Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[N:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:9]=[C:8]([CH2:20][CH2:21][CH3:22])[C:7]=1[C:23]#[N:24])(=[O:3])[NH2:2].Cl.Cl.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][CH2:35][CH:36]([OH:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[CH2:30][CH2:29]1.C[O-].[Na+].CO>CN(C=O)C>[NH2:24][C:23]1[C:7]2[C:6](=[N:11][C:10]([N:28]3[CH2:33][CH2:32][CH:31]([NH:34][CH2:35][CH:36]([OH:45])[CH2:37][O:38][C:39]4[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=4)[CH2:30][CH2:29]3)=[CH:9][C:8]=2[CH2:20][CH2:21][CH3:22])[S:5][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: OC(CNC1CCNCC1)COc1ccncc1
Reactant: CCCc1cc(OS(=O)(=O)C(F)(F)F)nc(SCC(N)=O)c1C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCc1cc(N2CCC(NCC(O)COc3ccncc3)CC2)nc2sc(C(N)=O)c(N)c12
Temperature: 70 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
To a sealed tube was added trifluoro-methanesulfonic acid 6-carbamoylmethylsulfanyl-5-cyano-4-propyl-pyridin-2-yl ester (66.7 mg, 0.174 mmol) in 4 mL of dry DMF, followed by the addition of 1-(piperidin-4-ylamino)-3-(pyridin-4-yloxy)-propan-2-ol trihydrochloride salt (69 mg, 0.191 mmol) and N-N-diisopropylethylamine (180 mg, 1.39 mmol). The reaction mixture was stirred at 70° C. for 2 h. DMF was removed in vacuo. The residue was dissolved in 5 mL of MeOH, followed by the addition of sodium methoxide, 0.5 M solution in MeOH (1.74 mL, 0.86 mmol). The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was loaded onto a flash chromatography column. The column was eluted with 0–5% 2M NH3 in MeOH/CH2Cl2. The product fractions were collected, concentrated and dried under high vacuum pump to afford 24 mg (28.5%) of the title compound as a light brown solid product. (TLC: Rf=0.4, 5% 2M NH3 in MeOH/CH2Cl2, UV). ES+ 485.29 m/z (MH+)
Reaction SMILES: [CH:1]([C@H:3]([NH:8]C(=O)OC(C)(C)C)[CH2:4][CH2:5][S:6][CH3:7])=[O:2].S(=O)(O)[O-].[Na+].[C-]#N.[K+].[C:24]([O:27]CC)(=[O:26])C>O>[NH2:8][C@H:3]([CH2:4][CH2:5][S:6][CH3:7])[CH:1]([OH:2])[C:24]([OH:27])=[O:26]
Reactant: CSCC[C@H](C=O)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: O=S([O-])O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CSCC[C@@H](N)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of Example 1B (9.00 g, 38.5 mmol) and sodium bisulfite (3.80 g, 36.6 mmol) in water (200 mL) was stirred at 5° C. for 72 hours, warmed to ambient temperature, treated with a mixture of potassium cyanide (2.51 g, 38.6 mmol) in ethyl acetate (250 mL), and stirred for 4 hours. The separated ethyl acetate layer was washed sequentially with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in dioxane (75 mL) and 12M HCl (75 mL), heated to reflux for 16 hours, concentrated, dissolved in water (8 mL) and acetone (300 mL), adjusted to pH 5.5 with 1M NaOH, and filtered. The filter cake was dried under vacuum to provide the desired product (5.81 g). MS (ESI(+)Q1MS) m/e 180 (M+H)+, 202 (M+Na)+; MS (ESI(−)) m/e 178 (M−H)−; 1H NMR (300 MHz, D2O) δ 4.25 (d, 0.5H), 4.14 (d, 0.5H), 3.78 (m, 0.5H), 3.66 (m, 0.5H), 2.65 (m, 2H), 2.13 (s, 1.5H), 2.09 (s, 1.5H), 1.93 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11](I)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Br:17][C:18]1[CH:19]=[C:20]([C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH:14]=[C:13]([CH3:15])[N:12]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(I)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 4-(3,4-dichloro-phenyl)-2-iodo-6-methylpyridine (example A.52) (5.5 g, ca. 60% pure, ca. 9 mmol) and commercially available 3-bromo-benzene-boronic acid (1.82 g, 9.1 mmol) according to the general procedure IVb. Obtained as a white solid (1.3 g, 36%). MS (ISP) 391.9 [(M+H)+], 394.0 [(M+2+H)+], 396.0 [(M+4+H)+] and 398.0 [(M+6+H)+].
