Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:39]=[CH:38][C:18]3[NH:19][C:20]([C:22]4[C:26]([NH:27][C:28](=[O:37])[C:29]5[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=5[F:36])=[CH:25][NH:24][N:23]=4)=[N:21][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOC(C)=O>CO>[F:35][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([F:36])[C:29]=1[C:28]([NH:27][C:26]1[C:22]([C:20]2[NH:19][C:18]3[CH:38]=[CH:39][C:15]([CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:16][C:17]=3[N:21]=2)=[N:23][NH:24][CH:25]=1)=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3[nH]c(-c4n[nH]cc4NC(=O)c4c(F)cccc4F)nc3c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCNCC3)ccc2[nH]1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.7 %

Procedure:
A mixture of 4-{2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazol-5-ylmethyl}-piperazine-1-carboxylic acid tert-butyl ester (84 mg), MeOH (3 mL) and saturated HCl/EtOAc (3 mL) was stirred at r.t. for 16 h and then reduced in vacuo azeotroping with toluene to give the title compound (21 mg) as a yellow solid. (LC/MS: Rt 1.60, [M+H]+ 438.09).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.CO[CH:21]1[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:24]([CH3:34])([CH3:33])[CH2:23][CH2:22]1.[NH4+].[Cl-]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:29]([O:28][C:26]([N:25]1[C:24]([CH3:34])([CH3:33])[CH2:23][CH2:22][CH:21]1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)CC(=O)OC
Reactant: COC1CCC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(C(=O)OC)C1CCC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
TiCl4 (1.9 mL, 1.9 mmol) as a 1M DCM solution was added to a solution of dimethyl malonate (0.195 mL, 1.70 mmol) in DCM (10 mL) at 0° C. under N2, and the reaction was stirred for 10 minutes. DIEA (0.3 mL, 1.7 mmol) was then added slowly, and the reaction was stirred for an additional 30 minutes at 0° C. A DCM (2 mL) solution of tert-butyl 5-methoxy-2,2-dimethylpyrrolidine-1-carboxylate (325 mg, 1.4 mmol) was then slowly added dropwise, and the reaction was stirred at 0° C. for 10 minutes. Saturated NH4Cl was then added, and then reaction was diluted with DCM and washed with saturated NaHCO3. The organic fractions were then dried, filtered, and concentrated to give the crude product, which was purified by column chromatography (500:50-500:90 hexanes:EtOAc) to give dimethyl 2-(1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)malonate (0.35 g, 75%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:28]([NH:30][C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[O:29])[CH3:27])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].C(O)(=O)C.Br>CCOCC>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:28]([NH:30][C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[O:29])[CH3:27])=[O:24])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.10 g of Z-Ile-Leu-Leu-Ala-Gln-OH was added 15 ml of acetic acid solution containing 25% of hydrogen bromide, then the mixture was stirred at a room temperature for 1 hour. After completion of the reaction, dried ether was added to the reaction mixture to obtain H-Ile-Leu-Leu-Ala-Gln-OH.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:18][O:19][C:20]3[C:27]([CH3:28])=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[CH3:29])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:18][O:19][C:20]3[C:27]([CH3:28])=[CH:26][C:23]([C:24]4[N:36]=[N:37][NH:38][N:25]=4)=[CH:22][C:21]=3[CH3:29])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C#N)cc(C)c1OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nn[nH]n2)cc(C)c1OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 31, [rac]-4-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3,5-dimethyl-benzonitrile (example 51) was reacted with sodium azide in the presence of triethylamine hydrochloride in DMF to obtain the title compound as brown solid. MS: m/e=527.4 [M+H+].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:10])([CH3:9])[C:7]2[CH:11]=[CH:12][C:13]([N+]([O-])=O)=[CH:14][C:6]=2[S:5]1(=[O:19])=[O:18].ClCCN1C(CC)(CC)C2C=CC=CC=2S1(=O)=O.ClCCN1C(C)(C)C2C(Cl)=CC=CC=2S1(=O)=O>>[Cl:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:10])([CH3:9])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5]1(=[O:19])=[O:18]
Reactant: CC1(C)c2ccc([N+](=O)[O-])cc2S(=O)(=O)N1CCCl
Agent: CC1(C)c2c(Cl)cccc2S(=O)(=O)N1CCCl
Agent: CCC1(CC)c2ccccc2S(=O)(=O)N1CCCl
Product: CC1(C)c2ccccc2S(=O)(=O)N1CCCl

