Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[C:44](=[O:46])=[O:45]>C1COCC1>[Br:15][C:13]1[CH:14]=[C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([F:16])=[C:11]([CH:12]=1)[C:44]([OH:46])=[O:45]
Reactant: O=C=O
Reactant: Fc1ccc(Br)cc1N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(Br)cc(N(Cc2ccccc2)Cc2ccccc2)c1F
Reaction time: 0.75 h
Yield: 40 %

Procedure:
Add dropwise a solution of dibenzyl-(5-bromo-2-fluorophenyl)-amine (4.00 g, 10.8 mmol) in THF (12 mL) to a solution of lithium diisopropylamide, freshly prepared by adding n-butyllithium (1.6 M in hexanes, 7.09 mL, 11.3 mmol) to diisopropylamine (1.74 mL, 12.4 mmol) in THF (25 mL) at −78° C. Stir the resulting yellow solution at −78 C. for 45 min. Pour into a dry ice slurry containing about 100 g in dry THF (40 mL). Stir the solution until it reaches room temperature. Concentrate the solution and dissolve the residue in 10% aqueous potassium hydroxide solution (40 mL) and extract with diethyl ether (70 mL). Acidify the aqueous layer to about pH=3 with concentrated HCl. Extract the aqueous layer with diethyl ether (2×200 mL). Combine the organic layers and wash with water (150 mL), dry (magnesium sulfate) and concentrate to give the title compound as a solid (1.81 g, 40%).
Reaction SMILES: [CH2:1]([O:4][NH:5][CH:6]1[CH2:11][NH:10][C@@H:9]([C:12]([NH2:14])=[O:13])[CH:8]=[C:7]1[CH2:15][C:16]([NH2:18])=[O:17])[CH:2]=[CH2:3].[CH2:19]([O:22]N1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O)C=C>>[CH2:1]([O:4][N:5]1[C:19](=[O:22])[N:10]2[CH2:11][C@H:6]1[C:7]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:8][C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Reactant: C=CCONC1CN[C@@H](C(N)=O)C=C1CC(N)=O
Product: C=CCON1C(=O)N2C[C@H]1C(CC(N)=O)=C[C@H]2C(N)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared from (R)-5-(allyloxyamino)-4-(2-amino-2-oxoethyl)-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 177, 132 mg, 0.52 mmol) following the procedure described for Intermediate 16. The reaction mixture was stirred at 0° C. for 2 h. The volatile was removed under vacuum and the crude was subjected to silica column eluting with 0-100% ethyl acetate/hexanes and then 95% ethyl acetate/5% MeOH to give a pale yellow solid. 62 mg, 43%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:3]1.[CH3:14][C:15]([O:18][C:19]([NH:21][C@H:22]([C:31](O)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:20])([CH3:17])[CH3:16].C(Cl)CCl>N1C=CC=CC=1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C@H:22]([NH:21][C:19](=[O:20])[O:18][C:15]([CH3:16])([CH3:14])[CH3:17])[C:31]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[CH:5]=2)=[O:32])=[CH:25][CH:26]=1
Reactant: Cn1nc(-c2ccncc2)cc1N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 99.1 %

Procedure:
To a 100 ml flask was added 1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-amine 17.B (540 mg, 3.10 mmole), Boc-L-4-fluorophenylalanine (970 mg, 3.41 mmole), EDC (710 mg, 3.72 mmole), and 10 ml of pyridine. The reaction was stirred at room temperature for 5.5 hours at which time the solvent was removed by rotary evaporation. The residue was suspended in ethyl acetate, and washed successively with saturated sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 103.1.A (1.35 g, 99% yield) as colorless amorphous.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[CH2:10][C:11]1([C:16]([NH:18][CH:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[CH2:10][C:11]1([C:16]([NH:18][CH:19]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:33][CH:34]=2)[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)C1(CC(=O)OCc2ccccc2)CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)C1(CC(=O)OCc2ccccc2)CCCC1
Reaction time: 1 h
Yield: 114.2 %

