Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:25][C:26](=[O:51])[C@H:27]([CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@@H:28]([N:32]([CH:40]=[O:41])[O:33]C1CCCCO1)[CH2:29][CH2:30][CH3:31])[C:17](=[O:24])[NH:18][C:19]1[S:20][CH:21]=[N:22][N:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:25][C:26](=[O:51])[C@H:27]([CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@@H:28]([N:32]([CH:40]=[O:41])[OH:33])[CH2:29][CH2:30][CH3:31])[C:17](=[O:24])[NH:18][C:19]1[S:20][CH:21]=[N:22][N:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC[C@@H]([C@@H](CCCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Nc1nncs1)N(C=O)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Product: CCC[C@@H]([C@@H](CCCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Nc1nncs1)N(O)C=O
Yield: 68.5 %

Procedure:
A solution of (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(3-phenyl-1-propyl)hexanoic acid [(1s)-5-benzyloxycarbonylamino-1-(1,3,4-thiadiazol-2-ylcarbamoyl)-1-pentyl]amide (23 mg, 0.032 mmol) in acetic acid-water (4:1, 1 mL) is heated to 50° C. for 16 h. The reaction mixture is concentrated, then dissolved in toluene and concentrated in vacuo. The procedure is repeated once again to afford the crude product which is recrystallized from dichloromethane-methanol-diethyl ether to provide (2R,3S)-3-(formyl-hydroxyamino)-2-(3-phenyl-1-propyl)hexanoic acid [(1S)-5-benzyloxycarbonylamino-1-(1,3,4-thiadiazol-2-ylcarbamoyl)-1-pentyl]amide as a solid (14 mg, 69% yield).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:46]=[CH:45][C:15]([O:16][CH2:17][C:18]#[C:19][CH:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH2:31][O:32][CH3:33])=[CH:27][CH:28]=3)[O:23][CH2:22][C:21]2([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:37][CH:36]=2)[CH3:34])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OCCCCCCCCCC1C2C(=CC(OC)=CC=2)SCC1(C1C=CC(OC)=CC=1)C)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH2:31][O:32][CH3:33])=[CH:27][CH:28]=3)[O:23][CH2:22][C:21]2([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:39][CH:40]=2)[CH3:34])=[CH:45][CH:46]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2C#CCOc2ccc(CCCO[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCOc2ccc(CCCO[Si](C)(C)C(C)(C)C)cc2)cc1

Procedure:
The title compound was prepared from 4-{3-[4-(3-t-butyldimethylsilyloxypropyl)phenoxy]-1-propynyl}-7-methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-methylchroman according to the same method for the synthesis of 4-[9-(t-butyldimethylsilyloxy)-1-nonyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman described in International Patent Appln. No. PCT/KR97/00265.
Reaction SMILES: C[C:2]1[C:7]2[O:8][C@:9]3(C)[O:12][CH:13]=C[C@H](OC)[C@@H](C)[C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)C=CC=C(C)C(N[C:30]4[C:33](/[CH:36]=N/N5CCN(C)CC5)=[C:34]([OH:35])[C:5]([C:6]=2[C:10]3=O)=[C:4]([C:31]=4O)C=1O)=O.C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[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](N)[C@H]2O)[C@@H]1N>>[CH3:36][CH2:33]/[CH:30]=[CH:31]\[CH2:4][CH:5]1[C:34](=[O:35])[CH2:2][CH2:7][CH:6]1[CH2:10][C:9]([O:12][CH3:13])=[O:8]
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(/C=N/N5CCN(C)CC5)c(O)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(/C=N/N5CCN(C)CC5)c(O)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Product: CC/C=C\CC1C(=O)CCC1CC(=O)OC
Reaction time: 8 h