Procedure:
2-(2-Chloroethyl)-3,3-dimethyl-6-nitro-2,3-dihydro-1, 2-benzoisothiazole 1,1-dioxide, 2-(2-chloroethyl)-3, 3-diethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide and 2-(2-chloroethyl)-4-chloro-3,3-dimethyl-2,3-dihydro-1, 2-benzoisothiazole 1,1-dioxide can be prepared in an analogous manner.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29].Br[C:34]1[C:35]([CH3:43])=[N:36][C:37]([O:41][CH3:42])=[CH:38][C:39]=1[CH3:40].F.[K]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([C:34]2[C:35]([CH3:43])=[N:36][C:37]([O:41][CH3:42])=[CH:38][C:39]=2[CH3:40])[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: COc1cc(C)c(Br)c(C)n1
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1cc(F)c(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: F
Agent: [K]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1cc(F)c(-c2c(C)cc(OC)nc2C)cc1F
Temperature: 110 °C

Procedure:
A mixture of ethyl 5-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate synthesized in accordance with Example 53 (430 mg), 3-bromo-6-methoxy-2,4-dimethylpyridine obtained in Preparation Example 23 (223 mg), potassium hydrogen fluoride (254 mg), Pd(PPh3)4 (90 mg) and tripotassium phosphate n-hydrate (400 mg) in DME (8 mL) and water (2 mL) was heated under reflux at 110° C. for seven hours. The reaction mixture was cooled to room temperature and partitioned by adding ethyl acetate and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane: 16% to 37% to 46%) and silica gel column chromatography (ethyl acetate/n-heptane: 28% to 49% to 54%) to give the title compound (144 mg). This compound was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26]#[N:27])=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8]1.O=[C:29]([CH3:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[NH2:27][C:26]1[C:3]2[C:2](=[CH:25][CH:24]=[CH:23][C:4]=2[O:5][CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[N:1]=[C:29]([CH3:36])[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCC1CCCN(C(=O)OCc2ccccc2)C1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCNC3)c2c1N

Procedure:
Prepared as in Example 2a from benzyl 3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 110c) and ethyl 3-oxobutanoate as a yellow oil (21%). MS 344 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[O:7])=[CH:4][C:3]=1[N+:21]([O-])=O>C1COCC1.[Pt]>[NH2:21][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH2:1])[C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=1)=[O:7]
Reactant: Nc1ccc(C(=O)Nc2ccc(C(F)(F)F)nc2)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)Nc2ccc(C(F)(F)F)nc2)cc1N

Procedure:
A suspension of 4-amino-3-nitro-N-(6-trifluoromethylpyridin-3-yl)-benzamide (500 mg, 1.53 mmol) in THF (20 mL) was hydrogenated at one atm over Pt/C (50 mg) for 3 hours. The catalyst was filtered through Celite and washed with THF. The solvent was removed under reduced pressure to give 3,4-diamino-N-(6-trifluoromethylpyridin-3-yl)-benzamide as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:26][CH3:27])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[NH2:20])=[CH:15][C:14]=1[CH2:22][CH2:23][CH2:24][CH3:25].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:26][CH3:27])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=1[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1cc(C(N)=O)ccc1OCCCNc1cnn(CC)c(=O)c1Br
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCc1cc(C#N)ccc1OCCCNc1cnn(CC)c(=O)c1Br

