Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ncccn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ncccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(pyrimidin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.78 min.; [M+H]+: 404.37 g/mol.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][N:31]([C:39](=[O:38])[CH2:40][OH:41])[CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f43) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:20])=[C:4](Cl)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:18]=1.[ClH:21]>C(O)C.[Zn]>[Cl:21][C:18]1[C:6]2[CH2:7][C@H:8]([C:15]([OH:17])=[O:16])[C@H:9]([C:11]([F:14])([F:13])[F:12])[O:10][C:5]=2[CH:4]=[C:3]([Cl:20])[C:2]=1[Cl:1]
Reactant: O=C(O)C1=Cc2cc(Cl)c(Cl)c(Cl)c2OC1C(F)(F)F
Reactant: Cl
Agent: [Zn]
Solvent: CCO
Product: O=C(O)[C@H]1Cc2c(cc(Cl)c(Cl)c2Cl)O[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6,7,8-trichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (0.28 g, 0.81 mmol, prepared as described in WO98/47890, in ethanol (10 mL) was treated with concentrated HCl (5 mL) and zinc powder (1.21 g, 18.5 mmol). The mixture was stirred at room temperature for 3 hours, filtered, and concentrated in vacuo. The residue was extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo to give a white solid (0.31 g) which was a 3:2 mixture of cis and trans isomers. The isomers were separated by reverse phase HPLC to obtain the desired cis isomer as a white solid (0.11 g, 39%): mp 207.3-208.5° C. 1H NMR (acetone-d6/300 MHz) 7.23 (s, 1H), 5.17-5.31 (m, 1H), 3.58-3.72 (m, 1H), 3.19 (dd, 1H, J=17.9 Hz, 6.5 Hz), 3.10 (dd, 1H, J=17.9 Hz, 7.7 Hz) 19F NMR (acetone-d6/282 MHz) −74.6 (d, J=7.2 Hz). ESHRMS m/z 346.9270 (M−H, Calc'd 346.9256). Anal. Calc'd for C11H6Cl3F3O3: C, 37.80; H, 1.73; Cl, 30.43. Found: C, 37.66; H, 1.75; Cl, 30.71.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.Cl[C:21]1[C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=[C:23]([Cl:36])[N:22]=1>CN(C=O)C>[Cl:36][C:23]1[N:22]=[C:21]([S:4][CH2:1][CH2:2][CH3:3])[C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=1
Reactant: CCCS
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCSc1nc(Cl)ccc1C(=O)NC1CCCCC1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a solution of propane thiol (2.975 mL, 32.89 mmol)l in DMF (25 mL) was added slowly a solution of 1N NaHMDS in THF (33 ml, 33.00 mmol). The mixture was stirred for ten minutes at room temperature and then added slowly to a solution of 2,6-dichloro-N-cyclohexyl-pyridine-3-carboxamide (Intermediate 1, 8.95 g, 32.89 mmol) in DMF (50 mL). The reaction was stirred at room temperature for two hours. The reaction was stopped and most of the THF and DMF was evaporated. The product was extracted with DCM (150 mL), washed with water (2×25 ml) and brine (25 mL). The solution was dried over MgSO4 and evaporated under reduced pressure to give a slightly pink solid. The solid was triturated in hexane and filtered; all of the coloured impurity went into solution to leave a white solid (7.84 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([CH3:30])[CH:20]=1)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([CH3:30])[CH:20]=3)[CH3:18])=[O:13])[C:6]=2[C:14]=1[F:15]
Reactant: Cc1cc(C(C)N)ccc1C(C)(C)C#N
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(C)NC(=O)Cn2cnc3ccc(F)c(F)c32)ccc1C(C)(C)C#N
Yield: 67 %

Procedure:
To a solution of (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (500 mg, 2.36 mmol) prepared according to scheme 2, 2-{4-[1-aminoethyl]-2-methylphenyl}-2-methylpropanenitrile (477 mg, 2.36 mmol) prepared according to scheme 16 and DMAP (570 mg, 4.71 mmol) stirred in anhydrous DMF (4.0 mL) is added HATU (896 mg, 2.36 mmol) after 18 hours of stirring, the mixture is diluted with EtOAc (100 mL). The organic phase is washed with distilled water, dried over anhydrous MgSO4. The mixture is filtered and concentrated. The product is purified on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-2-(6,7-difluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-methylphenyl]ethyl}acetamide (627 mg, 67%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.48 (d, J=7.03 Hz, 3 H) 1.75 (s, 6H) 2.61 (s, 3H) 4.99 (q, J=7.03 Hz, 1H) 5.12 (s, 2H) 7.12-7.25 (m, 3H) 7.33 (d, J=8.20 Hz, 1H) 7.42 (ddd, J=8.89, 3.61, 1.17 Hz, 1H) 8.13 (s, 1H), MS [M+H], calcd: 397.2. found: 397.2.