Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[CH:8]1([N:11]2[C:15]3[C:16]([O:32][C@@H:33]([C@H:35]4[CH2:39][NH:38][C:37](=[O:40])[CH2:36]4)[CH3:34])=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][N:21]=4)=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:10][CH2:9]1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:1]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:24]=[CH:25][C:20]([C:18]3[CH:17]=[C:16]([O:32][C@@H:33]([C@H:35]4[CH2:39][NH:38][C:37](=[O:40])[CH2:36]4)[CH3:34])[C:15]4[N:11]([CH:8]5[CH2:9][CH2:10]5)[CH:12]=[N:13][C:14]=4[CH:19]=3)=[N:21][CH:22]=2)[CH2:31][CH2:30]1)(=[O:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H](Oc1cc(-c2ccc(N3CCNCC3)cn2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(c2ccc(-c3cc(O[C@H](C)[C@H]4CNC(=O)C4)c4c(c3)ncn4C3CC3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the TFA salt of (R)-4-((R)-1-((1-cyclopropyl-5-(5-(piperazin-1-yl)pyridin-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (45 mg, 0.1 mmol) in DCM (1 mL) and TEA (0.07 mL, 0.5 mmol) was added acetic anhydride (0.014 mL, 0.15 mmol). The reaction was stirred at rt for 2 h. The mixture was then concentrated and purified by prep-HPLC (MeCN:water gradient; TFA modified) to give (R)-4-((R)-1-((5-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-1-cyclopropyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: 3.59 as a TFA salt. The salt was then converted to the free base by treatment with MP carbonate resin.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[CH:4][CH:3]=1.[N:18]1[NH:19][C:20](=O)[CH:21]=[CH:22][CH:23]=1.CNCCNC>N1C=CC=CC=1.C(Cl)Cl.[Cu]I>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][NH:19]2)=[CH:3][CH:4]=1
Reactant: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: O=c1cccn[nH]1
Agent: [Cu]I
Agent: CNCCNC
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(N2C=CC=CN2)cc1

Procedure:
A solution of the product from Example 34F, 1-{[(1S,2S)-2-(4-bromophenyl)cyclopropyl]methyl}-(2S)-2-methylpyrrolidine (100 mg, 0.340 mmol), pyridazin-3(2H)-one (52.3 mg, 0.544 mmol), N1,N2-dimethylethane-1,2-diamine (0.088 mL, 0.816 mmol) and copper(I) iodide (78 mg, 0.408 mmol) in pyridine (2 mL) under a nitrogen atmosphere in a sealed vial was heated in an oil bath to 135° C. for 16 hours. The reaction mixture was cooled and diluted with DCM (10 mL), filtered through diatomaceous earth and washed with DCM. The filtrate was washed sequentially with H2O, 28-30% NH4OH (10 mL×2), and H2O, dried with MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with concentrated NH4OH/MeOH/DCM (0.4/4/96) to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 0.90-0.97 (m, 1H), 1.03-1.09 (m, 1H), 1.15 (d, J=6 Hz, 3H), 1.23-1.33 (m, 1H), 1.39-1.49 (m, 1H), 1.70-1.80 (m, 2H), 1.82-2.05 (m, 3H), 2.26-2.42 (m, 2H), 3.16 (dd, J=12 Hz, J=6 Hz, 1H), 3.21-3.28 (m, 1H), 7.07 (d, J=6 Hz, 2H), 7.21 (dd, J=6 Hz, J=1.5 Hz, 2H), 7.43 (d, J=6 Hz, 2H), 7.47 (dd, J=9 Hz, J=3 Hz, 1H), 8.02 (dd, J=6 Hz, J=1.5 Hz, 1H). MS (DCl—NH3) m/z 310 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:34][C@H:35]([C:56]1[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=1)[C@H:36]([NH:40][C:41](=[O:55])[C@@H:42]([NH:45][C:46](=[O:54])[CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[CH2:43][OH:44])[C:37](O)=[O:38].[NH2:64][C@@H:65]([CH2:72][C:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=1)[C:66]([C@@:68]1([CH3:71])[CH2:70][O:69]1)=[O:67]>CN(C=O)C>[C:73]1([CH2:72][C@H:65]([NH:64][C:37](=[O:38])[C@@H:36]([NH:40][C:41](=[O:55])[C@@H:42]([NH:45][C:46](=[O:54])[CH2:47][N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH2:43][OH:44])[C@H:35]([OH:34])[C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)[C:66]([C@@:68]2([CH3:71])[CH2:70][O:69]2)=[O:67])[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=1
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)O)cc1
Reactant: C[C@]1(C(=O)[C@@H](N)CC2=CCCCC2)CO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)N[C@@H](CC2=CCCCC2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
