Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN([C:15]([O:19][N:20]1N=NC2C=CC=N[C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CONC.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:20]([O:19][CH3:15])[CH3:21])=[O:9]
Reactant: O=C(O)c1cnc(O)c(Br)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cnc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Bromo-6-hydroxy-nicotinic acid (Preparation 238, 4 g, 18.4 mmol), HATU (13.95 g, 36.71 mmol), O,N-Dimethyl-hydroxylamine hydrochloride (2.15 g, 22.02 mmol) and DIPEA (15.82 mL, 91.75 mmol) were taken in anhydrous DMF (30 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (150 mL), washed with saturated aq. Na2CO3 (2×50 mL), water (4×30 mL), brine (30 mL), dried (Na2SO4) and evaporated in vacuo. The crude mixture was purified by column chromatography on silica gel (gradient of EtOAc:Hex 4:6 to 6:4) to afford the title compound as light yellow sticky solid in 38%, 1.8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([O-:12])([OH:11])=[O:10].[N:13]#[C:14][NH2:15]>CCO>[N+:9]([O-:12])([OH:11])=[O:10].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]([NH2:15])=[NH:13])=[CH:4][CH:3]=1
Reactant: N#CN
Reactant: Nc1ccc(Cl)cc1
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
A solution of 4-chloroaniline (70 mmol, 8.88 g) in EtOH (5 mL) on an ice bath was treated with nitric acid (69% aq soln.; 5 mL). To this mixture cyanamide (50% aq. soln.; 5.4 mL) was added. The reaction mixture was stirred at r.t. for 10 min and then refluxed under N2 for a further 22 h. The solvent was evaporated. The dark brown solid residue was washed with EtOH and was dried under high vacuum to afford the title compound as a white powder (7.16 g, 44%). 1H-NMR (300 MHz, d6-DMSO) δ 7.27-7.54 (m, 4H, Ph-H), 9.65 (br. s, 2H, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[N:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1.CN1CCOCC1>ClCCl.CN(C)C=O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:39][C:36]3[CH:37]=[N:38][C:33]([C:32]([F:41])([F:31])[F:40])=[CH:34][CH:35]=3)=[O:16])[C:9]2=[O:17])=[CH:19][CH:20]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)Nc1ccc(C(F)(F)F)nc1
Reaction time: 1 h

Procedure:
To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.255 g, 0.771 mmol; Example 58D) in dichloromethane (3 mL) was added a catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (2.0 Min dichloromethane) (0.617 mL, 1.234 mmol). The reaction was stirred for 1 hour, after which a reddish solution resulted. The reaction was concentrated and dried under high vacuum. The residue was dissolved in dichloromethane (3 mL) and 6-(trifluoromethyl)pyridin-3-amine (0.100 g, 0.617 mmol) and 4-methylmorpholine (0.136 mL, 1.234 mmol) were added. After stirring for 1 hour, the reaction was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.51 (d, J=2.5, 1H), 8.11 (dd, J=2.3, 8.7, 1H), 7.64-7.58 (m, 1H), 7.33-7.23 (m, 4H), 7.06-6.96 (m, 4H), 4.17 (s, 2H), 3.60 (t, J=6.5, 2H), 2.83 (t, J=6.5, 2H); MS (ESI+) m/z 476.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:13][CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:8][C:7]1[C:2]([O:9][CH:10]2[CH2:11][CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:13]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)NC1CC(O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CC(Oc2nccnc2Cl)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a mixture of 2,3-dichloro-pyrazine (3.0 g, 20 mmol) and tert-butyl (3-hydroxycyclobutyl)carbamate (see PREPARATION 4B; 3.65 g, 20 mmol) in DMSO (50 mL) was added Cs2CO3 (13.2 g, 40 mmol), and then the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with water and filtered. The filtrate cake was washed with water, and dried to give tert-butyl (3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)carbamate (4.5 g, 15.2 mmol, 76%). ESI-MS (M+1): 300 calc. for C13H18ClN3O3 299.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:34]([O:37][CH2:38][C:39](Cl)=[O:40])(=[O:36])[CH3:35]>ClCCl>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11](=[N:10][N:9]=[C:8]3[C@H:15]3[CH2:16][CH2:17][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]3)[CH2:12][N:13]([C:39](=[O:40])[CH2:38][O:37][C:34](=[O:36])[CH3:35])[CH2:14][C:5]=2[CH:4]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](OC(C)C)CC2)C1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-isopropoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.090 g, 0.23 mmol) and triethylamine (0.066 ml, 0.48 mmol) in dichloromethane (5 ml) was added acetoxy acetyl chloride (0.031 g, 0.25 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.073 g, 70%) as white solid. MS m/e: 461 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:28]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:14])[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 5.3 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5 parts of 1-(diphenylmethyl)piperazine, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanonephase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol. The product is filtered off and dried, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 153.6° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1-c1n[nH]c2ncc(Br)cc12
Temperature: 70 °C
Yield: 97 %