Procedure:
Ten colonies of the transformed Agrobacteria containing a promoter construct of interest were picked from a fresh plate and inoculated into 10 ml YEB, containing 50 mg/l rifampicin, and 50 mg/l kanamycin, in a 50 ml flask. Cell cultures were incubated overnight at 28° C. with shaking. Approximately 1 ml of overnight culture was taken. Cultures were diluted with 50 ml YEB plus antibiotics so that the OD600 was approximately 0.3. Agrobacteria were grown at 28° C. with shaking until the OD600 was approximately 0.6. The cells were then pelleted by centrifugation. Supernatants were removed and Agrobacteria were resuspended in 40 ml fresh YEB by pipetting with a 1 ml tip. Wild type tobacco leaves were cut into small pieces under sterile conditions and put in a 50 ml beaker. Agrobacteria solution was poured onto the tobacco leaves and the mixture was swirled together and left for 5 min for the Agrobacteria to infect the leaves. Infected leaves were put on MS plates with filter paper (to limit Agrobacteria grow). The MS plates did not contain antibiotics. Plates were left for 2 days in the dark. After 2 days the tobacco pieces were transferred onto MS plates containing 1 mg/l 6 BA, 500 mg/l cefotaxin and 100 mg/l kanamycin. Samples were left in the light at 28° C. After 1 month small transgenic tobacco plants were visible. The plants were transferred to pots with ½ MS medium with 150 mg/l kanamycin. Several week old plants were transplanted into soil and grown under standard greenhouse conditions. Seeds from primary transformants were collected and germinated on ½ MS medium with 150 mg/l kanamycin and 500 mg/l cefotaxin. Transgenic seedlings were tested for promoter activity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[C:4]([CH3:13])[CH:3]=1>CCO.O=[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(F)ccc1/C=C/C(=O)O
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1cc(F)ccc1CCC(=O)O
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of (E)-3-(4-fluoro-2-methylphenyl)acrylic acid (13 g, 72.22 mmol) in EtOH (250 mL) was added PtO2 (250 mg) and then hydrogenated at 30 psi for 3 h. The reaction mixture was filtered on a Celite® pad, washed with MeOH (100 mL), and the filtrate was concentrated, washed with diethyl ether (20 mL), n-pentane (50 mL) and dried in vacuo to give 3-(4-fluoro-2-methylphenyl)propanoic acid as an off-white solid (10 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([S:19]([N:22]2[CH2:27][CH2:26][CH:25]([F:28])[CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([S:19]([N:22]2[CH2:27][CH2:26][CH:25]([F:28])[CH2:24][CH2:23]2)(=[O:20])=[O:21])[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: O=S(=O)(N1CCC(F)CC1)C1(c2cc(F)ccc2F)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC(c2cc(F)ccc2F)(S(=O)(=O)N2CCC(F)CC2)CC1
Yield: 63.4 %

Procedure:
The product of Step 2 (2.99 g, 7.14 mmol) and p-toluenesulfonic acid (1.62 g, 8.56 mmol) in acetic acid/water (40 ml/10 ml) were heated at 50° C. for 3 hours and then diluted (water) and extracted (diethyl ether). The organic phase was washed (saturated sodium hydrogen carbonate, brine), dried (magnesium sulfate) and evaporated in vacuo. The crude product was azeotroped with toluene, followed by ethyl acetate, followed by dichloromethane. The crude product then was chromatographed on silica, eluting with 30% ethyl acetate/isohexane to give the cyclohexanone (1.7 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.C(Cl)Cl.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([F:27])[CH:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:24])=[O:25])=[C:19]([F:27])[CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: Nc1nccs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 2-aminothiazole (4.51 g, 0.0450 mol) and pyridine (24.26 mL, 0.3000 mol) in methylene chloride (40 mL, 0.6 mol) at 0° C. was added portionwise 4-bromo-2-fluorobenzenesulfonyl chloride (8.2 g, 0.030 mol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc, washed with 1N HCl solution, H2O and brine. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to give the crude product that was purified via automated flash chromatography (silica gel, 25% EtOAc in hexanes to 100% EtOAc) to give the product as a light brown solid (3.6 g, 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1.[NH2:28][C:29]([NH2:31])=[S:30]>C(O)C>[NH2:31][C:29]1[S:30][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:28]=1
Reactant: O=C(CC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: NC(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Product: Nc1nc(-c2ccc(F)cc2)c(C(=O)c2ccc(F)cc2)s1
Temperature: 25 °C