Sequentially HATU (537 mg, 1.41 mmol) and DIEA (1.02 mL, 5.88 mmol) were added to a 0° C. solution of (2S,3R)-3-hydroxy-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(4-methoxyphenyl)propanoic acid (500 mg, 1.18 mmol) and (S)-2-amino-3-(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan-1-one (TFA salt, 364 mg, 1.18 mmol) in DMF (10 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (DCM/MeOH=50:1 to 30:1) twice to afford (2S,3R)-N-((S)-3-(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(4-methoxyphenyl)propanamide (500 mg, 57% yield) as a colorless solid. 1H NMR (300 MHz, DMSO-d6): δ 7.97 (d, J=7.5 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.26 (d, J=8.7 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H), 5.61 (d, J=4.5 Hz, 1H), 5.40-5.38 (m, 1H), 5.23-5.21 (m, 1H), 5.04-5.02 (m, 1H), 4.62-4.51 (m, 1H), 4.45-4.35 (m, 2H), 3.71 (s, 3H), 3.68-3.41 (m, 6H), 3.33 (s, 1H), 3.21 (d, J=5.1 Hz, 1H), 2.97-2.80 (m, 3H), 2.39-2.21 (m, 4H), 2.11-1.71 (m, 4H), 1.56-1.40 (m, 4H), 1.26 (s, 3H), 1.28-1.22 (m, 1H). MS(EI) for C31H44N4O9, found 617.4 (MH)+.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:17])[C:11](=[C:14]([Cl:16])[CH:15]=1)[CH:12]=O.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Cl:16][C:14]1[CH:15]=[C:8]([Cl:7])[CH:9]=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]=1/[CH:12]=[CH:15]/[CH:8]1[O:2][C:1](=[O:4])[CH2:11][CH:10]([OH:17])[CH2:9]1
Reactant: BrCc1ccccc1
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CC(O)CC(/C=C/c2c(Cl)cc(Cl)cc2OCc2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 143.1 %

Procedure:
Potassium carbonate (9.4 g, 67.8 mmole) was added to a stirred solution of 4,6-dichlorosalicylaldehyde (10.8 g, 56.5 mmole) in dimethylformamide (80 ml). The resulting mixture was stirred at 60° for 30 minutes and treated with benzyl bromide (10.6 g, 62.1 mmole). This mixture was stirred one hour at 60° C. and then poured into ice water (1000 ml) to give the title compound (15.9 g, 100%) which melted at 98°-100° C. after recrystallization from hexane. pmr (CDCl3) δ5.10 (2H, s), 7.33 (5H, s), 10.40 (H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].CN(C(ON1N=[N:31][C:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:40](N(CC)C(C)C)(C)[CH3:41].CN(C=O)C.[ClH:54]>C(OCC)C>[ClH:54].[N:30]12[CH2:29][CH2:28][CH:27]([CH2:40][CH2:41]1)[C@@H:26]([NH:31][C:12]([C:10]1[S:11][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=3[CH:9]=1)=[O:14])[CH2:25]2
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2s1

Procedure:
420 mg (1.88 mmol) of 5-nitro-1-benzothiophene-2-carboxylic acid, 374.7 mg (1.88 mmol) of R-3-aminoquinuclidine dihydrochloride, 858.6 mg (2.26 mmol) of HATU, 875.5 mg (6.78 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted according to the general procedure (variant B). The resulting precipitate is suspended in 1N HCl in diethyl ether, filtered off, washed twice with dichloromethane and dried under high vacuum. 523 mg (75.6% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:28]=[C:27]([CH3:29])[C:18]([O:19][CH2:20][CH2:21]OS(C)(=O)=O)=[C:17]([CH2:30][CH3:31])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:32])[N:5]=1)[CH3:2].[NH3:35]>CO>[NH2:35][CH2:21][CH2:20][O:19][C:18]1[C:27]([CH3:29])=[CH:28][C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[C:6]([CH3:32])[N:5]=[C:4]([N:3]([CH2:33][CH3:34])[CH2:1][CH3:2])[N:9]=3)[O:14][N:13]=2)=[CH:16][C:17]=1[CH2:30][CH3:31]
Reactant: N
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OCCOS(C)(=O)=O
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OCCN
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of methanesulfonic acid 2-{4-[5-(2-diethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethyl ester (850 mg, 1.74 mmol), derived from Example 102, in 7M NH3 in MeOH (20 mL) is stirred at 60° C. for 18 h. Volatiles are then evaporated and the residue is purified by CC (eluting with EA/MeOH 10:1) to give (4-{-3-[4-(2-amino-ethoxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-6-methyl-pyrimidin-2-yl)-diethyl-amine as a yellow solid (700 mg); LC-MS: tR=0.92 min; [M+H]+=410.95.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[O:7][CH:8]=[CH:9][C:10]=1[CH:11]=[O:12].C(O)=O.C([O-])(O)=O.[Na+].CCOC(C)=O>O>[O:7]1[CH:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:6]1[CH:2]=[O:1]