Procedure:
To a solution of 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (260 mg, 0.60 mmol) in THF (3 mL) was added tetrabutylammonium fluoride (6 mL of 1 M in THF solution, 6.00 mmol) and molecular sieves. The solution was heated under reflux (70° C.) for 4 hours without stirring. The solution was cooled to ambient temperature and acidified to pH=5 by adding dropwise a dilute solution of acetic acid in MeOH. The solution was filtered and the filtrate was concentrated via rotary evaporation. The material was extracted into EtOAc and washed 3×H2O. The organic layer was dried over Na2SO4 and concentrated down to afford 5-bromo-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine as an orange solid (177 mg, 97% yield). MS: m/z 303.9, 305.9 [M+H+]. The material was used directly in step 2 without further purification.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])([O:3]C)=[O:2].[OH-].[Na+].Cl>CC(C)=O>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]1[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])([OH:3])=[O:2]
Reactant: COC(=O)C1OC2C(C(=O)N2C(C(=O)OCc2ccccc2)=C(C)C)N1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)O)N2C(=O)OCc1ccccc1
Reaction time: 0.75 h
Yield: 88.2 %

Procedure:
To a solution of 1.482 g of benzyl α-(3ξ-carbomethoxy-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 20 ml of acetone is added 5 ml of 0.6 M aqueous solution of sodium hydroxide under ice-cooling, and the mixture stirred for 45 minutes, then neutralized with 2 N hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure to yield 1.27 g of benzyl α-(3ξ-carboxy-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product in 88.5% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2)=[C:8]2[C:3]=1[N:4]=[CH:5][C:6]([OH:22])=[N:7]2.BrC1C=CC(C2C=C(OC)C=C(OC)C=2)=[C:28]2C=1N=C(O)C=[N:29]2.C([Cu])#N>CN1C(=O)CCC1.CCOC(C)=O.C(N)CN>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:9]2[C:8]3[N:7]=[C:6]([OH:22])[CH:5]=[N:4][C:3]=3[C:2]([C:28]#[N:29])=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1
Reactant: COc1cc(OC)cc(-c2ccc(Br)c3nc(O)cnc23)c1
Reactant: COc1cc(OC)cc(-c2ccc(Br)c3ncc(O)nc23)c1
Agent: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: NCCN
Product: COc1cc(OC)cc(-c2ccc(C#N)c3ncc(O)nc23)c1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-8-(3,5-dimethoxy-phenyl)-quinoxalin-2-ol and 8-bromo-5-(3,5-dimethoxy-phenyl)-quinoxalin-2-ol (Step 85.6) (609 mg, 1.7 mmol) (Step 1.4) and CuCN (183 mg, 2.0 mmol, 1.2 equiv) in NMP (5 mL) was stirred at 180° C. for 2 h. The reaction mixture was allowed to cool to rt, diluted with EtOAc/10% aqueous solution of ethylenediamine (25 mL) and extracted with EtOAc. The aqueous phase was acidified to pH 5 and extracted with EtOAc. The combined organic extracts were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 7:3) to afford 103 mg of the title compound as a yellow solid: ES-MS: 308.1 [M+H]+; tR=4.05 min (System 1); Rf=0.35 (Hex/EtOAc, 7:3).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]([Cl:16])([Cl:15])[CH2:10][O:11][C:12](Cl)=[O:13].[CH3:17][C:18]1[NH:19][C:20](=[O:24])[CH2:21][S:22][CH:23]=1>>[CH3:17][C:18]1[NH:19][C:20](=[O:24])[CH2:21][S:22][C:23]=1[CH:7]1[CH:6]=[CH:5][N:4]([C:12]([O:11][CH2:10][C:9]([Cl:16])([Cl:15])[Cl:8])=[O:13])[N:3]=[C:2]1[CH3:1]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC1=CSCC(=O)N1
Reactant: Cc1cccnn1
Product: CC1=NN(C(=O)OCC(Cl)(Cl)Cl)C=CC1C1=C(C)NC(=O)CS1
Yield: 10 %

