Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:13](OCC)(OCC)OCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[O:12]1[C:11]2=[CH:10][CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[C:3]2[N:2]=[CH:13]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: O=C(O)c1cccc2ocnc12
Temperature: 25 °C
Yield: 100.6 %

Procedure:
A mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (300 mg, 1.28 mmol), triethyl orthoformate (0.85 mL, 5.1 mmol), pyridinium p-toluenesulfonate (64 mg, 0.26 mmol) and xylenes (15 mL) was refluxed for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the benzoxazole-4-carboxylic acid (210 mg, quantitative) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.86 (s, 1H), 8.03 (dd, J=8.1, 0.9 Hz, 1H), 7.92 (dd, J=8.1, 0.9 Hz, 1H), 7.54 (t, J=8.1 Hz, 1H); MS (ESI+) m/z 164 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][N:4]([CH2:9][C@H:10]1[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12][N:11]1C(OC(C)(C)C)=O)[S:5]([CH3:8])(=[O:7])=[O:6].[ClH:31]>CCOC(C)=O>[ClH:31].[ClH:31].[CH3:1][CH:2]([CH3:30])[CH2:3][N:4]([CH2:9][C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1)[S:5]([CH3:8])(=[O:6])=[O:7]
Reactant: CC(C)CN(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@H]1CNCCN1)S(C)(=O)=O
Temperature: 70 °C
Yield: 105 %

Procedure:
A 250-mL round-bottomed flask was charged with di-tert-butyl (2R)-2-(((2-methylpropyl)(methylsulfonyl)amino)methyl)-1,4-piperazinedicarboxylate (0.840 g, 1.87 mmol), HCl (4.0 M in 1,4-dioxane, 2.4 mL, 9.6 mmol, Sigma-Aldrich, St. Louis, Mo.) and EtOAc (20 mL). The reaction mixture was heated at 70° C. for 24 h and then was allowed to cool to room temperature. The resulting white solid was collected via filtration and washed with EtOAc to give N-(2-methylpropyl)-N-((2R)-2-piperazinylmethyl)methanesulfonamide dihydrochloride (0.633 g) as a white solid.
Reaction SMILES: O.[ClH:2].[C:3]([N:11]1[CH2:16][CH2:15][O:14][C:13]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[CH:38]=2)([CH2:17][CH2:18]N2CCC(NC(N(C)C)=O)(C3C=CC=CC=3)CC2)[CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N1CCOC(CCN2CCC(C3C=CC=CC=3)(NC(N(C)C)=O)CC2)(C2C=CC(F)=C(F)C=2)C1)(=O)C1C=CC=CC=1.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:99]([C:106]1([NH:112][C:113]([N:115]2[CH2:119][CH2:118][CH2:117][CH2:116]2)=[O:114])[CH2:111][CH2:110][NH:109][CH2:108][CH2:107]1)[C:100]1[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:2].[C:3]([N:11]1[CH2:16][CH2:15][O:14][C:13]([CH2:17][CH2:18][N:109]2[CH2:110][CH2:111][C:106]([CH2:99][C:100]3[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=3)([NH:112][C:113]([N:115]3[CH2:119][CH2:118][CH2:117][CH2:116]3)=[O:114])[CH2:107][CH2:108]2)([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[CH:38]=2)[CH2:12]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Reactant: O=C(NC1(Cc2ccccc2)CCNCC1)N1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1(Cc2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1)N1CCCC1
Yield: 131.8 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 45 from 1.2 g of the compound obtained in step C of EXAMPLE 37, 1.5 g of 4-benzyl-4-(pyrrolidin-1-ylcarbonylamino)piperidine p-toluenesulfonate, 1.2 g of K2CO3 and 3 ml of DMF to give 0.83 g of the expected product. M.p.=140° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[CH3:14][O:15][CH2:16][CH2:17][C:18](O)=O>>[CH3:14][O:15][CH2:16][CH2:17][C:18]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1
Reactant: COCCC(=O)O
Reactant: NC(C(=O)O)C(O)c1ccccc1
Product: COCCc1nc(C(=O)O)c(-c2ccccc2)o1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures W, X with 3-methoxy-propionic acid, Y and Z. LC-MS-conditions 01: tR=0.77 min; [M+H]+=247.96.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Cl)=[CH:44][CH:43]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:26][CH2:27][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:30]4)=[N:21][N:22]3[CH2:46][C:45]3[CH:48]=[CH:49][C:42]([Cl:41])=[CH:43][CH:44]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(CCC4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccc(Cl)cc3)c3cc(CCC4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A solution of 4-{2-[3-(l-tert-butoxycarbonylmethyl-piperidin-4-yl)-1H-indazol-6-yl]-ethyl}-piperidine-1carboxylic acid tert-butyl ester (0.25 g, 0.475 mmol) in dry DMF (5 ml) was treated with sodium hydride (0.021 g, 0.523 mmol, 60% dispersion in oil) and the mixture was stirred at 23° under nitrogen for 30 min. A solution of 4-chlorobenzyl chloride (0.080 g, 0.497 mmol; Aldrich) in DMF (5 ml) was added and the mixture was stirred at 23° for 20 h. The solvent was removed in vacuo, the residue treated with water and extracted with dichloromethane (3×30 ml); the extracts were evaporated in vacuo to give an orange gum. Purification by flash chromatography on silica gel (Merck 9385), eluant ether: cyclohexane:triethylamine (50:50:2 to 100:0:2), gave the title compound as a colourless gum (0.107 g, 35%).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:33])[C@H:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25]CC3C=CC=CC=3)=[CH:21][CH:20]=2)[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCCCC=1>[Pd].C(O)C>[CH:1]1([NH:7][C:8](=[O:33])[C@H:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC1CCCCC1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NC1CCCCC1
Yield: 99.2 %

