Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[CH2:3][OH:4].Cl[O-].[Na+]>C(O)(=O)C>[OH:4][CH2:3][C:2]([CH3:24])([CH3:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:21])([CH3:22])[CH2:19][OH:20]
Reactant: CC(C)(CO)CCCCCCC(O)CCCCCCC(C)(C)CO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Product: CC(C)(CO)CCCCCCC(=O)CCCCCCC(C)(C)CO
Yield: 34.5 %

Procedure:
To a solution of 211i (2.42 g, 7.02 mmol) in acetic acid (10 mL) was added dropwise sodium hypochlorite solution (1.76 mL, ca. 3.5 mmol) at 18° C. Additional sodium hypochlorite solution (3×1.0 mL, ca. 6.0 mmol) was added after 20, 40, and 60 min under monitoring by TLC. The reaction was quenched with 2-propanol (4 mL) and diluted with deionized water (100 mL). The reaction mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with saturated NaHCO3 solution (3×60 mL), water (60 mL) and brine (60 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification of the crude product (2.38 g) by column chromatography (silica gel, ethyl acetate/hexanes=1/1) gave 214i (0.83 g, 35%) as a colorless wax. 1H NMR (CDCl3): δ (ppm): 3.33 (s, 4H), 2.41 (t, J=7.4, 4H), 1.85 (br, 2H), 1.62-1.45 (m, 4H), 1.35-1.18 (m, 16H), 0.87 (s, 12H). 13C NMR (CDCl3): δ (ppm): 212.09, 72.10, 42.99, 38.75, 35.20, 30.48, 29.42, 24.05, 23.99, 23.82. HRMS (LSIMS, gly): Calcd for C21H43O3 (MH+): 343.3212, found: 343.3208. HPLC: 96.4% pure.
Reaction SMILES: C([O:8][C:9](=[O:48])[CH:10]([N:17]([CH2:29][CH2:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH2:34]1)=[O:32])[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:44]([O:43][C:41]([CH2:40][NH:39][CH:36]1[CH2:35][CH2:34][N:33]([C:31](=[O:32])[CH2:30][CH2:29][N:17]([CH:10]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[C:9]([OH:48])=[O:8])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:38][CH2:37]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCC(NCC(=O)OC(C)(C)C)CC2)C(C(=O)OCc2ccccc2)C2CCCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCC(NCC(=O)OC(C)(C)C)CC2)C(C(=O)O)C2CCCCC2)cc1
Yield: 100.3 %

Procedure:
To a solution of [{3-[4-(tert-butoxycarbonylmethylamino)piperidin-1-yl]-3-oxopropyl}(4-methoxybenzenesulfonyl) amino]cyclohexylacetic acid benzylester (1.89 grams, 2.76 mmol) in ethanol (90 mL) was added 10% palladium on activated carbon (0.32 grams). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 2 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated leaving [{3-[4-(tert-butoxycarbonylmethyl-amino) piperidin-1-yl]-3-oxo-propyl}(4-methoxybenzenesulfonyl)amino]cyclohexylacetic acid as a white foam (1.65 grams, 100%).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.N1C=CC=CC=1.[CH3:34][NH:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38][CH2:37]1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8](=[O:27])[N:35]([C@H:36]3[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38][CH2:37]3)[CH3:34])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: CN[C@H]1CC[C@@H](O)CC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N(C)[C@H]3CC[C@@H](O)CC3)nc12
Reaction time: 16 h

Procedure:
To a stirred solution of 100 mg (0.26 mmol) (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester and 0.06 ml (0.78 mmol) pyridine in 5 ml chloroform at room temperature was added 47 mg (0.36 mmol) cis-4-methylamino-cyclohexanol and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (1/1 acetone/heptane then acetone) followed by trituration in ether and hexane afforded 75 mg (69%) (+)-cis-3-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-1-(4-hydroxy-cyclohexyl)-1-methyl-urea as a white solid. [α]D20=+18.8° (c=1.07, CHCl3), ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [S:1]1[CH:3]([C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH2:5])[CH2:2]1>C1C=CC=CC=1>[CH2:6]([C:4]1[CH2:3][S:1][CH2:2][CH:5]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=C(CCCCCC)C1CS1
Solvent: c1ccccc1
Product: CCCCCCC1=CCSC1
Yield: 95 %

