Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:11][C:10]2[N:9]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:8]3[CH2:7][N:6]=[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:4]=2[CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:16][CH2:15][C:12]1[N:9]2[C:10]3[S:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:6][CH2:7][C:8]2=[N:14][N:13]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: c1ccncc1
Product: CC(=O)OCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 30 °C

Procedure:
1 g of 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-methanol is dissolved in 10 ml of absolute pyridine and treated with 1 ml of acetic anhydride. The solution is maintained at 30° C. for 15 hours and then evaporated under vacuum. The residue is partitioned between methylene chloride and water. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. By recrystallization of the residue from ethyl acetate, there is obtained 9-acetoxymethyl-2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]-diazepine of melting point 191°-193° C.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([C:42]([NH:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[O:43])=[N:40][CH:41]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([NH:5][CH2:4][C:3]2[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:2]=2[C:36]2[CH:37]=[CH:38][C:39]([C:42]([NH:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[O:43])=[N:40][CH:41]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)c(Br)c1
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Temperature: 25 °C

Procedure:
N-(2-bromo-4-(trifluoromethyl)benzyl)-2′,4′-dichloro-[1,1′-biphenyl]-4-amine (386 mg, 0.8 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate, prepared as in step a, (424 mg, 1.2 mmol), Pd(dppf)Cl2 (67 mg, 0.1 mmol), and K2CO3 (225 mg, 1.6 mmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([C:21]#[N:22])[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:20][C:15]1[CH:14]=[C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[C:21]#[N:22])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: N#CC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: N#CC1CNCC1c1ccc(Cl)c(Cl)c1
Reaction time: 4 h
Yield: 37.7 %

Procedure:
To a solution of (3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbonitrile (2.0 g, 6.6 mmol) dissolved in CH3CN (30 mL) was added 2,2,2-trichloroethyl chloroformate (1.22 mL, 9.91 mmol) and stirring was continued for 4 hours at RT. Volatiles were removed under vacuo, and the residue was dissolved in AcOH (25 mL) before a total of 1.20 g of Zn dust was added portion wise. After three hours at RT, the reaction mixture was filtered on celite, the solvent removed under vacuo, followed by an extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were dried on Na2SO4 and the crude reaction product obtained used in the next reaction step, yielding 0.6 g (55%) of the title compound as a light yellow oil. ES-MS m/e: 242.1 (M+H+).
Reaction SMILES: CS(O)(=O)=O.[C:6]([C:10]1[C:15]2[CH2:16][CH2:17][O:18][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:19])([CH3:9])([CH3:8])[CH3:7].[C:20](O)([CH3:23])([CH3:22])[CH3:21].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:6]([C:10]1[C:15]2[CH2:16][CH2:17][O:18][C:14]=2[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=1[OH:19])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)c1c(O)ccc2c1CCO2
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1O)CCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 5.6 %

Procedure:
Methanesulfonic acid (10 ml) was added dropwise, under ice cooling, to a solution consisting of 4-tert-butyl-5-hydroxy-2,3-dihydrobenzofuran [J. Org. Chem., 53, 4135 (1988); 2.84 g, 15 mmol], tert-butyl alcohol (10 g, 120 mmol) and chloroform (20 ml). After stirring at 0° C. for 15 min, the mixture was poured into ice water. The mixture was neutralized with an aqueous solution of 1N sodium hydroxide and subjected to extraction with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (n-hexane) to afford 4,6-di-tert-butyl-5-hydroxy-2,3-dihydrobenzofuran [210 mg (yield, 6%)].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[C:4]=1[NH2:22].[OH-].[Na+].[C:25](OC(=O)CC)(=O)[CH2:26][CH3:27]>C(Cl)(Cl)Cl>[CH2:26]([C:27]1[N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:5]3[C:10]([N:9]=[CH:8][N:7]=2)=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:4]=3[N:22]=1)[CH3:25]
Reactant: CCC(=O)OC(=O)CC
Reactant: COc1cc2ncnc(Nc3ccccc3)c2c(N)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCC1=Nc2c(OC)c(OC)cc3ncnc(c23)N1c1ccccc1

