Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.C1C[O:5]CC1.[Cl:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:15][C:16](=O)[CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25](=O)[N:26]([CH3:28])[CH3:27])([CH3:14])[CH3:13])=[CH:10][CH:9]=1.[ClH:33]>C1COCC1.CCOCC>[OH2:5].[ClH:7].[ClH:33].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][N:26]([CH3:27])[CH3:28])([CH3:14])[CH3:13])=[CH:31][CH:32]=1.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][N:26]([CH3:27])[CH3:28])([CH3:14])[CH3:13])=[CH:31][CH:32]=1.[ClH:7].[ClH:7]
Reactant: C1CCOC1
Reactant: CN(C)C(=O)c1ccccc1OCC(=O)NC(C)(C)c1ccc(Cl)cc1
Agent: B
Agent: Cl
Solvent: CCOCC
Product: CN(C)Cc1ccccc1OCCNC(C)(C)c1ccc(Cl)cc1
Product: O
Temperature: 25 °C

Procedure:
A solution of borane/THF (27 ml, 1M solution) was added to a solution of N-(4-chloro-α,α-dimethylbenzyl)-2-(2-dimethylcarbamoylphenoxy)acetamide (2.0 g) in THF (20 ml) at 0° C. with stirring under a nitrogen atmosphere. The mixture was warmed to ambient temperature and then boiled under reflux for 1 hour. The mixture was evaporated to dryness and 2M hydrochloric acid (50 ml) was added carefully. The mixture was heated on a steam bath for 2 hours, then cooled, washed with ethyl acetate, basified with 2M sodium hydroxide solution and extracted into dichloromethane to give an oil which was distilled under high vacuum to give an oil, b.p. 150° C. at 0.13 mbar. The oil was dissolved in ether and acidified with ethereal hydrogen chloride. The precipitate was collected by filtration to give 2-[2-(4-chloro-α,α-dimethylbenzylamino) ethoxy]-N,N-dimethylbenzylamine dihydrochloride hemihydrate m.p. 140° C. (with effervescence).
Reaction SMILES: [NH2:1][C:2]1([C:5]([NH:7][C@@H:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[O:6])[CH2:4][CH2:3]1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][C:2]2([C:5](=[O:6])[NH:7][C@@H:8]3[CH2:14][CH2:13][C:12]4[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=4[N:10]4[CH:19]=[CH:20][N:21]=[C:9]34)[CH2:3][CH2:4]2)=[O:28])=[CH:25][CH:24]=1
Reactant: NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1)c1ccc(Cl)cc1
Yield: 79.2 %

Procedure:
Combine 1-amino-N-[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]cyclopropanecarboxamide (160 mg, 0.57 mmol), 4-chlorobenzoic acid (106 mg, 0.68 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (259.0 mg, 0.68 mmol;) in N,N-dimethylformamide (4 mL). Add diisopropylethylamine (DIEA) (0.25 mL, 1.42 mmol) and stir the reaction at ambient temperature for approximately 5 hours under nitrogen. Dilute the reaction with ethyl acetate, wash with sodium bicarbonate, water (2×), and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure. Purify the residue by flash chromatography (40% EtOAc/hexanes to 100% EtOAc) to give the title compound (190.0 mg, 80%): MS (m/z): 421 (M+1).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH:32]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38].CC(O)=O.[BH3-]C#N.[Na+]>C1COCC1.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCn1c(-c2ccccc2C=O)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Reactant: CN(C)CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)CCn1c(-c2ccccc2CNCCN(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-cyclohexyl-2-(2-formylphenyl)-1-(3-methoxy-3-oxopropyl)-1H-indole-6-carboxylate in THF (0.1 M), N,N-dimethylethane-1,2-diamine (10 eq) was added and the pH adjusted to pH=6 with HOAc. The solution was stirred at RT for 1 h, before the THF was concentrated in vacuo and the residue taken up in MeOH. To the methanolic solution (0.1 M) NaBH3CN (2 eq) was added and the mixture stirred at RT overnight. The reaction mixture was diluted with EtOAc. The organic phase was washed with NaHCO3 (s.s.), H2O and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The title compound was used as crude in the next step; MS (ES+) m/z 520 (M+H)+.
