Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:30][CH2:29][CH2:28][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([NH:19][C@H:20]([C:25]([NH2:27])=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]>C(O)C>[NH:1]1[CH2:30][CH2:29][CH2:28][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([NH:19][C@H:20]([C:25]([NH2:27])=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Solvent: CCO
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1)C(N)=O
Yield: 86.8 %

Procedure:
Starting from 3.722 g (7 mmol) of Boc-Pro-Trp-Met-NH2 (VI) and operating as in Step 2 of Example 1, 2.621 g (80% yield) of VII were obtained from absolute ethyl alcohol; [α]D20 =-23.0° (c=1 MeOH); RfC 0.41; E1.2 0.76.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:5][C:4]=1F)#[N:2].[NH2:25][CH3:26]>CC#N>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:5][C:4]=1[NH:25][CH3:26])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccc(C#N)c(F)c2)CC1
Reactant: CN
Solvent: CC#N
Product: CNc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Temperature: 120 °C

Procedure:
To a solution of tert-butyl 4-[2-(4-cyano-3-fluorophenyl)ethyl]piperazine-1-carboxylate (100 mg, 0.30 mmol) in CH3CN (10 mL) was added aqueous NH2CH3 (10 mL) in a sealed tube, and then heated to 120° C. overnight. The mixture was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified via prep-TLC to afford tert-butyl 4-{2-[4-cyano-3-(methylamino)phenyl]ethyl}piperazine-1-carboxylate.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][N:9]([C:16]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=3[Cl:25])[C:8]2=[O:26])=[C:4]([F:29])[CH:3]=1.[C:30]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O)(=[O:37])=[O:36])([CH3:33])([CH3:32])[CH3:31]>[Pd]>[CH2:12]([C:11]1[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][C:2]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[S:35](=[O:37])(=[O:36])[NH:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[CH:3][C:4]=2[F:29])[C:8](=[O:26])[N:9]([C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=2[Cl:25])[N:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(Br)cc1F
Agent: [Pd]
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 52 %

Procedure:
The palladium(0)-catalyzed coupling of 4-(4-bromo-2-fluorobenzyl)-5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) with 2-(N-t-butylsulfamoyl)phenylboronic acid was carried out according to the procedure of Example 76, Step F. Purification of the crude product by flash chromatography on silica gel (gradient elution with 6:1 to 4:1 hexane-EtOAc) provided a 52% yield of the title compound as a pale yellow, stiff foam, mp 124°-126° C.; homogeneous by TLC in 4:1 hexane-EtOAc); mass spectrum (FAB) m/e 616 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:39])=[N:4][O:5][C:6]=1[N:7]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20]([OH:32])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)(=[O:10])=[O:9].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:39])=[N:4][O:5][C:6]=1[N:7]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[C:20](=[O:32])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)CCc2ccc3c(c2)OCO3)sc2ncccc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(=O)CCc2ccc3c(c2)OCO3)sc2ncccc12
Yield: 73.3 %

Procedure:
The title compound was prepared by the method of Example 12(B) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[1-hydroxy-3-(3,4-methylenedioxyphenyl)propyl]thieno[2,3-b]pyridine-3-sulfonamide (0.51 g, 0.85 mmoles), CH2Cl2 (20 ml), celite, and PCC (0.27 g, 1.3 mmoles) except the reaction mixture was stirred 24 hours prior to filtering. Flash chromatography (40% EtOAc/hexanes) provided 0.37 g (74%) of the title compound as a yellow oil/solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])S[C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12].[Mn]([O-])(=O)(=O)=O.[K+].[S:21](=[O:25])(=O)(O)[OH:22].S(=O)(O)[O-].[Na+].N>O.C(#N)C>[NH2:10][C@H:7]1[C:8](=[O:9])[N:4]2[C@@H:5]1[S:21](=[O:25])(=[O:22])[C:2]([CH3:14])([CH3:1])[C@@H:3]2[C:11]([OH:13])=[O:12]
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: O=S(=O)(O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: N
Agent: O=S([O-])O
Solvent: O
Solvent: CC#N
Product: CC1(C)[C@H](C(=O)O)N2C(=O)[C@H](N)[C@H]2S1(=O)=O
Yield: 78 %