Reactant: O=Cc1ccoc1C1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=Cc1ccoc1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 114.1 %

Procedure:
2-(3-Bromo-2-furyl)-1,3-dioxolane (438 mg, 2.0 mmol) is dissolved in Et2O (5 mL) in a dry flask under nitrogen, cooled to −78° C., treated dropwise with tert-butyllithium (2.59 mL, 4.4 mmol) and stirred for 1 h. DMF (178 μL, 2.3 mmol) in Et2O (2 mL) is added dropwise, the mixture stirred for 4 h at −78° C., then treated with oxalic acid dihydrate (504 mg, 4.0 mmol) followed by water (2 mL). The cooling bath is removed and the mixture allowed to warm to RT over 1 h. The mixture is diluted with water (20 mL) and EtOAc (20 mL), the layers are separated and the aqueous layer extracted with EtOAc (1×20 mL). The organics are dried over Na2SO4 and concentrated to a yellow oil. The crude material is chromatographed over 12 g slurry-packed silica gel, eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 228 mg (68%) of 2-(1,3-dioxolan-2-yl)-3-furaldehyde as a pale yellow oil. MS (EI) m/z: 168 (M+). 2-(1,3-Dioxolan-2-yl)-3-furaldehyde (2.91 g, 17.31 mmol) is combined with formic acid (17 mL, 451 mmol) and water (4.25 mL) and stirred at RT for 18 h. The mixture is slowly transferred into a solution of NaHCO3 (45 g, 541 mmol) in water (600 mL), then stirred for 0.5 h. EtOAc (200 mL) is added, the layers separated and the aqueous layer extracted with EtOAc (2×200 mL). The combined organics are dried over Na2SO4 and concentrated to a yellow oil (3.28 g). The crude material is chromatographed over 90 g slurry-packed silica gel, eluting with 20% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 2.45 g of furan-2,3-dicarbaldehyde slightly contaminated with ethylene glycol diformate as a yellow oil. 1H NMR (CDCl3): δ 7.00 (d, J=2 Hz, 1H), 7.67 (d, J=2 Hz, 1H), 10.07 (s, 1 H), 10.49 (s, 1 H) ppm.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Cl:11][C:12]([Cl:20])([Cl:19])[CH2:13][O:14][C:15](=[O:18])[CH:16]=[CH2:17].COC(=O)C([Cl:34])CC1C=CC(CO)=CC=1>>[Cl:11][C:12]([Cl:20])([Cl:19])[CH2:13][O:14][C:15](=[O:18])[CH:16]([Cl:34])[CH2:17][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC(Cl)(Cl)Cl
Reactant: COC(=O)C(Cl)Cc1ccc(CO)cc1
Reactant: Nc1ccc(CCO)cc1
Product: O=C(OCC(Cl)(Cl)Cl)C(Cl)Cc1ccc(CCO)cc1

Procedure:
The title compound was prepared from 2-(4-amino phenyl)ethanol (6.68 g, 48.7 mmol) and commercially available acrylic acid 2,2,2-trichloroethylester (19.82 g, 97.44 mmol) in the same manner as described for 2-chloro-3-(4-hydroxymethyl-phenyl)-propionic acid methyl ester. The crude product was purified by repeated flash chromatography using DCM/MeOH 95:5 as the eluent and the product was obtained as an oil (1.87 g, 10.7%). 1H NMR (300 MHz, CDCl3): δ 7.15-7.29 (m, 4H), 4.54-4.59 (t, 1H), 3.82-3.85 (m, 3H), 3.38-3.45 (dd, 1H), 3.18-3.25 (dd, 1H), 2.79-2.87 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1(C)C=CC=CC=1>ClCCl.[Cu]I>[CH3:1][C:2]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: C1CNCCN1
Reactant: CC(C)(C(=O)c1ccc(F)cc1)N1CCOCC1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C(=O)c1ccc(N2CCNCC2)cc1)N1CCOCC1
Temperature: 25 °C

Procedure:
