Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N12CCCN=C1CCCCC2.Cl>ClCCl>[C:25]([Si:22]([CH3:24])([CH3:23])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccc(O)cc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(N3C(=O)c4ccccc4C3=O)c2c1
Yield: 79.6 %

Procedure:
To a suspension of 32.26 g (0.115 mol) of 2-(5-hydroxy-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione in 320 ml of dichloromethane, a solution of 43.54 g (0.288 mol) of TBDMS chloride in 150 ml of dichloromethane was added. The resulting mixture was treated dropwise with 35.5 ml (0.23 mol) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature, obtaining a clear solution. After 3 hours the reaction mixture was poured in 300 ml of a solution 0.1 N of hydrochloric acid. The aqueous layer was separated and extracted with 200 ml of dichloromethane. Organic extracts were dried over sodium sulfate and the solvent evaporated under vacuum. The raw product was purified by flash chromatography over silica gel eluiting with dichloromethane-cyclohexane-ethyl acetate (4:4:2). 36.03 g of product as white solid were obtained. Yield=79.2%. mp=225-228° C. HPLC r.t. 8.3 [M+H]+=394 [2M+H]+=787
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][SH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:15][CH:16]=[C:17]([F:19])[F:18]>>[C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][S:11][C:17]([F:19])([F:18])[CH2:16][Cl:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CS)C(=O)O
Reactant: FC(F)=CCl
Product: CC(C)(C)OC(=O)N[C@@H](CSC(F)(F)CCl)C(=O)O

Procedure:
N-Boc-L-cysteine is reacted with 2-chloro-1,1-difluoro-ethene in the same manner as described in J. Chem, Res. Miniprint 12, 1990; p 2868 to form N-Boc-S-(2-chloro-1,1-di fluoroethyl)-L-cysteine. N-Boc-S-(2-chloro-1,1-difluoroethyl)-L-cysteine is reacted with potassium phthalimide in DMF at 100° C. to form the phthalimide. The phthalimide is treated with hydrazine in ethanol to form the amine. The amine is treated with ethyl acetimidate hydrochloride to form the amidine. This material is purified via C-18 chromatography to afford the Boc compound. The Boc group is removed with HCl/dioxane (4 N) in acetic acid to afford the title compound.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:58][O:59][CH3:60])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([S:55][CH2:56][Cl:57])=[C:35]3[C:39]([O:41]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:40])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OC(C)C)(C)C.[F:68][C:69]([F:74])([F:73])[C:70]([OH:72])=[O:71]>CCOCC>[F:68][C:69]([F:74])([F:73])[C:70]([OH:72])=[O:71].[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:58][O:59][CH3:60])[C:27]([NH:29][C@H:30]2[C:37](=[O:38])[N:36]3[C@@H:31]2[CH2:32][S:33][C:34]([S:55][CH2:56][Cl:57])=[C:35]3[C:39]([OH:41])=[O:40])=[O:28])[N:25]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCCl)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Product: CON=C(C(=O)N[C@H]1C(=O)N2C(C(=O)O)=C(SCCl)SC[C@H]12)c1csc(N)n1
Temperature: 0 °C

Procedure:
162 mg of the product of step A in 1.5 ml of trifluoroacetic acid was stirred at 0° C. in an inert atmosphere for 5 minutes and the solution obtained was poured into 25 ml of isopropy ether. The mixture was cooled to 0° C. stirred for several minutes. and then centrifuged. The residue was suspended in 25 ml of ether and this was centrifuged again and the operation was repeated. The trifluoracetate was dried under reduced pressure to obtain 88 mg of syn isomer of racemic cis 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-chloromethylthio-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid trifluoroacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]([O:26][CH3:27])=[CH:5][C:4]=1[N+:28]([O-])=O.[H][H]>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]([O:26][CH3:27])=[CH:5][C:4]=1[NH2:28]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCOc1cc(OC)c([N+](=O)[O-])cc1OC
Agent: [Ni]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOc1cc(OC)c(N)cc1OC