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[N:21]=1)([CH3:19])[CH2:9][O:10][C@@:11]([C:17]#[N:18])([CH3:16])[C:12]([F:15])([F:14])[F:13])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[N:21]=1)([CH3:19])[CH2:9][O:10][C@@:11]([CH3:16])([C:12]([F:13])([F:15])[F:14])[C:17]#[N:18]
Reactant: CC(C)(C)OC(=O)NC(C)(CO[C@](C)(C#N)C(F)(F)F)c1cccc(Br)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)(CO[C@](C)(C#N)C(F)(F)F)c1cccc(Br)n1

Procedure:
A solution of [(RS)-1-(6-bromo-pyridin-2-yl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-carbamic acid tert-butyl ester (0.456 g, 1.008 mmol) and TFA (1.554 ml, 2.299 g, 20.17 mmol) in DCM (5 ml) was stirred at rt for 30 min, concentrated and triturated with 7N NH3/MeOH at rt for 20 min and again concentrated to give the title compound that was used for the next step without further purification. HPLC RtH4=0.69, 0.73 min (diastereomers); ESIMS: 352, 354 [(M+H)+].
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[N:10][C:11]([N:12]3[CH2:18][CH:17]4[O:19][CH:14]([CH2:15][CH2:16]4)[CH2:13]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:29]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:29][C:5]1[C:6]2[C:7](=[N:8][C:9]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[N:10][C:11]=2[N:12]2[CH2:13][CH:14]3[O:19][CH:17]([CH2:16][CH2:15]3)[CH2:18]2)[N:3]([CH2:1][CH3:2])[N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(Br)c2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Yield: 29.3 %

Procedure:
To a solution of 1-ethyl-6-(4-nitrophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (7.9 g)(20.8 mmol) in DMF (140 mL) was added N-bromosuccinimide (18.5 g) and heated to 85 C for 24 hr. The reaction was cooled and poured into water (1.0 L) to precipitate tan solids. The solids were filtered off and washed with water. The crude solid was purified by silica gel chromatography (EtOAc/Hexanes) to give 2.8 g of a yellow solid. MS m/z=459.2 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[N:8]=2
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2cc(C(F)(F)F)ccn2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4cc(C(F)(F)F)ccn4)cc3)C2=N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
5-Chloro-3-(4-(4-(trifluoromethyl)pyridin-2-yloxy)phenyl)pyridin-2-amine (470 mg) was added to a mixture of NaH (60%, 257 mg) and 2-chloroethanesulfonyl chloride (628 mg) in THF (dry) (10 mL) at room temperature. The mixture was stirred at room temperature overnight and 80° C. for 3 hr. Water was added and the mixture was concentrated in vacuo. The residue was washed with IPE to give the title compound (502 mg) as a yellow solid. The solid was crystallized from CH3CN-IPE to give a pale yellow solid (1st crop impure, 2nd crop (254 mg)). The 1st crop was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (263 mg) as a white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[I:30]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[I:30])[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)OC[C@@H]1C[C@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1C[C@H](n2c(I)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 39.6 %

Procedure:
(±)(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 1.13 mmol) was dissolved in dry N,N-dimethylformamide (4 mL) and heated to 95°-105° C. N-Iodosuccinimide (534 mg, 2.3 mmol as 95%) was added in portions over 5.5 hours. Volatiles were removed in vacuo and the residue chromatographed on silica gel. Elution with 10% ethyl acetate-hexanes followed by solidification from ethanol-water gave (±)(1R*,2S*,3S*,5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2-iodo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate as a white powder (255 mg, 40%), m.p.152.5°-153° C.; 1H-NMR(DMSO-d6) δ: 8.32 and 7.94 (both s, 2,2 aromatic CH), 5.8-5.7 (m, 1, OCH), 5.4-5.3(m, 1, OCH), 5.2-5.0 (m, 1, NCH), 4.35-4.2 (m, 2, OCH2), 2.7-2.6 (m, 1, CH), 2.35-2.25 (m, 2, CH2), 2.11, 2.08, and 1.93 (all s, 3 each, 3 CH3); mass spectrum(CI) 569 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].[NH2:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:28][C:22]1([CH3:29])[CH2:21][CH:20]([NH:19][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:13]([OH:14])=[C:12]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:11]=2)[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC1(C)CC(NC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC(C)(C)N1

Procedure:
To a stirred solution of 25 grams (0.1 mole) of 3,5-di-t-butyl-4-hydroxybenzoic acid and 15.6 grams (0.1 mole) of 4-amino-2,2,6,6-tetramethylpiperidine in 100 milliliters of dry tetrahydrofuran was added dropwise a solution of 20.6 grams (0.1 mole) of dicyclohexylcarbodiimide in 75 milliliters of dry tetrahydrofuran. The mixture was stirred for several hours and the white solid (dicyclohexyl urea) was filtered off and discarded. Evaporation of the filtrate gave a white solid, which was recrystallized from 1:1 benzenehexane to give N-(2,2,6,6-tetramethyl-4-piperidinyl)-3,5-di-t-butyl-4-hydroxybenzamide; melting point 256°-258° C.