Procedure:
A mixture comprising 316 mg of 4-bromo-5-[3-(2-n-butyl-4-carbamoylphenoxy)propylamino]-2-ethyl-3(2H) pyridazinone (Compound No. 180), 174 mg of p-toluenesulfonyl chloride, 110 mg of pyridine and 5 ml of N,N-dimethylformamide, was stirred at 95° C. for 1.5 hours. The reaction mixture was subjected to distillation under reduced pressure. Water was poured into the residual oily substance, and the mixture was extracted with ethyl acetate. The extract was washed sequentially with 5% dilute hydrochloric acid, water and a saturated sodium hydrogen carbonate aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a pale yellow oily substance. The oily substance was crystallized from ethyl ether to obtain 248 mg of the above identified compound as colorless crystals having a melting point of from 107.5° to 108.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[CH:50]([N:53]([CH3:62])[C:54](N1C=C[N+](C)=C1)=[O:55])([CH3:52])[CH3:51].C(Cl)Cl.C(N(CC)CC)C>>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:19]2[N:20]=[C:21]([CH3:23])[N:22]=[C:17]([C:16]3[CH:15]=[C:14]([CH2:43][N:44]4[CH2:49][CH2:48][N:47]([C:54]([N:53]([CH:50]([CH3:52])[CH3:51])[CH3:62])=[O:55])[CH2:46][CH2:45]4)[CH:13]=[N:12][C:11]=3[NH:10][C:4]3[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[N:18]=2)=[CH:36][CH:37]=1
Reactant: CC(C)N(C)C(=O)n1cc[n+](C)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCNCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)N(C)C(C)C)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1

Procedure:
To a 50 mL round-bottomed flask was added 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(piperazin-1-ylmethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.350 g, 0.526 mmol), 1-(isopropyl(methyl)carbamoyl)-3-methyl-1H-imidazol-3-ium (0.479 g, 2.63 mmol), DCM (25 mL, 0.526 mmol), triethylamine (0.366 mL, 2.63 mmol). After 1 hour the mixture was washed with 1.0 N HCl (2×5 mL) and brine, the organic layer was dried over sodium sulfate, filtered and concentrated under a vacuum to give 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N-isopropyl-N-methylpiperazine-1-carboxamide, which was treated with trifluoroacetic acid (5 mL, 67.3 mmol), trifluoromethanesulfonic acid (0.2 mL, 0.278 mmol). The solution was stirred at 80° C. for one hour. The dark solution was cooled down to room temperature and concentrated to slurry. The slurry was neutralized to pH 8 with NaHCO2. The precipitate was dissolved in DCM/MeOH and adsorbed onto a plug of silica gel and chromatographed through a silica gel column (40 g), eluting with a gradient of 5% to 10% 2 M NH3.MeOH in DCM, to provide 4-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N-isopropyl-N-methylpiperazine-1-carboxamide (0.033 g, 0.063 mmol, 26.7% yield). m/z (ESI, Positive ion) 525.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.85 Hz, 6H) 2.44 (s, 3H) 2.64 (s, 3H) 2.97 (dd, J=5.38, 4.60 Hz, 4H) 3.09 (d, J=7.24 Hz, 1H) 3.25 (d, J=4.89 Hz, 4H) 3.95 (s, 3H) 4.12 (s, 2H) 7.83 (br. s., 1H) 7.96 (br. s., 1H) 8.33-8.37 (d, 1H) 8.40 (s, 1H) 8.44 (s, 1H) 8.87 (dd, J=2.15, 0.39 Hz, 1H) 12.01 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[CH2:13][CH2:12][N:11]([CH2:26][C:27]([F:30])([F:29])[F:28])[C:10]1=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[O:31]=[C:10]1[N:11]([CH2:26][C:27]([F:28])([F:29])[F:30])[CH2:12][CH2:13][NH:14][CH2:15][CH:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCN(CC(F)(F)F)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CNCCN(CC(F)(F)F)C1=O
Reaction time: 18 h
Yield: 102.2 %

