Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[NH2:24][C:25]1[N:26]=[CH:27][C:28]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:29][C:30]=1[C:31]([F:34])([F:32])[F:33]
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N)c(C(F)(F)F)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 2-amino-3-(trifluoromethyl)pyridine-5-boronic acid pinacol ester (stage 25.1.1, 37 mg, 0.128 mmol) to give the title compound as a pinkish solid. (HPLC: tR 2.40 min (Method A); M+H=454 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.93 (s, 1H), 8.43-8.36 (m, 1H), 8.16-8.11 (m, 1H), 8.09-8.02 (m, 1H), 7.97-7.90 (m, 1H), 7.76-7.70 (m, 1H), 7.45-7.39 (m, 1H), 6.76 (s, br, 2H), 3.88 (s, 3H), 3.56 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)=O.C(N(CC)CC)C.Cl.Cl.[CH2:23]([NH:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[CH2:23]([N:30]1[C:5]2[C:4](=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NNCc1ccccc1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nn(Cc2ccccc2)c2ccc([N+](=O)[O-])cc12

Procedure:
2-Fluoro-5-nitroacetophenone (H. Sato et al, Bioorganic and Medicinal Chemistry Letters, 5(3), 233-236, 1995) (0.24 g) was treated with triethylamine (0.73 ml) and benzyl hydrazine dihydrochloride (0.255 g) in ethanol (20 ml) at reflux under N2 for 8 days. The mixture was cooled and the solid 1-benzyl-3-methyl-5-nitroindazole (0.16 g) was collected by filtration; m/z (M+1)+ 268.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:24][CH2:23][C:5]2=[C:6]([C:9]3[O:13][N:12]=[C:11]([C:14]4[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[C:16]([CH3:22])[CH:15]=4)[N:10]=3)[S:7][CH:8]=[C:4]2[CH2:3]1.[OH-].[Na+].[CH2:28]([CH:30]1[O:32][CH2:31]1)Cl>C(O)(C)C.O>[CH3:22][C:16]1[CH:15]=[C:14]([C:11]2[N:10]=[C:9]([C:6]3[S:7][CH:8]=[C:4]4[CH2:3][C:2]([CH3:25])([CH3:1])[CH2:24][CH2:23][C:5]=34)[O:13][N:12]=2)[CH:19]=[C:18]([CH3:20])[C:17]=1[O:21][CH2:28][CH:30]1[CH2:31][O:32]1
Reactant: Cc1cc(-c2noc(-c3scc4c3CCC(C)(C)C4)n2)cc(C)c1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(-c2noc(-c3scc4c3CCC(C)(C)C4)n2)cc(C)c1OCC1CO1
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
A solution of 4-[5-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (35 mg, 1.18 mmol) in isopropanol (17 mL) is treated with 2 N aq. NaOH (8.6 mL) followed by epichlorohydrine (660 mg, 7.14 mmol). The mixture is stirred at 50° C. for 18 h before it is diluted with water and extracted twice with EA. The combined organic extracts are dried over Na2SO4, filtered, evaporated and dried to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazole (480 mg) as a pale yellow oil; LC-MS: tR=1.24 min, [M+1]+=411.31.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.C(Cl)(=O)C([Cl:13])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([Cl:13])=[O:9])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nccc1C(=O)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A suspension of 800 mg (6.03 mmol) of 2-methyl-2H-pyrazole-3-carboxylic acid in 30 mL of DCM is placed under argon and cooled to 0° C. When the temperature is reached, 1.32 mL (15.07 mmol) of oxalyl chloride and a catalytic amount of DMF are added. The reaction mixture is stirred at room temperature for 2 hours and then evaporated to dryness and the residue is taken up in DCM and evaporated again to give 850 mg of 2-methyl-2H-pyrazole-3-carbonyl chloride, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[O:8].[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>[OH-].[Na+]>[CH:13]1([C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[O:8])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NCCC[C@H](NC(=O)C1CCCCC1)C(=O)O
Temperature: 25 °C
Yield: 77.5 %

Procedure:
L-Citrulline (35.2 g., 0.2 mole) was dissolved in 200 mL of 2N sodium hydroxide. Cyclohexanoyl chloride (29 mL, 0.2 mole) was added dropwise to the mixture. The reaction mixture was maintained at about 25° C. for 1 hour. The mixture was then acidified to pH 2.6 with aqueous (4:1) hydrochloric acid. The precipitate which formed was separated by decantation. The solids were dissolved in 2N sodium hydroxide to pH 6.5 and dried by lyophilization to furnish 44.2 g of N-cyclohexanoyl-(L)-citrulline. The product was a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(-c2ccccc2)c(CCO)c2ncnn12
Solvent: c1ccncc1
Product: CC(=O)OCCc1c(-c2ccccc2)nc(N)n2ncnc12
Reaction time: 16 h

