Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.O.[S-2:19].[Na+].[Na+].Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4](=[S:19])[NH2:5]
Reactant: [S-2]
Reactant: N#Cc1c(F)cccc1F
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1c(F)cccc1F
Temperature: 25 °C
Yield: 76 %

Procedure:
Into a 3 L three necked round bottom flask equipped with a mechanical stirrer, dry ice condenser, dropping funnel, and outlet to a trap filled with bleach was added pyridine (550 mL), 2,6-difluorobenzonitrile (208 g, 1.50 mol), triethylamine (202 g, 279 mL, 2.0 mol), and sodium sulfide hydrate (521 g, 2.17 mol-broken into pieces small enough to fit into the flask). The temperature of the stirred mixture was lowered to approximately 5° C. and to the slurry was added dropwise concentrated hydrochloric acid (143 g, 288 mL, 3.99 mol). An exotherm was noted and the rate of addition of the hydrochloric acid was such that the temperature of the reaction mixture did not exceed 25° C. for a total addition time of 75 min. The cooling bath was removed and the slurry was allowed to warm to RT and to stir over night. The mixture was poured into water (2 L) and was extracted with ether (3×500 mL). The ether layer was washed with dilute sulfuric acid, water, brine, dried (MgSO4), and the solvent removed in vacuo to give 232 grams of crude product. The starting material was removed from the product via kugelrohr distillation to give 197 g (76%) of 2,6-difluorobenzenethioamide. This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:35][CH2:34][CH2:33][CH2:32][NH:31][C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(NCCCN)cc1OC
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1ccc(NCCCNCCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 3-(3,4-dimethoxyphenylamino)-propylamine analogously to Example 1. M.p.: 206°-212° C. (decomp.)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][C@@H:10]([C:12]([OH:14])=O)[NH2:11])=[CH:4][CH:3]=1.[O-:17][C:18]#[N:19].[K+].Cl>O.[OH-].[Na+]>[Cl:1][C:2]1[CH:16]=[C:15]2[C:5](=[CH:4][CH:3]=1)[NH:6][CH:7]=[C:8]2[CH2:9][CH:10]1[NH:11][C:18](=[O:17])[NH:19][C:12]1=[O:14]
Reactant: N#C[O-]
Reactant: N[C@@H](Cc1c[nH]c2ccc(Cl)cc12)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C1NC(=O)C(Cc2c[nH]c3ccc(Cl)cc23)N1

Procedure:
A mixture of 5-chlorotryptophan (32 g, 0.14 mole) and potassium cyanate (22.6 g, 0.28 mole) in 500 ml of H2O was heated on the steam bath for 3 hours, cooled and acidified with concentrated HCl. The solid was collected, suspended in 500 ml of 10% HCl and heated on the steam bath for 2 hours. The solid, obtained on cooling, was dissolved in dilute NaOH, filtered and acidified with dilute HCl. The solid obtained was recrystallized from aqueous 2-PrOH. Yield 17 g (37.6%), m.p. 226°-8°, contains a mole of 2-PrOH.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[CH2:19][C:20]#[N:21].I[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([F:29])[F:28].O>C1CCCCC1.O1CCCC1>[Cl:9][C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([F:29])[F:28])[C:20]#[N:21]
Reactant: FC(F)CCCCI
Reactant: N#CCc1c(Cl)sc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: O
Product: N#CC(CCCCC(F)F)c1c(Cl)sc2ccccc12
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
A solution of lithium diisopropylamide in cyclohexane (5.13 mmol, 3.42 ml of a 1.5M solution) was added dropwise to a solution of (2-chlorobenzo[b]thiophen-3-yl)acetonitrile (1.06 g, 5.13 mmol) in tetrahydrofuran (10 ml) cooled to -70° C. under nitrogen. The resulting solution was stirred at -70° C. for 20 min, then a solution of 5-iodo-1,1-difluoropentane (1.2 g, 5.13 mmol) in tetrahydrofuran (5 ml) was slowly added at -70° C. The reaction mixture was stirred at -70° C. for 1 hr, then slowly allowed to warm to room temperature and left at that temperature overnight. Water (60 ml) was added to the reaction solution and the resulting mixture was extracted with ethyl acetate (3×70 ml). The combined ethyl acetate extracts were washed with brine (80 ml), dried (sodium sulfate) and concentrated in vacuo. The crude product (2.1 g) was purified by column chromatography on silica gel (200 g), eluting with 4:1 hexane/dichloromethane followed by 7:3 hexane/dichloromethane to yield the title compound as an oil (950 mg, 59% yield). 1H NMR (300 MHz, CDCl3) δ1.4-1.7 (c, 4H), 1.7-2.05 (c, 3H), 2.2 (c, 1H) 4.3 (t, 1H), 5.6, 5.78, 5.98 (3t, total 1H), 7.42 (m, 2H), 7.75 (d, 1H), 7.95 (d, 1H).
Reaction SMILES: CC(O[Hg][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:12]([O-:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B([O-])([O-])[O-].[Br-].[Cl-]>>[C:12]([O:20][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)O[Hg]c1ccccc1
Reactant: O=C([O-])c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [O-]B([O-])[O-]
Product: O=C(Oc1ccccc1)c1ccccc1