Procedure:
To a 0° C. solution of 6-aminopenicillanic acid (10.0 g, 0.046 mol) in a mixture of water (32 mL) and acetonitrile(48 mL) was added, dropwise, a solution containing potassium permanganate (9.6 g, 0.061 mol) and concentrated sulfuric acid (6 mL) in water (120 mL). At the end of the addition, a 50% aqueous sodium bisulfite solution was added, dropwise, to the reaction mixture until a clear solution was observed. Anhydrous ammonia gas was passed through the solution at 0° C. until pH 3, at which time the sulfone product precipitated. The solid was filtered, washed with acetone and dried in vacuo to obtain 9.0 g(78%) of the desired product.
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6](I)[CH:7]=1)=[O:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.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>[CH:1]([C:3]1[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=1)=[O:2]
Reactant: CCOC(=O)Cn1cc(I)cc1C=O
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(-c2ccccc2)cc1C=O
Temperature: 110 °C
Yield: 27.1 %

Procedure:
A solution of ethyl 2-(2-formyl-4-iodo-pyrrol-1-yl)acetate (3.0 g, 9.77 mmol) in dimethylformamide (25 mL) was purged with argon gas for 10 min. Bis-(triphenylphosphine)-palladium(II) chloride (0.48 g, 0.68 mmol) was added and the mixture was purged with argon gas for 5 min. Anhydrous potassium phosphate (6.18 g, 29.3 mmol) and phenylboronic acid (1.43 g, 11.7 mmol) were added successively and the reaction mixture purged with argon gas for 10 min, then heated to 110° C. and maintained at that temperature for 4 h. The resulting mixture was allowed to cool to ambient temperature and diethyl ether added. The reaction mixture was filtered, the filtrate being washed with water and the separated aqueous phase being further extracted with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude product. Purification by column chromatography over silica gel (100-200 mesh) using 8% ethyl acetate in petroleum ether as eluent afforded ethyl 2-(2-formyl-4-phenyl-pyrrol-1-yl)acetate (680 mg, 27%).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][O:7][C:8]=1[CH3:9].C([Mg]Cl)(C)C.[Cl-].[NH4+]>C1COCC1>[C:3]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][O:7][C:8]=1[CH3:9])#[CH:2]
Reactant: Cc1onc(-c2ccccc2)c1C=C(Br)Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#Cc1c(-c2ccccc2)noc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a stirred solution of 4-(2,2-dibromo-vinyl)-5-methyl-3-phenyl-isoxazole (1.0 g, 2.92 mmol) in THF (6 mL) was added dropwise isopropylmagnesium chloride solution (2M in THF, 2.92 mL, 5.84 mmol) and the resulting solution stirred under argon for 1 h at 0° C. Saturated aqueous ammonium chloride (15 mL) was added and the resulting mixture extracted with ethyl acetate (3×25 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, heptane) afforded the title compound (486 mg, 91%) which was obtained as a yellow oil. MS: m/e=184.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:14]>CN(C)C=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:1][C:13]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[O:14])=[CH:3][C:4]=1[CH3:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(N)cc1C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)n2ccnc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To a mixture of methyl 4-amino-2-methylbenzoate (208.9 mg, 1.230 mmol) in N,N-dimethyl formamide (5 mL) was added 1,1′-carbonyldiimidazole (Aldrich, 215 mg, 1.29 mmol). After it was stirred at rt overnight under an argon atmosphere, the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 4-[(Imidazole-1-carbonyl)-amino]-2-methyl-benzoic acid methyl ester (342.0 mg) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=O)=O)=[CH:4][CH:3]=1.[S:20]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>C(O)(=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[N:28]([C:27]3[CH:29]=[CH:30][C:24]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:25][CH:26]=3)[CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=CC(CC(=O)c1ccc(F)cc1)c1ccccc1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(-n2cc(-c3ccccc3)cc2-c2ccc(F)cc2)cc1
Yield: 71.3 %