Procedure:
A solution of 25.5 g (0.1 mole) of the title compound of Example 1 and 11 ml (ca. 0.11 mole) of acetic anhydride in 150 ml of pyridine was allowed to stand for about 16 hours at room temperature. Approximately half of the solution was separated and concentrated in vacuo to dryness and chromatographed on silica gel, giving the title compound, m.p. 181°-182°.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].O=[C:6]1[CH:10]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[CH2:9][CH2:8][CH:7]1[C:21](OCC)=[O:22].O>CO>[F:19][C:17]([F:18])([F:20])[C:14]1[N:13]=[CH:12][C:11]([CH:10]2[C:6]3[N:1]=[C:2]([OH:3])[N:4]=[C:21]([OH:22])[C:7]=3[CH2:8][CH2:9]2)=[CH:16][CH:15]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C1CCC(c2ccc(C(F)(F)F)nc2)C1=O
Solvent: CO
Solvent: O
Product: Oc1nc(O)c2c(n1)C(c1ccc(C(F)(F)F)nc1)CC2
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a melt of urea (748 mg, 12.45 mmol) at 150° C. was added ethyl 2-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentanecarboxylate (750 mg, 2.49 mmol) dropwise. The reaction was stirred overnight. The reaction mixture was cooled and the resulting solid mass was broken up and suspended in MeOH. The mixture was diluted with a large excess of water and cooled in an ice bath. The suspension was filtered and the residue was washed with water and dried to afford the semi-pure product, 7-(6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diol (334 mg, 1.124 mmol, 45.1% yield). LC-MS (M+H)+=298.0.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2].[C:25](O)(=[O:28])[CH2:26][OH:27].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:26](=[O:27])[CH2:25][OH:28])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2]
Reactant: N#CC=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Reactant: O=C(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: N#CC=C1CCN(c2ccc(N3C[C@H](CNC(=O)CO)OC3=O)cc2F)CC1
Reaction time: 3 h
Yield: 70 %

Procedure:
The mixture of (S)-N-{3-[4-(4-cyanomethylidene-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine (2.87 mmol), glycolic acid (5.74 mmol), dicyclohexylcarbodiimide (7.17 mmol), 4-dimethylaminopyridine (100 mg) in dichloromethane (50 ml) was stirred for 3 hours. The reaction mixture was filtered. The filtrate was evaporated and the residue was purified by column chromatography over a silica gel to give title compound in 70% yield.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[CH:21][C:20]=1[CH3:30])[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.CO>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[CH:21][C:20]=3[CH3:30])[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(C(C)(C)C#N)ccc1C(C)N
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
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: CO
Product: Cc1cc(C(C)(C)C#N)ccc1C(C)NC(=O)Cn1cnc2cccc(C#N)c21
Yield: 43.1 %

