Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1=[N:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9]1.[C:10]1([C:16]2[O:17][C:18](=[O:21])[CH2:19][N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.[OH-].[Li+].O>C1COCC1>[C:10]1([C:16]2[N:4]3[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:3]3=[C:19]([C:18]([OH:21])=[O:17])[N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CN=C(c2ccccc2)O1
Reactant: COC1=NCCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccccc2)n2c1CCOCC2
Temperature: 150 °C

Procedure:
(E)-5-methoxy-2,3,6,7-tetrahydro-1,4-oxazepine (50 mg, 0.387 mmol) was dissolved in THF (1 mL) in a screw-cap vial and 2-phenyloxazol-5(4H)-one (62.4 mg, 0.387 mmol) was added to give a orange solution. The reaction was heated to 150° C. for 5 minutes. LCMS shows two peaks of the corresponding product mass (tautomers of the condensation), Rt 0.73 and 0.78 minutes. The reaction was concentrated under reduced pressure and the residue was dissolved in 1 mL MeOH and treated with lithium hydroxide monohydrate (81 mg, 1.936 mmol) and water (200 μL). The reaction was heated at 120° C. for 5 minutes using microwave irradiation to provide a new desired product (same MW as intermediate) with Rt=0.50 minutes. The reaction was concentrated to remove MeOH and then diluted with water (1 mL). The solution was acidified to pH2 with 5N HCl. The solution was extracted with DCM (3×2 mL). The combined organic extracts were dried and evaporated to provide the title compound as a brown oil (23 mg). Additional material was recovered by concentrating the aqueous layer and repeated extraction with DCM. The combined material (45 mg, 45%) was used without further purification. LCMS (+ESI) m/z: 130.2 [M+H]+
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([CH:9]([CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:10]([O:12]C)=[O:11])(=O)[CH3:7]>>[CH3:7][CH:6]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]([CH3:15])=[C:9]1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(C(C)=O)C(C)c1ccccc1
Agent: O=S(=O)(O)O
Product: CC1=C(C(=O)O)C(C)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Concentrated sulphuric acid (15 ml) is added to methyl 2-acetyl-3-phenylbutyrate (2.75 g, 12.5 mmol) maintaining the temperature below 30° C. The reaction is stirred at ambient temperature for 5 hours, poured on to ice and extracted with EtOAc. The combined organic extracts are evaporated and the residue is diluted with water and the pH adjusted to 8 with saturated NaHCO3. After washing with EtOAc, the aqueous phase is acidified with concentrated HCl and extracted with EtOAc. The combined organic phases are washed with brine, dried (MgSO4) and evaporated to afford the title compound, MH+189.
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[C:6]([NH:9][C@@H:10]([CH3:13])[CH2:11][OH:12])[C:5](Cl)=[C:4](Cl)[N:3]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd].C(O)C>[N:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]([CH3:13])[CH2:11][OH:12])=[CH:7][CH:2]=1
Reactant: C[C@@H](CO)Nc1c(Cl)c(Cl)nc(Cl)c1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H](CO)Nc1ccncc1
Reaction time: 24 h
Yield: 101.6 %

Procedure:
A mixture of (S)-2-(2,3,5,6-tetrachloro-pyridin-4-ylamino)-propan-1-ol (6 g), 10% palladium on carbon (3 g), potassium carbonate (14.3 g) and ethanol (110 ml) was stirred under an atmosphere of hydrogen for 24 h. The reaction mixture was filtered through Harbolite™ and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (3.2 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:20][S:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14](C(=O)C)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:1][C:2]1[C:3]([CH2:20][S:21][C:22]2[NH:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(=O)N1CCN(CCSc2ccnc(CSc3nc4ccccc4[nH]3)c2C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(SCCN2CCNCC2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2-((3-Methyl-4-(2-(4-acetylpiperazin1-yl)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole (38 g) was dissolved in 6N hydrochloric acid and the mixture was stirred at 50° C. for 2 hours. After the completion of the reaction, the mixture was made alkaline with potassium carbonate and extracted with a mixed solvent of chloroform-methanol. The chloroform-methanol layer was dried over anhydrous magnesium sulfate, the solvent was distilled away and the residue was recrystallized from ethanol to give 2-((3-methyl-4-(2-(piperazin1-yl)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole as crystals, melting point 166°-168° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.C([O:13][C:14](=O)[CH2:15][C:16]([C:18]([F:21])([F:20])[F:19])=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:14]([OH:13])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: N=C(N)c1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Reaction time: 24 h

Procedure:
To a solution of compound of example 12 (0.1 g, 0.73 mmol) in water (5 mL) and ethanol (2.5 mL) was added ethyl-4,4,4-trifluoroacetoacetate (0.216 g, 1.17 mmol) and sodium carbonate (0.140 g, 1.32 mmol) at room temperature, and the reaction mixture was stirred for about 24 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 1% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:5]2=[N:6][CH:7]=1.[F:32][C:33]([F:39])([F:38])[CH2:34][CH2:35][CH2:36][NH2:37]>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13]([NH:37][CH2:36][CH2:35][CH2:34][C:33]([F:39])([F:38])[F:32])[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc(I)c21
Reactant: NCCCC(F)(F)F
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc(NCCCC(F)(F)F)c21
Temperature: 150 °C

Procedure:
150 mg (0.186 mmol, approx. 66% purity) of the compound obtained in example 16A was dissolved in 1-methyl-2-pyrrolidone (3 ml) in a reaction vessel suitable for a microwave and 0.4 ml of 4,4,4-trifluorobutylamine was added. Then it was sealed with a corresponding septum and it was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 47 mg of the title compound was obtained (48% of theor.).
Reaction SMILES: [I:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[Si:23]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([I:1])[C:3]([NH2:17])=[N:4][C:5]2=[O:16])[CH2:8][C@@H:9]1[OH:10])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c(N)nc2=O)C[C@@H]1O
Temperature: 0 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
To a solution of 5-iodo-2′-deoxycytidine (2.2 g, 6.23 mmol) in DMF (130 ml) was added imidazole (467 mg, 6.85 mmol). The mixture was cooled at 0° C. and tert-butyldimethylsilyl chloride (TBDMSCl) (1.33 g, 6.85 mmol) added over 5 minutes. After 18 h at room temperature, the volatiles were evaporated under reduced pressure and the residue purified by flash chromatography on silica gel with EtOAc:MeOH (95:5 to 90:10) to give the expected product (39) (2.10 g, 72%) together with unreacted starting material (490 mg) 1H NMR (d6 DMSO) δ 0.11 (s, 3H, CH3), 0.12 (s, 3H, CH3), 0.89 (s, 9H, 3CH3), 1.90 (ddd, J=13.2, 7.7 and 5.7 Hz, 1H, 2.18 (ddd, J=13.2, 5.7 and 2.3 Hz, 1H, HH-2′), 3.72 (dd, J=11.5, 3.6 Hz, 1H, HH-5′), 3.80 (dd, J=11.5, 2.8 Hz, 1H, HH-5′), 3.86-3.89 (m, 1H, H-4′), 4.14-4.18 (m, 1H, H-3′), 5.22 (1H, d, J=4.1 Hz, OH), 6.09 (1H, dd, J=7.8, 5.8 Hz, H-1′), 6.60 (br s, 1H, NHH), 7.81 (br s, 1H, NHH), 7.94 (s, 1H, H-6); MS (ES): m/z (%) (M+H) 468 (90%).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CN(C3SC=CN=3)C2)=NC=1CC.Br[C:34]1[N:39]=[CH:38][CH:37]=[CH:36][N:35]=1.[CH2:40]([O:42][C@H:43]1[CH2:47][NH:46][CH2:45][C@H:44]1[NH:48][C:49]1[C:54]([CH2:55][CH3:56])=[N:53][C:52]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=2[CH3:65])=[C:51]([CH2:66][CH3:67])[N:50]=1)[CH3:41]>>[CH2:40]([O:42][C@H:43]1[CH2:47][N:46]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:45][C@H:44]1[NH:48][C:49]1[C:54]([CH2:55][CH3:56])=[N:53][C:52]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=2[CH3:65])=[C:51]([CH2:66][CH3:67])[N:50]=1)[CH3:41]
