Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:25])([F:24])[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:15][CH:16]=1)=[O:9]>C(Cl)Cl>[Cl:1][S:2]([C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]([F:25])([F:24])[F:6])=[CH:12][C:13]=1[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)CCc1cccc(NC(=O)C(F)(F)F)c1
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Yield: 30.6 %

Procedure:
ClSO3H (2 g, 17.3 mmol) was cooled to 0° C. and ethyl 3-(3-(2,2,2-trifluoroacetamido) phenyl)propanoate (1 g, 3.46 mmol) was added portionwise with vigorous stirring keeping the temperature below 5° C. The reaction mixture was stirred at room temperature overnight, and cautious poured onto ice. The solid produced was dissolved in CH2Cl2. The combined organic phase was washed with saturated NaHCO3 and saturated brine, dried over MgSO4 to give the product ethyl 3-(2-(chlorosulfonyl)-5-(2,2,2-trifluoroacetamido)phenyl)propanoate (0.41 g, yield 31%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5].[CH3:16][Mg]Br.O.[Cl-].[NH4+]>O1CCCC1>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:4](=[O:5])[CH3:16])=[N:7]1
Reactant: CON(C)C(=O)c1n[nH]c2ccccc12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1n[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 20 h

Procedure:
In a round-bottomed flask, 2.4 g of N-methoxy-N-methyl-1H-indazole-3-carboxamide are placed in 140 ml of tetrahydrofuran at 0° C. and under argon. 19 ml of methylmagnesium bromide (3M in ethyl ether) are added dropwise. The mixture is stirred for one hour at 0° C. and 20 h at ambient temperature. It is cooled to 0° C. and 80 ml of water and 40 ml of a saturated solution of ammonium chloride are added. The mixture is extracted with 40 ml of ethyl acetate. The organic phase is washed with 40 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 1.6 g of compound are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=O)[N:3]1[C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:16]([NH:18][CH:19]1[CH2:21][CH2:20]1)=[O:17].[BH4-].[Na+].Cl>CO.C(Cl)Cl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]1[C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:16]([NH:18][CH:19]1[CH2:21][CH2:20]1)=[O:17]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N1C(=O)Cc2ccccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.8 %

Procedure:
To a solution of 3-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-cyclopropyl-4-methylbenzamide (385 mg) in methanol (8 ml) and methylene chloride (19 ml) under an atmosphere of argon was added NaBH4 (48 mg) portionwise and the reaction stirred at room temperature for 17 hours. Concentrated hydrochloric acid (0.1 ml) was added and the reaction stirred for a further 30 minutes. The reaction mixture was concentrated and the residue resuspended in ethyl acetate, washed 1N NaOH, water, brine, dried (magnesium sulfate) and concentrated to give a white solid which was purified by column chromatography with a gradient of iso-hexane to 80% ethylacetate/iso-hexane to give 3-(1-Oxoisoquinolin-2(1H)-yl)-N-cyclopropyl-4-methylbenzamide as a white solid (190 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.10 (s, 3H), 2.85 (m, 1H), 6.75 (d, 1H), 7.34 (d, 1H), 7.49 (d, 1H), 7.58 (m, 1H), 7.75-7.82 (m, 3H), 7.88 (d, 1H), 8.26 (d, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 319.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:17]=[C:16]([C:18](O)=[O:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[C:22]1([NH2:29])[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[C:22]1([NH:29][C:18]([C:16]2[CH:15]=[CH:14][C:12]3[NH:13][C:9]([C:6]4[CH:5]=[CH:4][C:3]([N:2]([CH3:21])[CH3:1])=[CH:8][CH:7]=4)=[N:10][C:11]=3[CH:17]=2)=[O:19])[CH:27]=[CH:26][C:25]([NH:28][C:18]([C:16]2[CH:15]=[CH:14][C:12]3[NH:13][C:9]([C:6]4[CH:5]=[CH:4][C:3]([N:2]([CH3:21])[CH3:1])=[CH:8][CH:7]=4)=[N:10][C:11]=3[CH:17]=2)=[O:19])=[CH:24][CH:23]=1
Reactant: CN(C)c1ccc(-c2nc3ccc(C(=O)O)cc3[nH]2)cc1
Reactant: Nc1ccc(N)cc1
Product: CN(C)c1ccc(-c2nc3cc(C(=O)Nc4ccc(NC(=O)c5ccc6[nH]c(-c7ccc(N(C)C)cc7)nc6c5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 283 was prepared according to the procedure similar to that described in Scheme V from 2-(4-dimethylaminophenyl)benzimidazole-5-carboxylic acid and 1,4-phenylenediamine. [M+H]+ calcd for C38H34N8O2: 635.28; found: 635.05.
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8](=O)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:23])=O>ClCCl>[Cl:23][C:8]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][N:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=1
Reactant: O=c1[nH]c(C2CC2)ncc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(C2CC2)nc1Cl
Reaction time: 2 h

