Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:37].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[NH2:37][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[C:6]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCCCC(N)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3cccnc3c2n1CCCCCC(N)=O
Reaction time: 1 h

Procedure:
A modification of the method described in Part F of Example 53 was used to treat 6-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)hexanamide (1.20 g, 3.7 mmol) with mCPBA (2.47 g of 70-77% purity) followed by ammonium hydroxide (4 mL), and p-toluenesulfonyl chloride (0.70 g). After the amination reaction was stirred for one hour, a precipitate was present and was isolated by filtration and washed with chloroform and water. The precipitate was ground up and dried for three days at 70° C. and then overnight at 95° C. to provide 0.46 g of 6-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)hexanamide as a white solid, mp 216.5-217.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1.[NH4+].[Cl-]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)=[CH:3][CH:4]=1
Reactant: O=C1CCC1
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A flame dried flask under N2 was charged with 1,4-dibromobenzene (7.52 g, 31.9 mmol) and anhydrous THF (50 mL). The reaction mixture was cooled to −78° C. and 2.5 M n-BuLi in hexanes (12.8 mL, 32 mmol) was added keeping the temperature below −60° C. The reaction mixture was stirred-at −78° C. for 30 min and then cyclobutanone (2 mL, 26.8 mmol) was added slowly keeping the temp below −60° C. After one hour, the reaction was poured into a saturated NH4Cl solution (40 mL). The salts were filtered through Celite™ and washed with EtOAc (2×20 mL). The layers were separated and the aq. phase was extracted with additional EtOAc (20 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to a pale yellow oil (5.51 g). The material could be used without further purification. 13C NMR (400 MHz, CDCl3) d 145.5, 131.7, 127.1, 121.3, 76.8, 37.2, 13.2; MS (AP/Cl) 209.0, 211.0 (M+H—H2O)+.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.O[CH2:14][C:15]([CH2:23][OH:24])([CH2:20][CH:21]=[CH2:22])[C:16]([O:18][CH3:19])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CN(C([S-])=S)C.CN(C([S-])=S)C.[Zn+2]>[CH2:20]([C:15]1([C:16]([O:18][CH3:19])=[O:17])[CH2:14][O:24][CH2:23]1)[CH:21]=[CH2:22]
Reactant: C=CCC(CO)(CO)C(=O)OC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CN(C)C(=S)[S-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: C=CCC1(C(=O)OC)COC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
DEAD (1.2 eq., 2.64 g) was added to a solution of methyl 2,2-bis(hydroxymethyl)pent-4-enoate (1 eq., 2.2 g), Ziram® (1.2 eq., 4.64 g) and triphenylphosphine (1.2 eq., 3.98 g) in PhMe (32 ml). The mixture was stirred at room temperature for 2 days and filtered. The filter cake was washed with 3×DCM. The filtrate was concentrated at 50 torr and 40° C. Silica gel chromatography using straight DCM yields the title compound as colorless oil (1.27 g, 64%).
Reaction SMILES: [N+]([CH:4]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:7][N:6]([C:17]2[CH:22]=[CH:21]C=CN=2)[CH2:5]1)([O-])=O>C(Cl)Cl.[Pd]>[C:13]([O:12][C:10]([N:9]1[CH2:4][CH2:5][N:6]([C:17]2[CH:22]=[CH:21][N:6]=[CH:5][C:4]=2[NH2:9])[CH2:7][CH2:8]1)=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccn2)CC1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2N)CC1
Reaction time: 8 h
Yield: 197.6 %

Procedure:
Step 2) 3-Nitro-4-boc piperizinyl pyridine 3 (37 g, 0.12 mol) was dissolved in DCM (500 mL). The resulting solution was subjected Pd/C (10%, 14.8 g) and was kept under hydrogen atmosphere at room temperature. Overnight stirring and monitored the reaction progress until the reaction is complete. The reaction solution was filtered through celite, washed with DCM/MeOH and concentrated to give the product, 4-(3-Amino-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester 4 (33 g) in the yield of around 99%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Mg]Cl)(C)C.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[N:20]=[C:21]([NH:30][C:31]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)=[O:32])[S:22][C:23]=1[C:24](=[O:29])N(OC)C.[Cl-].[NH4+]>C1COCC1>[Br:8][C:4]1[N:3]=[C:2]([C:24]([C:23]2[S:22][C:21]([NH:30][C:31]([C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)=[O:32])=[N:20][C:19]=2[C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)=[O:29])[CH:7]=[CH:6][CH:5]=1
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Reactant: Brc1cccc(Br)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)c2cccc(Br)n2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
A THF solution (10 mL) of 2,6-dibromopyridine (4.97 g, 21.0 mmol) was added to a 2.0 mol/L solution of isopropylmagnesium chloride in THF (9.56 mL, 10.1 mmol) at 0° C., followed by stirring for 3 hours at room temperature. A THF solution (5 mL) of Compound 98 (1.37 g, 3.82 mmol) was added dropwise to the reaction mixture, followed by stirring for 3 hours at room temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=9:1) to afford the entitled Compound 300 (520 mg, 31%).
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31]C)[CH:27]=2)[CH2:22]1)[C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].C(N(C1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)CCC1C=CC=CC=1)C>>[CH2:1]([N:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=2[CH2:22]1)[CH3:2]
Reactant: CCN(C(=O)Cc1ccccc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCN(CCc1ccccc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Product: CCN(CCc1ccccc1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1

