Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
(+)-[2-Fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (1.00 g, 2.6 mmol, prepared in example 1a), 4-carboxybenzene boronic acid (627 mg, 3.8 mmol), potassium carbonate (520 mg, 3.8 mmol), tetrakis(triphenyl phosphine)palladium(0) (206 mg, 0.2 mmol) and dioxane/water (112 mL, 3:1) were mixed together in a 250 mL single neck flask and stirred at 80° C. for 4 hours. The reaction was cooled to room temperature and poured into 1N HCl and the desired product was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 1.43 g as a dark oil. This material was purified via silica gel chromatography employing the chromatotron and using a 4000 micron rotor while eluting with a solvent of methylene chloride/methanol 9:1 to yield the title compound (355 mg, 36%) as a tan solid. Ion spray M.S. 378.3 (M*−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[C:20]([F:28])[CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:14])[F:16])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(Br)cc2)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(Br)cc2)cc1F
Yield: 51.7 %

Procedure:
A mixture of 2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-hydroxy-4-trifluoromethyl-4,5-dihydro-1H-imidazole (3.05 g, 6.33 mmol) and p-toluenesulfonic acid monohydrate (0.300 g) in toluene (250 mL) was heated to reflux for 21 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride (150 mL) and the whole washed with water, aqueous NaHCO3 (50 mL), and brine. After dried over MgSO4, and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (3/1) to give the subtitle compound (1.517 g, 51.8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([CH2:24][NH2:25])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C(N(CC)CC)C.[C:37](O)(=[O:40])[CH2:38][CH3:39]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:27])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([CH2:24][NH:25][C:37](=[O:40])[CH2:38][CH3:39])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CCC(=O)O
Reactant: NCc1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCc1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
1-{2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoro-methyl)-1,3-thiazol-5-yl}methanamine (0.1 g) and triethylamine (0.05 g) were added to dichloromethane (20 mL), followed by the dropwise addition of dichloromethane solution (10 mL) comprising anhydrous propionic acid (0.05 g) under ice cooling. After the dropwise addition was completed, the reaction solution was stirred at room temperature for one hour. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (0.1 g, 90%).
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10](=O)[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>N1C=CC=CC=1>[NH2:2][C:1]1[S:29][C:10]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[N:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)NC(=O)c1c(F)cccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2c(F)cccc2F)sc1N
Yield: 25 %

Procedure:
To a solution of the ethyl 2-cyano-2-(2,6-difluorobenzamido)acetate (1 eq) in pyridine (0.1 M) was added Lawesson's reagent (1.5 eq.). The mixture was stirred at reflux under Ar for 18 hours. Solvents were removed under reduced pressure. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to give the ethyl 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylate in 25% yield. LC/MS (m/z): 284.9 (MH+), Rt: 0.76 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].CO.C(=O)([O-])[O-].[NH4+:43].[NH4+]>ClCCl.CO>[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:43])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 78 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 78% of theory, C26H27N7O3 (485.6) Rf value: 0.31 (silica gel; dichloromethane/methanol=5:1) ##EQU43##
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:16])[C:6]2[C:12]([OH:13])=[CH:11][C:10]([O:14][CH3:15])=[CH:9][C:7]=2[CH:8]=1.[C-:17]#[N:18].[Na+].O>CS(C)=O>[C:17]([CH2:2][C:3]1[O:4][C:5](=[O:16])[C:6]2[C:12]([OH:13])=[CH:11][C:10]([O:14][CH3:15])=[CH:9][C:7]=2[CH:8]=1)#[N:18]
Reactant: [C-]#N
Reactant: COc1cc(O)c2c(=O)oc(CCl)cc2c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(O)c2c(=O)oc(CC#N)cc2c1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
5.00 g (20.78 mmol) of the 3-chloromethyl-8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran obtained in Example 2 was dissolved in 70 ml of dimethyl sulfoxide. 4.29 g (83.11 mmol) of sodium cyanide was added thereto, and the resulting mixture was stirred under an atmosphere of nitrogen at 15° C. for 30 minutes. After the addition of 300 ml of water, the reaction mixture was extracted with 600 ml and 250 ml×3 portions of ethyl acetate. The organic layer was washed three times with 200 ml portions of a 20% aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated to about 300 ml under reduced pressure. After the addition of 3 g of activated carbon, this solution was heated under reflux for 10 minutes. The activated carbon was removed by filtration through Celite, and the filtrate and the washings were concentrated to about 100 ml. The precipitated crystals were dissolved by heating under reflux, and then cooled with ice. The reprecipitated crystals were filtered off to obtain 4.08 g of the title compound in an 84% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[CH:34]1([C:32]([NH:31][C:27]2[CH:26]=[C:25]([CH:22]3[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:12]([C:9]4([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])[CH2:10][CH2:11]4)=[O:14])[CH2:24][CH2:23]3)[CH:30]=[CH:29][CH:28]=2)=[O:33])[CH2:35][CH2:36]1
Reactant: O=C(O)C1(c2ccc(Cl)cc2Cl)CC1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4Cl)CC3)CC2)c1)C1CC1