Procedure:
A solution of 1,2-epithio-3-hexyl-3-butene (40 mg, 0.24 miol) and Cu(hfacac)2 (1.2 mg, 2.4 μmol) in benzene (1 mL) was heated at 100° C. for 1 h in a pressure tube. Concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography (n-pentane) to give 3-Hexyl-2,5-dihydrothiophene (38 mg, 95%) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([CH2:15][CH:16]=[CH2:17])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1CCC[CH2:19]1.C[Li].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)C>[Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:19])([OH:14])[C:11]([CH2:15][CH:16]=[CH2:17])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: C=CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C
Solvent: CCOCC
Product: C=CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1(C)O
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution mixture of 5 g of (RS)-3-allyl-4-oxo-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether and 50 ml of tetrahydrofuran was added under nitrogen stream 23.7 ml of 1.07 M diethyl ether solution of methyllithium at -78° C. and the resulting mixture was stirred at the same temperature for 2 hours. Then, the reaction liquid was poured into ice-cooled 5% aqueous solution of citric acid and extracted two times with diethyl ether. The combined ether layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 4.7 g of (1RS,4RS)-3-allyl-4-methyl-4-hydroxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 84%
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:1][C:13]1[S:9][C:10]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: c1csc(-c2cccs2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Brc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
N-Bromosuccinimide (NBS, 1.12 g, 6.3 mmol) was added in small portions to a stirred solution of 1.0 g (6.01 mmol) of 2,2′-bithiophene in 10 ml of glacial acetic acid and 10 ml of chloroform. After stirring for 1 h at room temperature, the mixture was poured into ice-water and extracted into chloroform (75 ml). The organic layer was washed with aqueous sodium bicarbonate solution, water, and then dried over magnesium sulfate and evaporated. The residue was subjected to flash chromatography on silica gel using hexane to give 1.3 g (88%) of a light green solid, m.p. 55-56° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[ClH:10].[NH2:11][CH2:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.O>[ClH:10].[NH2:5][CH2:4][C:3]1[CH:6]=[C:7]([C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]#[N:11])[CH:8]=[CH:9][CH:2]=1
Reactant: NCc1cccc(B(O)O)c1
Reactant: N#Cc1ccccc1Br
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccccc1-c1cccc(CN)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
