Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][C@H:12]3[C@H:17]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]3)=[CH:9][C:4]=2[CH2:3][O:2]1.FC(F)(F)C(O)=O.ClCCl>C1(C)C=CC=CC=1>[CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][C@H:12]3[C@H:17]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[CH2:16][CH2:15][NH:14][CH2:13]3)=[CH:9][C:4]=2[CH2:3][O:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc3c(c2)COC3)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Fc1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)COC3)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.9 %

Procedure:
To tert-butyl (3S,4R)-3-[(1,3-dihydro-2-benzofuran-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine-1-carboxylate (4.1 g, 9.6 mmol) described in Production Example 1-4 was added a mixed solution of trifluoroacetic acid (5 mL) and dichloromethane (30 mL) under ice cooling, followed by stirring at room temperature for 90 minutes. Toluene (30 mL) was added to the reaction mixture, and the solvent was distilled away under reduced pressure. The residue was purified by NH silica gel column chromatography (methanol:ethyl acetate=1:20) to give the title compound (2.7 g, 84% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:16])[N:10]2CC=C)=[CH:5][CH:4]=1.C[N+]1([O-])CC[O:21]CC1.O1CCCC1.O.[CH3:31][C:32]([CH3:34])=[O:33]>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[OH:33][CH:32]([CH2:34][OH:21])[CH2:31][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[N:7]=[CH:8][C:9]1=[O:16]
Reactant: C=CCn1c(=O)cnc2ccc(OC)cc21
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CC(O)CO)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
7-Methoxy-1-(2-propen-1-yl)quinoxalin-2(1H)-one (synthesized with reference to WO2008/9700; 2.77 g, 12.82 mmol) was dissolved in a mixed solvent (100 ml) of tetrahydrofuran/water/acetone (2:1:2). N-methylmorpholineoxide (3.47 g, 25.64 mmol) was added to this solution under cooling on ice and a 4% aqueous solution of osmium tetroxide (1.6 ml, 0.256 mmol) was subsequently added. The reaction solution was stirred for 2 days while the temperature was raised to room temperature. The reaction solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 3.16 g (99%) of the title compound in the form of a brown oily product.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:20]2[O:22][CH2:21]2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[CH3:23][O:24][C:25](=[O:33])[C:26]1C=CC(O)=[CH:28][CH:27]=1.[Na].C[O:36][C:37](=O)[C:38]1C=CC(O)=C[CH:39]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:27]=[CH:28][C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:2]([CH3:11])([CH3:1])[CH2:3][O:4][CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][O:6]3)=[CH:17][CH:16]=2)=[CH:19][C:20]=1[O:22][CH2:21][CH:37]([OH:36])[CH2:38][CH3:39]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(COC1CCCCO1)c1ccc(CCC2CO2)cc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCC(O)COc1cc(-c2ccc(C(C)(C)COC3CCCCO3)cc2)ccc1C(=O)OC

Procedure:
30.4 g (0.100 Mol) 4-{4'-[1,1-dimethyl-2-(tetrahydropyran-2-yl)oxyethyl]phenyl}-1,2-epoxy butane, 15.2 g (0.100 Mol) 4-hydroxybenzoic acid methyl ester and 1.74 g (0.010 Mol) 4-hydroxy benzoic acid methyl ester sodium salt are heated in 100 ml dimethyl formamide for 23 hours while stirring to 100°-110° C. The cooled reaction mixture is poured into water, the precipitating product taken up in ethyl acetate and the organic phase washed with water. After drying over sodium sulfate the solvent is removed in vacuum and the residue chromatographed on silica with dichloromethane/methanol 99/1. A highly viscous oil is obtained; yield 32.5 g (71%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:23])=[C:7]([C:18](OCC)=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[F:24].C(N(C(C)C)C(C)C)C.Cl.[NH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:23])=[C:7]([C:18]([NH:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:19])[C:8](=[O:17])[C:9]32[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:4][C:3]=1[F:24]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(F)c(Cl)cc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)c(Cl)cc2C2(CCOCC2)C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 4.2 %