Procedure:
To a suspension of the 2-cyclopropyl-5-nitro-3H-pyrimidin-4-one (900 mg, 4.9 mmol) in dichloromethane (15 ml) was added triethylamine (505 mg, 5 mmol). To the clear solution obtained, phosphorous oxychloride (1.5 g, 10 mmol) was slowly added and the reaction mixture kept at room temperature for 2 hours. TLC showed a single spot. The reaction mixture was diluted with dichloromethane, washed with water and dried over MgSO4, filtered and evaporated to dryness to give brown oil. This material was used as such for the next step.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][OH:9])[N:7]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[N:23]([CH3:29])[C:22]=3[CH:30]=2)[C:14](=[O:31])[CH:13]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH:26]1([C:24]2[N:23]([CH3:29])[C:22]3[CH:30]=[C:18]([N:15]4[CH:16]=[CH:17][C:12]([O:9][CH2:8][C:6]5[N:7]=[C:3]([CH:2]([F:10])[F:1])[S:4][CH:5]=5)=[CH:13][C:14]4=[O:31])[CH:19]=[CH:20][C:21]=3[N:25]=2)[CH2:27][CH2:28]1
Reactant: OCc1csc(C(F)F)n1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)F)n4)cc3=O)cc21
Temperature: 100 °C
Yield: 50.2 %

Procedure:
To a suspension of (2-(difluoromethyl)thiazol-4-yl)methanol (44 mg) and 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)-one (66.5 mg) in toluene (1 ml) was added potassium tert-butoxide (49.8 mg) at 100° C., and the mixture was stirred at 100° C. under dry atmosphere (CaCl2 tube) for 30 min. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by recrystallization from EtOH-water to give the title compound (47.7 mg) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24]C(=O)OC(C)(C)C)[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=2)[N:6]=[C:7]([CH:9]=[CH2:10])[CH:8]=1.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[C:4]2[N:5]([C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH2:24])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=2)[N:6]=[C:7]([CH:9]=[CH2:10])[CH:8]=1
Reactant: C=Cc1cc(OC)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=Cc1cc(OC)c2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a solution of tert-butyl {1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-12 (40 mg, 0.081 mmol) in dioxane (1.7 mL) was added trifluoromethanesulfonic acid (0.61 mL, 1.8 mmol, 10.0 eq), and the resulting mixture was stirred at room temperature for 12 h. The resulting mixture was added to ice water, made alkaline with aqueous sodium hydroxide (2 N), and extracted with EtOAc (3×25 mL). The combined organic phases were washed, dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; 10 g SNAP cartridge: 100% DCM 3.0 min., gradient to 95% DCM/5% MeOH 1 min., 95% DCM/5% MeOH 2.5 min., gradient to 90% DCM/10% MeOH 3 min., 90% DCM/10% MeOH 3.5 min.) to give 1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.022 g, 70%):
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH3:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.CCOC(C)=O>CN(C)C(=O)C>[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]4=[N:26][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:22]4[CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:27][CH:28]=1
Reactant: Cc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
2-Chloroethanesulfonyl chloride (0.885 g) in N,N-dimethylacetoamide (7.0 mL) was added dropwise to a solution of 3-[4-(4-methylphenoxy)phenyl]pyridin-2-amine (1.00 g) in N,N-dimethylacetoamide (3.0 mL) at 0° C. The mixture was stirred at 70° C. under N2 overnight. EtOAc and IPE was added dropwise to the mixture at room temperature. The solid was isolated by filtration and washed with water, IPE and EtOAc to give the title compound (1.07 g) as a gray solid.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[C:8](=[S:13])([S:11][CH3:12])[S:9][CH3:10].[F:14][B-:15]([F:18])([F:17])[F:16].[H+]>C(#N)C>[F:14][B-:15]([F:18])([F:17])[F:16].[CH3:10][S:9][C:8](=[S+:13][CH3:5])[S:11][CH3:12]
Reactant: COS(=O)(=O)OC
Reactant: CSC(=S)SC
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Product: CSC(SC)=[S+]C
Temperature: 90 °C
Yield: 83 %