Procedure:
Synthesized from N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-2-phenylacetamide according to an analogous synthetic method to Example 337 described below, ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]phenethylamine (137 mg) was used according to an analogous synthetic method to Example 111 described below to provide the title compound (77 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[C:18]1[N:23]=[N:22][C:21]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[CH:20][CH:19]=1.Br[C:37]1[N:38]=[CH:39][N:40]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:41]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:37]2[N:38]=[CH:39][N:40]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:41]=2)[CH:6]=[CH:5][C:4]=1[C:18]1[N:23]=[N:22][C:21]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:31])([CH3:32])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[CH:20][CH:19]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Reactant: C[Si](C)(C)CCOCn1cnc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2cn(COCC[Si](C)(C)C)cn2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 150 °C
Yield: 90.8 %

Procedure:
To a microwave vial was added 6-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 9-3, 50 mg, 0.10 mmol), 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (57.7 mg, 0.21 mmol), Na2CO3 (22 mg, 0.21 mmol), and Pd(PPh3)2Cl2 (7.3 mg, 0.01 mmol), followed by DME (1 mL)/EtOH 0.25 mL)/(H2O (0.25 mL). The vial was purged with N2 for 10 minutes and the reaction mixture was heated at 150° C. in a microwave reactor for 20 minutes. The reaction mixture was filtered through celite and the filter cake was washed with EtOAc. The filtrate was concentrated in vacuo to give the crude product which was purified by silica gel chromotography (5%-15% MeOH/DCM) to afford 6-(2-methoxy-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (50 mg). MS: 551.6 [M+H+]).
Reaction SMILES: [C:1]1([C@@H:7]([CH3:12])[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>CO.C1(C)C=CC=CC=1.[Rh]>[CH:1]1([C@@H:7]([CH3:12])[CH2:8][C:9]([Cl:16])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@H](CC(=O)O)c1ccccc1
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](CC(=O)Cl)C1CCCCC1

Procedure:
(S)-3-phenylbutyric acid was hydrogenated using Rh/C in MeOH at 60 psi and 60° C. for 3.2 hours. The reduced product was then converted to the title acid chloride by treating with 1 eq of oxalyl chloride, and a catalytic amount of DMF, in toluene for 90 minutes, followed by evaporation of the volatile materials.
Reaction SMILES: C(O[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=[O:22].[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1.[Rh]>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]([OH:22])[CH2:5][CH3:4])=[CH:8][CH:9]=1
Reactant: O=S(=O)([O-])[O-]
Reactant: CCOC(=O)C=Cc1ccc(F)cc1
Agent: [Rh]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
This ester (6.52 g, 33.6 mmol) was dissolved in ethyl acetate (100 ml), and 5% rhodium/alumina (1.30 g) was added thereto followed by stirring under a hydrogen atmosphere for 8 hours at room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure, and then the residue was dissolved in anhydrous tetrahydrofuran (30 ml). This solution was added dropwise to a suspension of lithium aluminium hydride (126 g, 33.2 mmol) in anhydrous tetrahydrofuran (60 ml) in the ice bath. The reaction mixture was stirred for 30 minutes at the same temperature, and a saturated aqueous sodium sulfate solution was added thereto followed by stirring for 10 minutes at room temperature. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=5:1-1:1) to give 4-fluorophenylpropan-1-ol (4.86 g, 95% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[F:19])[CH:9]=1)[C:5]#[N:6].C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:18][C:13]1[C:12]([F:19])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[C:16]([Cl:17])=[CH:15][CH:14]=1
Reactant: Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Reaction time: 4 h
Yield: 78.7 %