Procedure:
0.32 g (1.25 mmol) of 3-(4-fluorobenzoyl)-2-phenylpropionaldehyde [prepared as described in step (i) above] and 0.26 g (1.5 mmol) of 4-sulfamoylaniline were dissolved in 20 ml of acetic acid, and the mixture was heated under reflux for 4 hours. The solvent was then removed by distillation under reduced pressure and water was added to the residue, which was then extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was applied to a silica gel chromatography column and eluted with a 3:2 by volume mixture of hexane and ethyl acetate, to give 0.35 g (yield 60%) of the title compound as a slightly yellow powder, melting at 192-194° C.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][SiH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]#[N:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1.[C:21]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[OH:33])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([N:16]=[N:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][SiH2:4][CH:3]=[C:2]([CH3:20])[CH3:1])=[CH:10][C:11]=2[N+:17]([O-:19])=[O:18])[C:26]=1[OH:33])([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Reactant: CC(C)=C[SiH2]CCCOc1ccc([N+]#N)c([N+](=O)[O-])c1
Product: COc1cc(N=Nc2ccc(OCCC[SiH2]C=C(C)C)cc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1

Procedure:
Para-aminophenol is acetylated by reaction with acetic anhydride to form 4-acetoxyacetanilide, which is then nitrated to form 4-acetoxy-2-nitroacetanilide (V). V is then reacted with 3-chloropropyldimethylvinylsilane to form 4-(3'-dimethylvinylsilylpropoxy)-2-nitroacetanilide (VI). VI is hydrolyzed to form VII, which is then reacted with nitrous acid to form a 4-(3'-dimethylvinylsilylpropoxy)-2-nitrobenzenediazonium ion (VIII). The diazonium ion VIII is then reacted with 2-t-butyl-4-methoxyphenol to form 2-t-butyl-6-[4'-(3"-dimethylvinylsilylpropoxy)-2'-nitrophenylazo]-4-methoxyphenol (IX). The azo compound IX is then reacted with glucose and base, and then with zinc to form 2-(3'-t-butyl-2'-hydroxy-5'-methoxyphenyl)-5-(3"-dimethyl-vinylsilylpropoxy)benezotriazole (X).
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.C([Li])(C)(C)C.CN(C)[CH:27]=[O:28]>O1CCCC1>[CH:27]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:28]
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(C=O)cc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
To a slurry of potassium hydride (20% suspension in mineral oil, 4.30 g, 21.50 mmol) in 80 mL of anhydrous tetrahydrofuran at 0° C. was slowly added dropwise 5-bromo-3-(1-methylpiperidin-4-yl)-1H-indole (6.0 g, 20.5 mmol) in 80 mL of anhydrous tetrahydrofuran. After stirring at 0° C. for 30 minutes, the mixture was cooled to −78° C., and tert-butyl lithium (1.7 M solution in pentane, 45.0 mmol, 26.5 mL) was added dropwise. After 15 minutes, a solution of anhydrous N,N-dimethylformamide (30.7 mmol, 2.4 mL) in 10 mL of anhydrous tetrahydrofuran was added dropwise. The stirred mixture was allowed to warm to room temperature, and was quenched with a 5N aqueous sodium hydroxide solution. The aqueous phase was extracted with diethyl ether, and the ether extracts were separated, washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel (flash) chromatography (dichloromethane:methanol 9.5:0.5) to give 2.26 g (45%) of the title product as an oily solid. MS(FD) m/e=242 (M+). EA calculated for C15SH18N2O. ½ H2O: C, 71.69; H, 7.21; N, 11.14. Found: C, 71.38; H, 6.87; N, 11.06.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[N+:18]([O-])=O.O.O.Cl[Sn]Cl>CCO>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[NH2:18]
Reactant: COC(=O)c1ccccc1Sc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccccc1Sc1ccc(Cl)cc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
To a mixture of 2-(4-chloro-2-nitro-phenylsulfanyl)-benzoic acid methyl ester (189JO09) (232 mg, 0.72 mmol) in EtOH (5 mL) was added SnCl2.2H2O (812 mg, 3.6 mmol) and the resulting mixture was stirred at 80° C. for 2 h and then concentrated. The residue was treated with ice, and then Na2CO3 was added until a pH of 10 was reached. EtOAc was added and the slurry was filtered through celite. The EtOAc-phase was washed with water and brine, dried (Na2SO4) and concentrated to give 149 mg (70%) of the title compound (189JO11). 1H NMR (CDCl3) δ 8.02 (dd, 1 H, J=1.6, 7.8 Hz), 7.39 (d, 1 H, J=8:2 Hz), 7.29 (m, 1 H), 7.15 (dt, 1 H, J=1.2, 7.8 Hz), 6.87 (d, 1 H, J=2.2 Hz), 6.80 (dd, 1 H, J=2.2, 8.2 Hz), 6.76 (dd, 1 H, J=1.2, 8.0 Hz), 3.96 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH:14]=[C:15]([F:17])[CH:16]=1>CO.[Pd]>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][NH:18][C:13]1[CH:12]=[C:11]([C:3]2[C:2]([NH2:1])=[C:7]([NH2:8])[CH:6]=[N:5][CH:4]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: CN(C)CCNc1cc(F)cc(-c2cncc([N+](=O)[O-])c2N)c1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCNc1cc(F)cc(-c2cncc(N)c2N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
To a solution of N1-(3-(4-amino-5-nitropyridin-3-yl)-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine (LXXVII) (2.1 g, 6.58 mmol) in MeOH (40 mL) was added 10% Pd/C (300 mg, 15% by wt). The solution was purged with hydrogen and stirred for 4 h at room temperature under hydrogen. The suspension was filtered through Celite® and concentrated under vacuum to produce 5-(3-(2-(dimethylamino)ethylamino)-5-fluorophenyl)pyridine-3,4-diamine (LXXVIII) as a brown solid (1.90 g, 6.57 mmol, 99.8% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.20 (s, 6H), 2.46 (t, J=7 Hz, 2H), 3.12 (q, J=6 Hz, 2H), 4.79 (s, 2H), 5.21 (s, 2H), 5.91 (t, J=5 Hz, 1H), 6.28 (dd, J=9 Hz, J=1 Hz, 1H), 6.36 (t, J=2 Hz, 1H), 6.37-6.42 (m, 1H), 7.46 (s, 1H), 7.64 (s, 1H); ESIMS found C15H20FN5 m/z 290.1 (M+H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH2:27][CH:28]=O)[CH3:26])[CH:20]=1)[CH3:18]>C1CCCCC1>[CH:17]([C:19]1[CH:20]=[C:21]([CH:25]([CH3:26])[CH2:27][CH:28]2[O:4][CH2:1][CH2:2][O:3]2)[CH:22]=[CH:23][CH:24]=1)([CH3:18])[CH3:16]
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC(C)c1cccc(C(C)CC2OCCO2)c1
Temperature: 25 °C
Yield: 97 %