Procedure:
In an autoclave 49.5 g (0.117 mole) of 2,5-dimethoxy-4-hexadecyloxy nitrobenzene dissolved in 120 ml of ethanol were hydrogenated using 2.5 ml of Raney-nickel, a hydrogen pressure between 750 and 1500 psi and a temperature of 70° C. After 3 h of agitation the catalyst was filtered off and the filtrate was cooled in ice. The residue formed was filtered off, stirred in ethanol and dried. Yield: 39.5 g (86%). Melting point: 61° C.
Reaction SMILES: [I-:1].[Na+].I.Cl[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1>CC(C)=O>[I:1][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1
Reactant: [I-]
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: I
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(I)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium iodide (20.59 g, 137.40 mmol) was cooled to -78° C. under argon and then hydriodic acid (97.13 g, 759.34 mmol) was added. The cooling bath was removed and the suspension was stirred for 5 minutes. To this mixture was added 6-chloronicotinic acid (22.09 g, 140.20 mmol) and the resulting mixture was slowly warmed to ambient temperature with stirring. The mixture was heated to reflux at 125° C. for 24 hours, cooled to ambient temperature and poured into acetone (500 ml) at 0C. The yellow solid was collected by filtration and washed with 200 ml of 1N aqueous NaHSO3 solution. Recrystallization from methanol (crystals were washed with ethyl ether) afforded the title compound as white crystals: mp 177°-179° C. [lit. mp 187-192, Newkome et al. "Reductive Dehalogenation of Electron-Poor Heterocycles: Nicotinic Acid Derivatives" J Org. Chem. 51: 953-954 (1986). 1H NMR (DMSO-d6): δ8.81 (1H, dd, J=0.8, 2.4 Hz), 8.01 (1H, dd, J=0.8, 8.2 Hz), 7.91 (1H, dd, J=2.4, 8.2 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH:8]([P:11]([CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:13][NH2:14])([CH3:10])[CH3:9]>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N:14][CH2:13][CH2:12][P:11]([CH:15]([CH3:17])[CH3:16])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)P(CCN)C(C)C
Reactant: O=Cc1ccc[nH]1
Product: CC(C)P(CCN=Cc1ccc[nH]1)C(C)C
Yield: 97.2 %

Procedure:
Replicate the preparation of the ligand used in Ex. 7 except use 0.2 g (2.103 mmol) of pyrrole-2-carbaldehyde and use adding 0.356 g (2.208 mmol) of 2-(di-isopropylphosphino)ethanamine instead of N1,N1-dimethylethane-1,2-diamine to give 0.487 g (97%) of N-((1H-pyrrol-2-yl)methylene)-2-(di(propan-2-yl)phosphino)ethanamine as a colorless, semi solid, which is analytically pure by GC-MS and 1H-NMR: 1H NMR (400 MHz, Benzene): δ 10.05 (s, 1H), 7.83 (s, 1H), 6.51 (s, 1H), 6.44 (m, J=2.2 Hz, 1H), 6.28-6.14 (m, 1H), 3.67 (dd, J=15.2, 6.9 Hz, 2H), 1.75-1.64 (m, 2H), 1.58 (dq, J=6.9, 5.3 Hz, 2H), 1.00 (ddd, J=14.8, 12.3, 7.1 Hz, 12H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-5-Chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([OH:17])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:20])=O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([Cl:20])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Product: O=C(Cl)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1

Procedure:
Was prepared by stirring a mixture of 5-(4-nitrophenyl)-2-furoic acid (1.0 g, 4.3 mmol) and thionyl chloride (10 ml) at reflux for 2 hours. The mixture was evaporated and co-evaporated with anhydrous toluene. The acid chloride was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)O)[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:26])=O>ClCCl>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)[Cl:26])[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Cc1cccc(C(O)c2cccc(CC(C)C)c2)c1
Solvent: ClCCl
Product: CC(C)Cc1cccc(C(Cl)c2cccc(CC(C)C)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of bis(3-isobutylphenyl)methanol (2.87 g) and oxalyl chloride (1 ml) in dichloromethane (10 ml) was stirred at 25° C. for 2 hours. After evaporation of the solvent, the oily residue was distilled to give bis(3-isobutylphenyl)chloromethane (2.45 g) as pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[S:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15]Br>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8](=[S:10])[CH2:9][Br:15]
Reactant: CC(=S)c1cccc(C)c1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C(=S)CBr)c1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
m-Methylthioacetophenone (7.14 g, 43 mmol) was dissolved in chloroform (100 ml). Aluminium chloride (catalytic amount) and bromine (2.2 ml, 43 mmol) were added and stirred for 1 h. The reaction was quenched with aqueous sodium chloride-sodium bicarbonate and the organic layer separated, dried (MgSO4) and evaporated under reduced pressure. The residue was taken up in ethyl acetate, washed with aqueous sodium bicarbonate, then brine, dried (MgSO4) and evaporated under reduced pressure to yield m-Methylthiophenacyl bromide (7.64 g, 73%); δH(CDCl3) 7.1-7.9(4H,m, aryl), 4.40(2H,S,CH2), 2.45(3H,S,SCH3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[O:8][CH2:27][CH:29]1[CH2:30][O:31]1
Reactant: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOCC
Product: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1OCC1CO1
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A solution of 3-(3-chloro-4-hydroxy-5-methoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (550 mg, 1.41 mmol, Intermediate 14) in isopropanol (10 mL) and 3 N aq. NaOH (4 mL) is treated with epichlorohydrine (0.88 g, 7.04 mmol). The dark red reaction mixture is stirred at 60° C. for 1 h. The mixture is diluted with diethyl ether (150 mL) and washed with sat. aq. NaHCO3 followed by water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 3-(3-chloro-5-methoxy-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (400 mg) as a pale yellow oil; LC-MS: tR=1.14 min, [M+1]+=447.21; 1H NMR (CDCl3): δ 6.85-6.81 (m, 1H), 6.71-6.67 (m, 1H), 4.13 (dd, J=4.1, 11.1 Hz, 1H), 4.01 (dd, J=5.9, 11.1 Hz, 1H), 3.83 (s, 3H), 3.44-3.36 (m, 1H), 3.08-2.75 (m, 8H), 2.37 (s, 3H), 1.92-1.86 (m, 2H), 1.11 (s, 3H), 0.70 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][C:27]=1[CH:32]=O)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][C:27]=1[CH:32]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:12][C:11]1=[O:17])=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3F)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (57.5 mg, 50%).
Reaction SMILES: [CH2:1]([N:7]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](OC)([O:24]C)[C:20]([F:23])([F:22])[F:21])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].FC(F)(F)C(O)=O.C(N(CCCC(OCC)=O)CCOC1C=CC(CCC(=O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:28]([N:7]([CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19](=[O:24])[C:20]([F:22])([F:23])[F:21])=[CH:15][CH:16]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCN(CCCCCC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Agent: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCN(CCCCCC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Yield: 78.2 %