Procedure:
1,3-Bis-(4-fluoro-phenyl)-propane-1,3-dione and NBS (1.05 eq) were heated neat at 60° C. for 10 minutes then cooled. The resulting mixture was dissolved in ethanol (0.2 M) and treated with thiourea (1.5 eq). It was heated at reflux for 15 hours and cooled to room temperature. It was evaporated to dryness and the residue was partioned between EtOAc and saturated NaHCO3. Organic fraction was dried over MgSO4, filtered and concentrated. The title compound was collected by trituration with heptanes. 1H NMR (400 MHz, DMSO-d6) 6.86-7.01 (m, 4H) 7.22-7.32 (m, 2H) 7.35-7.45 (m, 2H) 8.11 (br. s., 2H). LCMS Method A Rt=1.18 m/z 317.0 (M+1), 315 (M−1).
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:21])[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].[CH2:22]([O:25][NH2:26])[CH:23]=[CH2:24]>C(O)C>[CH2:22]([O:25][N:26]=[C:1]([C:6]1[C:7](=[O:21])[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH:23]=[CH2:24]
Reactant: C=CCON
Reactant: CCCC(=O)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Solvent: CCO
Product: C=CCON=C(CCC)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Into 20 ml of ethanol was dissolved 1.5 g of 2-butyryl-3-hydroxy-5-(4-methylthiophenyl)-2-cyclohexen-1-one and to the solution was added 0.5 g of allyloxyamine. The mixture was kept for 15 hours at room temperature and it was poured into ice water. The crystal sedimented was collected with a filtering step and recrystallized with methanol. Thus, 1.4 g of colorless objective crystals having a melting point of 72°-74° C. was obtained.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(NC(C(O)=O)C(C)C)(=O)C1C=CC=CC=1.Cl.ClC1C=CC(C2CCNCC2)=CC=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:26][CH2:27][N:28]([C:15](=[O:17])[CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: CC(C)CC(NC(=O)c1ccccc1)C(=O)O
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Agent: Cl
Agent: Clc1ccc(C2CCNCC2)cc1
Product: CC(C)CC(NC(=O)c1ccccc1)C(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
Example 215 was prepared in a similar manner as described for the preparation of Example 208 with the exceptions that benzoyl-DL-leucine and 4-(4-chlorophenyl)-4-hydroxypiperidine were substituted for benzoyl-DL-valine and 4-(4-chlorophenyl)piperidine hydrochloride, respectively. MS found: (M+H)+=430.
Reaction SMILES: [F:1][C:2]([F:12])([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=1)[CH2:3][NH2:4].[CH2:13]([O:15][C:16](=[O:28])[CH2:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:20](F)[C:19]=1[F:27])[CH3:14]>CS(C)=O>[CH2:13]([O:15][C:16](=[O:28])[CH2:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:20]([NH:4][CH2:3][C:2]([F:1])([F:12])[C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=2)[C:19]=1[F:27])[CH3:14]
Reactant: CCOC(=O)Cc1c(C#N)ccc(F)c1F
Reactant: Cc1ccc(C(F)(F)CN)nc1
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(C#N)ccc(NCC(F)(F)c2ccc(C)cn2)c1F
Temperature: 90 °C
Reaction time: 20 h
Yield: 48.2 %

Procedure:
A mixture of 2,2-Difluoro-2-(5-methyl-pyridin-2-yl)-ethylamine (1.85 g, 10.76 mmol, 2×) and (6-Cyano-2,3-difluoro-phenyl)-acetic acid ethyl ester (1.2 g, 5.33 mmol), prepared as described in Example 2f, was dissolved into DMSO (3 mL) and heated to 90° C. under argon. After 20 h, the reaction was partitioned between EtOAc (50 mL) and H2O (50 mL). The aqueous phase was re-extracted with EtOAc (30 mL) and the combined organic phase dried over Na2SO4 and concentrated to afford a yellow oil. Purification via flash chromatography (20% EtOAc/hexanes) afforded the product as a clear oil (968 mg, 2.57 mmol, 48% yield). 1H NMR (300 Hz, CDCl3) δ 8.49 (s, 1H), 7.59 (m, 2H), 7.30 (m, 1H), 6.79 (t, J=8.2 Hz, 1H), 4.13 (m, 4H), 3.80 (d, J=2.0 Hz, 2H), 2.41 (s, 3H), 1.27 (t, J=6.9 Hz, 3H); LC/MS (m/z) [M+1]+ 378.0 (calculated for C19H19F3N3O2, 378.4).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6].C([Li])CCC.B(OC)(OC)[O:21]C.[OH-].[Na+].OO.Cl>C1COCC1.O.CC(=O)OCC>[C:11]([C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([OH:21])[CH:10]=1)[C:5]([OH:7])=[O:6])([CH3:14])([CH3:13])[CH3:12]
Reactant: COB(OC)OC
Reactant: CC(C)(C)c1cc(Br)cc(C(=O)O)c1
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(O)cc(C(=O)O)c1
Reaction time: 0.5 h