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH2:24][CH2:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O:33][C:34]([C:37](Cl)=[O:38])([CH3:36])[CH3:35])(=O)C.C(N(CC)CC)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:37](=[O:38])[C:34]([OH:33])([CH3:36])[CH3:35])[CH2:24][CH2:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)CCN2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)CCN2C(=O)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with compound of Example 633 (200 mg, 0.48 mmol), 1-chlorocarbonyl-1-methylethyl acetate (104.3 μL, 0.72 mmol), triethylamine (133 μL, 0.96 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C. for 20 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.5 mL) and MeOH (2.0 mL) was added and stirred for 20 min to give the title compound. The compound precipitated out of solution. The precipitate was filtered and washed with water and diethyl ether to obtain a white solid (240 mg, 99%). 1H NMR (400 MHz, (DMSO) δ 8.0 (d, J=8.3, 1H), 7.6 (q, J=8.6 and 6.9 Hz, 1H), 7.3 (td, J=2.5 and 7.8 Hz, 1H), 7.1 (td, J=1.75 and 6.7 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.58 (s, 1H), 5.25 (s, 2H), 4.3 (t, J=8.3 Hz, 2H), 3.42 (t, J=5.4 Hz, 1H), 3.35 (t, J=5.2 Hz, 1H), 3.0 (t, J=8.2 Hz, 2H), 2.3 (s, 3H), 1.3 (s, 6H) ppm. ES-HRMS m/z 503.1561 (M+H calcd for C26H26ClF2N2O4 requires 503.1544).
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[CH2:8]([O:10][C:11](=[O:36])[CH2:12][NH:13][C:14](=[O:35])[CH2:15][NH:16][C:17](=[O:34])[C@H:18]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[NH:19]C(OC(C)(C)C)=O)[CH3:9]>C(OCC)(=O)C.C(OCC)C>[ClH:1].[CH2:8]([O:10][C:11](=[O:36])[CH2:12][NH:13][C:14](=[O:35])[CH2:15][NH:16][C:17](=[O:34])[C@H:18]([CH2:27][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[NH2:19])[CH3:9]
Reactant: CCOC(=O)CNC(=O)CNC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1CCCCC1
Yield: 86.8 %

Procedure:
After 3.0 mL (12 mmol) of 4M hydrogenchloride/ethyl acetate solution was added to a solution of 506.2 mg (1.22 mmol) of N-t-butoxycarbonyl-β-cyclohexyl-L-alanyl-glycyl-glycine ethylester in ethyl acetate (1 mL) with stirring under ice cooling, the reaction mixture was stirred at room temperature for 4.5 hours. Diethyl ether (12 mL) was added to the mixture and the mixture was stirred under ice cooling. Then the precipitates were collected by filtration to obtain hygroscopic crude crystals. The crude crystals were suspended in diethyl ether (10 mL), and then collected by filtration, to give 370.3 mg of β-cyclohexyl-L-alanyl-glycyl-glycine ethyl ester hydrochloride (yield 86%) as a colorless crystalline power.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.[C:18](=[O:20])=[O:19].CCOCC>O1CCCC1.O>[CH3:10][O:9][C:5]1[C:4]([C:18]([OH:20])=[O:19])=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:8]=[CH:7][CH:6]=1
Reactant: O=C=O
Reactant: COc1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(C(F)(F)F)c1C(=O)O

Procedure:
A solution of 3-trifluoromethylanisol (50.0 g, 0.28 mole) in tetrahydrofuran was cooled to -78° C. under nitrogen atmosphere with stirring. To this solution was added n-butyl lithium (114 ml of 2.5M, 0.28 mole), dropwise at such a rate that the temperature did not exceed -65° C. When the addition was complete, the mixture was stirred at -78° C. for three hours. The mixture was then poured over a slurry of dry ice/ether and allowed to come to room temperature. The solvent was removed under reduced pressure to give a white solid. This solid was dissolved in a minimum amount of water, extracted with diethyl ether (2×100 ml) and the aqueous phase was acidified to pH 2 with dilute hydrochloric acid. An oil formed and was extracted with diethyl ether, washed several times with water and dried over magnesium sulfate. The solvent was removed to give 45.6 g (74 percent of theory) of the title compound as a white solid of m.p. 129°-130° C.
