][O:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[N:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]1=[O:8]
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: CN1CCCNC1=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1N1CCCN(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
450 mg (3.94 mmol) of 1-methyltetrahydropyrimidin-2(1H)-one in 15 ml of DMF are admixed at 0° C. with 663 mg (5.91 mmol) of potassium tert-butoxide, and the mixture is stirred at room temperature for 30 min. 742 mg (4.33 mmol) of 1-fluoro-2-methoxy-4-nitrobenzene are added and the mixture is stirred at RT. After 2 h, the mixture is admixed with 150 ml of water and 8 ml of saturated aqueous sodium chloride solution, and extracted three times with 30 ml each time of ethyl acetate. The combined organic phases are washed with 30 ml of water and then dried over sodium sulfate. After filtration, the solvents are removed under reduced pressure. The residue is purified by chromatography on silica gel (1:5→1:10 cyclohexane/ethyl acetate). This affords 457 mg (43% of theory) of the desired compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](F)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC([O:24]C(Cl)=O)C.CO>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([OH:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: FC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Solvent: CO
Solvent: ClCCl
Product: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 55 %

Procedure:
To 1-benzyl-4-fluoro-4-phenyl-piperidine (0.22 g) in dry DCM (5 mL) was added 1-chloroethylchloroformate (1 mmol). The mixture was stirred for 1 hour and then methanol (5 mL) was added and the mixture stirred overnight. The solvent was removed under vacuum, and the resulting solid triturated from diethyl ether to give the title compound as a white solid (0.12 g). LCMS m/z 180.1 [M+H]+. R.T.=2.27 min (Analytical Method 4).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](I)[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C>[CH2:23]([N:20]1[CH2:19][CH2:18][N:17]([C:9]2[CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:22][CH2:21]1)[CH3:24]
Reactant: CCI
Reactant: c1ccc(-c2cc(N3CCNCC3)nc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCN1CCN(c2cc(-c3ccccc3)c3ccccc3n2)CC1
Yield: 85.1 %

Procedure:
A stirred suspension of 3.0 g of 4-phenyl-2-(1-piperazinyl)quinoline, 1.9 g of ethyl iodide and 1.1 g of sodium carbonate in 30 ml of methyl ethyl ketone was heated under reflux for 12 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added water and the resulting mixture was extracted with ethyl acetate. The dried extracts were concentrated to give an oily residue, which was chromatographed on silica gel (30 g) using chloroform as an eluent. There was obtained the title compound (2.8 g, 85%), m.p. 87°-88° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Product: O=C(O)CCC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
3-(4-Bromobenzoyl)propionic acid was added in portions to well stirred fuming nitric acid at -15° C and the resultant mixture stirred a further 30 minutes then poured into ice-water to give 3-(4-bromo-3-nitrobenzoyl)propionic acid.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][OH:6])=[CH2:2].[CH2:7]([CH:9]1[O:11][CH2:10]1)Br.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH:9]1[O:11][CH2:10]1)=[CH2:2]
Reactant: C=COCCO
Reactant: BrCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COCCOCC1CO1
Temperature: 80 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a 1000 ml three-necked round bottom flask, equipped with a thermocouple, magnetic stirrer and heating mantle, was added ethylene glycol vinyl ether (35.2 g; 0.400 moles), epibromohydrin (62.4 g; 0.456 mole), toluene (200 ml), and tetrabutylammonium bromide (1.5 g). Sodium hydroxide pellets (32 g 0.8 moles) were then added portionwise, with the reaction temperature maintained at 80° C. The reaction mixture was vigorously stirred for a period of time of about 1 hour at a temperature of 80° C. The mixture was then filtered and rinsed with a small amount of toluene. The toluene was removed using a rotary evaporator under reduced pressure and the crude product distilled under vacuum to yield 2-vinyloxyethylglycidyl ether (“VEGE”) (34.6 g; 60% yield), b.p. 55-57° C. at 0.75 torr. The structure of VEGE was confirmed by 1H NMR analysis (300 MHz; CDCl3): δ 6.5 (q, 1H, CH2═CH—), δ 4.0 and 4.2 (two d, 2H, CH2═CH—), δ 3.85 (m, 4H, O—CH2—CH2—O), δ 3.8 and 3.45 (m, 2H, O—CH2—CH—), δ 3.2 (m, 1H, epoxide ring —CH(CH2)—O), δ 2.6 and 2.8 (m, 2H, epoxide ring —CH(CH2)—O).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>CCC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[CH2:19]([O:11][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=1[F:10])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: CCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1c(F)c(F)cc(F)c1F
Yield: 99.6 %