Procedure:
A solution of 6,7-dimethoxy-N4-phenyl-quinazoline-4,5-diamine (130 mg, 0.44 mmol) (from Example 1, Step C, supra) in propionic anhydride (3 mL) (Aldrich) was heated at 170° C. for 2 hours. Aqueous NaOH solution was added to the reaction mixture to a pH 10–12. The solution was diluted with chloroform (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This residue was purified by chromatography using EtOAc/Et3N (1:0.05) as eluent to give the desired 2-ethyl-8,9-dimethoxy-3-phenyl-3H-1,3,4,6-tetraaza-phenalene as an orange solid. (Yield 21 mg, 14%).
Reaction SMILES: [Li+].[BH4-].[CH3:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][C@@H:10]([CH2:26][CH3:27])[C:11](N2[C@@H](C)[C@@H](C3C=CC=CC=3)OC2=O)=[O:12])=[C:7]([CH:30]=[CH2:31])[CH:6]=1.O.[NH4+].[Cl-]>C1COCC1.CO>[CH3:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][C@@H:10]([CH2:26][CH3:27])[CH2:11][OH:12])=[C:7]([CH:30]=[CH2:31])[CH:6]=1
Reactant: C=Cc1cc(OC)ccc1C[C@@H](CC)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=Cc1cc(OC)ccc1C[C@@H](CC)CO
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
LiBH4 (1.66 g, 76.1 mmol) is added to a solution of (4S,5R)-3-[(R)-2-(4-methoxy-2-vinylbenzyl)-butyryl]-4-methyl-5-phenyloxazolidin-2-one (13.1 g, 33.3 mmol) in THF/MeOH (132 mL, 10:1, v/v) at 0° C. After 5 min at 0° C., the mixture is stirred at RT for 30 min. Water is carefully added, followed by addition of aq. NH4Cl solution. The mixture is partitioned between EtOAc and water layer. The organic extract is dried with MgSO4, concentrated and purified by chromatography to give the title compound as an oil: 1H NMR (CDCl3) δ 0.94 (t, J=7.6 Hz, 3H), 1.36-1.43 (m, 2H), 1.62-1.68 (m, 1H), 2.59-2.69 (m, 2H), 3.49-3.55 (m, 2H), 3.81 (s, 3H), 5.30 (dd, J=1, 11 Hz, 1H), 5.64 (dd, J=1, 17 Hz, 1H), 6.76 (dd, J=3, 8 Hz, 1H), 6.99 (dd, J=11, 17 Hz, 1H), 7.02 (d, J=3 Hz, 1H), 7.06 (d, J=8 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([OH:29])=O)[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[NH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([NH:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[O:29])[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:31][CH:32]=1
Reactant: O=C(O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Reactant: Nc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21)Nc1ccncc1
Reaction time: 8 h

Procedure:
20 mg (0.042 mmol) of [4-(4-chlorobenzoyl)-2-oxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl]acetic acid trifluoroacetate was dissolved in 2 ml of dichloromethane. 5 mg (0.055 mmol) of 4-aminopyridine, 11 mg (0.055 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.018 ml (0.126 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: CS(O[CH2:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=2)[CH:8]=1)(=O)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:6][C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=3)[CH:8]=2)[CH2:30][CH2:29]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CS(=O)(=O)OCc1cc2ncc(C(F)(F)F)cc2s1
Product: COc1ccccc1N1CCN(Cc2cc3ncc(C(F)(F)F)cc3s2)CC1

Procedure:
The solution from Example 25C (2 mL) and 1-(2-methoxyphenyl)piperazine (192 mg) were processed as described in Example 25D to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 3.11 (4H, t, J=4.8 Hz), 3.45 (4H, J=4.8 Hz), 4.19 (s, 3H), 4.30 (s, 2H), 6.90 (4H, m), 7.80 (1H, s), 8.63 (1H, m), 9.20 (1H, m). MS (DCI/NH3) m/z 408.2 (M+H)+. Anal. Calcd for C20H20N3F3OS: C, 58.96;H, 4.95; N, 10.31. Found: C, 58.98;H, 4.95; N, 10.53.
Reaction SMILES: [N+](=[C:3]([C:17](=O)[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-].P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[N:46]1([CH2:51][C@@H:52]2[CH2:56][C@H:55]([SH:57])[CH2:54][N:53]2[C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=2)=[O:59])[CH:50]=[CH:49][N:48]=[CH:47]1.C(OCC)(=O)C>ClCCCl.C(#N)C.C(N(C(C)C)CC)(C)C.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17]([S:57][C@@H:55]1[CH2:54][N:53]([C:58]([O:60][CH2:61][C:62]3[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=3)=[O:59])[C@H:52]([CH2:51][N:46]3[CH:50]=[CH:49][N:48]=[CH:47]3)[CH2:56]1)=[C:3]2[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1Cn1ccnc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](Cn4ccnc4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: -7.5 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.28 g) in 1.2-dichloroethane (15 ml) was added rhodium (II) acetate (2 mg) under reflux. The mixture was reluxed for 30 minutes under nitrogen atmosphere and concentrated under reduced pressure to give a syrup. The syrup was dissolved in acetonitrile (15 ml) and N,N-diisopropyl-N-ethylamine (0.37 ml). Diphenyl chlorophosphate (0.16 ml) was added thereto at -10--5° C. in a nitrogen stream, followed by stirring at -10--5° C. for 30 minutes. To the solution were added a solution of (2S,4S)-2-(imidazol-1-yl)methyl-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.26 g) in acetonitrile (2 ml) at -30--25° C. and the mixture was stirred at 0-10° C. for 2 hours. The mixture was poured into ethyl acetate (75 ml), washed with water (50 ml ×2), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on sili.COPYRGT.a gel (20 g) and eluted with a mixture of acetone and dichloromethane (50:50, V/V) to give 4-nitrobenzyl (4R,5S,6S)-6-[(lR)-1-hydroxyethyl]-3-[(2S,4S)-2-(imidazol-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-4-methyl -7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (0.19 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][CH2:19]OS(C)(=O)=O)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]1=[O:25].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[NH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][CH2:19][N:51]2[CH2:50][CH2:49][CH:48]([NH:47][C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:53][CH2:52]2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]1=[O:25]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2=O)cc(OC)c1OC
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 16.7 using 1-(3,4,5-trimethoxybenzyl)-3-(2-methanesulfonyloxyethyl)-3-phenyl-2-oxopyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound: Rf=0.34 (silica gel, 2% triethylamine/5% methanol/ethyl acetate).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1(Cl)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C1C=CC=CC=1>[CH:5]1([C:5]2[C:6]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)=[C:7]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[CH:8]=[CH:9][CH:10]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: ClC1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: c1cc(C2CCCCC2)c(C2CCCCC2)c(C2CCCCC2)c1
Temperature: 3 °C
Yield: 50.7 %