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:22]([OH:23])[C@@H:21]([CH2:24][O:25][C@H:26]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@@H:27]3[OH:28])[O:20][C@H:15]([O:16][CH2:17][CH2:18][NH2:19])[C@H:14]2[OH:37])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].O=C1CCC(=O)N1[O:45][C:46](=O)[CH2:47][CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]>CN(C=O)C>[C@H:1]1([O:12][C@H:13]2[C@H:22]([OH:23])[C@@H:21]([CH2:24][O:25][C@H:26]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@@H:27]3[OH:28])[O:20][C@H:15]([O:16][CH2:17][CH2:18][NH:19][C:46](=[O:45])[CH2:47][CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[O:52])[C@H:14]2[OH:37])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Reactant: O=C(CCCCC(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(CCCCC(=O)OCc1ccccc1)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-aminoethyl α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranoside (1.23 g, 2.247 mmol, WO 2010/088294 A1) in DMF (20 mL) at 0° C. was added benzyl 6-[(2,5-dioxopyrrolidin-1-yl)oxy]-6-oxohexanoate (1.02 g, 3.06 mmol) and TEA (0.5 mL, 3.59 mmol). After stirring at 0° C. for 1 hour, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse silica gel column (275 g), eluting with 0-40% AcCN in H2O to give the title compound. UPLC Method B: calculated for C33H51NO19 765.31, observed m/e=766.26 [M+1]; Rt=4.04 min. 1H NMR (D2O) δ 7.43-7.37 (5H, m), 5.14 (2H, s), 5.07-5.06 (1H, m), 4.82-4.81 (1H, m), 4.77-4.76 (1H, m), 4.06-4.01 (2H, m), 3.96-3.92 (2H, m), 3.87-3.81 (5H, m), 3.79-3.77 (1H, m), 3.74-3.67 (5H, m), 3.65-3.60 (4H, m), 3.53-3.49 (1H, m), 3.37-3.35 (2H, m), 2.43-2.40 (2H, m), 2.22-2.19 (2H, m), 1.62-1.52 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:25]([O-])=O)[N:9]=2)=[CH:4][CH:3]=1>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH2:25])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nc3cccc([N+](=O)[O-])c3nc2-c2ccc(C)cc2)cc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc3cccc(N)c3nc2-c2ccc(C)cc2)cc1

Procedure:
2.02 g of 2,3-di(4-methylphenyl)-5-nitroquinoxaline was dissolved in 30 g of dioxane, followed by purging with argon and adding 0.6 g of 5% Pd/C (hydrous). After purging with argon again, the system was purged with hydrogen for reaction at room temperature for 18 hours. After completion of the reaction, the system was filtered. The filtration residue was washed with acetone and then with dioxane and re-filtered. The solvent was removed from the resulting filtrate, followed by extracting a reaction product by use of a silica gel column.