Procedure:
N-Hexyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]dodecylamine (353 mg, 0.63 mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4-(4,4,4-trifluoro-3-oxobut-1-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester. The residue was chromatographed on silica gel (dichloromethane/methanol 98:2 to 94:6) to afford the title compound (253 mg, 78%) as a pale yellow oil
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:12]([O-:14])=[O:13])=[N:9][C:10]=1[CH3:11])([CH3:3])[CH3:2].[Li+].[OH-].O.CCOC(C)=O>C1COCC1.O>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[N:9][C:10]=1[CH3:11])([CH3:3])[CH3:2]
Reactant: Cc1nc(C(=O)[O-])ccc1OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
5-Isopropoxy-6-methylpicolinate (1.3 g, 6.22 mmol) was dissolved in THF/water 2:1 (9 mL). LiOH*H2O (0.26 g, 6.22 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was poured into a mixture of water and EtOAc and the layers were separated. The aqueous layer was acidified to pH 4 with 2 N HCl and was extracted with EtOAc (2×). The combined organics were dried (Na2SO4) and concentrated in vacuo to give 5-isopropoxy-6-methylpicolinic acid (860 mg, 74%) as a beige solid. 1H-NMR (300 MHz, DMSO) 1.31 (d, 6H), 4.73 (m, 1H), 7.44 (d, 1H), 7.86 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([OH:16])(=[O:15])[CH2:11]C(O)=O.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][CH:6]([C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:11][C:10]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: [NH4+]
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1ccc(Br)cc1

Procedure:
4-Bromobenzaldehyde (50.0 g, 270 mmol), malonic acid (28.1 g, 270 mmol) and ammonium acetate (27.7 g, 359 mmol, 1.3 eq.) are dissolved in ethanol (400 ml). The mixture is heated at reflux for 16 h. The resulting solid is collected on a glass filter funnel, collected with suction filtration and washed with ethanol. The residue is then recrystallized from methanol (80 ml). It is subsequently triturated with ethyl acetate and collected by suction filtration. 41.0 g (0.16 mmol, 62% of theory) of the title compound are obtained as a colorless crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1.[N+:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([O-:21])=[O:20].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:22]([N+:19]([O-:21])=[O:20])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: COc1ccc(/C=C/C(=O)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(CC(=O)c1ccccc1)c1ccc(OC)cc1)[N+](=O)[O-]
Yield: 92.5 %