Procedure:
Example 117 was prepared from 1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropane carboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.00–7.82 (br, 1H), 7.52–7.04 (m, 6H), 6.86 (d, 1H, J=7.2 Hz), 5.92–5.73 (br, 1H), 3.35–3.12 (m, 4H), 2.74–2.58 (m, 2H), 2.58–2.42 (m, 1H), 2.40–2.20 (m, 2H), 2.01–1.61 (m, 7H), 1.15–0.90 (m, 6H), 0.89–0.71 (m, 2H); ESMS m/e: 514.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:14]3[C:10](=[CH:11][N:12]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[N:13]=3)[CH:9]=2)=[CH:5][CH:4]=1.B(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:14]3[C:10](=[CH:11][N:12]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[N:13]=3)[CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc3nn(-c4ccc(C#N)cc4)cc3c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: N#Cc1ccc(-n2cc3cc(Oc4ccc(O)cc4)ccc3n2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
A solution of 4-[5-(4-Methoxy-phenoxy)-indazol-2-yl]-benzonitrile (0.075 grams, 0.22 mmol) in 1.6 mL of methylene chloride was treated with tetrabutylammonium iodide (0.13 grams, 0.36 mmol). After cooling to −78° C., the mixture was treated dropwise with a solution of BCl3 in methylene chloride (0.81 mL, 1 M, 0.81 mmol). After stirring for 20 minutes, the mixture was slowly warmed to room temperature and was stirred for 1 hour. The mixture was cautiously neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo, affording 0.070 grams of 4-[5-(4-Hydroxy-phenoxy)-indazol-2-yl]-benzonitrile as a colorless solid. MS: 328.4 [M+H]+; 326.4 [M−H]−
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([N+:14]([O-])=O)[C:12]=2[NH2:13])[CH2:3][CH2:2]1>CO.[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[C:11]([NH2:14])[CH:10]=[N:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1c(N2CCOCC2)cncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cncc(N2CCOCC2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of 3-morpholino-5-nitropyridin-4-amine (LIII) (1 eq) in MeOH was added 10% Pd/C. The solution was purged with hydrogen and stirred overnight at r.t. under hydrogen. The suspension was filtered through Celite and concentrated under vacuum to produce 5-morpholinopyridine-3,4-diamine (LIV) as a purple solid (37% yield). 1H NMR (DMSO-d6, 400 MHz,): δ 3.09-3.11 (m, 4H), 3.64-3.66 (m, 4H), 3.92 (s, 2H), 5.23 (s, 2H), 6.94 (s, 1H), 7.33 (s, 1H). ESIMS found C9H14N4O m/z 195 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:16]=2)[CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a mixture of (7-hydroxy-naphthalen-1-yl)-carbamic acid tert-butyl ester (5.11 g, 19.7 mmol) and potassium carbonate (3.26 g, 23.6 mmol) in N,N-dimethylformamide is added benzyl bromide (3 mL, 4.31 g, 25.2 mmol) slowly. The mixture is then stirred at room temperature over night and poured into ice-water (150 mL). The resulting mixture is extracted with ethyl acetate (4×100 mL) and the organic portions are combined, washed with water and brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography (Hexanes/EtOAc=15/1) to give (7-benzyloxy-naphthalen-1-yl)-carbamic acid tert-butyl ester (5.93 g, 86.3%); 1H NMR 400 Hz (CDCl3) δ1.60 (s, 9H), 5.22 (s, 2H), 6.63 (br, 1H), 7.27 (m, 2H), 7.38 (m, 2H), 7.45 (m, 2H), 7.44 (d, J=7.44 Hz, 2H), 7.61 (d, J=8.11 Hz, 1H), 7.80 (m, 2H); MS m/z (M+Na+) 372.10.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[OH-].[Na+]>CN(C)C=O>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][C:21]([OH:24])=[O:22])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(CC#CCCCCO)cc1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(CC#CCCCC(=O)O)cc1

Procedure:
7-[p-(n-octyl)phenyl]-5-heptyn-1-ol (1.7 mmole) is dissolved in dimethyl formamide and to the resulting solution is added, with stirring, pyridinium dichromate (11.7 mmoles). After stirring for 48 hours at room temperature, the reaction mixture is poured onto a 10% sodium hydroxide solution and extracted with ethyl ether. The aqueous layer is acidified to pH of 2-3 with concentrated hydrochloric acid and extracted with chloroform. The chloroform layer is separated, the solvents removed by evaporation and the residue distilled under reduced pressure to afford the title compound, 7-[p-(n-octyl)phenyl]hept-5-ynoic acid.
Reaction SMILES: I[C:2]1[C:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:5]=2[N:4](C(OCC)=O)[N:3]=1.[N:23]1[CH:24]=[CH:25][N:26]2[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][C:27]=12.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[N:23]1[CH:24]=[CH:25][N:26]2[CH:31]=[C:30]([C:2]3[C:6]4[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:9][CH2:10][C:5]=4[NH:4][N:3]=3)[CH:29]=[CH:28][C:27]=12
Reactant: CCOC(=O)n1nc(I)c2c1CCN(C(=O)OC(C)(C)C)C2
Reactant: OB(O)c1ccc2nccn2c1
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: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc4nccn4c3)c2C1
Temperature: 160 °C