Procedure:
6.83 g of aluminum chloride was added to 20.0 g of benzene, and the mixture was stirred under cooling at 3° C. Subsequently, 40.4 g of cyclohexyl chloride was slowly added dropwise and after the dropwise addition, the reaction solution was stirred at room temperature for 5 hours and then poured in ice water. The organic layer was extracted with ethyl acetate, and the obtained organic layer was distilled off under reduced pressure at 40° C., further distilled off under reduced pressure at 170° C., then cooled to room temperature and recrystallized by charging 50 ml of acetone thereinto. The precipitated crystals were collected by filtration to obtain 14 g of tricyclohexylbenzene.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[CH:13]=O)[C:8]#[N:9].[C:15](=[O:20])([O:17][CH2:18][CH3:19])[NH2:16]>>[C:8]([C:7]1[CH:10]=[CH:11][C:12]([CH:13]([NH:16][C:15](=[O:20])[O:17][CH2:18][CH3:19])[NH:16][C:15](=[O:20])[O:17][CH2:18][CH3:19])=[C:5]([F:4])[CH:6]=1)#[N:9]
Reactant: CCOC(N)=O
Reactant: N#Cc1ccc(C=O)c(F)c1
Agent: [Ca+2]
Agent: [Cl-]
Product: CCOC(=O)NC(NC(=O)OCC)c1ccc(C#N)cc1F
Temperature: 150 °C
Reaction time: 3 h

Procedure:
In a three-necked round bottom flask equipped with a drying tube filled with calcium chloride and an inlet for nitrogen, 3-fluoro-4-formylbenzonitrile (5.00 g, 33.5 mmol) and ethyl carbamate (6.57 g, 73.7 mmol) are heated at 150° C. The flask is being purged with a flow of nitrogen, and concentrated sulfuric acid (200 μL) is added drop by drop within 10 min. The mixture is heated at 150° C. for 6 h and then cooled at room temperature. The mixture is ground, treated with water (400 mL) and then stirred for 3 h. The precipitate is filtered and dried. Yield: 6.50 g; ESI mass spectrum: [M+Na]+=332; Retention time HPLC: 0.58 min (Z011_S03).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33].C(N(CC)CC)C.O>O1CCCC1>[CH3:30][N:31]([CH3:35])[C:32]([N:27]1[CH2:28][CH2:29][C:22]2([S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:4])=[O:5])=[N:24][CH2:23]2)[CH2:25][CH2:26]1)=[O:33]
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCC2(CC1)CN=C(c1cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]1)S2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a solution of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (82 mg) and dimethylcarbamoyl chloride (100 μL) in tetrahydrofuran (3 ml) was added triethylamine (100 μL), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (43 mg, yield 46%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 245° C.
Reaction SMILES: [N:1]([C:4]1[NH:5][C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([O:21][C:22]3[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]([Cl:30])[CH:23]=3)[C:15]=2[F:31])=[O:11])=[C:7]([Cl:9])[N:8]=1)=[N+]=[N-]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C>[NH2:1][C:4]1[NH:5][C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([O:21][C:22]3[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]([Cl:30])[CH:23]=3)[C:15]=2[F:31])=[O:11])=[C:7]([Cl:9])[N:8]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CNC(=O)c3[nH]c(N=[N+]=[N-])nc3Cl)c2F)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CNC(=O)c3[nH]c(N)nc3Cl)c2F)c1
Reaction time: 7 h
Yield: 44.7 %