Procedure:
3-Bromo-5-tert-butylbenzoic acid (5 g) was dissolved in THF (180 ml), and n-butyllithium (18.7 ml, 2.5 M in hexane) was added dropwise under argon and at −75° C., and stirred for a further 30 min. Then trimethyl borate (6.63 ml) was added dropwise and the mixture was allowed to come to RT within 1 h. Thereafter, sodium hydroxide (0.778 g), dissolved in 2 ml of water, and hydrogen peroxide (12.89 ml, 30%) were added in succession. After stirring at RT for 3 h, the mixture was left to stand over the weekend. Then water and EA were added, the mixture was adjusted to pH 3 with 1 N hydrochloric acid and the EA phase was removed. This phase was washed three times with water, dried, filtered and concentrated. The residue was purified using silica gel (120 g cartridge, n-heptane/MtB ether gradient of 0-50% in 60 min). 1.94 g of the title compound were obtained.
Reaction SMILES: Cl.C(OC([N:9]1[C@@H:13]([C:14](=[O:24])[NH:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][C@@H:11]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:10]1=[O:33])=O)(C)(C)C.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[CH2:17]([O:16][NH:15][C:14]([C@H:13]1[CH2:12][C@@H:11]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:10](=[O:33])[NH:9]1)=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc([C@@H]2C[C@H](C(=O)NOCc3ccccc3)N(C(=O)OC(C)(C)C)C2=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc([C@@H]2C[C@H](C(=O)NOCc3ccccc3)NC2=O)cc1
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
Hydrogen chloride gas was bubbled for 3 minutes through a solution of (3S, 5R)-5-benzyloxycarbamoyl-3-(4-methoxyphenyl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester (270 mg, 0.61 mmol) in methylene chloride (40 mL). After stirring for an additional 10 minutes, the solvent was evaporated to leave a white foam. The title compound (169 mg, 80%) was isolated by flash chromatography (eluting with ethyl acetate) and recrystallization from a mixture of ethyl acetate and hexane.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]3=[O:21])=[CH:11][CH:10]=2)[CH:8]=1>CO.[Pd]>[NH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3=[O:21])=[CH:13][CH:14]=2)[CH:8]=1
Reactant: NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cn(-c2ccc(N3CCCCC3=O)cc2)cn1
Yield: 99.9 %

Procedure:
A mixture of 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one hydrochloride (60 mg, 0.20 mmol) and Pd—C (10%, 31 mg) in MeOH (6 mL) was hydrogenated under balloon H2 overnight. It was then filtered through celite. The filtrate was concentrated in vacuo to give 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)piperidin-2-one (54 mg).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:6][CH:5]([NH:7]C(=O)OC(C)(C)C)[CH2:4]2)[CH2:2]1.[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH2:2]1[C:3]2([CH2:6][CH:5]([NH2:7])[CH2:4]2)[CH2:1]1
Reactant: CC(C)(C)OC(=O)NC1CC2(CC2)C1
Solvent: O=C(O)C(F)(F)F
Product: NC1CC2(CC2)C1
Reaction time: 0.17 h