4.2 g of 2-methyl-1-[4-fluorophenyl]-2-morpholinopropan-1-one (0.0167 moles), 5.75 g of piperazine (0.0669 moles), 0.063 g of copper (I) iodide and 15 ml of toluene were mixed in a three necked flask equipped with a stirrer, nitrogen inlet, condenser, nitrogen outlet and a temperature probe. The mixture was heated to reflux for a total of 24 hours under a constant flow of nitrogen gas. The mixture was then cooled to room temperature, after which it was dissolved in 75 ml of dichloromethane. The mixture was then extracted with 100 ml of a saturated aqueous sodium chloride solution and then with 2×100 ml of water. The dichloromethane layer was then dried using anhydrous magnesium sulphate. The magnesium sulphate was removed by filtration and the organic solvent was then removed on a rotary evaporator to yield the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][NH:17][C:16](=[O:19])[C:15]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)[CH2:23][CH2:24]N(C)C.C([Li])CCC.C(I)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([CH2:23][CH3:24])([CH3:20])[C:16]([OH:19])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C2CCN(C(=O)OC(C)(C)C)CC2)[nH][nH]c1=O
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1(C)C(O)=NN=C1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 255 mg (0.9 mmol) of 1-tert-butoxycarbonyl-4-(4-methyl-(1H)-pyrazol-3-one-5-yl)piperidine (from Piperidine 15, Step C) and 0.155 mL (1.0 mmol) of freshly distilled tetramethylethylene diamine in 3 mL of THF at −78° C. was treated with 0.8 mL (2.0 mmol) of 2.5 M n-butyl lithium in hexanes (J. Med. Chem. 1996, 39, 3920–3928). After stirring for 15 minutes at −78° C., the reaction was warmed to 0° C. for 15 minutes. Upon recooling to −78° C., 0.11 mL (1.3 mmol) of ethyliodide was added. After warming to rt and stirring for 19 hours, the reaction was cooled to 0° C. and quenched with 1 N HCl. The reaction mixture was partitioned between 100 mL of EtOAc and 100 mL of 1 N HCl. After separating phases, the organic layer washed with 100 mL of brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 99:1 v/v CH2Cl2/MeOH, 98:2 v/v CH2Cl2/MeOH and 97:3 v/v CH2Cl2/MeOH as the gradient to afford the title compound as a white solid: RF: 0.40 (19:1 v/v CH2Cl2/MeOH); 1H-NMR (500 MHz) δ 0.73 (t, J=7.4, 3H), 1.26 (s, 3H), 1.47 (s, 9H), 1.59–1.85 (m, 6H), 2.38 (m, 1H), 2.76–2.81 (m, 2H), 4.16–4.21 (m, 2H), 8.61 (br s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:15]4=[N:16][S:17](=[O:21])(=[O:20])[CH2:18][CH2:19][N:14]4[CH:13]=[CH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].I[CH2:25][CH3:26].O>CN(C=O)C.CCOC(C)=O>[CH2:25]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:15]4=[N:16][S:17](=[O:21])(=[O:20])[CH2:18][CH2:19][N:14]4[CH:13]=[CH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:26]
Reactant: CCI
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc4[nH]ccc4c3)C2=N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccc2cc(C3=CC=CN4CCS(=O)(=O)N=C34)ccc21
Reaction time: 0.17 h

Procedure:
To a mixture of 9-(1H-indol-5-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (131 mg) in DMF (dry) (15 ml) was added NaH (60%, 18.38 mg) at room temperature. The mixture was stirred at the same temperature for 10 min. Iodoethane (0.039 mL) was added and the mixture was stirred at room temperature overnight. Water and EtOAc were added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with MeOH in EtOAc) to give the title compound (34.6 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:27])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>O1CCCC1.O.C(OCC)(=O)C>[N:42]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[N:17]=[CH:18][N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:2]([F:27])([F:1])[C:3]([F:6])([F:5])[F:4])=[CH:9][CH:10]=3)[N:15]=2)=[CH:20][CH:21]=1)=[N+:43]=[N-:44]
Reactant: OCc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
To (4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanol (2.00 g, 5.19 mmol) in tetrahydrofuran (25 mL) was added diphenylphosphoryl azide (1.30 g, 5.71 mmol), followed by dropwise addition of 1,8-diazabicycloundec-7-ene (0.861 mL, 5.71 mmol). The mixture was stirred at room temperature for 6 hours. The mixture was diluted with water and ethyl acetate. The organic phase was separated and rinsed with brine, dried over magnesium sulfate, and concentrated to provide the title compound as a yellow solid (1.85 g, 83%): ESIMS m/z 411 ([M+H]+).