Procedure:
To a solution of (7-cyano-1H-benzimidazol-1-yl)acetic acid (250 mg, 1.24 mmol) prepared according to scheme 3, 2-[4-(1-aminoethyl)-3-methylphenyl]-2-methylpropanenitrile (251 mg 1.24 mmol) prepared according to scheme 15 and DMAP (150 mg, 1.24 mmol) stirred in anhydrous DMF (4.0 mL) is added HATU (473 mg, 1.24 mmol) after 18 hours of stirring, the mixture is diluted with Methanol (200 μL) the solution is purified directly 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 4 N 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 2-(7-cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-2-methylphenyl]ethyl}acetamide (206 mg, 43%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.45 (d, J=6.84 Hz, 3H) 1.66 (s, 6H) 2.37 (s, 3H) 5.20 (q, J=6.84 Hz, 1H) 5.30 (s, 2H) 7.25 (d, J=1.95 Hz, 1H) 7.32 (dd, J=8.20, 2.15 Hz, 1H) 7.38 (dd, J=8.11, 7.71 Hz, 1H) 7.44 (d, J=8.20 Hz, 1H) 7.67 (dd, J=7.42, 0.78 Hz, 1H) 7.96 (dd, J=8.20, 0.98 Hz, 1H) 8.24 (s, 1H), MS [M+H], calcd: 386.2. found: 386.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[C:10]=2[N:11]=1.[Cl:21][C:22]1[C:27]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])(=[O:31])=[O:30])=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:21][C:22]1[C:27]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])(=[O:31])=[O:30])=[CH:26][C:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]4[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=4)[C:10]=3[N:11]=2)=[CH:24][N:23]=1
Reactant: COc1ccc(Nc2ncnc3ccc(Cl)nc23)cn1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccc(F)cc5F)c4)nc23)cn1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
A mixture of 6-chloro-N-(6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine (Intermediate 22) (0.040 g, 0.139 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.066 g, 0.153 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.011 g, 0.014 mmol) and 1 N aq. sodium bicarbonate (0.278 ml, 0.278 mmol) in dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(6-methoxypyridin-3-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.024 g, 31%) as a yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 3.89 (3H, s), 6.94 (3H, s), 6.89-7.05 (1H, d, J=8.4 Hz), 7.17-7.28 (1H, m), 7.50-7.65 (1H, m), 7.74-7.86 (1H, m), 8.17 (1H, dd, J=2.4, 8.8 Hz), 8.33 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz), 8.57 (1H, d, J=8.8 Hz), 8.62 (2H, s), 8.82 (1H, s), 9.48 (1H, s), 10.33 (1H, s), 10.98 (1H, br s). m/z=556.2 [M+1]+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cnc2ccc(Oc3ccccc3)nc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(Oc3ccccc3)nc2c1Cl
Temperature: 50 °C

Procedure:
A mixture of ethyl 4-hydroxy-6-phenoxy-1,5-naphthyridine-3-carboxylate (3.0 g) and phosphorus oxychloride (25 ml) was heated at 50° C. for 1 hour and then worked up as described in Example B1 to give ethyl 4-chloro-6-phenoxy-1,5-naphthyridine-3-carboxylate, m.p. 133°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH2:20][O:21][CH3:22])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O.C(OC(Cl)=O)C(C)C.CN1CCOCC1.[CH:39]1([NH2:43])[CH2:42][CH2:41][CH2:40]1>O1CCCC1.Cl>[CH:39]1([NH:43][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:19][C:18]([CH2:20][O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH:6]=[CH:7][C:8]=2[O:14][CH3:15])[CH2:42][CH2:41][CH2:40]1
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)O)c2)c(Cl)c1
Reactant: NC1CCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)NC3CCC3)c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a solution of the title compound of Step D (238 mg, 0.67 mmol) in tetrahydrofuran (7 ml) at 0° C. under nitrogen was added isobutylchloroformate (0.13 mL, 1 mmol) and N-methylmorpholine (0.15 ml, 1.3 mmol). After stirring for about 30 minutes at 0° C., cyclobutylamine (0.11 ml, 1.3 mmol) was added. The reaction mixture was warmed to room temperature and stirred for about 19 hours. The reaction solution was diluted with 1N HCl (30 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with 1N HCl (2×50 ml), brine (50 ml), dried, filtered, and concentrated. The crude product was purified by preparative TLC (50% ethyl acetate in hexanes) to afford the title compound (170 mg) as a viscous oil. MS (APCl+) Calc: 409.1, found: 409.7 (M+1)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:12])[C:8](=[S:11])[NH:9][N:10]=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.ClCCl.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH:15]1([CH2:14][S:11][C:8]2[N:7]([CH3:12])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[N:10][N:9]=2)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: Cn1c(CCCCO)n[nH]c1=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(CCCCO)nnc1SCC1CC1
Temperature: 60 °C