Procedure:
5-Tert-butyl 1-ethyl 3-iodo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-1,5(4H)-dicarboxylate (1 g, 0.002 mol), (synthesized from patent procedure: WO 2004014374 A1) was added to a vial containing imidazo[1,2-a]pyridin-6-ylboronic acid (0.577 g, 0.00356 mol) and tetrakis(triphenylphosphine)palladium (0.1372 g, 0.00011 mol). After purging the vial with nitrogen gas, dioxane: ethanol: water solution (7:3:2, 7.125 mL) and 2M sodium carbonate (0.007125 mol) was added to the vial respectively. The reaction mixture was stirred and was heated in the microwave at 160° C. for 20 min. Upon completion, the mixture was concentrated under vacuo. The residue was dissolved in ethyl acetate, and filtered through a fitted reservoir. The ethyl acetate layer was concentrated and columned using flash chromatography (0-100% ethyl acetate in hexane and 0-20% methanol in dichloromethane. The remaining residue that didn't dissolve in ethyl acetate was dissolved in methanol and filtered through a fritted reservoir. The methanol layer was concentrated and submitted for reverse phase prep. Pure product (quantitative yield) was recovered.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: Oc1cc2ccsc2c(Cl)c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2ccsc2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
A mixture of 3.6 g of 6,7-dichloro-5-hydroxybenzo[b]thiophene, 3.0 g of ethyl bromoacetate, 1.5 g of potassium carbonate and 40 ml of anhydrous dimethylformamide is stirred at 70°-80° for 16 hours. The cooled mixture is diluted with ice-water (200 g) and the solid collected by filtration. Recrystallization of the crude product from acetone-hexane gives 3.2 g of ethyl [(6,7-dichlorobenzo[b]thien-5-yl)oxy]acetate as yellowish needles, mp 92°-93°.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH2:15]([C:17]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:36]2([OH:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[C:30]([CH3:44])[CH:29]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:18][CH3:19])[CH3:16].C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[CH2:15]([C:17]([C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]2([OH:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)=[C:30]([CH3:44])[CH:29]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCCCCC2)c(C)c1
Agent: COCCO[Al+]OCCOC
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C2(O)CCCCCC2)c(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
Sodium bis(2-methoxyethoxy)aluminum hydride (65 wt % solution in toluene, 1.4 mL, 4.66 mmol) was added to a solution of 1-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenylethynyl}-cycloheptanol (Example 128-(1); 624 mg, 1.54 mmol) in tetrahydrofuran (7.5 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred at 0° C. for two hours. Brine and ethyl acetate were added to the reaction mixture, which was stirred for 20 minutes. Then, celite was added and the mixture was further stirred for 30 minutes. The mixture was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=90:10 to 50:50) to give the target compound as a colorless oil (629 mg, 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)C=O.F[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>O>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCOCC1
Reaction time: 3 h
Yield: 97.7 %

Procedure:
Morpholine (190 μl, 2.17 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (209 mg, 1.00 mmol, commercially available product). The resulting mixture was stirred for three hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=3/1). Thus, 4-[2-nitro-4-(trifluoromethyl)phenyl]morpholine (270 mg, 97.7%) was yielded as an orange-colored oily material.
Reaction SMILES: [NH2:1][P:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[OH:3].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C.Cl>O>[CH2:13]([O:20][C:21]([NH:1][P:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[OH:4])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NP(=O)(O)CCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=C(NP(=O)(O)CCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Compound 2 (1.1 g, 6 mmole) is dissolved in 10 ml of water and then the pH of this solution is adjusted to 9.5 with the aid of a 4N soda solution. To this mixture cooled in an icebath is gently added benzylchloroformate (1.2 ml, 7.5 mmole), whilst maintaining the pH of the reaction at 9.5 by successive soda additions. Stirring of the reaction mixture is maintained at 0° C. for 30 min. and then for 1 h at ambient temperature. After diethyl ether treatment, the mixture is cooled, and then acidified by the addition of hydrochloric acid. The product which precipitates is filtered, washed with cold water and dried. The expected compound 3 is obtained with a 76% yield (1.5 g), RF(1)=0.57, RF(2)=0.76, m.p. 110° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C(COC)OC.O.C(Cl)(Cl)Cl.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:1][C:2]1[C:7]([CH3:8])=[C:6]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1c(Cl)ncnc1Cl
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: COCCOC
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)ncnc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 65.8 %

Procedure:
To a solution of 4,6-dichloro-5-methylpyrimidine (1 g, 6.13 mmol) in dimethoxyethane (28 mL) and water (14 mL) was added sodium carbonate (1.69 g, 16.0 mmol), 4-trifluoromethylphenylboronic acid (1.165 g, 6.13 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.14 g). The resulting mixture was heated at reflux under nitrogen for 18 h, the reaction mixture was allowed to cool to room temperature and diluted with water (100 mL) before extraction into CHCl3 (2×100 mL). The organic solution separated by hydrophobic frit and the solvents removed in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting with 19:1 cyclohexane:EtOAc afforded the title compound as a white solid (1.1 g).