Procedure:
10% Palladium on carbon (77 mg) was added to a solution of benzyl 6-[(tert-butoxycarbonyl)amino]-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-diazepane-1-carboxylate (590 mg, 1.32 mmol) in ethanol (20 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated to give the title compound (420 mg). MS 312 (M+1). 1H NMR (500 MHz, CDCl3) δ 5.83 (s, 1H), 4.53-4.49 (m, 1H), 4.29-4.20 (m, 1H), 3.96-3.88 (m, 1H), 3.81-3.77 (m, 1H), 3.38 (d, J=15.6 Hz, 1H), 3.26 (d, J=12.9 Hz, 1H), 3.16-3.13 (m, 1H), 2.81-2.79 (m, 1H), 2.72-2.67 (m, 1H), 1.83 (br s, 1H), 1.45 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH:11]=[C:10]([OH:12])[CH:9]=1
Reactant: CC(C)=CCBr
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc(O)cc(OCC=C(C)C)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl 3,5-dihydroxybenzoate (11.3 g, 67 mmol), potassium carbonate (18.5 g, 134 mmol), and 1-bromo-3-methyl-but-2-ene (10 g, 67 mmol). Purification by column chromatography eluting with 20% EtOAc in hexane gave a pale yellow solid (3.41 g, 20% yield). 1H NMR (400 MHz, CDCl3) δ 7.17-7.20 (m, 1 H) 7.12-7.17 (m, 1 H) 6.63 (t, J=2.27 Hz, 1 H) 5.41-5.51 (m, 1 H) 5.50 (s, 1H) 4.53 (d, J=6.57 Hz, 2 H) 3.91 (m, 3 H) 1.80 (s, 3 H) 1.69 (s, 3 H); LCMS for C13H16O4 m/z 237.10 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1)[C@H:3]([OH:6])[CH2:4][OH:5].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>C1COCC1>[F:15][C:10]1[CH:9]=[C:8]([CH:13]=[C:12]([F:14])[CH:11]=1)[CH2:7][C@H:2]([NH:1][C:17](=[O:16])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:3]([OH:6])[CH2:4][OH:5]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CO
Reaction time: 8 h

Procedure:
Aminodiol 27 was dissolved in THF and BOC2O was added and stirred overnight. Solvent removal afforded 28, which was carried directly into the next step; analytical sample m.p.=122°.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([NH:19][C@@H:20]2[CH2:25][CH2:24][C@H:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH2:21]2)[C:16]([N+:30]([O-:32])=[O:31])=[CH:15][N:14]=1>C1COCC1>[N+:30]([C:16]1[C:17]([NH:19][C@@H:20]2[CH2:21][CH2:22][C@H:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:25]2)=[CH:18][C:13]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:14][CH:15]=1)([O-:32])=[O:31]
Reactant: OCCN1CCCCC1
Reactant: COC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ncc2[N+](=O)[O-])CC1
Reaction time: 0.5 h

Procedure:
To a nitrogen purged, cooled (0° C.) suspension of 2-(piperidin-1-yl)ethanol (0.577 g, 4.46 mmol) in THF was added sodium hydride (0.196 g of 60% oil dispersion, 4.91 mmol), and the resulting mixture was stirred for 30 minutes. A solution of cis-methyl 4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylate (1.40 g, 4.46 mmol) in THF (14 mL) was added, and the reaction was stirred overnight at RT. The reaction mixture was quenched with water (10 mL) and the product extracted with DCM (30 mL). The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-30% of 90/10/1 DCM/MeOH/NH4OH in DCM) to afford cis-methyl 4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxylate (0.6 g, 33.1% yield). MS m/z=407.2 [M+H]. Calc'd for C20H30N4O5: 406.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:30]([NH:34][CH2:35][CH:36]([OH:39])[CH2:37]O)([CH3:33])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1.C1COCC1.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([O:14][CH2:37][CH:36]([OH:39])[CH2:35][NH:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC(C)(C)NCC(O)CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)NCC(O)COC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.9 %