A solution of 2-bromobenzonitrile (1.10 g), 3-aminomethylphenylboronic acid hydrochloride (1.13 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (0.10 g), and tripotassium phosphate (5.20 g) in a 4:1 dimethoxyethane-water mixed solvent (60 mL) was stirred at 70° C. for 3 hours. 2-Bromobenzonitrile (0.070 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (0.10 g) were added thereto, and the mixture was stirred at 70° C. for 2 hours. The reaction solution was cooled to room temperature, filtered through celite, and then separated into organic and aqueous layers. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated saline, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (Biotage Ltd., elution solvent: dichloromethane/methanol), and a fraction containing the desired compound was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and concentrated hydrochloric acid was added to the solution. The resulting suspension was filtered, and the product collected by filtration was washed with ethyl acetate and dried under reduced pressure to obtain the title compound (0.483 g).
Reaction SMILES: [CH:1]([C@H:4]1[N:9]([C:10]2[N:15]=[C:14]([CH3:16])[C:13]([C:17](OC)=[O:18])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:21]3[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[C:25]([C:32](OC)=[O:33])=[CH:24][C:22]=3[N:23]=[C:5]12)([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[OH:33][CH2:32][C:25]1[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:27][C:21]2[N:6]3[CH2:7][CH2:8][N:9]([C:10]4[N:15]=[C:14]([CH3:16])[C:13]([CH2:17][OH:18])=[CH:12][N:11]=4)[C@H:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[N:23][C:22]=2[CH:24]=1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(=O)OC)c(C)n1)[C@@H]3C(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cc1nc(N2CCn3c(nc4cc(CO)c(S(C)(=O)=O)cc43)[C@H]2C(C)C)ncc1CO
Temperature: -78 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To a solution of (R)-methyl 1-isopropyl-2-(5-(methoxycarbonyl)-4-methylpyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (15 mg, 0.03 mmol) in toluene (2 mL) was added DIBAL H (1M in toluene, 0.3 mL, 0.3 mmol) at −78° C. The mixture was stirred at −78° C. for 2 h and then rt for 30 mins. Sat. NH4Cl solution (5 mL) was added slowly at 0° C. and the mixture was filtered. The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-methylpyrimidin-5-yl)methanol (1.6 mg, 12.3% yield) as a colorless oil. LC-MS MS (ESI) m/z 446.2 [M+H]+. 1H NMR (CD3OD 400 MHz): δ 8.26 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 6.00 (d, J=8.8 Hz, 1H), 5.17 (s, 2H), 4.90-4.79 (m, 1H), 4.67 (s, 2H), 4.45-4.44 (m, 1H), 4.25-4.18 (m, 1H), 4.15-4.04 (m, 1H), 3.31 (s, 3H), 2.58-2.49 (m, 1H), 2.45 (s, 3H), 1.25 (d, J=6.8 Hz, 3H), 1.12 (d, J=6.8 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:20][CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]=3[CH:9]2[C:21]2[CH:22]=[CH:23][C:24]3[O:28][CH2:27][CH2:26][C:25]=3[CH:29]=2)=[N:6][CH:7]=1.[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH3:36].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:28]1[C:24]2[CH:23]=[CH:22][C:21]([CH:9]3[C:10]4[NH:11][C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:18]=4[CH2:19][CH2:20][N:8]3[C:5]3[N:4]=[CH:3][C:2]([C:35]4[N:31]([CH3:30])[C:32]([CH3:36])=[N:33][CH:34]=4)=[CH:7][N:6]=3)=[CH:29][C:25]=2[CH2:26][CH2:27]1
Reactant: Cc1nccn1C
Reactant: Brc1cnc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)CCO3)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ncc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)CCO4)nc2)n1C