Procedure:
A mixture of N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine cyclohexylamide (0.68 g) obtained in Example 4, palladium black (0.10 g), cyclohexene (4 ml), and ethanol (20 ml) was allowed to react under reflux of ethanol for one hour, while stirring. After cooling, the solid was filtered off and the filtrate was concentrated under reduced pressure to obtain N-(t-butyloxycarbonyl-4-hydroxy-L-phenylalanine cyclohexylamide (I) (0.54 g). The compound (I) (0.54 g) was dissolved, without purification, in N,N-dimethylformamide (10 ml), followed by adding sodium hydride (0.06 g) thereto. The mixture was stirred at room temperature for 30 minutes. To this solution was added a solution of phenacyl bromide (0.30 g) in N,N-dimethylformamide (5 ml). The reaction was carried out at room temperature for 4 hours, followed by adding ice-water thereto. The resultant oily product was extracted with ethyl acetate. After a conventional post-treatment, N-(t-butyloxycarbonyl)-4-phenacyloxy-L-phenylalanine cyclohexylamide (II) (0.61 g) was obtained. From the compound (II), N-(trans-4-aminomethylcyclohexylcarbonyl)-4-phenacyloxy-L-phenylalanine cyclohexylamide hydrochloride (0.38 g) was obtained, following the procedure of Example 7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[OH-].[NH4+].[CH3:19]O>>[NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:19])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)c1ccc(N)cc1O
Temperature: 70 °C
Yield: 60 %

Procedure:
To a suspension of 9.18 g (0.06 mole) 4-aminosalicylic acid (7) (Aldrich A7,960-4) in 40 mL of dry methanol was added 8 mL of concentrated sulfuric acid slowly. The mixture was heated under reflux at 70° C. for 1.5 hours and then it was cooled in an ice-water bath. Enough concentrated ammonium hydroxide solution was added to adjust the pH to 9 and the precipitate was filtered, rinsed with water and dried to give 6.01 g (60%) of 9 as a solid, mp 118-120° (ref. 120-121°). Infrared (IR) and NMR analysis gave the following results:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:18][C@@H:19]([C@@H:45]1[NH:50][C@@H:49]([CH3:51])[C:48](=[O:52])[O:47][CH2:46]1)[C@@H:20]([N:30]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([O:18][C@@H:19]([C@@H:45]1[NH:50][C@@H:49]([CH3:51])[CH:48]([OH:52])[O:47][CH2:46]1)[C@@H:20]([N:30]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:21][C:22]1[CH:23]=[C:24]([F:29])[CH:25]=[C:26]([F:28])[CH:27]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@@H]1N[C@@H]([C@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@@H]1N[C@@H]([C@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
Add diisobutylaluminum hydride (2.48 mL, 2.48 mmol, 1.0 M in toluene) to a solution of (3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-3-methylmorpholin-2-one (1.09 g, 1.91 mmol) in dry toluene (20 mL) at −78° C. under nitrogen and stir at this temperature for 15 minutes. Quench by adding methanol (1.0 mL). Add saturated aqueous potassium sodium tartrate (Rochelle salt) and ethyl acetate, warm to room temperature and stir vigorously for 30 minutes. Separate the organic layer and extract the aqueous with ethyl acetate. Combine the organic layers, dry (magnesium sulfate), filter and concentrate to give the desired compound as a mixture of the two possible epimers as a white solid which is used directly in the next step without further purification (1.08 g, 99% yield).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])=[N:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=2)=[O:12])=[N:7][CH:6]=1
Reactant: COC(=O)Cc1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ncc(CCO)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 44.2 (10 mmol) in dry THF (50 mL) was added lithium aluminum hydride (“LAH”; 30 mmol; 1.0 M in THF) at room temperature. After stirring for 30 minutes, the reaction mixture was cooled and treated with the cautious addition of ice water. The solvent was removed, diluted with saturated sodium bicarbonate and extracted with EtOAc. The organic layers were combined, dried, concentrated and purified by flash column chromatography on silica gel to provide 1-[5-(2-hydroxy-ethyl)-thiazol-2-yl]-3-(3-trifluoromethyl-phenyl)-urea (compound 44.3) in 95% yield. EIMS (m/z): calcd. for C13H12F3N3O2S (M+)+H 332.06. found 332.10.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH2:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:37][CH:36]=2)=CC=1)([O-])=O>>[CH2:42]([O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][CH2:33][NH:32][C:31]([NH:20][CH2:19][CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:30])=[CH:40][CH:39]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN)c1
Reactant: O=C(NCCc1ccc(OCc2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCNC(=O)NCCc2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.6 %