Reaction SMILES: CO[CH:3]([O:17]C)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1Br.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:25]=O)[CH3:20].[C:32]([C:38]([O:40][CH3:41])=[O:39])#[C:33][C:34]([O:36][CH3:37])=[O:35]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([C:25]2[C:5]3[C:4](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH3:13])[C:6]=3[O:14][CH3:15])[C:3]([OH:17])=[C:33]([C:34]([O:36][CH3:37])=[O:35])[C:32]=2[C:38]([O:40][CH3:41])=[O:39])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH3:20]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: COC(=O)C#CC(=O)OC
Reactant: COc1cc(C(OC)OC)c(Br)c(OC)c1OC
Product: CCOc1cc(-c2c(C(=O)OC)c(C(=O)OC)c(O)c3cc(OC)c(OC)c(OC)c23)ccc1OC
Yield: 65 %

Procedure:
2-Bromo-3,4,5-trimethoxybenzaldehyde dimethylacetal, 3-ethoxy-4-methoxybenzaldehyde and dimethyl acetylenedicarboxylate are treated in the same manner as described in Example 1, whereby 1-(3-ethoxy-4-methoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene is obtained as colorless needles. Yield: 65%
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[C:8](SC)[CH2:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[C:4]([CH3:20])=[N:3]1.[CH2:21]([NH2:24])[C:22]#[CH:23]>C(O)C>[CH3:1][N:2]1[C:6]2[N:7]=[C:8]([NH:24][CH2:21][C:22]#[CH:23])[CH2:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[C:4]([CH3:20])=[N:3]1
Reactant: C#CCN
Reactant: CSC1=Nc2c(c(C)nn2C)C(c2ccccc2)=NC1
Solvent: CCO
Product: C#CCNC1=Nc2c(c(C)nn2C)C(c2ccccc2)=NC1

Procedure:
A mixture of 2.9 g. of 1,6-dihydro-1,3-dimethyl7-(methylthio)-4-phenylpyrazolo[3,4-e][1,4]diazepine (prepared as disclosed in U.S. Pat. No. 3,770,762), 1.5 g. of 2-propynylamine and 50 ml. of ethanol is heated at reflux for 48 hours, then evaporated at reduced pressure to give a residue of 1,6-dihydro-1,3-dimethyl-4-phenyl-7-(2-propynylamino)pyrazolo[3,4-e][1,4]diazepine; m.p. 193°-195° C. after crystallization from ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C[Si]([C:14]#[N:15])(C)C.C(N(CC)C(C)C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:15][CH2:14][CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=1)[OH:6]
Reactant: O=Cc1cccc(Br)c1
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NCC(O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled solution of 3-bromobenzaldehyde (1.58 mL) in THF (15 mL) were added trimethylsilyl cyanide (1.7 mL) and N,N-diisopropylethylamine (0.23 mL). The mixture was stirred at room temperature for 2d and at reflux for 2 h. The solution was allowed to cool to room temperature and then was slowly added to a cooled suspension of lithium aluminium hydride (769 mg) in THF (10 mL). The mixture was stirred at 0° C. for 10 min, the cooling bath was removed, and the mixture was heated at reflux for 3 h. After cooling to room temperature, ethylacetate was added slowly, followed by a mixture of Na2SO4/silicagel/H2O. After stirring the suspension for 30 min, the mixture was filtered, the filtrate was dried (Na2SO4), and concentrated in vacuo. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/ammonia 90:10:2) to give (1.59 g) 2-amino-1-(3-bromo-phenyl)-ethanol as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.O.NN.[OH-].[K+]>COCCOCCOC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C(CCC(F)(F)F)c1cccc(Br)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOC
Solvent: O
Product: FC(F)(F)CCCc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A mixture of 1-(3-bromo-phenyl)-4,4,4-trifluoro-butan-1-one (3.1 g, 11 mmol) and diglyme was treated with hydrazine mono hydrate (5.5 g, 110.3 mmol), and stirred at 100° C. for 2 hours then treated with powder KOH (3.1 g, 55.1 mmol). The stirring continued at 150° C. for 6 hours. The mixture was cooled to room temperature, poured into a mixture of ice/water and extracted with ethyl ether. The extracts were combined, dried over MgSO4 and concentrated in vacuo. The crude product was purified on silica gel (ISCO) using hexanes as the eluting solvent to give 1-Bromo-3-(4,4,4-trifluoro-butyl)-benzene as a colorless oil (2.4 g, 88% yield). m/e (M)+ 266; 1H NMR (400 MHZ, DMSO-d6) δ ppm, 1.7-1.8 (m, 2 H), 2.1-2.2 (m, 2 H), 2.6 (t, J=7.6 Hz, 2 H), 7.2-7.25 (m, 2 H), 7.3-7.35 (m, 1 H), 7.4 (s, 1 H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOCC.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:30]([C:27]4[CH:26]=[N:25][C:24]([CH3:23])=[CH:29][N:28]=4)=[O:31])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Reactant: Cc1cnc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cnc(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cccc(F)c4)nc23)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 6, Step A; 50 mg, 0.17 mmol, prepared as described in a previous example), 5-methylpyrazine-2-carboxylic acid (46 mg, 0.34 mmol), and HATU (128 mg, 0.34 mmol) was added 0.7 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.088 mL, 0.5 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 2 hours. The reaction mixture was directly filtered, rinsing with acetonitrile and then with ether, to provide the final product as a beige solid (44 mg, 63% yield). MS (apci) m/z=418.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.I.[C:31](SC)(=[NH:33])[CH3:32]>CO>[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1)(=[NH:33])[CH3:32]