Procedure:
The above obtained Compound 3-3 (1 g, 5.1 mmol) was dissolved in 5 mL of trifluoroacetic acid, stirred for 10 minutes, rotary evaporated to remove trifluoroacetic acid to give 1.1 g of Compound 3-4 and used directly in the next step reactions.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])=[CH:10][CH:9]=1)=[O:7].[H-].[Na+].I[CH3:28]>CN(C=O)C>[CH3:28][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])=[CH:10][CH:9]=1)=[O:7]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C(=O)c3ccc[nH]3)cc2)C(=O)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)c3cccn3C)cc2)C(=O)O1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
The title compound of Example 47 (0.14 g, 0.43 mM) in DMF (1.4 ml) was stirred under nitrogen and cooled to 5° C. Sodium hydride (0.019 g of a 60% dispersion in mineral oil, 0.47 mM) was added and the mixture stirred for 15 minutes. Iodomethane (30 μl) was added, the mixture stirred for 10 minutes at 5° C. and at ambient temperature for 2 hours. The mixture was evaporated and the residue partitioned between EtOAc and water. The organic layer was washed with water dried (MgSO4) and evaporated. The residue was purified by column chromatography in dichloromethane, eluting with a gradient increasing in polarity from 2% to 10% MeOH/dichloromethane to give the title product as an oil (0.13 g). MS: 342 (MH+); NMR: 1.83 (3H, s); 3.28 (nH+H2O); 3.42 (2H, t); 3.80 (1H, m); 3.92 (3H, s); 4.9 (1H, t); 4.75 (1H, m); 6.16 (1H, m); 6.64 (1H, m); 7.23 (1H, m); 7.67 (2H, d); 7.80 (2H, d); 8.22 (1H, t).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH2:34]([CH:36]1[CH2:41][O:40][CH2:39][CH2:38][NH:37]1)[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:34]([CH:36]1[CH2:41][O:40][CH2:39][CH2:38][N:37]1[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]1[C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=1)[CH3:35]
Reactant: CCC1COCCN1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC1COCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 150 °C
Yield: 31.9 %

Procedure:
A sealable vial was charged with ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (100 mg, 0.189 mmol, Intermediate B), 3-ethylmorpholine (43.6 mg, 0.378 mmol, ChemBridge Corporation, San Diego, Calif.), potassium carbonate (52.3 mg, 0.378 mmol), and 4 mL of MeCN. The vial was sealed and heated to 150° C. for 90 min. Afterwards, the reaction mixture was filtered and the filtrate was concentrated. The crude material was purified via preparatory TLC using 5% MeOH in CH2Cl2 eluent to yield 2-(4-((2S)-2-((3-ethyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (33 mg) as a mixture of four isomers.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.[Sn].[C:17]([C:21]1[CH:26]=[C:25](C)[CH:24]=[C:23](C(C)(C)C)[C:22]=1O)(C)(C)[CH3:18]>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:21]1([C:17]#[C:18][C:2]2[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=2[C:9]=34)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: [Sn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCc2c(C#Cc3ccccc3)[nH]c3cccc1c23
Temperature: 60 °C
Yield: 55 %

Procedure:
Tricyclic bromide 11 (58.6 mg, 0.22 mmol) in DMF (1 mL) was degassed and treated with tributylephenylethynyl)tin (95.2 mg, 0.24 mmol) and tetrakis(triphenylphosphine) palladium(0) (13 mg, 2 mol %). One crystal of 2,6-di-t-butyl-4-methyl phenol was added, and the solution was heated at 60° C. for 10 h. Starting material was still present, so the solution was heated at 100° C. for an additional 2 h. The reaction mixture was cooled to ambient temperature and diluted with water (2 mL) and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by radial chromatography (2 mm SiO2; 3% MeOH in CH2Cl2) to yield 17 as a white solid (34.8 mg, 55%). mp 255-256° C. (dec); 1H NMR (DMSO-d6) δ11.86 (s, 1H), 8.17 (m, 1H), 7.75 (d, 1H, J=7.6 Hz), 7.63 (m, 3H), 7.51 (m, 3H), 7.33 (t, 1H, J=7.6 Hz), 3.50 (m, 2H), 3.09 (m, 2H); HRMS (FAB, M+H) Calcd for C19H14N2O+H: 287.1184, Found: 287.1192; Anal. (C19H14N2O.0.6 H2O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].O[C@H:13]1[CH2:17][CH2:16][O:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:13]1[CH2:17][CH2:16][O:15][CH2:14]1)[N:6]=[C:5]2[I:11]
Reactant: O[C@H]1CCOC1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: Fc1ccc2c(c1)c(I)nn2[C@@H]1CCOC1
Yield: 56 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and (S)-3-hydroxytetrahydrofuran in 56% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 2.47-2.52 (2H, m), 3.95-4.00 (1H, m), 4.12-4.19 (2H, m), 4.19-4.28 (1H, m), 5.24-5.30 (1H, m), 7.12 (1H, dd, J=2.0, 8.4 Hz), 7.21 (1H, td, J=1.6, 8.8 Hz), 7.45 (1H, dd, J=4.0, 9.2 Hz).