Procedure:
To 20.0 g of 2,3,5,6-tetrafluorophenol (1) dissolved in 100 mL of MEK there were added 18.3 g of potassium carbonate, 4.26 g of TBAB and 32.0 g of bromodecane dissolved in 50 mL of MEK, with heating under reflux for 4 hours. After cooling and addition of water, the organic layer was separated and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. The solvent was evaporated to yield 36.8 g (120 mmol) of 4-decyloxy-2,3,5,6-tetrafluorobenzene (10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[N:16][NH2:17])[CH2:11]1)=[O:9].C(N(CC)CC)C.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]2[C:30]([C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)=[N:17][N:16]=[C:12]2[CH2:11]1)=[O:9]
Reactant: O=C(Cl)c1ccco1
Reactant: NN=C1CN(C(=O)c2ccccc2Cl)CCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1Cl)N1CCn2c(nnc2-c2ccco2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-[(2-chlorophenyl)carbonyl]-2-piperazinone hydrazone (140) (715 mg, 2.83 mmol) and triethylamine (0.986 mL, 7.08 mmol) were dissolved in Dichloromethane (DCM) (10 mL). 2-furancarbonyl chloride (0.306 mL, 3.11 mmol, commercially available from e.g. Sigma-Aldrich, Apollo or Acros) was added and the solution stirred at 25° C. for 4 hr. Solvents were removed in vacuo and the residue was dissolved in n-butanol (10.00 mL). The solution was heated at reflux for 4 hours and the solvents were removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was extracted with ethyl acetate (3×25 mL), the combined extracts were washed with water (3×50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated to a crude solid in 925 mg. The product was purified by flash chromatography (Isolera, 100 g, 0-100% Methanol:Dichloromethane (1:9)/Dichloromethane) to afford product in 260 mg. This was further purified by MDAP to afford product in 85 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH:30](O)(C)C>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)=[O:5])([CH3:30])[CH3:2]
Reactant: CC(C)O
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c2c1COC
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c12

Procedure:
0.2 g (5 mmol) of 5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester is refluxed for 2 hours in 35 ml of isopropanol with 0.15 ml (0.5 mmol) of titanium tetraisopropylate. The mixture is filtered and the filtrate concentrated by evaporation to approximately a third. 0.112 g (54% of theory) of 5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester crystallizes out, melting point 187°-189° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N:3]=1.[OH-:10].[K+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N+:3]=1[O-:10]
Reactant: CCc1cccc(Br)n1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCc1cccc(Br)[n+]1[O-]
Temperature: 50 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of 2-bromo-6-ethyl-pyridine (15.4 g, 82.8 mmol) (S. G. Davies and M. R. Shipton, J. Chem. Soc., Perkin Trans. 1, 1991, 3, 501) in acetic acid (15 ml) peracetic acid (26 ml of a 39% solution) was added maintaining T<50° C. After completed addition the mixture was stirred at 50° C. for 5 hr and then cooled to rt. Crushed ice (40 g) was added and the mixture was made basic (pH 12) using 40% KOH solution. After extraction with CHCl3 (6×60 ml) the combined organic phases were dried (Na2CO3) and evaporated to give 20.0 g (>100%) of the title compound, MS: m/e=201 (M+) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.[H-].[Na+].Br[CH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.O>CN(C=O)C.CCOC(C)=O>[CH:36]1([CH2:35][CH2:34][N:23]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:22]=2)[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: Cn1nnnc1C(=NOCc1cccc(NC(=O)OC(C)(C)C)n1)c1ccccc1
Reactant: BrCCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnnc1C(=NOCc1cccc(N(CCC2CCCCC2)C(=O)OC(C)(C)C)n1)c1ccccc1
Reaction time: 1 h
Yield: 106.5 %