Reactant: CSC(C)=N
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Agent: I
Solvent: CO
Product: CC(=N)Nc1ccc(CCc2nc(NC(C)=O)sc2Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
N-{4-[2-(4-Aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (200 mg), methyl ethanimidothioate hydroiodide (202 mg) and MeOH (4 ml) were combined under N2 atmosphere. The reaction mixture was refluxed for 3 hours. After cooled to room temperature, the mixture was concentrated in vacuo. The residue was purified by preparative NH silica gel chromatography with CHCl3/MeOH (10:1) as an eluent. The amorphous substance was solidified with ethyl ether to give N-{4-{2-[4-(ethanimidoylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (102.4 mg) as a pale yellow amorphous solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9](/[CH:14]=[CH:15]/[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:34][C:35]1[CH:39]=[CH:38][S:37][C:36]=1[C:40](Cl)=[O:41].C(=O)([O-])O.[Na+]>C1COCC1>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](/[CH:15]=[CH:14]/[C:9]2[CH:8]=[C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:25][CH3:26])[CH:12]=[CH:11][C:10]=2[NH:13][C:40]([C:36]2[S:37][CH:38]=[CH:39][C:35]=2[CH3:34])=[O:41])=[N:17]1
Reactant: Cc1ccsc1C(=O)Cl
Reactant: CCN(CC)CCOc1ccc(N)c(/C=C/c2n[nH]c3ccccc23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(NC(=O)c2sccc2C)c(/C=C/c2n[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
Crude (E)-N-(2-{3-[2-(1H-indazol-3-yl)vinyl]-4-nitrophenyloxy}ethyl)diethylamine (2.0 g, 5.2 mmol) obtained in Step 1 was dissolved in ethanol (20 mL) and the solution was treated by tin (1.9 g, 16 mmol) and concentrated hydrochloric acid (1.0 mL) at room temperature in a similar manner to Example 2, to obtain (E)-{4-[2-(diethylamino)ethoxy]-2-[2-(1H-indazol-3-yl)vinyl]phenyl}amine. In a similar manner to Example 29, (E)-{4-[2-(diethylamino)ethoxy]-2-[2-(1H-indazol-3-yl)vinyl]phenyl}amine (0.49 g, 1.4 mmol) was dissolved in THF (15 mL) and the solution was added with triethylamine (0.58 ml, 4.2 mmol) and 3-methylthiophenecarbonyl chloride (0.23 g, 1.4 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was triturated in ethyl acetate to obtain Compound 237 (0.42 g, 63%).
Reaction SMILES: C(O)C.C[O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][CH:16]1[C:25]2[C:20]3=[C:21]([N:26]=[C:27]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:19]3[CH2:18][CH2:17]1)[CH:22]=[CH:23][CH:24]=2)=[O:7].[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][CH:16]1[C:25]2[C:20]3=[C:21]([N:26]=[C:27]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:19]3[CH2:18][CH2:17]1)[CH:22]=[CH:23][CH:24]=2)([OH:7])=[O:5]
Reactant: COC(=O)c1ccccc1COC1CCn2c(CCc3ccccc3)nc3cccc1c32
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccccc1COC1CCn2c(CCc3ccccc3)nc3cccc1c32
Yield: 61.7 %

Procedure:
Ethanol (4 mL) was added to 0.62 g of the 5,6-dihydro-6-(2-methoxycarbonylphenyl)methoxy-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinoline obtained in Example 19; to the solution, another solution having potassium hydroxide (0.19 g) dissolved in water (0.4 mL) was added and the mixture was heated under reflux for 1 hr. After standing to cool, the reaction solution was poured into water and its pH was adjusted to 4-5 using 10% aqueous citric acid; after extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to yield the titled compound as pale yellow crystals (0.37 g).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[CH:23][C:22]([C:25]([OH:27])=O)=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][N:67]=[CH:66][CH:65]=1>CN(C=O)C>[CH3:61][N:62]([CH2:63][C:64]1[CH:69]=[CH:68][N:67]=[CH:66][CH:65]=1)[C:25]([C:22]1[CH:21]=[N:20][C:19]([N:16]2[CH2:17][CH2:18][CH:13]([C:10]3[CH:9]=[CH:8][C:7]([C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:6])=[CH:12][CH:11]=3)[CH2:14][CH2:15]2)=[N:24][CH:23]=1)=[O:27]
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(C(=O)O)cn3)CC2)cc1