Procedure:
Next, to the solution of the crude tert-butyl 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-4-(biphenyl-4-yl)butanoate (38 mg) in DCM (0.7 ml), TFA (0.263 ml, 3.42 mmol) is added. After stirring for 1 hour, the reaction mixture is concentrated to give crude 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-4-(biphenyl-4-yl)butanoic acid (39 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH2:10]C=O)=N)[CH:5]=[CH:6][CH:7]=1.[NH2:13][C:14]([NH2:16])=[O:15].[CH2:17](O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:10]=[N:13][C:14]([OH:15])=[N:16][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: N=C(CC=O)c1cccc(Cl)c1
Reactant: NC(N)=O
Product: Oc1ncc(-c2cccc(Cl)c2)cn1

Procedure:
By the procedure described in Example 4, (m-chlorophenyl)formimidoylacetaldehyde is reacted with urea to give the product of the Example (recrystallized from ethanol), m.p. 235°-236° C.
Reaction SMILES: FC1C(NC2C=C(OC(C)C)NN=2)=NC([NH:10][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])=C(C=1)C#N.[CH3:31][OH:32]>[Ni]>[NH2:10][C:11]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)([CH2:12][OH:13])[CH2:31][OH:32]
Reactant: CO
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(C#N)cc2F)n[nH]1
Agent: [Ni]
Product: NC(CO)(CO)c1ccc(F)cc1
Reaction time: 2 h
Yield: 61 %

Procedure:
A suspension of 2-(4-fluorophenyl)-2-nitroproane-1,3-diol (Method 11; 4.5 g, 20.9 mmol) and Raney nickel (0.45 g, 5.23 mmol) in MeOH (50 ml) was degassed and stirred under H2 (48 psi) for 2 hours. The catalyst was removed by filtration. The filtrate was concentrated and recrystallized from hexane:EtOAc (1:1) to give the title compound (2.35 g, 61%) as a white solid. NMR (400 MHz) □ 7.55 (m, 2H), 7.07 (m, 2H), 4.65 (t, J=5.2 Hz, 2H), 3.49 (m, 4H), 1.76 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22](O)=[O:23])=[N:20][CH:21]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:58]1[CH2:63][CH2:62][NH:61][CH2:60][C:59]1=[O:64]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([N:61]4[CH2:62][CH2:63][NH:58][C:59](=[O:64])[CH2:60]4)=[O:23])=[N:20][CH:21]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cnc(Nc3ccc(C(=O)O)nc3)nc2)cc1
Reactant: O=C1CNCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(Nc3ccc(C(=O)N4CCNC(=O)C4)nc3)nc2)cc1
Reaction time: 0.03 h

Procedure:
To a solution of 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-pyridine-2-carboxylic acid 5 (0.05 mmol) in DMF (1 mL) is added HATU (0.06 mmol) and DIEA (0.14 mmol) at rt. The resulting mixture is stirred for 2 min and then piperazine-2-one (0.05 mmol) is added. The reaction mixture is stirred at it for 12 h and then directly purified by preparative LCMS to give 4-{5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]pyridine-2-carbonyl}-piperazin-2-one A2 as a white solid. 1H NMR (400 MHz, d4-CH3OH) δ 8.98 (d, J=4.0 Hz, 1H), 8.77 (s, 1H), 8.53-8.52 (m, 2H), 7.74-7.73 (m, 2H), 7.58-7.56 (m, 2H), 7.07-7.05 (m, 2H), 3.94 (bs, 2H), 3.81 (s, 3H), 3.46 (bs, 2H), 3.45 (bs, 2H). MS (m/z) (M+1)+: 405.2.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][N:31]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH:25][C:27]2[N:35]=[CH:34][N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][NH:31]3)[CH3:24])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 90 °C