Procedure:
A stirred solution of tert-butyl {6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (0.2 g, 0.488 mmol, 1 eq.) in 3 ml of dry DMF was treated with NaH (60% dispn in mineral oil, 0.020 g, 0.513 mmol, 1.05 eq.) added in one portion. After 20 mins (2-bromoethyl)cyclohexane (0.098 g, 0.513 mmol, 1.05 eq.) was added and the reaction was stirred for 1 hr. Water was added followed by EtOAc. The aqueous layer was separated and extracted with EtOAc. Then the organics were combined, dried over MgSO4 and evaporated to give tert-butyl (2-cyclohexylethyl){6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (0.27 g, 85%) as a viscous oil
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:3]1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=2[CH:51]=1>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:3][CH:2]2[O:1][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=3[CH:51]=2)=[CH:9][CH:10]=1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: COc1ccccc1OCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 1.08 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxyphenoxy)propoxy]phenyl}piperidine-1-carboxylate and 0.714 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a colourless oil. Rf=0.33 (1:1 EtOAc-heptane); Rt=5.75.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH:16]([CH3:18])[CH3:17].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][C@@H:20]([NH:19][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:42])([F:41])[F:43]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(C(C)C)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(C(C)C)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.2 %

Procedure:
To a solution of 5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylic acid (137 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [Prepared in Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.572 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide (211 mg, 0.334 mmol, 64.2% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[S:5][C:6]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Cl:16][S:17](O)(=[O:19])=[O:18].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[P+]=O>C(Cl)Cl>[C:13]([NH:12][C:4]1[S:5][C:6]([C:7]2[S:8][C:9]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:10][CH:11]=2)=[C:2]([CH3:1])[N:3]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1nc(C)c(-c2cccs2)s1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=[P+]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N-[4-methyl-5-(2-thienyl)-1,3-thiazol-2-yl]acetamide, prepared in Step I (500 mg; 2.10 mmol; 1 eq.) is dissolved in DCM (30 ml). The reaction mixture is cooled down to 0° C. and chlorosulfonic acid (0.70 ml; 10.49 mmol; 5 eq.) dissolved in DCM (30 ml) is added dropwise over 15 min. The solution becomes pink. It is stirred 15 minutes at 0° C. Phosphorus pentachloride (873.7 mg; 4.20 mmol; 2 eq.) and phosphorus oxide chloride (0.78 ml; 8.39 mmol; 4 eq.) are added successively. The reaction mixture is stirred for 2 additional hours at room temperature. It is poured on ice and the desired product is extracted with 2 portions of EtOAc, dried over MgSO4, and evaporated, affording 5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride as yellow solid (650 mg; 92%). M− (ESI): 335.08; M+ (ESI): 337.08.
Reaction SMILES: [Cl-].C[SiH](C)C.Br[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH3:8].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:16][C:17]1[CH:22]=[C:21]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH3:8])[N:20]=[CH:19][N:18]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(Br)c1cccc(F)c1
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1cccc(F)c1)c1cc(Cl)ncn1
Reaction time: 0.33 h
Yield: 18.4 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 2.0 g of 1-(1-bromoethyl)-3-fluorobenzene dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution M). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.2 g of tetrakistriphenylphosphine palladium, to which the above solution M was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.43 g of 4-chloro-6-(1-(3-fluorophenyl)ethyl)pyrimidine.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=O)[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[C:22]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24]>>[C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:19][C:20]3[CH:21]=[C:22]([C:23](=[O:24])[NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=4)[CH:36]=[CH:37][C:38]=3[CH3:39])=[O:18])[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)Nc1nccc2c(C(=O)O)cccc12
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1N
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Yield: 100 %