Procedure:
Ethyl 7-chloro-6-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (580 mg, 1635 μmol) was dissolved in 1,4-dioxane (3270 μL) and N-ethyl-N-isopropylpropan-2-amine (854 μL, 4905 μmol). tert-Butyl 2-aminoacetate hydrochloride (411 mg, 2452 μmol) was added, and the reaction was stirred at 80° C. for 2 hours. The reaction was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 75 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title (30 mg) compound as a white solid after flash chromatography. MS m/e=440 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[N:10]([O-])=O.[Na+].[O:14]=[C:15]1[O:21][C@H]([C@H](CO)O)C(O)=[C:16]1[OH:17]>O>[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[N:5]([C:16](=[O:17])[C:15]([OH:21])=[O:14])[NH2:10]
Reactant: O=N[O-]
Reactant: Nc1ccccc1Cl
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NN(C(=O)C(=O)O)c1ccccc1Cl
Temperature: -1 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a 500 ml flask under a nitrogen atmosphere, concentrated HCl (80 ml, 32%, 0.81 moles) was charged and cooled to −2 to 0° C. 2-Chloroaniline (16 ml, 19.4 g, 0.15 moles) was added dropwise at −2 to 0° C. Sodium nitrite (12.4 g, 0.18 moles) dissolved in water (25 ml) was added dropwise to the acidic mixture through an addition funnel over a period of 30 minutes at −2 to 0° C. The resulting mixture was stirred for 1 hour at −2 to 0° C. L-Ascorbic acid (26.6 g, 0.15 moles) dissolved in water (130 ml) was added through an addition funnel over a period of 1 hour at −2 to 0° C. The reaction was allowed to come to room temperature (18-20° C.) over a period of 30 minutes, then heated to 40° C. and stirred for 3 hours at that temperature, cooled and stirred overnight at 18-20° C. The resultant orange slurry was filtered; the solid was washed with water, then repulped three times in hot methylene chloride (450 ml) and finally in water (115 ml) at 30° C. The product was dried to constant weight to afford 20.4 g of 2-chlorophenylhydrazido oxalic acid as a yellow solid (HPLC purity calculated as area percent:>99%).
Reaction SMILES: C1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])C=CC=CC=1.[CH2:15]([Ba:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(C1C=CC=CC=1)C.O1CCCC1>[C:24]1([C:23]([Ba:22][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=C(c1ccccc1)c1ccccc1
Reactant: c1ccc(C[Ba]Cc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: c1ccc(CCC([Ba]C(CCc2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 14 h

Procedure:
2.50 ml (14.15 mmol) of 1,1-diphenylethylene were added at 25° C. to a suspension of 1.78 g (5.58 mmol) of dibenzylbarium in 70 ml of ethylbenzene and 10 ml of tetrahydrofuran (THF). Stirring for 14 hours resulted in a deep red solution. The solution was filtered off from small amounts of insoluble constituents and then evaporated to dryness. Solvent-free bis(1,1,3-triphenylpropyl)barium was firstly obtained as a very viscous, red-violet oil and, after prolonged drying, as a tough solid. The conversion was virtually quantitative.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH:23]=O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:18]
Reactant: CCOc1cc(C=O)ccc1F
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)ccc1F
Yield: 30 %