Reaction SMILES: CC1C=CC2C(=CC=CC=2N2CCN(CCC3C=C(C=CC=3)N)CC2)N=1.[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([CH3:38])=[N:35]2)=[C:30]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([N+:53]([O-])=O)[CH:48]=3)[CH2:41][CH2:40]2)[CH:29]=1>>[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([CH3:38])=[N:35]2)=[C:30]([N:39]2[CH2:40][CH2:41][N:42]([CH2:45][CH2:46][C:47]3[CH:48]=[C:49]([CH:50]=[CH:51][CH:52]=3)[NH2:53])[CH2:43][CH2:44]2)[CH:29]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cc(Cl)cc2n1
Agent: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cc(Cl)cc2n1
Yield: 92 %

Procedure:
The title compound was prepared in 92% yield using a similar procedure to description D6 starting from 7-Chloro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline (D17).
Reaction SMILES: C(OC(=O)C)(=[O:3])C.[CH2:8]([N:10]1[C:15]2[N:16]=[C:17]([S:21][CH3:22])[N:18]=[C:19]([CH3:20])[C:14]=2[CH:13]=[C:12]([C:23]2[NH:27][CH:26]=[N:25][CH:24]=2)[C:11]1=N)[CH3:9]>>[CH2:8]([N:10]1[C:15]2[N:16]=[C:17]([S:21][CH3:22])[N:18]=[C:19]([CH3:20])[C:14]=2[CH:13]=[C:12]([C:23]2[NH:27][CH:26]=[N:25][CH:24]=2)[C:11]1=[O:3])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CCn1c(=N)c(-c2cnc[nH]2)cc2c(C)nc(SC)nc21
Product: CCn1c(=O)c(-c2cnc[nH]2)cc2c(C)nc(SC)nc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (15.0 mL) was added to a flask charged with crude 8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-imine and heated to 100° C. After 30 minutes, the reaction was allowed to cool to room temperature and concentrated in vacuo. The acetylated residue was then treated with 6 N HCl (16 mL) and heated to 95° C. for 30 minutes then transferred to a large flask. A saturated solution of NaHCO3 (150 mL) was added at 0° C. to about pH=8.0. The aqueous phase was washed thrice with ethyl acetate (100 mL) and the organic layers combined, then washed with brine and dried over Na2SO4. The drying agent was filtered off and the organic layers were concentrated in vacuo to afford crude 8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one which was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].S(Cl)([Cl:12])(=O)=O>C(Cl)Cl>[Cl:12][C:2]1([CH3:1])[C:6](=[CH2:7])[O:5][C:4](=[O:8])[O:3]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1oc(=O)oc1C
Solvent: ClCCl
Product: C=C1OC(=O)OC1(C)Cl
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
To a solution of 75 g of 4,5-dimethyl-1,3-dioxolene-2-one (IV) in 750 ml of methylene chloride was added 97.6 g of sulfuryl chloride dropwise at 40°-42° C. over 2 hours. The mixture was stirred for 40 minutes at the same temperature and evaporated in vacuo to remove the solvent. NMR spectrometry of the resulting oil revealed that the product was 4-chloro-4-methyl-5-methylene-1,3-dioxolane-2-one (III) containing a trace amount of unreacted 4,5-dimethyl-1,3-dioxolene-2-one (IV). This oil was heated at 90° C. with stirring for 2 hours without isolating 4-chloro-4-methyl-5-methylene-1,3-dioxolane-2-one (III) and then distilled in vacuo. 75.4 g (corresponding to an overall yield from 4,5-dimethyl-1,3-dioxolene-2-one (IV) of 77%) of 4-chloromethyl-5-methyl-1,3-dioxolene-2-one (II) having the physicochemical properties described in Reference Example 1 was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C@@H:9]([CH2:18][CH2:19][CH3:20])[C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=[O:12].[C:21](OC=O)(=[O:23])C>N1C=CC=CC=1>[CH:21]([N:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[C@@H:9]([CH2:18][CH2:19][CH3:20])[C@@H:10]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:11]([OH:13])=[O:12])=[O:23]
Reactant: CCC[C@H](NOC1CCCCO1)[C@@H](CC(C)C)C(=O)O
Reactant: CC(=O)OC=O