Procedure:
To a solution of 2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethylamine (EXAMPLE 2 Step D, 39 mg in 1 mL dry methanol) was added 64 mg [2-(4-benzyloxyphenyl)-ethyl]-carbamic acid 4-nitrophenyl ester and the mixture stirred at room temperature. After 24 hours, the mixture was concentrated in vacuo and the residue re-solvated in ethyl acetate. This was washed with saturated aqueous potassium carbonate (3×) and brine, dried over sodium sulfate and purified by flash chromatography on silica gel (hexane:ethyl acetate, 5:4; then 1:1) to give the title compound (73 mg).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][C:29](=O)[CH2:28][CH2:27]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([Br:23])[CH:25]=3)[CH2:30]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC1CCc2cc(Br)ccc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6-bromo-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 19.6, 24.3, 26.6, 27.8, 28.0, 29.1, 30.0, 36.0, 36.5, 36.6, 36.9, 53.0, 53.1, 56.0, 59.1, 59.1, 60.5, 60.7, 67.3, 104.7, 104.8, 119.6, 119.7, 129.0, 131.1, 131.1, 131.5, 131.6, 133.7, 134.2, 127.3, 137.3, 138.2, 138.5, 172.4, 172.4; MS m/z 516.3, 518.3 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Sn](C)(C)C)=[CH:17][CH:16]=1)[CH3:2].I[C:26]1[CH:38]=[CH:37][CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:26][C:27]=2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nn2c1Cc1ccc([Sn](C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nn2c1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 71.8 %

Procedure:
To a solution of 0.149 g (0.35 mmol) of the product of Step G and 0.132 g (0.43 mmol) of t-butyl 2-iodobenzoate in 1 mL of anhydrous DMF was added 5 mg of bis(triphenylphosphine)palladium(II) chloride. The mixture was degassed, flushed with nitrogen, then magnetically stirred under a nitrogen atmosphere for 12 hours at 100° C. The reaction mixture was cooled to room temperature, then partitioned between EtOAc and water. The organic layer was extracted, separated, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.111 g (73%) of the title compound as an off-white amorphous solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:6]=1[CH2:7]Cl>O.[Cl-].C1([N+](CC)(CC)CC)C=CC=CC=1>[F:4][C:5]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:6]=1[CH2:7][C:1]#[N:2]
Reactant: [C-]#N
Reactant: Fc1ccc(F)c(CCl)c1F
Agent: CC[N+](CC)(CC)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CCc1c(F)ccc(F)c1F
Reaction time: 0.67 h
Yield: 65.4 %

Procedure:
To a solution of sodium cyanide (1.94 g) in water (4 ml) is added phenyltriethylammonium chloride (0.09 g), and thereto is added with stirring 2,3,6-trifluorobenzyl chloride (5.0 g), and the mixture is stirred at 90° to 100° C. for 40 minutes. The reaction mixture is poured into water (20 ml) and is extracted with diethyl ether. The extract is dried over potassium carbonate and the solvent is distilled off to give 2-(2,3,6-trifluorophenyl)acetonitrile (3.1 g), b.p. 80°-85° C. (5 mmHg).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([O:36][Si](C(C)(C)C)(C)C)[CH:35]=1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([OH:36])[CH:35]=1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(OCc1ccccc1)c1cc(O)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
A 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuiran (26.6 mL, 26.6 mmol) was added to neat benzyl ester 24 (5.00 g, 13.3 mmol), the reaction stirred 10 minutes at ambient temperature, and evaporated in vacuo. The crude product was dissolved in methylene chloride, the solution washed with dilute aqueous NaHCO3, dried overNa2SO4, and filtered. The evaporated filtrate was then washed repeatedly with hexanes and dried in vacuo giving product 25 as a gold oil (3.40 g, 98%). 1H NMR (300 MHz, CDCl3) δ 7.35 (m, 7H), 7.1 (t, 1H, J=2.1 Hz), 5.28 (s, 2H).
Reaction SMILES: [Ti](Cl)(Cl)(Cl)[Cl:2].[CH:6]([O:9][Ti:10](OC(C)C)([O:15][CH:16]([CH3:18])[CH3:17])[O:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7]>ClCCl>[Cl:2][Ti:10]([O:15][CH:16]([CH3:18])[CH3:17])([O:11][CH:12]([CH3:14])[CH3:13])[O:9][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Reactant: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)O[Ti](Cl)(OC(C)C)OC(C)C