Procedure:
3-Chloro-5-[(6-chloro-2-fluoro-3-methylphenyl)oxy]benzonitrile (1.8 g, 6.1 mmol) was dissolved in CCl4 (200 mL). NBS (1.2 g, 6.7 mmol) and AIBN (0.63 g, 3.8 mmol) were added and the reaction mixture was placed in oil bath at 85° C. and stirred for 4 h. The reaction was monitored by TLC and more AIBN and NBS were added as necessary. The reaction was cooled, filtered and the solid washed with CCl4. The solvent was evaporated. Purification was accomplished by column chromatography (hexane/EtOAc eluent) to afford the title compound (1.8 g, 79%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.81 (s, 1H), 7.49-7.59 (m, 3H), 7.47 (d, 1H), 4.73 (s, 2H). GC-MS, 372.9 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:27])=[CH:8][C:9](=[O:26])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][CH:4]=1.[O:28]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][CH:39]=O)=[CH:37][C:32]=2[O:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>O.C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:28]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][CH2:39][N:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[C:7]([CH3:27])=[CH:8][C:9]4=[O:26])[CH:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17]3)=[CH:37][C:32]=2[O:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)C1CNCCN1CCn1c(=O)cc(C)c2ccc(OC)cc21
Reactant: O=CCc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1CN(CCc2ccc3c(c2)OCCO3)CCN1CCn1c(=O)cc(C)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To 2.4 mL of dichloromethane solution containing 89 mg of ethyl 1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperazine-2-carboxylate and 94 mg of (2,3-dihydro-1,4-benzodioxin-6-yl)acetaldehyde, 24 μL of acetic acid was added and stirred at room temperature for 30 min. To the reaction mixture, 76 mg of sodium triacetoxyborohydride was added, and stirred at room temperature for 1 hour. To the reaction mixture, chloroform and water were added, and adjusted to pH 1 with 6 mol/L hydrochloric acid. The organic layer was separated, and adjusted to pH 13 by adding 5 mol/L aqueous sodium hydroxide solution to the aqueous layer, thereafter extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=50:1], to give 87 mg of ethyl 4-(2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl)-1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperazine-2-carboxylate as a colorless oil.
Reaction SMILES: [C-:1]#[N:2].C([Al+]CC)C.C(O)(C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:32])([CH3:31])[CH:20]=[N:21][S@@:22]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:23])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:32])([CH3:31])[CH:20]([NH:21][S:22]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:23])[C:1]#[N:2])=[CH:15][CH:14]=1
Reactant: [C-]#N
Reactant: Cc1ccc([S@@](=O)N=CC(C)(C)c2ccc(Cl)cc2)cc1
Agent: CC[Al+]CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1ccc(S(=O)NC(C#N)C(C)(C)c2ccc(Cl)cc2)cc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
The diethyl aluminum cyanide (43.5 mL of a 1.0M solution in toluene, 43.5 mmol) was added to isopropanol (28.9 mL, 377 mmol) and stirred at 10° C. for 15 minutes. This solution was cannulated into the (R)-4-methylbenzenesulfinic acid [2-(4-chlorophenyl)-2-methyl-propylidene]-amide (9.28 g, 29.0 mmol) as a solution in 290 mL of THF at −78° C. This solution was allowed to stir for 15 minutes at −78° C. then allowed to warm slowly to room temperature overnight. The solution was quenched with the addition of diluted NaHCO3 solution and extracted with ethyl acetate. The combined organic was washed with brine, separated, dried over Na2SO4, filtered, and concentrated in vacuo to afford the 4-methyl-benzenesulfinic acid [2-(4-chlorophenyl)-1-cyano-2-methyl-propyl]-amide as a colorless oil (9.55 g, 95% yield). The material was heated to 110° C. (reflux) in concentrated HCl solution over the weekend. The solution was cooled to room temperature, washed with ether, then concentrated in vacuo to give the (S)-2-amino-3-(4-chlorophenyl)-3-methyl-butyric acid hydrochloride salt a white solid (1.61 g, 21%). 1H NMR (DMSO-d6, 400 MHz) δ 8.19 (brs, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 7.13 (s, 3H), 4.15 (s, 1H), 1.42 (s, 3H), 1.40 (s, 3H). LCMS (APCI+) m/z 228 [M+H]+; Rt=1.81 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][Si](C(C)(C)C)(C)C)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26](=[O:55])[N:27]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:28]=[C:29]([NH:31][C:32]([C:34]2[CH:35]=[N:36][N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)[CH:38]=2)=[O:33])[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26](=[O:55])[N:27]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:53])([CH3:52])[CH3:54])[CH:28]=[C:29]([NH:31][C:32]([C:34]2[CH:35]=[N:36][N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)[CH:38]=2)=[O:33])[CH:30]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(O[Si](C)(C)C(C)(C)C)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(O)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Intermediate (11d), 5-(tert-butyl-dimethyl-silanyloxy)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]indole-1-carboxylic acid tert-butyl ester (1.55 g, 1.97 mmol) was stirred in tetrahydrofuran (40 mL) and cooled to 0° C. Tetrabutylammonium fluoride solution 1.0M in tetrahydrofuran (2.08 mL, 2.08 mmol) was added drop wise at 0° C., and then the reaction was allowed to attain ambient temperature, where it was stirred for a further 2 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (30 mL), aqueous 0.5N hydrochloric acid solution (30 mL), brine, dried (Na2SO4) and concentrated in vacuo. The resultant green foam was purified via trituration using diethyl ether, to afford the title compound as a pale yellow solid, 0.946 g, 71%.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:8]1[O:9][CH:10]=[C:11]([CH2:13][N:14]2[N:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[N:15]2)[N:12]=1)([CH3:7])[CH3:6].[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][O:4][C:5]([C:8]1[O:9][CH:10]=[C:11]([CH2:13][N:14]2[N:18]=[C:17]([NH2:19])[CH:16]=[N:15]2)[N:12]=1)([CH3:7])[CH3:6]
Reactant: COC(C)(C)c1nc(Cn2ncc([N+](=O)[O-])n2)co1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COC(C)(C)c1nc(Cn2ncc(N)n2)co1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-(2-methoxypropan-2-yl)-4-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)oxazole (33 mg, 0.12 mmol), iron powder (21 mg, 0.37 mmol) and NH4Cl (33 mg, 0.62 mmol) in a mixture of EtOH (0.4 mL) and water (0.2 mL) was stirred at 85° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (5 mL) was added followed by 1N NaOH (5 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (5×5 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 07: tR=0.51 min; [M]+=237.17.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18](N(C)OC)=[O:19])=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1.[Li]CCCC.CCCCCC>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:18]([C:15]2[CH:16]=[N:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[O:19])=[C:3]([F:10])[CH:4]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccc(Cl)nc1)c1cc(F)c(Br)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
A mixture of 1,4-dibromo-2,5-difluorobenzene (1.36 g) in anhydrous THF (20 ml) and 1.6M n-BuLi in hexane (3.43 ml) was stirred at −78° C. under nitrogen for 20 min. The reaction mixture was added to 6-chloro-N-methyl-N-(methyloxy)-3-pyridinecarboxamide (0.921 g) in THF (20 ml) and stirred at −78° C. The mixture was then stirred at −70° C. for 30 min allowed to warm to room temperature then cooled again to −70° C. and treated with 10% aqueous ammonium chloride. The reaction mixture was warmed to room temperature and partitioned between ethyl acetate and 10% aqueous ammonium chloride. The organic layer was separated using a hydrophobic filter tube and the solvent was removed under vacuum. The residue was purified using a silica SPE cartridge eluting with petroleum ether/ethyl acetate (9:1 to 1:3) to give impure title compound (0.548 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][CH:17]([OH:27])[CH:18]([NH2:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1>O>[NH2:26][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:17]([OH:27])[CH2:16][N:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CC(C)CN(CC(O)C(N)Cc1ccccc1)S(=O)(=O)c1ccc(N)cc1
Solvent: O
Product: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc(N)cc1
Temperature: 6 °C

Procedure:
The obtained solution was then cooled to 40±3° C. followed by the addition of water. Adjustment of the pH of the solution to around 9.5 with aqueous solution of sodium hydroxide gave crystals 4-Amino-N-(3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide. Additional water was added to this solution to adjust the concentration of 4-Amino-N-(3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide to 5.5-5.8 wt %, and then this solution was cooled to 6±4° C. The resulting crystals were filtered off and washed with a mixed solution composed of water and ethanol and then washed with water. The resulting wet crystals were subjected to vacuum drying to give the product of (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-amino-benzenesulfonamide. Yields were 75˜85% based on (1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[CH:13](=O)[C:14]([CH3:16])=[O:15]>O>[C:1]1([NH:7][N:8]=[CH:13][C:14](=[O:15])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)C=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C=NNc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a solution of phenylhydrazine (10.0 g, 92.5 mmol) in water (30 mL) was added acetic acid (8.8 mL) followed by the dropwise addition of pyruvaldehyde (16.7 g, 92.5 mmol) in water (400 mL) over a 15 minute period. The solution was stirred at room temperature overnight. The reaction was filtered and the resultant solid was washed with water (2×30 mL) to provide 2-oxopropanal phenylhydrazone as a yellow solid (15.2 g, 101%).