Solvent: c1ccncc1
Product: CCC[C@@H]([C@@H](CC(C)C)C(=O)O)N(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A solution of (2R,3S)-3-(2-tetrahydropyranyloxyamino)-2-(2-methyl-1-propyl)hexanoic acid (7.90 g, 27.5 mmol) in 100 mL of anhydrous pyridine is cooled to 0° C. and treated with formic acetic anhydride (4.0 mL, 46 mmol). The reaction mixture is allowed to warm to 25° C., stirred for 6 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in 150 mL of EtOAc and washed successively with two 50-mL portions of 1 M aqueous sodium bisulfate and two 50-mL portions of saturated aqueous sodium chloride. The combined organic extracts are dried over sodium sulfate and filtered, and the solvents are removed under reduced pressure affording 8.67 g (99%) of (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(2-methyl-1-propyl)hexanoic acid obtained as a viscous oil.
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])C.[NH2:19][C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1.[OH-].[Na+]>C(Cl)Cl>[C:1]12([NH:11][C:12]([N:14]3[CH2:17][CH2:18][CH2:16][CH2:15]3)=[N:19][C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: Cn1ccnc1N
Reactant: CCN(CC)CC
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cn1ccnc1N=C(NC12CC3CC(CC(C3)C1)C2)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 18.85 g (0.1 mole) of dichloromethylenetetramethylene ammonium chloride in 100 ml of dry methylene chloride is added dropwise a solution of 15.13 g (0.1 mole) of 1-adamantylamine and 20.2 g (0.2 mole) of triethylamine in dry CH2Cl2 with cooling (ice bath) under dry N2. After the addition is complete, the mixture is stirred at room temperature for 3 hrs. Then a dry methylene chloride solution containing 9.71 g (0.1 mole) of 2-amino-1-methylimidazole and 10.1 g (0.1 mole) of triethylamine is added dropwise over 1 hr with cooling. After the addition the mixture is stirred under dry N2 overnight at room temperature. The mixture is then shaken with excess 3 N NaOH and the organic layer is separated, dried (K2CO3), filtered and the solvent and residual triethylamine is removed in vacuo giving N-(1-adamantyl)-N'-(1-methylimidazol-2-yl)-1-pyrrolidinecarboximidamide free base.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[OH:61][C:54]1[C:53]([CH2:52][NH:51][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:19])[CH3:9])=[CH:18][CH:17]=2)=[C:58]([CH3:59])[CH:57]=[C:56]([CH3:60])[N:55]=1
Reactant: Cc1ccccc1OC(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3C)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.2 %

Procedure:
To the solution of 4-(1-(o-tolyloxy)ethyl)benzoic acid (127 mg, 0.5 mmol) in dichloromethane (80 mL) was added o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol) and triethylamine (151 mg, 1.5 mmol). then the 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added, the solution was stirred at room temperature for 12 hours, then washed with water (50 mL*3), the organic layer was evaporated and purified by column chromatography (silica gel, dichloromethane/meth anol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(o-tolyloxy)ethyl)benzamide (57 mg, 30%). LRMS (M+H+) m/z: calcd: 390.19. found 390; 1H-NMR (300 MHz, CD3OD) δ 7.75 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.71-7.08 (m, 1H), 6.97-6.92 (m, 1H), 6.77-6.66 (m, 2H), 6.10 (s, 1H), 5.46-5.44 (m, 1H), 4.48 (s, 2H), 2.36 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 1.62 (d, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=O)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:8]1[NH:9][C:10]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: O=c1[nH]c2cccc(F)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cccc2nc(Cl)[nH]c12