Procedure:
Dimethyl sulfate (22.84 mL, 240 mmol) and dimethyl trithiocarbonate (26.48 mL, 240 mmol) were added to acetonitrile (80 mL). The resultant dark yellow solution was heated to 90° C. for 2 hours. The mixture was then allowed to cool to 55° C. and then a solution of tetrafluoroboric acid (54% in diethyl ether, 48 mL) was added over 5 min time. The resultant solution was stirred for an additional 15 min, followed by pouring it into a solution of ice-cold diethyl ether (600 mL), The white solid that formed was collected and washed with diethyl ether (3×50 mL) and dried in a vacuum oven to provide (bis-methylsulfanyl -methylene)-methyl-sulfonium tetrafluoroborate salt (47.3 g, 83%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:16][C:17](N(OC)C)=[O:18])=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:16][C:17](=[O:18])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:13][CH:14]=1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Reactant: Cc1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1[C@H](CC(=O)Cc1ccncc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
At −78° C., to a solution of 4-methylpyridine (308 mg) in THF (7 mL) n-butyllithium (1.6M in hexane, 2.07 ml) was added. The reaction mixture was warmed slowly to rt, stirred for 1 h at that temperature, and cooled down again to −78° C. (R)-3-(4-Bromophenyl)-N-methoxy-N-methyl-3-o-tolylpropanamide (example 142, step 1; 400 mg) in THF (3 mL) was added slowly and the reaction mixture was warmed to rt and stirred for 3 h. The mixture was poured into a saturated aqueous solution of NaHCO3 (10 mL), the phases were separated, and the inorganic one was extracted with EtOAc (2×10 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (30% to 60% EtOAc in n-heptane to CH2Cl2/MeOH 9:1) to yield the title compound as a yellow oil (220 mg, 51%), MS (ESI+): m/z=394.0 ([M+H]+, 1Br).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:24][CH3:25])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH:23][C:26](=[O:28])[CH3:27])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:24][CH3:25])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccc(N)cc12
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N1-(pyrid-3-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (100 mg, 0.30 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF (10 ml) containing pyridine (1.1 eq) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 1 h. THF was evaporated and the residue was purified by silica gel column chromatography using 25% acetone-chloroform as eluent to obtain 6 mg of N1-(pyrid-3-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: >250° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11]C)=[O:9])=[CH:4][CH:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([NH:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(N)nc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(C)(=O)=O)nc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 131.1 %

Procedure:
Ethyl 6-aminopyridine-3-carboxylate (738 mg, 4.44 mmol) was dissolved in pyridine (20 mL), cooled to 0° C. and methanesulfonyl chloride (1.72 mL, 22.2 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, concentrated in vacuo and partitioned between DCM (50 mL) and 1M aq citric acid (50 mL). The organic fraction was dried (MgSO4) and concentrated in vacuo to give the crude title compound (1.34 g) as a brown solid. LCMS (ES+): 245.1 [MH]+.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([NH:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=NCc1ccccc1
Reactant: Nc1nccs1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: S=C(NCc1ccccc1)Nc1nccs1
Temperature: 25 °C
Yield: 46.1 %

Procedure:
A solution of benzyl isothiocyanate (1.5 g, 10 mmol) and 2-aminothiazole (1.0 g, 10 mmol) in N,N-dimethyl-formamide (25 mL) was heated at 100° C. for 12 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 1.15 g (46%) of the title product:
Reaction SMILES: C([O:8][C:9](=[O:41])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:40])[C:18]([CH3:39])([CH3:38])[CH:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>CO.[OH-].[Pd+2].[OH-]>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:21]([NH:20][CH:19]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:18]([CH3:39])([CH3:38])[C:17]([N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][C:9]([OH:41])=[O:8])[CH2:16][CH2:15]2)=[O:40])=[O:31])=[CH:27][CH:26]=1)(=[NH:29])[NH2:30]
Reactant: CC(C)(C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1)C(NC(=O)c1ccc(C(=N)N)cc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C(=O)N1CCC(CC(=O)O)CC1)C(NC(=O)c1ccc(C(=N)N)cc1)c1ccccc1
Yield: 89.7 %