Procedure:
A mixture of 3-methylpyridazine (1.82 ml), 2,2,2-trichloroethylchloroformate (3.44 ml) and 5-methyl-2H-1,4-thiazin-3(4H)-one (1.29 g) was treated in the same manner as described in Example 2 (i) to give the titled compound (0.4 g, yield 10%) as white crystals. n-Hexane-ethyl acetate (=3:2) was used as a developing eluant.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])[CH:5]=[CH:4][NH:3]1.[C:28]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[CH3:28][N:3]1[CH:4]=[CH:5][C:6]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:7][C:2]1=[O:1]
Reactant: O=C(NCc1cc[nH]c(=O)c1)c1cccc2c1cnn2-c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cc1=O
Temperature: 60 °C

Procedure:
To a stirred solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-amide (50 mg, 0.1 mmol) in DMF (1.0 mL) was added K2CO3 (45.8 mg, 0.331 mmol) followed by iodomethane (0.017 mL, 0.28 mmol). The mixture was warmed at 60° C. for 3 hours. The mixture was diluted with water (10 mL), and a white solid was obtained by filtration. The solid was washed with water (5×10 mL) and air dried. The resulting solid was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:32][CH2:31][CH:27]([C:28](Cl)=[O:29])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[ClH:1].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][CH:27]([C:28]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[O:17])=[O:29])[CH2:31][CH2:32]2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Product: Cl
Product: O=C(Nc1ccc(Cl)cc1)c1ccccc1NC(=O)C1CCN(c2ccncc2)CC1
Yield: 146.1 %

Procedure:
Using the procedure described in Example 138, N-(4-chlorophenyl)-2-aminobenzamide (0.97 mmol) and N-(4-pyridyl)isonipecotoyl chloride (1.8 mmol), purifying with RPHPLC Method A, yielded 334 mg (37%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:13]([O:16]C)=[N:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.C([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])C.C(#[N:27])C>>[F:12][C:7]1[CH:6]=[C:5]2[C:10]([N:11]=[C:2]([N:27]3[CH2:24][CH2:23][NH:20][CH2:21][CH2:22]3)[C:3]3[N:4]2[C:13](=[O:16])[NH:14][N:15]=3)=[CH:9][CH:8]=1
Reactant: COc1nnc2c(Cl)nc3ccc(F)cc3n12
Reactant: CC#N
Reactant: CCN(CC)CC
Product: O=c1[nH]nc2c(N3CCNCC3)nc3ccc(F)cc3n12
Reaction time: 16 h

Procedure:
A solution of 300 mg of 4-chloro-8-fluoro-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, 221 mg of tert-butyl-N-(piperazine)carbamate, and 360 mg of triethylamine in acetonitrile (4.0 mL) was stirred at room temperature. After 16 hrs., the solvent was removed, and the residue was separated by silica gel chromatography to give 280 mg of a yellow foam. The foam was dissolved in a 1:1.5 mixture of 48% HBr/AcOH, and the mixture was heated to reflux for 2 hrs. The reaction mixture was concentrated to give 97 mg of a yellow solid. MS (M−H)−=287.1.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]2[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH:16]=2)[CH:9]=1)(=[O:5])=[O:4].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:49]([C:51]1[N:52]=[C:53]([C:64]([O-])=[O:65])[N:54]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[CH:55]=1)#[N:50].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:22][C:18]1([CH3:21])[CH2:19][CH2:20][C:15]([C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:4])(=[O:5])[N:2]([CH3:1])[CH3:23])[CH:13]=[CH:12][C:11]=2[NH:14][C:64]([C:53]2[N:54]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[CH:55]=[C:51]([C:49]#[N:50])[N:52]=2)=[O:65])=[CH:16][CH2:17]1
Reactant: CN(C)S(=O)(=O)CCc1ccc(N)c(C2=CCC(C)(C)CC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A solution of 215 mg (0.638 mmol) of 2-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethanesulfonic acid dimethylamide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 446 mg (0.957 mmol) of PyBroP, 214 mg (0.701 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) and 333 μL (1.91 mmol) of DIEA and stirred at RT for 18 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with water (1×20 mL). The aqueous layer was extracted with CH2Cl2 (1×20 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25% EtOAc-hexane afforded 355 mg (95%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C29H43N5O4SSi, 586.3 (M+H). found 585.9.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([CH2:12]O)[CH:10]=2)[C:5]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39]C(Cl)(Cl)C(Cl)(Cl)Br>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([CH2:12][Br:39])[CH:10]=2)[C:5]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: COc1cc(CO)cc2c(Br)ccc(OC(C)C)c12
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CBr)cc2c(Br)ccc(OC(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.7 %