Reactant: CNCc1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(C(=O)N(C)Cc4ccncc4)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 36.8 mg (0.1 mmol) (S)-2-{4-[4-(1-acetylamino-ethyl)-phenyl]-piperidin-1-yl}-pyrimidine-5-carboxylic acid (XVII.1) and 51 μL (0.3 mmol) DIPEA in 2 mL DMF is added 38.0 mg (0.1 mmol) HATU and the mixture is stirred for 15 min at rt. Subsequent the mixture is added to 12.2 mg (0.1 mmol) methylpyridin-4-ylmethylamine and stirring is continued for 12 h. The solvent is removed in vacuo and the residue is purified using reversed phase column chromatography (water+0.1% NH4OH/MeOH) and the corresponding fractions are concentrated to yield the desired product.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH:16]([C:18]1[CH:19]=[CH:20][C:21](O)=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:17]>C(Cl)Cl>[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:17]
Reactant: COC(=O)c1cc(C=O)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
Triflic anhydride (7.74 mL) was added to methyl 5-formyl-2-hydroxybenzoate (7.5 g) in 150 mL CH2Cl2 at 0° C., and the reaction mixture was stirred and allowed to warm to room temperature over 3 hours. The reaction mixture was diluted with CH2Cl2 (150 mL), washed 3× with brine, dried over Na2SO4, filtered, and concentrated. The product was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[C:1]([C:3]1[CH:17]=[C:16]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: OB(O)c1ccncc1
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2ccncc2)c2c(c1)ncn2-c1ccccc1
Yield: 32.4 %

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), pyridin-4-yl boronic acid (62 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight. The solvent was removed under reduced pressure and the crude product was purified on a 2 g silica Isolute® SPE column, eluting with dichloromethane/methanol (95:5). The eluent was concentrated under reduced pressure and the crude product was suspended in acetonitrile then treated with diethyl ether to precipitate the product. The mother liquors were removed by filtration and the residual solid was further purified on a Biotage silica gel cartridge, eluting with dichloromethane/methanol (98:2). Recrystallisation from dichloromethane/diethyl ether afforded the title compound (48 mg, 32%) m/z, 297.4 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6].[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19]>CCCCCC.C(OCC)C>[F:15][C:4]([F:3])([F:14])[CH:5]([O:6][S:18]([C:17]([F:23])([F:22])[F:16])(=[O:20])=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: OC(c1ccc(F)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Product: O=S(=O)(OC(c1ccc(F)cc1)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
NaH (640 mg, 16 mmol, 60% in mineral oil) was washed twice with hexane (20 mL) and then suspended in dried diethyl ether (20 mL). A solution of 2,2,2-trifluoro-1-(4-fluoro-phenyl)ethanol (1.94 g, 10 mmol) in diethyl ether (10 mL) was added at 0° C. After stirring for 2 h at room temperature, a solution of trifluoromethanesulfonyl chloride (1.68 g, 10 mmol) in diethyl ether (10 mL) was added. After 2 h, the reaction mixture was quenched by adding a solution of NaHCO3 and the product was extracted with diethyl ether. The extracts were washed with brine and dried, and the solvent was removed to yield trifluoromethanesulfonic acid 2,2,2-trifluoro-1-(4-fluorophenyl)ethyl ester (3.3 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2([CH3:31])[CH2:29][CH2:28][O:27][C:26]2=[O:30])(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:26](=[O:30])[C:25]([S:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)(=[O:24])=[O:23])([CH3:31])[CH2:29][CH2:28][OH:27])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(S(=O)(=O)c2ccc(Cl)cc2)CCOC1=O
Reactant: CC(C)(C)c1cc(N)on1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)C(C)(CCO)S(=O)(=O)c2ccc(Cl)cc2)on1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
To a solution of 3-tert-butyl-isoxazol-5-ylamine (0.421 g; 3.00 mmol) in methylene chloride (5 mL) was added dropwise trimethylaluminum (1.5 mL of a 2.0 M solution in toluene; 3.00 mmol). The mixture was stirred 15 minutes and 3-(4-chloro-benzenesulfonyl)-3-methyl-dihydro-furan-2-one (0.659 g; 2.40 mmol) added. The mixture was stirred 3 hours, heated to 45° C. for approximately 40 hours, cooled to room temperature and carefully quenched with 10% aqueous citric acid, aqueous sodium tartrate and chloroform. The organic layer was dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. Removal of the volatiles from the product-rich fractions provided 0.616 g of the desired product. 1H NMR (CDCl3) δ 9.85 (bs, 1H), 7.75 (d, 2H), 7.55 (d, 2H), 6.24 (s, 1H), 3.97 (m, 1H), 3.85 (m, 1H), 2.62 (m, 1H), 2.32 (m, 1H), 1.65 (s, 3H), 1.32 (s, 9H). MS (ESI): m/e 415, 417 (M+H).