Procedure:
2-(5-bromo-2-pyrimidinyl)-1-(2,3-dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-1H-β-carboline (0.45 g, 1.00 mmol), 1,2-dimethyl-1H-imidazole (0.18 g, 1.87 mmol), Pd(OAc)2 (12 mg, 0.05 mmol), PPh3 (26 mg, 0.1 mmol) and K2CO3 (0.28 g, 2 mmol) were stirred in 3.5 mL DMF at 140° C. for 14 hours. The mixture was poured into aqueous 10% NaOH solution (50 mL). The resulting solution was extracted with CH2Cl2 (3×50 mL) and dried over Na2SO4. Purification by preparative TLC yielded the title product as yellow powder.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:5]([OH:9])[C:6]([OH:8])=[O:7].[CH:17](O)([CH3:19])[CH3:18]>>[ClH:1].[CH:17]([O:7][C:6](=[O:8])[C@H:5]([OH:9])[C@@H:4]([NH2:3])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:19])[CH3:18]
Reactant: CC(C)O
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(=O)O
Agent: Cl
Product: CC(C)OC(=O)[C@H](O)[C@@H](N)CC1CCCCC1

Procedure:
Hydrogen chloride was passed into a suspension of 1.0 g of (2R, 3S)-3-amino-4-cyclohexyl-2-hydroxy butyric acid hydrochloride in 10 ml of isopropyl alcohol with stirring under ice-cooling, and the mixture was heated under reflux for 2 hours. After evaporation of the reaction mixture, benzene was added to the residue and the mixture was evaporated under reduced pressure. The residue was dissolved in 10 ml of ethyl acetate and the precipitated crystals were collected by filtration to obtain 1.0 g of (2R, 3S)3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester hydrochloride as a white powder.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:6][C@@H:5]1[OH:37])[CH3:2].[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1.C(O)C>[C:38]([O:37][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][C:24]([O:26][CH2:27][C:28]([Cl:29])([Cl:30])[Cl:31])=[O:25])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:6]1)(=[O:40])[CH3:39]
Reactant: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]12C

Procedure:
Ethyl 2β-ethoxy-3α-hydroxy-11α-(2,2,2-trichloroethoxy-carbonylamino)-5α-androstane-17β-carboxylate (1.83 g) in pyridine (6 ml) was treated with acetic anhydride. After b 18 h. the reaction mixture was diluted with ethanol and evaporated to give a foam (1.91 g). A portion was purified by preparative t.l.c. in ethyl acetate/Petrol (1:2) to give the title compound, [α]D +30.7°, νmax 1724 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54]O.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:54][CH2:53][N:52]([CH3:56])[CH3:51])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(O)cc2n1C(=O)OC(C)(C)C
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(OCCN(C)C)cc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
100 mg 6-hydroxy-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester and 175 mg triphenylphosphine are dissolved in 7 mL toluene and 2 mL THF. After dropwise addition of 84 μL 2-dimethylaminoethanol and 123 □L diethyl azodicarboxylate, the reaction mixture is stirred at room temperature for 5 hours. The solvent is removed in vacuo and the residue dissolved in dichloromethane. The organic phase is ished with water and the aqueous phase extracted twice with dichloromethane. The combined organic phases are dried over MgSO4 and concentrated in vacuo. Purification by HPLC afforded 35 mg (43%) 6-(2-dimethylaminoethoxy)-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N:9]([OH:11])[OH:10])=[CH:4][N:3]=1.[NH2:12][CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:5]([N:9]([OH:11])[OH:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: ON(O)c1cnc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1nc(Cl)ncc1N(O)O
Reaction time: 1 h
Yield: 71.3 %