Procedure:
0.38 g (2.0 mmol) of titanium tetrachloride and 2 mL of anhydrous dichloromethane were weighed in a test tube equipped with a lid, and 1.7 g (6.0 mmol) of tetra-iso-propoxy titanium was added dropwise thereto while stirring. After stirring at room temperature for 60 minutes, the reaction solution was transferred to a 10-mL volumetric flask, and anhydrous dichloromethane was added thereto for diluting to 10 mL, whereby a uniform, colorless and transparent dichloromethane solution (0.80 mol/L) of chloro-tri-iso-propoxy titanium was obtained.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8](OCC)OCC)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[N:28]([CH2:35][CH3:36])[C:27]2=[O:37])=[CH:22][CH:21]=1>>[CH2:35]([N:28]1[C:29]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:26]([C:23]2[CH:22]=[CH:21][C:20]([N:19]3[C:2]4=[N:3][C:4]5[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=5[N:6]4[CH:7]=[CH:8]3)=[CH:25][CH:24]=2)[C:27]1=[O:37])[CH3:36]
Reactant: CCn1c(=O)n(-c2ccc(N)cc2)c2ncccc21
Reactant: CCOC(Cn1c(Cl)nc2ccccc21)OCC
Product: CCn1c(=O)n(-c2ccc(-n3ccn4c5ccccc5nc34)cc2)c2ncccc21
Temperature: 150 °C
Yield: 31.5 %

Procedure:
A mixture of 2-chloro-1-(2,2-diethoxyethyl)-1H-benzimidazole (860 mg) and 3-(4-aminophenyl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (636 mg) was heated at 150° C. for 50 min. The reaction mixture was partitioned between AcOEt/THF (1/1) and 1 M NaOH aqueous solution. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with THF and recrystallized from THF to give 1-ethyl-3-[4-(1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (311 mg).
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[CH:19]=[O:20].[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[CH:19]=[O:20]
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(Br)c1C=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2cccc(OC(F)(F)F)c2)n(C)c1C=O
Temperature: 25 °C

Procedure:
A solution of 1.00 g (2.9 mmol) of 5-bromo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carbaldehyde in 25 ml of MeOH was treated with 3.20 ml (17.3 mmol) sodium methoxide-solution (5.4 molar in MeOH) and then stirred at reflux for 48 hours. After cooling down to RT, the solvent was evaporated, cold water and EtOAc were added and the mixture then extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (n-heptane/EtOAc 4:1 to 1:1) to give 0.926 g (quant.) of the title compound as light yellow solid. MS: 301.1 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1N1CCN2C3CCCCC=3C=C2C1=O)(=[O:3])[CH3:2].[N:41]1([CH2:45][C:46]2[N:50]([CH3:51])[N:49]=[C:48]([NH:52][C:53]3[C:54](=[O:61])[N:55]([CH3:60])[CH:56]=[C:57](Br)[CH:58]=3)[CH:47]=2)[CH2:44][CH2:43][CH2:42]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:57]1[CH:58]=[C:53]([NH:52][C:48]2[CH:47]=[C:46]([CH2:45][N:41]3[CH2:44][CH2:43][CH2:42]3)[N:50]([CH3:51])[N:49]=2)[C:54](=[O:61])[N:55]([CH3:60])[CH:56]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(N2CCn3c(cc4c3CCCC4)C2=O)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1nc(Nc2cc(Br)cn(C)c2=O)cc1CN1CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3cc(CN4CCC4)n(C)n3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 130 °C
Yield: 95.6 %

Procedure:
Following Example 121b, 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (202 mg, 0.42 mmol), 3-(5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 200c (105 mg, 0.3 mmol), 1M sodium carbonate solution (1.2 mL, 1.2 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol) and 1,2-Dimethoxyethane (3 mL) were heated at 130° C. for 10 minutes in the microwave reactor. Work-up and the resulting residue was purified by flash column chromatography (silica, 3:1 methylene chloride/methanol) to give 180 mg compound 200d (quant., contain 3% 200) as a yellow residue: MS (ESI+) m/z 628.1 (M+H).