Reaction SMILES: [Cl:1]CCN1CCOCC1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH2:33][CH:34]2[O:39][CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]2)[N:28]=[CH:27]3)[C:20](=[O:47])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.FC(F)(F)C(O)=O.Cl>C(Cl)Cl.C(OCC)(=O)C.CCOCC>[ClH:1].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH2:33][CH:34]2[O:39][CH2:38][CH2:37][NH:36][CH2:35]2)[N:28]=[CH:27]3)[C:20](=[O:47])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCOC(Cn2ncc3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc32)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CC2CNCCO2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
Following the procedure of Example 2, but substituting tert-butyl 2-(bromomethyl)morpholine-4-carboxylate for 4-(2-chloroethyl)morpholine, tert-butyl 2-((5-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1H-indazol-1-yl)methyl)morpholine-4-carboxylate (134 mg, 33%) was prepared as a white powder. A solution of this compound (134 mg, 0.26 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (148 mg, 1.3 mmol). After stirring at room temperature for 16 h, the reaction mixture was diluted with CH2Cl2 (50 mL) and washed with 1N NaOH (50 mL). The organics were dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH/NH4OH, 40:1:0.1 to 20:1.0.2) provided the free base. This was dissolved in ethyl acetate (0.3 mL) and treated with 1 equivalent of 1 M HCl in Et2O and the mixture was filtrated to provide the title compound (68.2 mg, 58%) as a yellow solid: melting point (mp) 221-223° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.18 (s, 1H), 7.75-7.70 (m, 2H), 7.62 (d, J=7.6 Hz, 1H), 7.49-7.40 (m, 4H), 7.39-7.35 (m, 2H), 6.11 (dd, J=7.6, 2.7 Hz, 1H), 5.99 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.64-4.60 (m, 2H), 4.20-4.15 (m, 1H), 3.93-3.88 (dd, J=12.6, 3.3 Hz, 1H), 3.68-3.60 (m, 1H), 3.36-3.32 (m, 1H), 3.15 (d, J=12.6 Hz, 1H), 2.96-2.84 (m, 2H); ESI MS m/z 417 [M+H]+.
Reaction SMILES: [I-].[Li+].CO[C:5]([C:7]1(C)[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:10]=2[NH:9][C:8]1=[O:30])=O>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]1[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:10]=2[NH:9][C:8](=[O:30])[CH:7]1[CH3:5]
Reactant: COC(=O)C1(C)C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccccc1OC
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccccc1C1Cc2cc(C(F)(F)F)ccc2NC(=O)C1C
Reaction time: 8.5 h
Yield: 100 %

Procedure:
Lithium iodide (5.26 g; 39.3 mmole) was added to 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(methoxyphenyl)-3-methyl-7-(trifluoromethyl)-2H-1-benzazepin-2-one (4.00 g; 9.82 mmole) in pyridine (40 ml) (five drops of water were added) and the mixture was refluxed with stirring for 8.5 hours. The solution was dissolved in ethyl acetate and washed with 1N hydrochloric acid (three times). The organic layer was dried (magnesium sulfate) and concentrated giving 3.43 g of the title compound as a solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:21][CH:22]=2)[C:13](F)=[N:14][CH:15]=1)(C(C)(C)C)(C)C.CO.C[O-].[Na+].C[N+]1([O-])CC[O:38][CH2:37]C1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(Cl)Cl.CCOC(C)=O.O>[CH3:37][O:38][C:13]1[C:12]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[CH:21][CH:22]=2)=[CH:11][C:10]([CH:9]=[O:8])=[CH:15][N:14]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(F)c(-c2ccc(OCC(F)(F)F)nc2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ncc(C=O)cc1-c1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-((tert-Butyldimethylsilyloxy)methyl)-2-fluoro-3-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)pyridine (0.204 g, 0.490 mmol) was placed into a microwave vial with MeOH (1.0 mL), and NaOMe (0.132 g, 2.45 mmol). The vial was sealed and irradiated at 130° C. for 7 min, worked up by adding H2O (5 mL) and EtOAc (5 mL). The layers were separated and the aqueous layer was washed with EtOAc (3×5 mL). The combined organic layers were then washed with 1M sodium phosphate buffer (pH 5.5) (2×5 mL), dried (MgSO4), filtered, and concentrated. This residue was then dissolved in 5 mL of tetra-butylammonium fluoride (1M in THF) and stirred at rt overnight. The reaction was then quenched by adding water (5 mL) and extracting with EtOAc (3×5 mL). The combined organic layers were then washed with brine (1×5 mL), dried (MgSO4), filtered, and concentrated. The resulting crude oil was then placed into a flame dried flask and to this was added N-methylmorpholine N-oxide (0.169 g, 1.44 mmol), 4 Å molecular sieves (10 mg), and CH2Cl2 (1.0 mL). Tetrapropylammonium perruthenate (8.43 mg, 0.024 mmol) was then added, and the suspension was stirred at rt overnight. The reaction mixture was then worked up by filtering through Celite® and concentrating the filtrate to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[N:14][CH:13]=[N:12]1>[Pd].CO>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[N:14][CH:13]=[N:12]1)[NH2:8]