Procedure:
The procedures of Step (3) of Example 1 were repeated, except for using 1-(t-butylamino)isoquinoline-5-carboxylic acid (0.33 g, 1.35 mmol) obtained in Step (6) of Preparation Example 1 and 3-amino-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide obtained in Step (2) above to obtain the title compound (88 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=2)[C:17]([CH3:42])=[C:16]3[CH3:43])=[O:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:44]1(B(O)O)[CH2:46][CH2:45]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:44]1([C:2]2[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]5[C:30]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:27][CH:28]=3)[C:17]([CH3:42])=[C:16]4[CH3:43])=[O:12])[CH3:9])[CH:5]=[CH:6][CH:7]=2)[CH2:46][CH2:45]1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(Br)c3)cc12
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C4CC4)c3)cc12

Procedure:
A mixture of (S)-tert-butyl 4′-((5-((1-(3-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (24 mg, 0.038 mmol), cyclopropylboronic acid (7 mg, 0.081 mmol), Palladium(II) acetate (3.5 mg, 0.016 mmol) tricyclohexylphosphine (9 mg, 0.032 mmol) and potassium phosphate, tribasic, (23 mg, 0.11 mmol) in toluene (0.7 mL) and water (0.07 mL) was heated at 100° C. for 1 h in a Biotage Microwave reactor. The solvent was removed; the residue was filtered and purified by preparative HPLC to yield the title compound as a white solid.
Reaction SMILES: C1(=O)CCCCC1.C#CCCCCCC.[CH:16](/[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:30])=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[CH:16](/[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:30])=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCC/C=C/C1CCCCC1=O
Agent: [Co+2]
Agent: [Mn+2]
Agent: C#CCCCCCC
Solvent: O=C1CCCCC1
Solvent: CC(=O)O
Product: CCCCCC/C=C\C1CCCCC1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 20 mmol of cyclohexanone, 2 mmol of 1-octyne, 0.01 mmol of manganese(II) acetate, 0.002 mmol of cobalt (II) acetate and 2 ml of acetic acid was stirred at 50° C. in an atmosphere of air (1 atm=0.101 MPa) for 8 hours. The resulting reaction mixture was analyzed to find that trans-2-(1-octenyl)cyclohexanone and cis-2-(1-octenyl) cyclohexanone were produced in yields of 16% and 13%, respectively, with a conversion from 1-octyne of 45%.
Reaction SMILES: NC1C=CC=C2C=1N(C)N=C2.I[C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>>[N+:22]([C:21]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])([O-:24])=[O:23]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1I
Agent: Cn1ncc2cccc(N)c21
Product: O=C(O)c1cccc([N+](=O)[O-])c1
Yield: 33 %

Procedure:
Reaction of 7-amino-1-methylindazole and 2-iodo-3-nitrobenzoic acid as above gave 2-8 (1-methyl-1H-indazol-7-yl)amino]-3-nitrobenzoic acid (33% yield); mp (EtOAc/n-hexane) 240-244° C.; 1H NMR [(CD3)2SO] δ 4.33 (s, 3 H, NCH3), 6.55 (d, J=7.5 Hz, 1 H, ArH), 6.84 (t, J=7.7 Hz, 1 H, ArH), 6.90 (t, J=7.7 Hz, 1 H, ArH), 7.36 (d, J=7.9 Hz, 1 H, ArH), 7.80 (dd, J=8.1, 1.7 Hz, 1 H, ArH), 8.00 (s, 1 H, ArH), 8.31 (dd, J=7.5, 1.7 Hz, 1 H, ArH), 13.47 (br s, 1 H, COOH).