Procedure:
5-(4-hydroxybutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.3 g), (bromomethyl)cyclopropane (0.17 ml) and triethyl ammine (0.27 ml) were dissolved in dimethylformamide (2 ml). Reaction was heated at 60° C. for 2 h. Dichloromethane and NaHCO3 saturated solution were added. Solvent was removed, under reduced pressure to give a crude that was purified by Silica column (eluting with DCM/MeOH from 0 to 10%) to give the title compound (0.2 g).
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@:7]2([OH:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C@H:2]2[CH3:1])=[CH:14][CH:13]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: C[C@@H]1NC(C)(C)COC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
A solution of 15 (357 mg, 2.50 mmol) in dry THF (2.5 mL, 1M) under an N2 atmosphere was cooled to −78° C. and treated with 4-chlorophenylmagnesium bromide (2 equiv., 5.00 mmol, 5.00 mL, 1M solution in ether). The reaction mixture was stirred at −78° C. for 2 h. A saturated aqueous solution of NH4Cl was added to the reaction vessel, and the mixture was allowed to warm to room temperature. EtOAc was added and the organic layer was separated and the aqueous phase was extracted with EtOAc (trice). The combined organic extracts were washed (water, brine), dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2 to CH2Cl2-MeOH (90:10) as the eluent to afford 180 mg (29%) of 4i as a white solid: [α]23D +33° (c 0.4, CHCl3): 1H NMR (CDCl3) δ 7.54 (d, 2H, J=8.5 Hz), 7.32 (d, 2H, J=8.5 Hz), 3.83 (d, 1H, J=11.3 Hz), 3.40 (d, 1H, J=11.3 Hz), 3.18 (q, 1H, J=6.5 Hz), 1.38 (s, 3H), 1.08 (s, 3H), 0.78 (d, 3H, J=6.5 Hz); 13C NMR (CDCl3) δ 128.5, 128.1, 127.6, 127.2, 101.6, 95.9, 69.5, 53.4, 49.7, 27.3, 22.8, 16.4; LCMS (ESI) m/z 256.3 [(M+H)+, M=C13H18ClNO2].
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:15]([S:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:15]([S:28]([C:29]2[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=2)=[O:6])[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Sc1ccc(S(C)(=O)=O)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1S(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Chloroperoxybenzoic acid (70% purity, 0.2 g) was added to a solution of the product from example 9 step (ii) (0.35 g) in DCM (10 ml) and stirred at 0° C. for 1 h. The mixture was partitioned between DCM/aq. sodium metabisulphite solution, the organics washed with aq. sodium hydrogencarbonate solution, water, dried and evaporated under reduced pressure. Yield 0.34 g
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[H-].[Na+].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Cc1ccn2c(-c3cccc(O)c3)cnc2c1
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccn2c(-c3cccc(Oc4ccccn4)c3)cnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
3-(7-Methylimidazo[1,2-α]pyridin-3-yl)phenol (310 mg, 1.4 mmol) in anhydrous N,N-dimethylformamide (5 ml) was treated with sodium hydride (60% dispersion in mineral oil, 70 mg, 1.75 mmol) and then stirred at ambient temperature for 30 minutes. 2-Bromopyridine (0.16 ml, 1.67 mmol) was added and the reaction mixture heated at 120° C. for 4 days, poured into water (25 ml) and extracted with ethyl acetate (2×30 ml). The combined organic phases were washed with water (3×20 ml), dried over anhydrous magnesium sulphate and concentrated in vacuo. Purification by preparative TLC gave the title compound as a colourless oil (100 mg, 24%). 1H NMR (400 MHz, CDCl3) δH 2.64 (3H, s), 7.08-7.10 (1H, m), 7.14-7.17 (1H, m), 7.33-7.37 (2H, m), 7.50-7.55 (2H, m), 7.66-7.70 (1H, m), 7.78 (1H, s), 7.85-7.90 (1H, m), 8.07 (1H, s), 8.15-8.16 (1H, m), 8.65 (1H, d, J 7); m/z (ES+) 302 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.CC(O)=O>CCO>[Cl:11][C:12]1[CH:19]=[CH:18][C:15](/[CH:16]=[N:1]/[C:2]2[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1cc(N)cn(C)c1=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(/N=C/c2ccc(Cl)cc2)cn(C)c1=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a stirred solution of 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2) (5.2 g, 37.6 mmol) in EtOH (100 mL) were added 4-chlorobenzaldehyde (5.04 g, 35.8 mmol) and AcOH (0.410 mL, 7.17 mmol). The resulting mixture was heated up and stirred at 85° C. for 1 hr. The reaction was concentrated under reduced pressure and the resulting crude mixture was triturated in Et2O to afford the title product (7.6 g, 29.2 mmol) as beige solid. tR: 0.92 min (LC-MS 2).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=O)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.C(P(=O)(OCC)OCC)#N>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:21])([CH3:22])[C:18]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:20])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)O)ccc2n1CC1CC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)N3CCOCC3)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
To a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoic acid (Example 1, Step H, 180 mg, 0.46 mmol), morpholine (Wako Pure Chemical Industries, Ltd., 48 mg, 0.55 mmol), N,N′-diisopropylethylamine (71 mg, 0.55 mmol) in N,N′-dimethylformamide (3 mL) was added diethyl cyanophosphonate (Aldrich, 90 mg, 0.55 mmol) at room temperature. The mixture was stirred at room temperature for 20 h and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:4 as eluent) to afford the title compound (102 mg, 48%) as a white solid.