Procedure:
Ethylene glycol (18 mL, 0.32 mol, 1.2 eq), paratoluene sulfonic acid (400 mg, 1% w/w) and cyclohexane (50 mL) were charged into a 1 L three-necked round-bottom flask, equipped with a dean and stark, a reflux condenser and a mechanical stirrer. Florhydral™ 3-(3-isopropylphenyl)butanal, 49.3 g, 0.26 mol) was added dropwise at ambient temperature. The stirred mixture was then heated for 3 h at reflux. The reaction mixture was cooled at ambient temperature and washed water (2×100 mL), dried over magnesium sulphate and concentrated. The resulting crude product was distilled with a Vigreux column (7.2 mBar, 146° C.), to give 2-[2-(3-isopropylphenyl)propyl]-1,3-dioxolane (239 g, gc purity>98%; yield 97%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1)=[O:4].[C:11]([O:15][C:16]([NH:18][C@@H:19]([C@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:20](O)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:20](=[O:21])[C@@H:19]([NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[C@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[S:8][CH:9]=1)=[O:4]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)c1csc(N)n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)c2ccccc2)n1
Yield: 42.8 %

Procedure:
2-Amino-thiazole-4-carboxylic acid methyl ester (0.57 g, 3.62 mmol) and (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid (Acros) (1.01 g, 3.62 mmol), 1-hydroxybenzotriazole and (0.59 g, 4.34 mmol) and O-benzeotrazol-1-yl-N,N,N′,N′-tetramethyluroniumhexaflurorophosphate (1.65 g, 4.34 mmol) in N,N-dimethylformamide (8 mL) were stirred at ambient temperature for 24 hours. The mixture was diluted with ethyl acetate, washed with water, brine and dried (magnesium sulfate). Evaporation of the solvents and chromatography of the residue over silica gel gradient eluted with 0.2-1.5% methanol in dichloromethane gave 2-((2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid methyl ester (0.65 g, 43%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1