Procedure:
Phenyl Mercuric Acetate, Benzoate, Borate, Bromide or Chloride
Reaction SMILES: C(S)C.[Cl-].[Al+3].[Cl-].[Cl-].[CH:8]([C:11]1[CH:21]=[C:20]([O:22]C)[CH:19]=[C:18]2[C:12]=1[C:13](=[O:24])[NH:14][S:15]2(=[O:17])=[O:16])([CH3:10])[CH3:9].Cl>C(Cl)(Cl)Cl>[CH:8]([C:11]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]2[C:12]=1[C:13](=[O:24])[NH:14][S:15]2(=[O:17])=[O:16])([CH3:10])[CH3:9]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCS
Product: CC(C)c1cc(O)cc2c1C(=O)NS2(=O)=O
Temperature: 60 °C
Yield: 97 %

Procedure:
Ethanethiol (43.9 g) was added with stirring to a suspension of aluminum chloride (62.74 g) in chloroform (500 mL) at 0° C. To the resulting solution was added a solution of 4-isopropyl-6-methoxysaccharin (20.0 g) in chloroform (550 mL) during 30 minutes. The resulting solution was warmed to and maintained at 60° C. for 3-4 hours, then poured into ice-water acidified with hydrochloric acid. The resulting solid was collected by filtration, washed with water and dried affording 4-isopropyl-6-hydroxysaccharin, 18.4 g., 97% yield.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8]([OH:19])([CH3:18])[C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:22]([C@:24]1([OH:31])[CH2:28][CH2:27][N:26]([CH3:29])[C:25]1=[O:30])#[CH:23]>>[OH:19][C:8]1([CH3:18])[C:9]2[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[N:11][C:10]=2[C:4]2[CH:3]=[C:2]([C:23]#[C:22][C@:24]3([OH:31])[CH2:28][CH2:27][N:26]([CH3:29])[C:25]3=[O:30])[CH:21]=[CH:20][C:5]=2[O:6][CH2:7]1
Reactant: COC(=O)c1nc2c(s1)C(C)(O)COc1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: COC(=O)c1nc2c(s1)C(C)(O)COc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Methyl 9-bromo-4-hydroxy-4-methyl-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate (0.11 g) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford methyl 4-hydroxy-9-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4-methyl-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate which was directly subjected to conditions described in General Procedure M to afford 5 mg and 5.6 mg (9% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined. M+1=414.0.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:24]2[CH2:27][CH2:26][CH2:25]2)=[CH2:23])[N:16]=3)=[C:9]([F:28])[CH:8]=1.[I-].[CH3:30][S+](C)(C)=O.CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([CH:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:30][CH2:23]2)[N:16]=3)=[C:9]([F:28])[CH:8]=1
Reactant: C[S+](C)(C)=O
Reactant: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCC1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(C4CCC4)CC3)nc2s1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-cyclobutylvinyl)-thiazolo[5,4-b]pyridine (167.1 mg, 0.421 mmol) in THF (8.0 mL) was added a solution of trimethylsulfoxonium iodide (557 mg, 2.53 mmol) and potassium 2-methylpropan-2-olate (284 mg, 2.53 mmol) in DMSO (4.80 mL) under argon, and the resulting solution was stirred at 60° C. for 2.5 h. The reaction mixture was then cooled to 25° C., THF was removed in vacuo, and the residual mixture was diluted with DCM (100 mL). The resulting solution was sequentially washed with sat. aq. NH4Cl (50 mL) and brine (20 mL). The combined aqueous layers were extracted with DCM (2×50 mL), and the combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-30% EtOAc/hexanes) furnished 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-cyclobutyl-cyclopropyl)thiazolo[5,4-b]pyridine as a white solid. MS (ESI) m/z: Calculated: 410.1; Observed: 411.1 (M++1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[CH:19]=3)=[C:16]([CH3:31])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.[CH2:39]([OH:42])[CH2:40][OH:41].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC.[Cu](I)I>[CH3:31][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:14]=2)[O:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([O:41][CH2:40][CH2:39][OH:42])=[CH:3][CH:4]=2)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:19]=1
Reactant: OCCO
Reactant: CC1=C(c2cccc(OC3CCCCO3)c2)C(c2ccc(I)cc2)Oc2ccc(OC3CCCCO3)cc21
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Product: CC1=C(c2cccc(OC3CCCCO3)c2)C(c2ccc(OCCO)cc2)Oc2ccc(OC3CCCCO3)cc21
Temperature: 125 °C