Procedure:
Lindlar Catalyst (0.167 g, 0.078 mmol) was added to a suspension of 2-azido-N-({4-bromo-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (0.824 g, 1.569 mmol) in ethyl acetate (30 mL) in a pressure vessel. The vessel was evacuated and flushed with nitrogen, then evacuated and filled with hydrogen (50 psi). The reaction mixture was stirred for 7 h, then filtered through celite. The filtrate was evaporated to dryness and the residue was triturated with ethanol and dried under vacuum to give the title compound (0.350 g, 44%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.95 (br. s., 1H), 7.80 (s, 1H), 7.76 (t, 1H), 7.60 (d, 1H), 7.48 (s, 1H), 7.42 (m, 1H), 7.26 (t, 1H), 5.79 (br. s., 2H), 4.45 (d, 2H). ES MS m/z 498 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)=[CH:4][CH:3]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[NH2:17][C:12]1[C:11]2=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:22]=4)[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34](=[O:36])[CH3:35])=[CH:3][CH:4]=3)[N:16]2[N:15]=[CH:14][N:13]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)cc1
Product: CC(=O)Nc1ccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)cc1
Yield: 10 %

Procedure:
Using a procedure similar to that of Example 5 with 7-(4-amino-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and acetyl chloride as starting materials, 17 mg (10%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 2.1 (s, 3 H); ES-MS m/z 474.23 [M+H]+, HPLC RT (min) 3.01.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[C:7]1=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:53][C@H:54]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH2:55][O:56][C:57]1[CH:66]=[CH:65][C:60]2[NH:61][C:62](=[O:64])[NH:63][C:59]=2[CH:58]=1.[NH4+].[Cl-]>CN1C(=O)CCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH:53][C@H:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH2:55][O:56][C:57]2[CH:66]=[CH:65][C:60]3[NH:61][C:62](=[O:64])[NH:63][C:59]=3[CH:58]=2)=[O:14])[C:7]1=[O:15]
Reactant: N[C@@H](COc1ccc2[nH]c(=O)[nH]c2c1)c1ccccc1
Reactant: O=C(O)c1nccn(Cc2ccc(F)c(F)c2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](COc1ccc2[nH]c(=O)[nH]c2c1)c1ccccc1)c1nccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (48 mg, 0.18 mmol) was placed in a 25-mL RBF under a nitrogen atmosphere followed by HATU (82 mg, 0.22 mmol), then NMP (1.0 mL) and finally N,N-diisopropylethylamine (0.11 mL, 0.63 mmol). The reaction was stirred for five minutes at room temperature, and was added to a solution of 5-[(2R)-2-amino-2-phenylethoxy]-1,3-dihydro-2H-benzimidazol-2-one (55 mg, 0.18 mmol) in NMP (1.0 mL). The reaction was allowed to stir at room temperature for forty minutes, then was added to a separatory funnel containing ethyl acetate (75 mL) and dilute aqueous NH4Cl (50 mL); the phases were separated and the organic layer was washed with saturated aqueous NaHCO3 (50 mL), followed by brine (50 mL) and dried over anhydrous Na2SO4, then concentrated in vacuo. The crude product was purified by silica gel chromatography (10-gram column) using 0-10% CH3OH in CH2Cl2, with the product eluting at 8% CH3OH in CH2Cl2, to afford 4-(3,4-difluorobenzyl)-3-oxo-N-{(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}-3,4-dihydropyrazine-2-carboxamide as a light yellow solid. 1H NMR (500 MHz, C2D6SO) δ 10.51 (s, 1H), 10.38 (s, 1H), 9.82 (d, 1H), 8.05 (d, 1H), 7.57 (d, 1H), 7.50 (m, 1H), 7.43 (m, 3H), 7.35 (t, 2H), 7.27 (t, 1H), 7.24 (m, 1H), 6.75 (d, 1H), 6.51 (d, 2H), 5.34 (m, 1H), 5.16 (s, 2H), 4.09 (m, 2H). LRMS (ESI) calc'd for (C27H23F2N5O4) [M+H]+, 518.2; found 518.2.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]([CH2:23][CH2:24][S:25]([CH3:27])=[O:26])[C:20](=[O:28])[C@H:19]([NH:29]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:29][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]([CH2:23][CH2:24][S:25]([CH3:27])=[O:26])[C:20]1=[O:28]
Reactant: CS(=O)CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylsulfinyl)ethyl]-2-oxoazepan-3-ylcarbamate (23 mg, 0.053 mmol) in dichloromethane (2 mL). After 3 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 331 (M+1).