Procedure:
Methyl ester 6.1 (53 mg) was stirred with 1N LiOH (2 ml) in 5 ml of MeOH/THF (4:1) over 18 h, concentrated, and partitioned between Et2O and H2O. The organic phase was extracted with 0.1 N NaOH (2×), and the combined aqueous extracts were acidified with conc. HCl and extracted with EtOAc (3×). The organic extracts were washed with H2O, brine, and dried (Na2SO4). The residue after concentration was triturated with hexanes/Et2O (10:1) to afford acid 6.2, 39 mg (100%). HRMS (ESI) calc'd for C25H29N2O3 405.2100, found 405.2198 (MH+); MS (ESI); 1H NMR (300 MHz, CDCl3) δ 7.48–7.34 (m, 5H), 7.27 (d, J=7.0, 2H), 7.06 (d, J=8.7, 2H), 6.01 (s, 1H), 5.13 (s, 2H), 4.06–3.98 (m, 1H), 3.02–2.97 (m, 2H), 2.85–2.81 (m, 2H), 1.91–1.83 (m, 6H), 1.26 (br s, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[C:17]([CH2:27][CH3:28])=[C:18]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29](=O)[CH3:30].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClC(Cl)C.C([O-])(O)=O.[Na+]>ClCCCl.O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:29][CH3:30])[C:16]2[C:17]([CH2:27][CH3:28])=[C:18]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1c(NC2CCC(NC(=O)OC(C)(C)C)CC2)cc(Cl)cc1C(=O)OC
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CCc1c(C(=O)OC)cc(Cl)cc1N(CC)C1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 0.83 h
Yield: 75.8 %

Procedure:
To a stirred solution of methyl 3-[(4-{[(tert-butoxy)carbonyl]amino}cyclohexyl)amino]-5-chloro-2-ethylbenzoate (200 mg, 0.49 mmol) in dry 1,2-dichloroethane (5.0 ml), was added acetaldehyde (54 μl, 1.0 mmol), followed by acetic acid (167 μl, 2.9 mmol). The reaction mixture was stirred for 50 minutes, sodium triacetoxyborohydride (309 mg, 1.5 mmol) was added over 2 hours and the reaction was stirred for 20 hours. The reaction mixture was treated with acetaldehyde (54 μl, 1.0 mmol) stirred for 1 hour and sodium triacetoxyborohydride (309 mg, 1.5 mmol) was added portionwise over 2 hours. The reaction mixture was stirred for a further 22 hours and then treated with acetaldehyde (136 μl, 2.4 mmol) and stirred for 1 hour, followed by sodium triacetoxyborohydride (516 mg, 2.4 mmol) over 1.5 hours and stirred for 22 hours. The reaction mixture was treated with acetaldehyde (109 μl, 2.0 mmol) and stirred for 1.5 hours before sodium triacetoxyborohydride (413 mg, 2.0 mmol) was added over 2 hours, along with dichloroethane (5.0 ml) to aid stirring. The reaction mixture was stirred for 19 hours before the addition of acetaldehyde (82 μl, 1.5 mmol), stirred for 1.5 hours, followed by sodium triacetoxyborohydride (309 mg, 1.5 mmol) over 45 minutes. The reaction mixture was stirred for a further 70 hours before being diluted with water (20 ml) and the pH was adjusted to 8 by the gradual addition of solid NaHCO3 (2.53 g). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×20 ml). The combined organic phases were washed with brine (60 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by flash column chromatography (10 g SNAP cartridge, Isolera, 0-30% EtOAc/Heptanes) to give the title compound (163 mg, 73%) as a yellow oil and a mixture of cis/trans-isomers. LC-MS 100%, 5.83 min (7 minute LC-MS method), m/z=439.2, 441.2; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.45-7.55 (m, 1H) 7.22 (dd, J=4.33, 2.13 Hz, 1H) 4.25-4.67 (m, 1H) 3.90 (d, J=2.21 Hz, 3H) 3.29-3.76 (m, 1H) 2.95-3.11 (m, 4H) 2.58-2.96 (m, 1H) 1.62-2.03 (m, 4H) 1.38-1.53 (m, 11H) 1.01-1.14 (m, 4H) 0.81-0.94 (m, 4H).