Procedure:
To a solution of 4.00 g (12.3 mmol) 1-bromo-7-hydroxymethyl-4-isopropoxy-5-methoxy-naphthalene in 40 mL dry dichloromethane, 3.24 g (12.3 mmol) triphenylphosphane and 4.00 g (12.3 mmol) 1,2-dibromotetrachloroethane were added under Ar. After stirring for 30 min at room temperature, the solvent was removed and subsequently the residue was filtered over a short silica gel column (petroleum/ethyl acetate, 4:1) to give 5.00 g (95%) 1-bromo-7-bromomethyl-4-isopropoxy-5-methoxy-naphthalene as a colorless solid (m.p. 126° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:31]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CC#N.O>[I:31][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18]
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCc1nc(O)c(I)c2cc(OC)c(OC)cc12
Reaction time: 2.5 h
Yield: 78 %

Procedure:
A mixture of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (2.00 g, 8.09 mmol) and p-toluenesulfonic acid monohydrate (1.50 g, 7.89 mmol) in dry CH3CN (20 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was stirred for 10 min at RT before portionwise addition of N-iodosuccinimide (1.82 g, 8.09 mmol) under vigorous stirring. After 2.5 h, the mixture was slowly poured into a cold solution of NaHCO3 (2.0 g) in 50 mL of water and the solid was filtered, washed with water (50 mL) and dried overnight under vacuum to yield 4-iodo-6,7-dimethoxy-1-propylisoquinolin-3-ol CCH 42098-1 as a brown solid (2.35 g, 78% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH2:14])[CH2:4][O:3]1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[S:26]>CCCCC.ClCCl>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]([NH:14][C@H:5]1[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][C@H:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[S:26]
Reactant: CC1(C)OC[C@H](N)[C@H](c2ccccc2)O1
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Solvent: CCCCC
Solvent: ClCCl
Product: CC1(C)OC[C@H](NC(=S)Nc2ccc(Cl)cc2Cl)[C@H](c2ccccc2)O1
Reaction time: 24 h
Yield: 67.4 %

Procedure:
To a solution of 130 mg (0.62 mmol) of (4S,5S)-amine 1 in pentane (2.0 mL) was added dropwise a solution of 116 mg (0.62 mmol) of 2,4-dichlorophenyl isothiocyanate in dichloromethane (0.15 mL). After stirring for ˜24 h, a white precipitate was collected, rinsed with pentane, and dried under reduced pressure to yield 172 mg (67%) of the title compound.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Br[C:15]1[C:24]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH3:29])[CH:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:28][S:25]([C:24]1[C:15]([S:9][C:6]2[CH:7]=[CH:8][C:3]([S:2]([F:10])([F:11])([F:12])([F:13])[F:1])=[CH:4][CH:5]=2)=[CH:16][C:17]([CH3:29])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20])(=[O:26])=[O:27]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Br)cc1C
Reactant: FS(F)(F)(F)(F)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Sc2ccc(S(F)(F)(F)(F)F)cc2)cc1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
0.28 g of 4-pentafluorosulfanylthiophenol, 0.36 g of methyl 4-bromo-5-methanesulfonyl-2-methylbenzoate and 0.33 g of K2CO3 were dissolved in 8 ml of anhydrous DMF and stirred at 110° C. for 2 h. The reaction mixture was then poured into 100 ml of water and extracted twice with 100 ml of EA each time. The EA phase was then washed twice with 30 ml of water each time. The residue after drying over MgSO4 and removal of the solvent in vacuo was chromatographed on silica gel with CH2Cl2/DIP 1:2. 320 mg of a colorless foam were obtained.