Procedure:
2,4-Dichloro-5-(dihydroxyamino)pyrimidine (2.5 g, 12.75 mmol), 1,1-dimethylethyl (2S)-2-(aminomethyl)-1-pyrrolidinecarboxylate (1.277 g, 6.38 mmol), and DIEA (1.114 mL, 6.38 mmol) were dissolved in DCM (75 mL). The mixture was stirred for 1 h, and when the reaction was complete as determined by LCMS, the solution was concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 0-100% ethyl acetate/hexanes) to provide 1,1-dimethylethyl (2S)-2-({[2-chloro-5-(dihydroxyamino)-4-pyrimidinyl]amino}methyl)-1-pyrrolidinecarboxylate (1.6362 g, 71%). LCMS: (M+H)+: 357.8.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:5][C:6]=1[NH:7][C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:28][CH3:29].O>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:5][C:6]=1[N:7]([CH2:28][CH3:29])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12]
Reactant: CSCC(C)C(=O)Nc1sc(-c2cccnc2)nc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)C(C)CSC)c1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a dry 50 ml round bottom flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 1.0 g (3.05 mmoles) of N-(4-chloro-2-(pyridin-3-yl)-1,3-thiazol-5-yl)-2-methyl-3-(methylthio)propanamide and 10 mLs of anhydrous N,N-dimethyl formamide. To the resulting solution was then added 1.1 g (3.36 mmoles) of cesium carbonate powder in one portion, followed by the dropwise addition of 0.523 g (3.36 mmoles) of iodoethane in 5 mLs of anhydrous N,N-dimethyl formamide. The heterogeneous mixture was stirred at ambient temperature for 12 hours. Analysis of an aliquot indicated incomplete reaction. An additional 100 ul of iodoethane was added and the reaction was heated at 60° C. for 3 hours, then poured into 200 mLs of water and extracted with methylene chloride (3×100 mLs). The combined organic extracts were washed with water (100 mLs), saturated aqueous sodium chloride solution (100 mLs) dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum on a rotary evaporator. The crude product was purified by silica gel flash chromatography, eluting with a gradient of 100% hexane to 100% ethyl acetate over 20 minutes to yield a yellow oil which crystallized upon standing (0.38 g, 35%): mp 80-81° C.; 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J=1.9 Hz, 1H), 8.72 (dd, J=4.8, 1.4 Hz, 1H), 8.22 (ddd, J=8.0, 2.2, 1.8 Hz, 1H), 7.43 (ddd, J=8.0, 4.8, 0.6 Hz, 1H), 4.03-3.80 (m, 1H), 3.80-3.59 (m, 1H), 2.97-2.68 (m, 2H), 2.60-2.39 (m, 1H), 2.03 (s, 3H), 1.30-1.16 (m, 6H); 13C NMR (101 MHz, DMSO-d6) δ 175.66, 162.63, 151.89, 147.14, 138.19, 133.49 133.23, 128.58, 123.90, 44.81, 38.94, 37.93, 18.16, 16.83, 12.90.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:25][C:23]([F:24])([F:26])[C:20]1[CH:21]=[CH:22][C:17]([O:16][CH:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][OH:7])[CH2:15][CH2:14]2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(OC2CCN(CCOC3CCCCO3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: OCCN1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Temperature: 65 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
A mixture of 1-[2-(tetrahydropyran-2-yloxy)ethyl]-4-(4-trifluoromethylphenoxy)piperidine (1.69 g, 4.53 mmol) prepared in Reference Example 13 and pyridinium p-toluenesulfonate (114 mg, 0.45 mmol) in ethanol (50 ml) was stirred at 60 to 70° C. for 6 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, 10% sodium hydroxide aqueous solution was added, and the mixture was extracted with methylene chloride. The extract was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford 2-[4-(4-trifluoromethylphenoxy)piperidin-1-yl]ethanol (1.19 g, yield 91%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=2)[C:16]([CH3:19])([CH3:18])[O:17]\1.[NH:28]1[CH2:37][CH2:36][CH:31]([C:32]([O:34][CH3:35])=[O:33])[CH2:30][CH2:29]1.C(O)(=O)C.C([BH3-])#N.[Na+].C1COCC1>CN(C=O)C.CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24][N:28]3[CH2:37][CH2:36][CH:31]([C:32]([O:34][CH3:35])=[O:33])[CH2:30][CH2:29]3)=[CH:22][CH:21]=2)[C:16]([CH3:18])([CH3:19])[O:17]\1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(C=O)cc1
Reactant: COC(=O)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CCN(Cc2ccc(C3=C/C(=C4\C(=O)Nc5cc(F)c(F)cc54)OC3(C)C)cc2)CC1
Reaction time: 16 h

Procedure:
A mixture of 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde (60 mg, 0.16 mmol), methyl isonipecotate (50 mg, 0.35 mmol), and 100 mg of 4 Å molecular sieves in 5 mL of anhydrous DMF was stirred under nitrogen for 16 hours. Acetic acid (20 mg) and 1M sodium cyanoborohydride/THF solution (0.35 mL, 0.35 mmol) were then added. The mixture was diluted with 5 mL of anhydrous methanol, stirred at room temperature for 1 hour, and poured into 100 mL of water with stirring. The resulting precipitates were filtered, washed with water, and dried in vacuo to give the crude product, which was purified through silica gel column with 1-5% MeOH/CHCl3 to give methyl 1-{4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}piperidine-4-carboxylate as yellow solid. Yield: 50 mg, 62%.