Procedure:
A mixture of (S)-1-[1-(trans-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (210 mg, 0.62 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (148 mg, 0.62 mmol) and DIPEA (0.55 mL, 3.09 mmol) in IPA (5 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded onto an Isolute® SCX-2 cartridge which was washed with DCM, MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) to afford the title compound as a colourless glassy solid (120 mg, 43%). LCMS (Method J): RT 2.72 min [M+H]+ 458
Reaction SMILES: [C:1]([O:4][OH:5])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:12][CH:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15]>O.CCOCC.C(Cl)(Cl)Cl>[Cl:12][CH:13]([CH2:17][CH3:18])[C:14]([O:5][O:4][C:1](=[O:3])[CH3:2])=[O:15]
Reactant: CCC(Cl)C(=O)Cl
Reactant: CC(=O)OO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: CCC(Cl)C(=O)OOC(C)=O
Temperature: -3 °C
Yield: 49.5 %

Procedure:
To 9.5 g. (0.05 moles) of 40% peracetic acid in 20 cc. H2O was added 3.2 g. (0.03 moles) of anhydrous sodium carbonate. The mixture was chilled to -3° C. with stirring and 7.1 g. (0.05 moles) of 2-chlorobutyryl chloride in 30 cc. chloroform added over a period of 8 minutes. After a total of 40 minutes at -3° to -6° C., ether and water were added. The organic phase was separated, washed once with cold 1% KOH solution, once with ice water, and once with cold saturated salt water. The concentrated material weighed 8.2 g., including 2.0 g. of dimethyl phthlate. Product A.O. analysis: theory, 8.14 found, 4.81; 59.1% pure; 49.5% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:6]([N+:15]([O-:17])=[O:16])=[CH:7][C:8]=1[S:9](=[O:14])(=[O:13])[N:10]([CH3:12])[CH3:11])[NH2:5].[OH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[OH-].[K+]>CS(C)=O>[CH3:11][N:10]([CH3:12])[S:9]([C:8]1[CH:7]=[C:6]([N+:15]([O-:17])=[O:16])[C:4]([NH2:5])=[CH:3][C:2]=1[N:22]1[CH:23]=[CH:24][C:19](=[O:18])[CH:20]=[CH:21]1)(=[O:14])=[O:13]
Reactant: Oc1ccncc1
Reactant: CN(C)S(=O)(=O)c1cc([N+](=O)[O-])c(N)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)c1cc([N+](=O)[O-])c(N)cc1-n1ccc(=O)cc1
Temperature: 130 °C
Yield: 46.2 %

Procedure:
First, a mixture containing 3.0 g of 3-chloro-4-dimethylsulfamoyl-6-nitroaniline, 1.39 g of 4-hydroxypyridine, 0.91 g of 86% potassium hydroxide, and 20 ml of dimethylsulfoxide was heated in an oil bath at 130° C. for 1.5 hours. The subsequent processes were conducted in the same way as in Reference Example 3 to give 1.675 g of 4-dimethylsulfamoyl-3-(4-oxo-4H-pyridin-1-yl)-6-nitroaniline.
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN(C=O)C.O>[NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:3]=1
Reactant: c1c[nH]cn1
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])c(N)cc1-n1ccnc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
In 5 ml of DMF were dissolved 1 g of 4-amino-2-fluoro-5-nitrobenzonitrile and 1.1 g of imidazole, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was then diluted with water and the resulting crystals were recovered by filtration to provide 1.2 g of 4-amino-2-(1-imidazolyl)-5-nitrobenzonitrile. Physicochemical properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([BH3-])#[N:16].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:16])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(C)=O)cc1OC
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C)N)cc1OC
Temperature: 25 °C
Reaction time: 67 h
Yield: 96.5 %