Procedure:
N-4-Amidinobenzoyl-β-phenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid benzyl ester (63 mg, 0.114 mmol) was dissolved in an 80% aqueous methanol solution (10 ml) containing 2% acetic acid. To the reulting solution was added palladium hydroxide (50 mg) and the mixture was stirred in a hydrogen atmosphere for 15 minutes. The solvents were distilled off and the res idue was dissolved in a 1N aqueous solution of acetic acid. The resulting solution was purified with a high performance liquid chromatography (HPLC) under the same conditions as described in (3) to yield a powder of N-(N-4-amidinobenzoyl-β-phenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid (47.5 mg, 89.9%). The obtained product was identified by NMR, MS and HPLC analyses to be the same compound as prepared by the solid phase method.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[Br:5][C:6]1[C:7]([C:13]#[N:14])=[N:8][CH:9]=[C:10](Cl)[N:11]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Br:5][C:6]1[C:7]([C:13]#[N:14])=[N:8][CH:9]=[C:10]([NH:4][CH2:3][CH2:1][OH:2])[N:11]=1
Reactant: N#Cc1ncc(Cl)nc1Br
Reactant: NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ncc(NCCO)nc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
0.061 g (1.00 mmol) of ethanolamine were added slowly at room temperature to a solution of 0.218 g (1.0 mmol) of the 3-bromo-5-chloro-pyrazine-2-carbonitrile and 0.264 g (2.0 mmol) of N-ethyldiisopropylamine in 15.0 ml of dioxane. The reaction mixture was stirred at room temperature for 18 hours. It was subsequently poured into 50 ml of an ice/water/sodium hydrogen carbonate mixture and extracted 3 times with 50 ml of ethylacetate. The combined ethylacetate phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 100:0 to 95:5 v/v gradient of dichloromethane and methanol as the eluent giving 0.131 g (0.539 mmol, 53.9% of theory) of the 3-bromo-5-(2-hydroxy-ethylamino)-pyrazine-2-carbonitrile as yellow solid; m.p. 158-160° C.; MS: 243 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(-c2ccco2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of 1-bromo-4-fluorobenzene (3.0 g, 17.14 mmol) in dioxane (100.0 mL) and water (3.0 mL) was added (furan-2-yl)boronic acid (5.76 g, 51.48 mmol), K3PO4 (10.76 g, 50.69 mmol) and Pd(PPh3)4 (980 mg, 0.85 mmol) with stirring for 2 h at 90° C. in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified via silica gel chromatography (1% ethyl acetate in petroleum ether) to afford 2-(4-fluorophenyl)furan as colorless oil (2.5 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[N:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1ncc2ccccc21

Procedure:
Using general procedure 4 and purification method E with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.25 g, 0.95 mmol) and indazole (0.56 g, 4.74 mmol) gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[C:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:3]=1.O.O.Cl[Sn]Cl>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[C:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2C2CCCCC2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2ccc(Cl)cc2C2CCCCC2)cc1

Procedure:
The nitro intermediate (10 mmol) obtained above was dissolved in MeOH (20 mL), and treated with SnCl2.2H2O (50 mmol), according to General Procedure I. The reaction mixture was heated under reflux until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo and the residue was treated with 4.0 N aqueous NaOH to pH˜8. The residue was extracted with EtOAc (2×50 mL), washed with 1.0 N aqueous NaOH, brine and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-chloro-2-cyclohexylphenoxy) aniline, which was used directly for further transformation without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:9]=[C:8]([C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=2)[S:7][C:6]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccsc1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(=O)c2ccc(Cl)cc2)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a stirred solution of 0.05 g (0.22 mmol) of 15 and 27 uL (0.22 mmol) of 4-chlorobenzoyl chloride in 5 mL of dry CH2Cl2 was added 15 mg (0.11 mmol) of AlCl3 in three portions at room temperature. The resulting mixture was stirred overnight. The reaction mixture was slowly poured onto 5 g of ice and allowed to warm to room temperature. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/Hex 1:9) to give 0.04 g (50%) of [5-(4-chlorobenzoyl)-2-phenylthiophene-3-yl]acetic acid methyl ester as a white solid: 1H NMR (600 MHz, CDCl3) δ 7.84 (d, J=8.2 Hz, 2H), 7.61 (s, 1H), 7.50-7.43 (m, 3H), 3.71 (s, 3H), 3.67 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 186.5, 171.1, 150.1, 140.8, 138.6, 137.3, 136.2, 132.6, 130.5, 129.2, 128.9, 128.8, 128.7, 52.2, 34.1; IR (KBr) cm−1 2949, 1737, 1623; LREIMS C20H15ClO3S requires 370.04. Found: 370 ([M+], 100%), 310 (40%), 139 (59%).