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:26]([F:29])([F:28])[F:27])[CH:15]=[C:16]([C:17]4[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=4)[C:10]=3[N:9]=2)[CH2:6][CH2:5][N:4]([C:30]2[N:35]=[CH:34][C:33]([CH2:36][OH:37])=[CH:32][C:31]=2[C:38]([F:41])([F:40])[F:39])[CH2:3]1>O=[Mn]=O>[CH3:1][C@H:2]1[N:7]([C:8]2[NH:9][C:10]3[C:16]([C:17]4[CH:18]=[C:19]([F:25])[C:20]([F:24])=[C:21]([F:23])[CH:22]=4)=[CH:15][C:14]([C:26]([F:29])([F:28])[F:27])=[CH:13][C:11]=3[N:12]=2)[CH2:6][CH2:5][N:4]([C:30]2[N:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][C:31]=2[C:38]([F:41])([F:39])[F:40])[CH2:3]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2C(F)(F)F)CCN1c1nc2c(-c3cc(F)c(F)c(F)c3)cc(C(F)(F)F)cc2[nH]1
Agent: O=[Mn]=O
Product: C[C@@H]1CN(c2ncc(C=O)cc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
(6-{(3R)-3-Methyl-4-[6-trifluoromethyl-4-(3,4,5-trifluoro-phenyl)-1H-benzoimidazol-2-yl]-piperazin-1-yl}-5-trifluoromethyl-pyridin-3-yl)-methanol (1.18 g, 2.0 mmol, Example 183 h) reacted with MnO2 (3.48, 40 mmol, Aldrich) under the conditions of Example 154a to give the title compound as a white solid, which was used in the next step without additional purification. MS (ESI, pos. ion) m/e: 588 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=O)([O-:3])=[O:2].[CH3:15][C:16]([CH3:18])=O.[NH3:19]>>[CH3:15][C:16]1[CH:18]=[C:7]([C:8]([NH2:19])=[O:13])[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:9]=1
Reactant: CC(C)=O
Reactant: N
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Product: Cc1cc(C(N)=O)c2cc([N+](=O)[O-])ccc2n1
Temperature: 100 °C
Yield: 79 %

Procedure:
To 5-nitroisatin (19.21 g, 0.1 mol) were added acetone (36.7 ml, 0.5 mol) and aqueous ammonia (100 ml) and the mixture was heated in an autoclave at 100° C. for 12 hr. The reaction mixture was cooled to room temperature and the resulting crystals were collected by filtration and washed with water. The obtained crystals were dried by heating under reduced pressure to give 2-methyl-6-nitroquinoline-4-carboxamide (18.30 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:18]([B-](F)(F)F)=[CH2:19].[K+].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:18]=[CH2:19])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[B-](F)(F)F
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A mixture of 1.0 g of the compound [1-1], 892 mg of potassium vinyltrifluoroborate, 468 mg of dichlorobis(triphenylphosphine) palladium (II), 10 mL of 2.0M aqueous sodium carbonate solution, and 20 mL of N,N-dimethylformamide, was stirred overnight at 90° C. After standing to cool, water was added to the reaction solution, which was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-75/25), to obtain 485 mg of tert-butyl[(1S)-1-(4-vinylphenyl)ethyl]carbamate [5-1] (hereinafter, referred to as the compound [5-1]) as a white solid.
Reaction SMILES: [H-].[Na+].[S:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH2:10](I)[CH3:11]>CN(C=O)C.O>[CH2:10]([N:5]1[C:6](=[O:8])[CH2:7][S:3][C:4]1=[O:9])[CH3:11]
Reactant: O=C1CSC(=O)N1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)CSC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a 100 ml three necked round bottom flask, sodium hydride (60% in paraffin) (0.188 g, 0.00470 mole) was taken in DMF (2.0 ml). Thiazolidine-2,4-dione (0.5 g, 0.00427 mole) in DMF (3 ml) was slowly added at 0° C. over 15 min under nitrogen atmosphere. After addition was complete, the reaction mixture was stirred for 1 hr at 50° C. The reaction was then cooled to 0° C., followed by drop wise addition of ethyl iodide (0.41 ml, 0.00512 mole) at 0° C. The reaction mixture was warmed up to RT and stirred for 1 hr. After completion of the reaction, the reaction mixture was poured in water and aq. layer was extracted with ethyl acetate. Organic layers were combined and washed with brine solution, dried over Na2SO4, filtered and concentrated to afford crude product which was purified using column purification by eluting the compound with 5% ethyl acetate in hexanes to yield 0.5 g of 3-ethylthiazolidine-2,4-dione.