Reactant: Cc1ncnn1-c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: Cc1ncnn1-c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
Step C (2): 10% Palladium on carbon (1.5 g, 14.1 mmol) was added under an atmosphere of nitrogen to a chilled (ice-water bath) solution of 1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (3.7 g, 17 mmol) dissolved in methanol (200 mL). The flask was repeatedly evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 18 h under the hydrogen atmosphere. The vessel was subsequently purged with nitrogen gas. The crude reaction mixture was filtered through a short plug of diatomaceous earth (Celite®). The reaction vessel and Celite® were rinsed with fresh methanol. The combined filtrates were concentrated in vacuo. The residue was dried under high vacuum to afford 3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (3.14 g, 91% yield) as a blackish/grey solid. LC-MS (M+H)+ 193.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.91 (s, 1 H) 7.14 (t, J=8.55 Hz, 1 H) 6.43-6.53 (m, 2 H) 4.04 (br. s., 2 H) 2.36 (s, 3 H).
Reaction SMILES: Cl.O1CCOCC1.C(OC(=O)[N:14]([C:22]1[C:27]([C:28]2[O:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:31][N:32]=2)=[N:26][C:25]([C:39]#[C:40][CH2:41][OH:42])=[CH:24][N:23]=1)C(OC(C)(C)C)=O)(C)(C)C>CO>[NH2:14][C:22]1[N:23]=[CH:24][C:25]([C:39]#[C:40][CH2:41][OH:42])=[N:26][C:27]=1[C:28]1[O:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:32]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C#CCO)nc1-c1nnc(-c2ccccc2)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncc(C#CCO)nc1-c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.2 %

Procedure:
4M HCl in dioxane (101.3 μL, 0.405 mmol) was added to a stirred solution of tert-butyl(5-(3-hydroxyprop-1-yn-1-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamate (40 mg, 0.08105 mmol) in MeOH (1 mL) and the reaction allowed to stir at ambient temperature for 20 hours then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an yellow solid (22.4 mg, 94% Yield). MS (ES+) 294.2.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.[CH:24]1([CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[C:42]([F:44])[C:41]([O:45]C)=[CH:40][C:39]=3[F:47])[CH2:34][CH2:33]2)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][N:35]([C:38]3[C:39]([F:47])=[CH:40][C:41]([OH:45])=[C:42]([F:44])[CH:43]=3)[CH2:34][CH2:33]2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cc(F)c(N2CCN(CCCC3CCCC3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: Oc1cc(F)c(N2CCN(CCCC3CCCC3)CC2)cc1F
Yield: 34.6 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 1-(3-cyclopentylpropyl)-4-(2,5-difluoro-4-methoxyphenyl)-piperazine (250 mg). The resulting crude product was purified on TLC (developer, chloroform: methanol=16:1) to provide 4-[4-(3-cyclopentylpropyl)piperazin-1-yl]-2,5-difluorophenol (83 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:14]([O:17][C@@H:18]([CH2:20][CH2:21][CH:22]=[CH2:23])[CH3:19])[CH2:15][CH3:16])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[Li+].[OH-].Cl>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:14]([O:17][C@@H:18]([CH2:20][CH2:21][CH:22]=[CH2:23])[CH3:19])[CH2:15][CH3:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCC[C@@H](C)O[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCC[C@@H](C)O[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,3S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((R)-hex-5-en-2-yloxy)pentanoate (458 mg, 1.39 mmol), THF (5 mL) and MeOH (5 mL). To the stirred solution was added aq. LiOH (2.0 M, 2 mL). The mixture was stirred for 16 h, then was concentrated in vacuo to afford an aqueous solution. The solution was acidified with aq. HCl (1 M) and then transferred to a separatory funnel. The mixture was twice extracted with EtOAc. The combined organics were washed with brine; dried over MgSO4; filtered; then concentrated in vacuo to afford (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-((R)-hex-5-en-2-yloxy)pentanoic acid as a white foam (438 mg, 100%).