Reactant: Brc1ncccn1
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC
Agent: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrazin-2-amine but substituting 2-bromopyrimidine and starting with N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.15, 1.28, 2.13, 2.48, 2.74, 3.51, 3.77, 3.85, 3.98, 4.25, 4.90, 5.20, 6.56, 6.81, 7.12, 8.37; IR (diffuse reflectance) 2970, 2402 (w), 2350 (w), 2307 (w), 2212 (w), 2169 (w), 1583 (s), 1568, 1548 (s), 1508 (s), 1475 (s), 1393, 1383, 1242, 798 cm−1 HRMS (ESI) calcd for C26H34N6O2+H1 463.2821. found 463.2816.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:25][CH2:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: COCCOCCCN
Solvent: CCN(CC)CC
Product: COCCOCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[3-(2-methoxyethoxy)propylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-(2-methoxyethoxy)propylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[S:22])=[C:15](C(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1>>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[S:22])=[C:15]([CH2:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: BrCC1CCCCO1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3CCCCO3)CS[C@H]12
Yield: 71 %

Procedure:
Diphenylmethyl 7-phenylacetamido-3-acetylthio-3-cephem-4-carboxylate (1.68 g) was reacted with 2-bromomethyltetrahydropyran (1.92 ml) in accordance with the procedure of Example 1(b). The crude reaction product was purified by a column chromatography on a silica gel column (40 g) with elution using benzene-ethyl acetate (4:1 by volume) as eluent to collect fractions containing the titled compound. The fractions collected were concentrated and the oily residue was triturated with diisopropylether to give the titled compound (1.42 g; 71%) as powder.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([CH3:19])[CH3:18])=[C:12]([O:20][CH3:21])[CH:11]=1)=O)=O.O=P(Cl)(Cl)Cl>C(#N)C>[CH:17]([O:16][C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][N:7]3[CH:1]=[N:3][CH:4]=[C:5]32)=[CH:11][C:12]=1[O:20][CH3:21])([CH3:19])[CH3:18]
Reactant: COc1cc(CCNC(=O)CNC=O)ccc1OC(C)C
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC(C)C)-c1cncn1CC2
Temperature: 80 °C
Yield: 34.5 %

Procedure:
To a 50 mL round bottom flask was added 2-formamido-N-(4-isopropoxy-3-methoxyphenethyl)acetamide (600 mg, 2.04 mmol) followed by acetonitrile (10.2 mL) and POCl3 (0.57 mL, 6.12 mmol). The reaction mixture was heated to 80° C. for one hour then concentrated in vacuo. To the resulting oil was added H2O and aqueous saturated sodium carbonate, then the solution was extracted with EtOAc (2×). The organic extracts were combined, dried with sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-10% MeOH in DCM) to afford 9-isopropoxy-8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinoline (182 mg) MS [M+H+]=259.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:12])([F:13])[F:14])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cc(Cl)ccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(Cl)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Add borane-THF complex (3.34 mL, 3.34 mmol) slowly to an ice-methanol cooled bath solution of 5-chloro-2-trifluoromethyl-benzoic acid (500 mg, 2.23 mmol) in THF (2 mL). Stir overnight at room temperature. Add water (1 mL) and solid potassium carbonate. Filter and concentrate to give an oil residue. Chromatograph on silica gel, eluting with 10:90 to 1:1 ethyl acetate:hexanes to give (5-chloro-2-trifluoromethylphenyl)-methanol as a white solid (347 mg, 75%). 