Procedure:
A mixture of 2-(4-iodophenyl)-4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromene (Intermediate 3, 1.0 g, 1.6 mmol), ethane-1,2-diol (0.49 g, 8.0 mmol), copper iodide (0.03 g, 0.16 mmol), 1,10-phenanthroline (0.058 g, 0.32 mmol), potassium carbonate (0.44 g, 3.2 mmol) in butyronitrile (3.2 mL) was degassed three times via nitrogen/vacuum cycles. The reaction mixture was heated at 125° C. for 2 days, allowed to cool to room temperature, and diluted with ethyl acetate. This mixture was filtered through Celite. The organic phase was washed twice with water, washed with brine, dried over Na2SO4, filtered, and concentrated to afford the crude product. This crude product was then purified by silica gel chromatography to give 2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethanol. 1H NMR (DMSO-d6): δ 7.27-7.13 (m, 3H), 6.98 (t, 1H), 6.93-6.84 (m, 3H), 6.80-6.76 (m, 3H), 6.59 (d, 1H), 5.97 (d, 1H), 5.43 (dt, 1H), 5.34 (br, 1H), 4.79 (t, 1H), 3.88 (t, 2H), 3.80-3.70 (m, 2H), 3.64 (q, 2H), 3.54-3.50 (m, 2H), 2.06 (s, 3H), 1.86-1.66 (m, 6H), 1.59-1.51 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH2:21]C)=[O:19])[CH2:14][CH2:13]1.C(#N)C.CCN(C(C)C)C(C)C>O.C(Cl)Cl>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:11][C@@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17]1)([O-:10])=[O:9]
Reactant: CCOC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@H]1CC[C@@H](Nc2ccncc2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A round bottom flask under nitrogen atmosphere was charged with 4-chloro-3-nitropyridine (1.65 g, 10.41 mmol), cis-ethyl 4-aminocyclohexanecarboxylate (2.454 g, 15.61 mmol), and ACN (26 mL). To the mixture was added DIPEA (3.63 mL, 20.81 mmol). The resulting mixture was stirred at 60° C. for 17 hours. The reaction was stopped, cooled to RT and diluted with water (20 mL) and DCM (50 mL). The layers were separated, and the organic layer was collected, dried over sodium sulfate and concentrated to afford an orange oil. The oil was purified by silica gel chromatography to afford the title compound (2.2 g, 76% yield) as a bright yellow solid. MS m/z=280.2 [M+H]. Calc'd for C13H17N3O4: 279.1.
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].O>[OH:8][CH2:9][C:10]1([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOCC1(COCc2ccccc2)CCC(=O)O1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOCC1(CO)CCC(=O)O1