Procedure:
The title compound (11 mg, 30%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3-ethoxy-4-fluoro-benzaldehyde. MS: 372.5 (MH+)
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:33]([C@:27]1([C:30]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:10]=[CH:9][N:8]=3)[CH2:2][CH2:3]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)n1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of 2-piperazin-1-yl-4-(trifluoromethyl)pyrimidine (250 mg, 1.08 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (300 mg, 1.1 mmol) and triethylamine (0.45 mL, 3.2 mmol) in methylene chloride (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (520 mg, 1.2 mmol). After being stirred overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. Purification by column chromatography on silica gel (20%-40% EtOAc/hexanes) provided 290 mg of desired product. MS calculated for C23H34F3N5O3: (M+H) 486; found 386.1 (M-Boc+1).
Reaction SMILES: [OH:1]O.[C:3]([NH:8][C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH:22][C:23]([NH:29][C:30]([O:32][CH3:33])=[O:31])=[N:24]C(OC)=O)(=[O:7])[CH2:4][CH2:5][CH3:6].[C:34]([O:37][C:38](=O)C)(=[O:36])C>>[C:3]([NH:8][C:9]1[CH:14]=[C:13]([S:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:1])[CH:12]=[CH:11][C:10]=1[N:22]([C:34]([O:37][CH3:38])=[O:36])[C:23]([NH:29][C:30]([O:32][CH3:33])=[O:31])=[NH:24])(=[O:7])[CH2:4][CH2:5][CH3:6]
Reactant: CCCC(=O)Nc1cc(Sc2ccccc2)ccc1NC(=NC(=O)OC)NC(=O)OC
Reactant: OO
Reactant: CC(=O)OC(C)=O
Product: CCCC(=O)Nc1cc(S(=O)c2ccccc2)ccc1N(C(=N)NC(=O)OC)C(=O)OC

Procedure:
2.3 ml of H2O2 (30%) are added dropwise to a solution of 8.9 g of N-(2-butyramido-4-phenylthiophenyl)-N',N"-bis-methoxycarbonyl-guanidine (m.p. 155° C, Example 4) in 1.4 1 of acetic acid anhydride. After 10 hours the batch is concentrated in vacuo, a mixture of ethyl acetate and petroleum ether added to the residue and filtered. 8.5 g of N-(2-butyramido-4-phenylsulphinylphenyl)-N,N'-bis-methoxycarbonyl-guanidine are obtained with a m.p. of 186° C (decomp.), (redissolved from methanol/ethyl acetate). The mass spectrum shows a mol peak of 460.
Reaction SMILES: Cl[C:2]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:4][N:3]=1.[C:25]([C:27]1([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28]1)#[CH:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:2]([C:26]#[C:25][C:27]3([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:3][CH:4]=[C:5]([CH:16]=2)[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:19][CH:20]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: C#CC1(O)CCCC1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(C#CC2(O)CCCC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 112, using 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide and 1-ethynylcyclopentanol as starting materials to yield the product as colorless solid, MS (ISP) 439.1, 441.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:5]=1[C:16]1[C:17]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:18][CH:19]=[CH:20][CH:21]=1.C1COCC1.[OH-].[Na+].Cl>CO.O>[CH2:23]([O:22][C:17]1[C:16]([C:5]2[CH:6]=[C:7]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:8]([O:10][CH3:11])=[CH:9][C:4]=2[C:3]([OH:30])=[O:2])=[CH:21][CH:20]=[CH:19][N:18]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Temperature: 70 °C
Yield: 96.9 %

Procedure:
step 3—To a suspension of 66 (960 mg, 2.36 mmol) in MeOH (15 mL), H2O (10 mL), and THF (10 mL) was added NaOH (1.00 g, 23.6 mmol). The reaction mixture was heated at 70° C. overnight and gradually became homogeneous. The mixture was cooled to 0° C., acidified to pH 3 with 1.0 M aq HCl and thrice extracted with EtOAc. The combined extracts were dried (MgSO4), filtered and concentrated under reduced pressure to afford 895 mg (97%) of 2-(2-benzyloxypyridin-3-yl)-4-tert-butyl-5-methoxybenzoic acid (68) as a beige solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:15][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)cc1C#N
Solvent: Cc1ccccc1
Product: COc1ccc(CCl)cc1C#N
Yield: 89.9 %