1H NMR (400 MHz, MeOH-d4) δ 7.84 (s, 1H), 7.68 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=8.4 Hz), 4.81 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1.[OH-].[Na+].C(Cl)(Cl)Cl>O1CCOCC1>[F:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:8][CH2:7][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Fc1ccc2[nH]cc(CCN3CCCC3)c2c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (2.94 g, 3.4 ml, 41.3 mmol) was dissolved in abs dioxane (100 ml), 3-(2-bromo-ethyl)-5-fluoro-1H-indole (5.00 g, 20.7 mmol) was added at RT and the mixture was stirred at 70° C. for 8 h. The solution was concentrated, the residue was taken up in CHCl3 (150 ml) and the mixture was washed with water (2×50 ml). The organic phase was dried over Na2SO4, filtered and concentrated i. vac. The residue obtained was purified by flash chromatography with 500 g of silica gel and chloroform/methanol (20:1→9:1→4:1→methanol. Only with methanol was a salt of the compound obtained, and it was then possible to liberate this by stirring with 2N NaOH and CHCl3. The phases were separated, the aqueous phase was extracted twice with CHCl3 and the combined organic phases were dried over Na2SO4, filtered and concentrated i. vac. The chloroform used was probably contaminated with HCl.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[Br:10]Br>CC(O)=O>[Br:10][C:7]1[C:6]([F:9])=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: BrBr
Reactant: Nc1cc(F)ccc1F
Solvent: CC(=O)O
Product: Nc1cc(F)c(Br)cc1F
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a stirred solution of 100 g of 2,5-difluoroaniline and 1150 mL of AcOH is added over 1.3 hours a solution of 40.2 mL of Br2 in 350 mL of AcOH at a temperature of 15°-20°. The pink suspension is stirred 30 minutes longer and then evaporated in vacuo. The residue is basified with 50% NaOH (ice is added to keep the temperature below 35°). Extraction of the free base with 1 L of CH2Cl2 and washing of the extract with 2×100 mL of H2O, drying with Na2SO4 and evaporation in vacuo gives 157 g (97.5% yield) of 4-bromo-2,5-difluoroaniline, m.p. 73°-75°. The mass spectrum had a M+1 ions at 208,210.
Reaction SMILES: [N:1]1([C:5]2[CH:10]=[C:9]([NH:11][C:12]3[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=3)[N:8]=[C:7]([S:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1.F[B-](F)(F)F.CN(C)C(O)=[N+](C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[N:1]1([C:5]2[CH:10]=[C:9]([NH:11][C:12]3[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=3)[N:8]=[C:7]([S:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:33][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:24])=[CH:21][CH:20]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(C(=O)O)cc3)n2)[nH]n1
Reactant: NC1CCCC1
Agent: CN(C)C(O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(C(=O)NC4CCCC4)cc3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 25 ml round bottom flask was charged with 4-[4-azetidin-1-yl-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-benzoic acid (200 mg, 0.48 mmol), cyclopentyl amine (85 mg, 1 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3, -tetramethyluroniumtetrafluoroborate (321 mg, 1 mmol), diisopropylethylamine (0.34 ml, 2 mmol) in dimethylformamide (5 ml), under nitrogen. The reaction mixture was stirred at room temperature for 18 hours and then was diluted with ethyl acetate (40 ml), washed with a saturated sodium hydrogen carbonate aqueous solution (40 ml) and brine (40 ml). The organic was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated in dichloromethane to afford the title compound. 1H NMR (DMSO-d6): 1.60-1.65 (4H, m), 1.70-1.80 (2H, m), 1.95-2.10 (5H, m), 2.20-2.30 (2H, m), 3.90-4.00 (4H, s), 4.30-4.35 (1H, m), 5.35-5.40 (1H, s), 7.70-7.75 (2H, d), 8.00-8.05 (2H, d), 8.45-8.50 (1H, d), 9.3 (1H, s). MS (ES+): 450.