Procedure:
A mixture containing 10.7 g (21.83 mmol) of the compund prepared in (e) above, 300 ml of a mixture of ethyl alcohol and water in a ratio of 9:1 and 1.5 g of 5% palladium on carbon (50% water content) was placed in a pressure bottle and hydrogenated at b 40° C. under a pressure of 50 lbs. of hydrogen until uptake was complete. The catalyst was then filtered off and the filtrate concentrated in vacuo. The residue was crystallized from methanol to yield a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[F:36][C:37]1[CH:60]=[CH:59][C:40]([CH2:41][N:42]2[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=[C:43]2[C:51]([CH:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[O:52])=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.CO>O1CCCC1.O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:56]2[CH2:57][CH2:58][CH:53]([C:51]([C:43]3[N:42]([CH2:41][C:40]4[CH:39]=[CH:38][C:37]([F:36])=[CH:60][CH:59]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)=[O:52])[CH2:54][CH2:55]2)([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1ccc(C2(CCS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C2(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Reaction time: 72 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dimethoxy-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.69 g, 1.32 mmol) and 4-[1-(4-fluoro-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidine (0.49 g, 1.42 mmol), and sodium bicarbonate (0.223 g, 2.64 mmol) in tetrahydrofuran/water (15/4) (30 mL). Heat to reflux. After 72 hours, cool and evaporate in vacuo to obtain a residue. Partition the residue between dichloromethane and 5% sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 5/1 ethyl acetate/methanol to give an oil. Combine the oil with dichloromethane and extract with 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Dry the residue in vacuo at 82° C. to give the title compound: Rf=0.27 (silica gel, 5/1 ethyl acetate/methanol); mp; 80-83° C. Elemental Analysis calculated for C44H49FN4O7: C 69.09; H 6.46; N 7.32; Found: C 68.82; H 6.44; N 7.42.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+].[CH3:57][O:58][C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:57][O:58][C:59]1[CH:60]=[C:61]([NH:65][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:62]=[CH:63][CH:64]=1
Reactant: COc1cccc(N)c1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COc1cccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 20.1 %

Procedure:
Compound 6 (50 mg, 0.22 mmol), Pd(OAc)2 (4 mg, 0.02 mmol), X-Phos (17 mg, 0.03 mmol), NaOtBu (125 mg, 1.30 mmol), and m-anisidine (0.04 mL, 0.33 mmol) were dissolved in dioxane (2 ml) and stirred for 72 hrs at 100° C. The crude material was purified directly via Biotage eluting with a gradient of 0 to 10% MeOH in CH2Cl2 to provide 231 (14 mg, 19% yield) as a white solid. LC-MS (M+H=318, obsd.=318).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[F:29][C:30]([F:34])([F:33])[CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[F:29][C:30]([F:34])([F:33])[CH2:31][NH:32][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(F)(F)F)ccc21
Yield: 85.1 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (102 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2,2,2-trifluoroethylamine (27 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 490.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 9.05 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.81 (d, 1H), 7.72 (d, 1H), 7.51 (d, 1H), 7.34 (d, 1H), 4.18-4.01 (m, 2H), 3.62 (bs, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:23])[CH:3]=1.Cl[C:25]1[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][N:28]=[C:27]([S:36][CH3:37])[N:26]=1.C(N(C(C)C)C(C)C)C.O1CCOCC1>C(Cl)Cl.O>[F:23][C:4]1[CH:3]=[C:2]([NH:1][C:29]2[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][N:26]=[C:27]([S:36][CH3:37])[N:28]=2)[CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:15])[CH:8]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)c(F)c1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)c(F)c1
Temperature: 60 °C

Procedure:
A mixture of N-(4-(4-amino-2-fluorophenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide (0.158 g, 0.5 mmol), ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (0.2 g, 1.0 mmol), N-ethyl-N-isopropylpropan-2-amine (0.1 g, 1.0 mmol) in 1,4-dioxane (1 g, 11 mmol) was heated in microwave (CEM) at 60 W and 60° C. for 40 min. The resultant was diluted with DCM (15 mL) and water (10 mL). The organic layer was separated, dried over sodium sulfate, and concentrated. The residue was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.[CH3:37][O:38][C:39]1[C:44](B(O)O)=[CH:43][CH:42]=[CH:41][N:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH:11]1([CH:10]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:22][CH:23]=2)[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([C:44]4[C:39]([O:38][CH3:37])=[N:40][CH:41]=[CH:42][CH:43]=4)=[CH:36][C:6]=3[C:7]=2[CH3:35])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Br)cc3c2C)C2CCCCC2)cc1
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(-c4cccnc4OC)cc3c2C)C2CCCCC2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 89.8 %

Procedure:
To a solution (15 mL) of ethyl 3-{[(4-{[(5-bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (0.53 g) synthesized in Example A174(3) in N,N-dimethylacetamide were added (2-methoxypyridin-3-yl)boronic acid (0.29 g), potassium carbonate (0.27 g) and tetrakistriphenylphosphine palladium (0.05 g), and the mixture was stirred at 90° C. for 12 hr under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through celite, and the residue was washed with diethyl ether. Water was added to the filtrate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give ethyl 3-[{[4-({cyclohexyl[5-(2-methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.50 g, 89%) as a pale-yellow oil. The obtained oil was dissolved in ethanol (1 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.47 g, quantitative) as a colorless solid.