Procedure:
To a solution of 5-hydroxymethyl-2-methoxy-benzonitrile (500 mg, 3.064 mmol) in toluene (10 mL) cooled to 0° C. was added thionyl chloride (338 μL, 4.596 mmol). The reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated in vacuo to afford 5-chloromethyl-2-methoxy-benzonitrile as a white solid (500 mg, 90%). The product was used without firther purification.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:19])[NH:6][C:7]1[CH:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1.[CH:22]([C:25]1[N:29]2[CH:30]=[C:31]([O:34][C@@H:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@@H:38]([NH2:45])[CH2:37][CH2:36]3)[CH:32]=[CH:33][C:28]2=[N:27][N:26]=1)([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([C:25]1[N:29]2[CH:30]=[C:31]([O:34][C@@H:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@@H:38]([NH:45][C:5]([NH:6][C:7]4[CH:8]=[N:9][N:10]([C:12]5[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=5)[CH:11]=4)=[O:19])[CH2:37][CH2:36]3)[CH:32]=[CH:33][C:28]2=[N:27][N:26]=1)([CH3:24])[CH3:23]
Reactant: Cc1ccc(-n2cc(NC(=O)OCC(Cl)(Cl)Cl)cn2)cc1
Reactant: CC(C)c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2cc(NC(=O)N[C@H]3CC[C@H](Oc4ccc5nnc(C(C)C)n5c4)c4ccccc43)cn2)cc1
Yield: 77.9 %

Procedure:
A solution of Intermediate 6c (65.0 mg, 0.19 mmol), Intermediate 5c (50.0 mg, 0.155 mmol), and DIPEA (0.127 mL, 0.8 mmol) in DMF (1 mL) was heated at 110° C. for 75 min and 50° C. for 64 h. After cooling, the mixture was concentrated to dryness and the residue purified by FCC, eluting with 0-10% MeOH in DCM, to give the impure product (63 mg). Further purification by HPLC (Method 6) gave the title compound as a white solid (45 mg, 56%). LCMS (Method 5): Rt 4.06 min, m/z 522.1 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.36-1.41 (6H, m), 1.76-1.85 (1H, m), 1.98-2.08 (1H, m), 2.13-2.28 (2H, m), 2.33 (3H, s), 3.59 (1H, quintet, J 6.8), 4.96-5.03 (1H, m), 5.62 (1H, t, J 4.6), 6.74 (1H, d, J 8.5), 7.24 (1H, dd, J 9.9, 2.1), 7.26-7.46 (6H, m), 7.62-7.66 (2H, m), 7.68 (1H, s), 7.70 (1H, dd, J 9.9, 0.8), 8.24 (1H, br d), 8.26 (1H, s), 8.31 (1H, s).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH2:14])[CH3:10].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([NH:14][CH2:13][CH:12]([O:15][CH2:16][CH3:17])[O:11][CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CN)OCC
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(CNCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Benzaldehyde (1.27 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.75 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (816 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH:7]2[C:12]1[C:20]([OH:21])=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1.[CH2:22]=[O:23].[OH-].[Na+].Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([C:12]1[C:20]([OH:21])=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)[CH2:22][OH:23]
Reactant: C=O
Reactant: O=C1Nc2c(Br)cccc2C1c1cc2c(cc1O)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1Nc2c(Br)cccc2C1(CO)c1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 52.7 %