Procedure:
A mixture of 3,4-dimethoxyphenylacetone (51.1 g, 0.26 m) is dissolved in methanol (780 ml), sodium cyanoborohydride (11.3 g, 0.18 m) is added and the mixture is stirred at room temperature for 67 hours. The reaction mixture is adjusted to pH 2 with concentrated HCl and the solvent is evaporated under reduced pressure. The residue is dissolved in H2O (250 ml), the aqueous layer is extracted with ether (3×) and then rendered alkaline with KOH and extracted with CH2Cl2 (3×). After drying, the solvent is evaporated under reduced pressure and the product is distilled at 112°-5°/0.5 mm to yield (VIII) (33.88 g, 67%).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[C:10]([C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH:9]=[CH:8][N:7]=2)=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].[CH3:30][N:31]([CH:33]=[O:34])[CH3:32]>CO>[CH3:24][N:25]([CH3:29])[C:26]([N:2]1[N:3]=[N:4][C:5]([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[N:15][N:14]([C:33](=[O:34])[N:31]([CH3:32])[CH3:30])[N:13]=3)[CH:9]=[CH:8][N:7]=2)=[N:1]1)=[O:27]
Reactant: c1cc(-c2nnn[nH]2)cc(-c2nnn[nH]2)n1
Reactant: CN(C)C=O
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)C(=O)n1nnc(-c2ccnc(-c3nnn(C(=O)N(C)C)n3)c2)n1

Procedure:
A solution of 0.5 g of 2,4-bis(5-tetrazolyl)pyridine, 1.6 ml of triethylamine and 0.43 ml of dimethylcarbamoyl chloride in 5 ml of abs. DMF was stirred at room temperature for 24 h, excess dimethylcarbamoyl chloride was decomposed with methanol, and the mixture was then concentrated in vacuo. The result was 1.86 g of an oil which was purified on a silica gel column (40 g) with CH2Cl2 methanol, gradient 20:1 to 9:1, as eluent. 0.38 g of 10 was obtained, colorless crystals of melting point 150° C. (decomposition).
Reaction SMILES: CCCCC.Cl[SiH](Cl)Cl.[CH3:10][NH:11][CH3:12].[CH2:13]([O:15][SiH:16]([O:18][CH2:19][CH3:20])Cl)[CH3:14]>C(O)C>[CH2:13]([O:15][SiH:16]([O:18][CH2:19][CH3:20])[N:11]([CH3:12])[CH3:10])[CH3:14]
Reactant: CCO[SiH](Cl)OCC
Reactant: CNC
Agent: Cl[SiH](Cl)Cl
Solvent: CCCCC
Solvent: CCO
Product: CCO[SiH](OCC)N(C)C

Procedure:
Following the same general procedure described in Example 1, 2 liters of pentane and 404 mls of trichlorosilane were charged in a 5 L flask. During reflux, 464 mls of anhydrous ethanol was added dropwise. After the alcoholysis was completed, 550 mls of dimethylamine was added to the unisolated diethoxychlorosilane. Distillation yielded 290 g of diethoxy(dimethylamino)silane (b.p. 138°-139° C.).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)O.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[C:24]#[N:25].S(=O)(=O)(O)[OH:32]>ClCCl>[Cl:1][CH2:2][CH:3]([NH:25][C:24](=[O:32])[C:23]1[C:22]([F:21])=[CH:29][CH:28]=[CH:27][C:26]=1[F:30])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: OC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(F)cccc1F
Solvent: ClCCl
Product: O=C(NC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2.0 g of α-(chloromethyl)-4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-methanol, 4.0 g of 2,6-difluorobenzonitrile, and 15 mL of dichloromethane was cooled to 5° C. and 0.8 mL of conc. sulfuric acid was added dropwise over 7 min. After 30 min, ice was added, the mixture was diluted with hexanes, and the crude product was filtered and dried to afford 1.0 g of product, m.p. 144-145° C. 1H-NMR (CDCl3): δ4.0 (dq, 2), 5.6 (m, 1H), 6.75 (br d, 1H), 6.85 (t, 1H, J=60 Hz), 7.0 (t, 2H), 7.4 (m, 1H), 7.5 (d, 2H), 7.6 (m, 6H). The filtrate was extracted with ethyl acetate; the extract was washed with water, concentrated, and chromatographed on silica gel to afford an additional 0.5 g of product, corresponding to a total yield of 52%.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].O>O1CCCC1.CCCCCC>[CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][C:12]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2nccs2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(Oc2ccc(OC(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of Example 1B (2.4 g, 0.01 mol) in dry tetrahydrofuran was added n-butyl lithium 4.4 mL, 2.5 M in hexane) at −78° C. drop wise. After stirring at this temperature, tributyltin chloride (3.0 mL, 0.011 mol) was added slowly. The solution was then stirred for 3 hours while warming up to room temperature. Water was added and the solution was extracted with ethyl acetate. The organic layer was washed with sat. NH4Cl, brine, and then dried over magnesium sulfate. The solution was filtered, concentrated, and purified to give 4.85 g of the title compound as a clear oil (93% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.77-1.74 (m, 33H) 4.40-4.63 (m, 1H) 6.84-6.95 (m, 2H) 7.12 (s, 1H) 7.14 (m, 2H). MS (ESI) m/z 526.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=O)[CH2:32]Br)=[CH:29][CH:28]=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:32]=[C:31]([C:30]3[CH:35]=[CH:36][C:27]([Cl:26])=[CH:28][CH:29]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccc(Cl)cc3)nc2-c2ccc(Cl)cc2)cc1
Yield: 54.9 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (30 mL), 4-chlorophenacyl bromide (1.05 g, 4.48 mmol) was added. After heating the reaction mixture at 80°-85° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed (silica gel, hexane/ethyl acetate, 6/4) to give 2,4-bis-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (545 mg, 55%) as a pale yellow solid: mp 169°-171° C. Anal. Calc'd. for C22H16N2SO2Cl12 : C, 59.60, H, 3.64, N, 6.32, S, 7.23. Found: C, 59.86, H, 3.80, N, 6.10, S, 7.27.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2ccccc2)c1
Temperature: 60 °C
Yield: 66 %