Procedure:
A solution of (2E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (5 g, 20.98 mmol) and ethyl nitroacetate (2.32 ml, 20.98 mmol) in triethylamine (8.77 ml, 62.94 mmol) was stirred at 75° C. for 4 h. Ethyl acetate (500 ml) was added and the solution obtained was washed with HCl 1N (4×250 ml), dried over Na2SO4 and evaporated under reduced pressure, to obtain 7.21 g of ethyl 3-(4-methoxyphenyl)-2-nitro-5-oxo-5-phenylpentanoate.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[C:5](O)([CH3:8])([CH3:7])[CH3:6].S(=O)(=O)(O)[OH:11]>C(O)(=O)C>[C:5]([NH:4][C:1](=[O:11])[CH:2]=[CH2:3])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)O
Reactant: C=CC#N
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: C=CC(=O)NC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of acrylonitrile (5.3 g), tert-butyl alcohol (7.4 g) and acetic acid (50 ml), cooled in an ice-bath, was added dropwise concentrated sulfuric acid (10.1 g, 97%) at a temperature below 40° C. The mixture was held at 40° C. for 1 hour and then poured into 200 g of ice water with constant stirring. The precipitate was filtered, washed with water and dried to afford N-tert-butylacrylamide (10.3 g, 82.4%); m.p. 124°-6° C.
Reaction SMILES: [Na+].[I-:2].CN[C@@H]1CCCC[C@H]1NC.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O)CCCC>[Cu]I>[I:2][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: [I-]
Reactant: Brc1ccccc1C1CCCCC1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCCCCO
Product: Ic1ccccc1C1CCCCC1
Temperature: 130 °C
Reaction time: 40 h
Yield: 98.9 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), NaI (300 mg, 2.00 mmol), evacuated and backfilled with argon. Racemic trans-N,N′-dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %), l-bromo-2-cyclohexylbenzene (97% pure; Lancaster; 186 μL, 1.00 mmol), n-pentanol (1 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 40 h. The resulting suspension was allowed to reach room temperature and filtered through silica gel (1×0.5 cm) eluting with hexane (50 mL). The filtrate was concentrated, and the residue was purified by flash chromatography on silica gel (hexane) to provide the known 1-iodo-2-cyclohexylbenzene (283 mg, 99% yield; ca. 97% pure) as a colorless liquid. See McGuine, T. H.; Dull, M. F. J. Am. Chem. Soc. 1947, 69, 1469. 1H NMR (400 MHz, CDCl3): δ 7.85 (dd, J=7.5, 1.2 Hz, 1H), 7.32 (td, J=7.5, 1.2 Hz, 1H), 7.23 (dd, J=7.5, 1.7 Hz, 1H), 6.90 (td, J=7.5, 1.7Hz, 1H), 2.81 (tt, J=11.7, 3.0Hz, 1H), 1.97-1.74 (m, 5H), 1.55-1.23 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 149.3, 139.5, 128.4, 127.6, 126.6, 101.5, 48.5, 33.4, 26.8, 26.1.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([N:13]([CH2:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][CH3:15])=[C:9]([C:11]#[N:12])[CH:10]=[C:5]2[N:4]([CH3:22])[CH:3]=1.[CH3:23][Mg]Br.O>C1COCC1>[CH:17]1([CH2:16][N:13]([C:8]2[N:7]=[C:6]3[C:2]([CH3:23])=[CH:3][N:4]([CH3:22])[C:5]3=[CH:10][C:9]=2[C:11]#[N:12])[CH2:14][CH3:15])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C[Mg]Br
Reactant: CCN(CC1CCCC1)c1nc2c(Br)cn(C)c2cc1C#N
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC1CCCC1)c1nc2c(C)cn(C)c2cc1C#N
Temperature: 75 °C
Reaction time: 22 h

Procedure:
A mixture of 3-bromo-5-[N-(cyclopentylmethyl)-N-ethylamino]-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile (1.05 g, 2.91 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (PdCl2(dppf)-CH2Cl2, 0.24 g, 0.29 mmol) in THF (20 mL) is treated with methylmagnesium bromide (0.93 M in THF, 7.8 mL) at 0° C. The reaction mixture is stirred at 75° C. for 22 hours. After cooling to room temperature, H2O is added, and the reaction mixture is extracted with EtOAc. The organic layer is washed with sat. NaHCO3 and brine, dried over sodium sulfate and concentrated. The residue is purified by silica-gel column chromatography to give 5-[N-(cyclopentylmethyl)-N-ethylamino]-1,3-dimethyl-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:11]([C:17]([O:19]C(C)(C)C)=[O:18])[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:11]([C:17]([OH:19])=[O:18])[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1S(C)(=O)=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1

Procedure:
To a magnetically stirred solution of tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfonyl-1H-imidazole-4-carboxylate (4.76 g, 9.49 mmol) in CH2Cl2 (60 ml) was added excess TFA (9.40 ml, 0.2124 mol) and Et3SiH (3.8 ml, 0.0238 mol). The solution was reacted at room temperature for 16 h and concentrated in vacuo. Water was added and the formed precipitate was collected by filtration and subsequently dried to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfonyl-1H-imidazole-4-carboxylic acid in quantitative yield, mp ˜130° C. (dec); 1H-NMR (400 MHz, CDCl3) δ 3.45 (s, 3H), 3.50 (br s, 1H), 7.40 (br d, J˜8 Hz, 2H), 7.42 (dd, J=8 and 2 Hz, 1H), 7.50 (br d, J˜8 Hz, 2H), 7.59 (d, J=2 Hz, 1H), 7.61 (d, J=8 Hz, 1H). Analogously was prepared 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfinyl-1H-imidazole-4-carboxylic acid 1H-NMR (400 MHz, CDCl3) δ 2.99 (s, 3H), 7.37-7.60 (m, 7H), 13.20 (br s, 1H).