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]2[C:20]3=[C:21]4[C:26](=[CH:27][CH:28]=[C:19]3[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=3[O:10]2)[NH:25][C:24]([CH3:30])([CH3:29])[CH:23]=[C:22]4[CH3:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:37]1[O:38][CH:39]=[CH:40][CH:41]=1)CCC>CN1CCCC1=O.C(OCC)(=O)C.[F-].[K+]>[O:38]1[CH:39]=[CH:40][CH:41]=[C:37]1[C:2]1[CH:3]=[C:4]([CH:9]2[C:20]3=[C:21]4[C:26](=[CH:27][CH:28]=[C:19]3[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=3[O:10]2)[NH:25][C:24]([CH3:30])([CH3:29])[CH:23]=[C:22]4[CH3:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: COc1cccc2c1-c1ccc3c(c1C(c1cc(C)cc(Br)c1)O2)C(C)=CC(C)(C)N3
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1-c1ccc3c(c1C(c1cc(C)cc(-c4ccco4)c1)O2)C(C)=CC(C)(C)N3
Temperature: 85 °C
Reaction time: 3 h

Procedure:
A solution of Example 11 (0.253 g, 0.531 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was deoxygenated with nitrogen, treated with 2-(tributylstannyl)furan (0.33 mL, 1.06 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.045 g, 0.005 mmol), heated to 85° C. for 13 hours, cooled to room temperature, diluted with ethyl acetate and saturated KF, stirred for 3 hours, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5-10% ethyl acetate/hexanes to provide the desired compound.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]([F:10])([F:9])[S:5](F)(=[O:7])=[O:6].[Li+:12].[OH-:13]>O>[F:9][C:4]([F:10])([S:5]([OH:13])(=[O:7])=[O:6])[C:3]([O-:2])=[O:11].[Li+:12]
Reactant: [OH-]
Reactant: COC(=O)C(F)(F)S(=O)(=O)F
Agent: [Li+]
Solvent: O
Product: O=C([O-])C(F)(F)S(=O)(=O)O
Temperature: 25 °C

Procedure:
In the first step, methyl-2,2-difluoro-2-(fluorosulfonyl)acetate (56.6 g, 0.29 mol) was added dropwise to an aqueous solution of 23.1 g (0.96 mol) LiOH in 200 mL of water at 0° C. After completing the addition, the reaction mixture was warmed gradually to room temperature and then heated to reflux for 16 h. The mixture was cooled to room temperature and insoluble inorganic salts were removed by filtration. The filtrate was acidified by slow addition of 5N HCl to a pH of 1. Water was distilled off and the crude product was dried under reduced pressure to produce the product lithium difluorosulfoacetate as crude and white waxy solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([NH:14][C:15](=[O:17])[CH3:16])[C:8]=2[N:7]=[C:6]1[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25].[CH3:31]I.[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N:14]([CH3:31])[C:15](=[O:17])[CH3:16])[C:8]=2[N:7]=[C:6]1[C:18]1[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=1[F:24]
Reactant: CC(=O)Nc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetamidobenzimidazole (Example 88) (2.44 g, 5.90 mmol) and methyl iodide (0.60 mL, 9.69 mmol) dissolved in THF (30 mL) was added excess NaH. After stirring overnight, the solution was concentrated to dryness, diluted with CH2Cl2, and washed with water, NaHSO4(10% soln) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol in CH2Cl2, yielding 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N-methylacetamido)-benzimidazole (0.89 g, 2.08 mmol, 63% yield). M.p. 155-156° C. 1H NMR (200 MHz, CD2Cl2): δ7.55 (m, 1H, H4′), 7.48 (br d, J=7.4 Hz, 1H, H5), 7.31 (dd, J=7.4, 7.7 Hz, 1H, H6), 7.27 (m, 1H, H4″), 7.14 (dd, J=1.1, 7.7 Hz, 1H, H7), 7.09 (m, 2H, H3′,5′), 6.84 (m, 2H, H3″,5″), 5.38 (s, 2H, CH2), 3.34 (s, 3H, NCH3), 1.83 (s, 3H, NAc).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:14]=[C:15]([C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][C:18]=1[F:19]>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([CH3:8])[CH2:21][O:22]2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CC(=O)c1ccc(F)c(Cl)c1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(F)c(Cl)c2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(3-chloro-4-fluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.