Procedure:
To 20 g (0.06 mole) of the 3,4-dibenzyloxybenzoic acid in 200 ml of toluene was added 60 g (0.33 mole) of thionyl chloride. The reaction mixture was evaporated to dryness in vacuo to give a solid; m.p. 85°-86°. The solid was dissolved in 100 ml of dry THF and added dropwise into a solution of 17.7 g (0.06 mole) 3-(t-butylamino)-1,2-propanediol in 50 ml of pyridine and 50 ml of toluene. The reaction mixture was stirred for 1 hour at 25° C. and partitioned between ether and 5% K2CO3 solution. The ether layer was evaporated to dryness to give 30 g of solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:19]=[CH:18][C:14]([CH:15]=[N:16]O)=[CH:13][C:12]=2[N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:21]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1(S(Cl)(=O)=O)C=CC=CC=1.N1C=CC=CC=1>O1CCCC1>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:21]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCN1CCN(c2cc(C=NO)ccc2C2CCC(C(C)(C)C)CC2)CC1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCN1CCN(c2cc(C#N)ccc2C2CCC(C(C)(C)C)CC2)CC1
Yield: 74.7 %

Procedure:
A mixture of the crude product of 4-(4-t-butylcyclohexyl)-3-(4-butylpiperazin-1-yl)benzaldehydeoxime produced in Example (101c) (269 mg), benzenesulfonyl chloride (0,11 mL, 0.862 mmol), pyridine (0.11 ml, 1.36 mmol) and tetrahydrofuran (15 mL) was refluxed for 4 hours and 30 minutes. After then distilling off tetrahydrofuran partially in the reaction mixture under reduced pressure, chloroform was added and the mixture was further refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure, the obtained residue was poured into ice water, and then ethyl acetate and saturated aqueous solution of ammonium chloride were added and extraction was performed with ethyl acetate. The separated organic layer was washed twice with saturated aqueous ammonium chloride and once with brine, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by NH silica gel column chromatography (ethyl acetate/hexane, followed by ethyl acetate/methanol), to give 192 mg of the title compound as an ochre oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:12][C:11]=2[C:21]2[NH:25][CH:24]=[N:23][N:22]=2)[OH:9])=[CH:4][CH:3]=1.Cl.[CH3:27]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:9][CH3:27])[C:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)[S:12][C:11]=2[C:21]2[NH:25][CH:24]=[N:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: OC(c1ccc(Cl)cc1)c1cc(-c2ccncc2)sc1-c1nnc[nH]1
Agent: Cl
Product: COC(c1ccc(Cl)cc1)c1cc(-c2ccncc2)sc1-c1nnc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of (4-chlorophenyl)[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol (100 mg, 0.271 mmol) in methanol (10 mL) was added conc. HCl (2.0 mL, 24 mmol) and the mixture was stirred at rt overnight. The reaction mixture was concentrated and basified by sodium bicarbonate, loaded on silica gel and purified by column chromatography (SiO2, elution with 0-5% MeOH in DCM) to afford the title compound (80 mg, 78%). LCMS: (AA) ES+ 383.3, 385.2; 1H NMR (300 MHz, d6-DMSO) δ: 8.70 (s, 1H), 8.57 (d, J=4.80 Hz, 2H), 7.79 (s, 1H), 7.68 (d, J=4.79 Hz, 2H), 7.56 (d, J=8.25 Hz, 2H), 7.38 (d, J=8.30 Hz, 2H), 6.50 (s, 1H), 3.31 (d, J=9.06 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22][N:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([O:31]C)=O)[C:24]2=[O:33])=[CH:4][C:3]=1[F:34].O.[NH2:36][NH2:37].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10][C@H:9]2[CH2:22][N:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:36][NH2:37])=[O:31])[C:24]2=[O:33])=[CH:4][C:3]=1[F:34]
Reactant: COC(=O)c1cccn(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO[C@H]2c2ccc(Cl)c(F)c2)c1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](Cn2cccc(C(=O)NN)c2=O)C1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-{[3-(methoxycarbonyl)-2-oxopyridin-1(2H)-yl]methyl}-1,4-oxazepane-4-carboxylate (155.7 mg) in ethanol (1.5 mL) was added hydrazine monohydrate (79 mg) at room temperature, and the mixture was heated under reflux for 2 days. The reaction mixture was allowed to cool to room temperature, and poured into water, and the mixture was partitioned with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (138 mg).