Temperature: 25 °C
Yield: 94.3 %

Procedure:
3-Fluorobenzene-1,2-diamine (0.600 g, 4.76 mmol) was dissolved in THF (14.82 ml) and 1,1′-carbonyldiimidazole (0.848 g, 5.23 mmol) was added at RT. The reaction mixture was stirred overnight at RT and then heated for 24 hours at 50° C. The mixture was cooled to RT and ammonia in MeOH (1.5 ml) was added and the mixture stirred for 30 minutes. The mixture was diluted with water (40 ml) and the resultant brown solid was collected by filtration, washed with water and then dried in vacuo to afford 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.700 g, 97%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 6.81 (2H, ddd), 6.88-6.95 (1H, m), 10.82 (1H, s), 11.08 (1H, s); m/z: (ES−) M-H−, 151.19. b) A solution of 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.7 g, 4.60 mmol) in phosphorus oxychloride (14.11 ml, 151.39 mmol) was heated at 100° C. for 18 hours. The reaction mixture was cooled to RT and excess phosphorus oxychloride was evaporated in vacuo. The residue was neutralized slowly (Care: exotherm) with saturated sodium bicarbonate solution (10 ml), and the mixture was then extracted with EtOAc (3×20 ml). The combined organic layers were washed with saturated brine and then dried over Na2SO4, filtered and evaporated to afford 2-chloro-7-fluoro-1H-benzo[d]imidazole (0.740 g, 94%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 7.01-7.11 (1H, m), 7.23 (1H, td), 7.32 (1H, s), 13.59 (1H, s); m/z: (ES+) MH+, 171.20. c) 2-Chloro-7-fluoro-1H-benzo[d]imidazole (1.7 g, 9.97 mmol) was charged to a high pressure autoclave PV10832 (Parr 160 ml) with methylamine (40% EtOH solution, 50 ml, 9.97 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The mixture was evaporated and the residue dissolved in MeOH and then added to an SCX column. The column was eluted with 7N ammonia in MeOH and fractions containing product were evaporated to leave a brown oil. The oil was purified by flash chromatography on silica, eluting with a gradient of 5 to 20% MeOH in DCM. Pure fractions were evaporated to afford 7-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (1.230 g, 75%); 1H NMR (400 MHz, DMSO-d6) 2.88 (3H, d), 6.54 (1H, bs), 6.67-6.73 (1H, m), 6.81 (1H, dd), 6.95 (1H, d); m/z: (ES+) MH+, 166.00.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12](SC)[S:11][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH2:28].[C:29](=O)([O-:31])[O-:30].[Cs+].[Cs+]>CN(C=O)C>[CH:29]([OH:31])=[O:30].[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH:28][C:12]1[S:11][N:10]=[C:9]([O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]=1[C:14]([NH2:16])=[O:15]
Reactant: CSc1snc(OCC2CCCCC2)c1C(N)=O
Reactant: O=C([O-])[O-]
Reactant: Nc1nc2ccccc2[nH]1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(OCC2CCCCC2)nsc1Nc1nc2ccccc2[nH]1
Product: O=CO
Temperature: 100 °C
Yield: 2.5 %

Procedure:
3-Cyclohexylmethoxy-5-methylsulfanyl-isothiazole-4-carboxylic acid amide (5) (30 mg, 0.094 mmol) is dissolved in DMF (0.3 mL) and the solution is agitated on a shaker plate. 1H-Benzoimidazol-2-ylamine (25 mg, 0.188 mmol) and cesium carbonate (61 mg, 0.188 mmol) are then added and the reaction mixture is heated to 100° C. and agitated for 4 hrs. The resulting solution is then filtered and the mother liquor is purified by preparative HPLC to provide 5-(1H-Benzoimidazol-2-ylamino)-3-cyclohexylmethoxy-isothiazole-4-carboxylic acid amide monoformate salt (1.0 mg). 1H NMR (d6 DMSO): δ 12.09 (1H, s), 11.88 (1H, s), 7.77 (1H, s), 7.45–7.47 (1H, m), 7.36–7.38 (1H, m), 7.05–7.10 (2H, m), 7.01 (1H, s), 4.19 (2H, d, J=6.4 Hz), 1.61–1.83 (6H, m), 1.14–1.31 (3H, m), 0.97–1.11 (2H, m); LRMS (M+): 372.1.