Procedure:
Dissolve N-methyl-N-propyl-5-tributylstannanyl-isophthalamic acid methyl ester (480 mg, 0.8 mmol), benzoyl chloride (117 mg), tris(dibenzylideneacetone)dipalladium (0) (19.3 mg) and 2-(di-tert-butylphosphino)biphenyl (34.5 mg) in chloroform (8 mL) in a previously degassed sealed vessel. Flush the mixture with nitrogen and heat the sealed mixture overnight at 60° C. Cool the reaction to room temperature and filter though a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with 0:100 to 30:70 ethyl acetate:hexanes) to give the title compound (66%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:8]2=[O:24])[S:5][CH:6]=1.[CH2:25](N(CC)CC)C.[C:32](C1C=C2C(=CC=1)CC1(C(=O)NC(=O)N1)CC2)([OH:34])=[O:33]>CO>[C:20]([O:19][C:17](=[O:18])[CH2:16][N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([C:4]2[S:5][CH:6]=[C:2]([C:32]([O:34][CH3:25])=[O:33])[N:3]=2)[C:8]1=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2nc(Br)cs2)c2ccccc21
Reactant: O=C1NC(=O)C2(CCc3cc(C(=O)O)ccc3C2)N1
Solvent: CO
Product: COC(=O)c1csc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1

Procedure:
To a suspension of tert-butyl [3-(4-bromo-1,3-thiazol-2-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate from Step A (250 mg, 0.609 mmol) and triethylamine (0.85 mL, 6.09 mmol) in MeOH (5 mL) was added bis(triphenylphosphine)palladium (1) chloride (86 mg, 0.122 mmol). The reaction mixture was heated at reflux under an atmosphere of carbon monoxide (ca. 1 atm) for 48 h, then partitioned between CHCl3 (20 mL) and saturated aqueous NaHCO3 (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 60:40, to give the title compound. MS: m/z=412 (M+23).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[CH3:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:19])=[CH:23][C:22]=1[CH3:28]
Reactant: Cc1cc(N)ccc1Cl
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Benzyloxycarbonylpiperidine-4-carboxylic acid (1.00 g, 3.80 mmol) and 4-chloro-3-methyl-aniline (0.592 g, 4.18 mmol) in CH2Cl2 (5 mL) were treated with HOBT (0.582, 3.80 mmol) and EDC (1.46 g, 7.60 mmol), and stirred at rt for 16 h. The mixture was directly purified on SiO2 (50 to 100% EtOAc, hexanes) to afford the title compound. HPLC/MS: 387.2/389.1 (M+1); Rt=1.22 min (LC2).