Procedure:
To a mixture of 7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (8.40 g, 24.1 mmol), para-formaldehyde (2.88 g, 96.0 mmol) and water (80 mL) was added sodium hydroxide (3.84 g, 96.0 mmol) at 0° C. The dark green solution was stirred at 0° C. for 4 h. The mixture was acidified with 3 N hydrochloride to pH 4 and extracted with ethyl acetate (3×100 mL). The combined ethyl acetate solution was washed with 25% ammonium chloride solution (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue was treated with toluene (300 mL) to give an off white precipitate. The precipitate was filtered and dried under reduced pressure to give 7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (4.80 g, 53%): 1H NMR (300 MHz, DMSO-d6) δ10.48 (s, 1H), 9.16 (s, 1H), 7.27 (dd, J=8.0, 1.0 Hz, 1H), 7.01 (s, 1H), 6.87-6.74 (m, 2H), 6.22 (s, 1H), 5.91 (s, 2H), 5.03 (br, 1H), 4.12 (d, J=10.0 Hz, 1H), 3.85 (d, J=10.0 Hz, 1H); MS (ES−) m/z 376 (M−1), 378 (M−1).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]C(C)(C)C.[Cl:32]N1C(=O)CCC1=O>C1COCC1.CCOC(C)=O>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([Cl:32])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(Cl)o1
Temperature: -78 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole (116 mg, 0.310 mmol) was dissolved in anhydrous THF (5 mL), cooled to −78° C. and t-BuLi (1.7 M in pentane, 1.3 equiv) was added dropwise under Ar. The reaction mixture was stirred for 2 h at −40° C., cooled to −78° C. and N-chlorosuccinimide (1.5 equiv) in THF (3 mL) was added dropwise. The reaction mixture was warmed to room temperature, diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude aryl chloride, which was purified by flash chromatography (0-2% EtOAc/hexanes) to afford the title compound as a clear oil (73 mg, 57%): 1H NMR (CDCl3, 600 MHz) 7.29-7.26 (m, 2H), 7.18-7.17 (m, 3H), 6.82 (s, 1H), 4.71 (t, 1H, J=7.2 Hz), 2.60 (t, 2H, J=7.8 Hz), 1.88-1.80 (m, 2H), 1.62-1.60 (m, 2H), 1.43-1.35 (m, 6H), 0.89 (s, 9H), 0.09 (s, 3H), −0.01 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 165.6, 143.6, 136.9, 129.3, 129.1, 126.5, 122.9, 69.5, 37.0, 36.8, 32.3, 29.9, 29.9, 26.6, 19.1, −4.2, −4.3.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[NH2:8][C:9]1[C:10]([C:17]([NH:19][CH2:20][C@@H:21]([N+:25]([CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=2)([CH3:27])[CH3:26])[CH2:22][CH2:23][CH3:24])=[O:18])=[N:11][C:12]([Cl:16])=[C:13]([NH2:15])[N:14]=1.B(Br)(Br)Br>C(Cl)Cl.CCCCCCC>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[NH2:8][C:9]1[C:10]([C:17]([NH:19][CH2:20][C@@H:21]([N+:25]([CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)([CH3:27])[CH3:26])[CH2:22][CH2:23][CH3:24])=[O:18])=[N:11][C:12]([Cl:16])=[C:13]([NH2:15])[N:14]=1
Reactant: CCC[C@@H](CNC(=O)c1nc(Cl)c(N)nc1N)[N+](C)(C)CCCc1ccc(OC)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])C(F)(F)F
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCC[C@@H](CNC(=O)c1nc(Cl)c(N)nc1N)[N+](C)(C)CCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ((S)-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-butyl)-[3-(4-methoxy-phenyl)-propyl]-dimethyl-ammonium trifluoroacetate (Example 120) (313 mg, 0.556 mmol) in DCM (100 mL) is added BBr3 (3.34 mL of a 1M solution in heptane, 3.34 mmol). The reaction mixture is stirred at RT overnight. The reaction mixture is quenched cautiously by the addition of water then the organic solvents are removed in vacuo. Purification by reverse phase column chromatography (Isolute™ C18, 0-50% acetonitrile in water with 0.1% TFA) affords the title compound. M+ 435. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (1H, t), 7.13 (2H, br), 6.89 (2H, d), 6.64 (2H, d), 5.29 (3H, br), 3.79-3.68 (1H, m), 3.57-3.43 (3H, m), 3.37-3.25 (1H, m), 3.04 (3H, s), 3.01 (3H, s), 2.41-2.30 (2H, m), 1.95-1.73 (3H, m), 1.64-1.35 (3H, m), 0.92 (3H, t).