Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:15])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nccc2ccc(Br)cc12
Solvent: ClC(Cl)Cl
Product: Clc1nccc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A solution of 7-bromoisoquinolin-1-ol (2.5 g, 11.1 mmol) and POCl3 (10.4 mL, 111 mmol) was stirred at 70° C. for 2.5 h. The reaction mixture was cooled to room temperature, poured into ice water, and the solution was stirred overnight. The aqueous mixture was diluted with chloroform, washed with a saturated solution of NaHCO3, saturated NaCl, dried (MgSO4), filtered, and concentrated under reduced pressure to afford 7-bromo-1-chloroisoquinoline (2.3 g): 1H NMR (300 MHz, DMSO-d6) δ 8.39-8.36 (m, 2H), 8.09-8.02 (m, 2H), 7.95 (d, J=6 Hz, 1H).
Reaction SMILES: [F:1][CH2:2][O:3][C:4]1[CH:40]=[CH:39][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([N:13]([CH2:21][C@H:22]([O:31][Si](CC)(CC)CC)[CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][C:6]=2[CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:1][CH2:2][O:3][C:4]1[CH:40]=[CH:39][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([N:13]([CH2:21][C@H:22]([OH:31])[CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][C:6]=2[CH:5]=1
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(OCF)cc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(OCF)cc2C1
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
Under nitrogen, to a solution of N-(3-fluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-tert-butoxycarbonyl-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-amine (300 mg) in tetrahydrofuran (5 ml) was added tetra-n-butylammonium fluoride (1M in tetrahydrofuran, 0.58 ml) at 5° C., and the mixture was stirred at the same temperature for 15 minutes. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give N-(3-fluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-tert-butoxycarbonyl-[(2S)-2-hydroxy-3-phenoxypropyl]amine (227 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1.C(N(CC)C(C)C)(C)C.ClCCC[NH:28][C:29]([C:31]1[C:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:33][O:34][C:35]=1[CH3:36])=[O:30].CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:32]3([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]([C:29]([NH2:28])=[O:30])=[C:35]([CH3:36])[O:34][NH:33]3)[CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(F)ccc1N1CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NCCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC1=C(C(N)=O)C(c2ccccc2)(N2CCN(c3ccc(F)cc3C)CC2)NO1
Temperature: 120 °C
Yield: 48.1 %

Procedure:
A stirred mixture of 0.380 g of Compound 31A, 0.50 mL of N,N-diisopropylethylamine, 0.545 g of Compound 2B and 3 mL of N,N-dimethylformamide was heated at 120° C. for 5 h. The solution was diluted with water (60 mL) and extracted with dichloromethane (3×30 mL); the organic layer was washed with water (3×20 mL), dried (anhydrous sodium sulphate) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (chloroform-2N methanolic ammonia 100:1) affording 0.373 g (43.7%) of the title compound as an ivory solid. M.p. 139-141° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:27]5[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23][C:22]=5[C:21]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=5)=[N:20]4)[CH2:12][CH2:11]3)=[C:8]([C:42]([OH:44])=O)[S:7][C:6]=2[CH:45]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:79][CH2:80][CH2:81][N:82]1[CH2:87][CH2:86][O:85][CH2:84][CH2:83]1>CN(C=O)C>[N:82]1([CH2:81][CH2:80][NH:79][C:42]([C:8]2[S:7][C:6]3[CH:45]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[C:9]=2[CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:27]4[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:23][C:22]=4[C:21]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][CH:33]=4)=[N:20]3)[CH2:14][CH2:15]2)=[O:44])[CH2:87][CH2:86][O:85][CH2:84][CH2:83]1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)O)sc4cc(F)ccc34)CC2)C1
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)NCCN4CCOCC4)sc4cc(F)ccc34)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A stirred solution of 20 mg (0.03 mmol) of 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylic acid in 0.3 mL of dry DMF was treated with 14 mg (0.036 mmol) of HBTU and 8 μL (0.045 mmol) of DIEA. The solution was stirred for 5 min before the addition of 20 μL (0.15 mmol) of 4-(2-aminoethyl)morpholine. The reaction was stirred at room temperature for 30 min then partitioned between EtOAc (30 mL) and saturated NaHCO3 (20 mL). The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography (silica, 5-10% of (2 N NH3 in MeOH)/CH2Cl2) afforded 15 mg (65%) of a white solid. MS (electrospray), exact mass calculated for C37H44F4N6O4S2: 776.28; m/z found, 777.3 [M+H]+. 1H NMR (CDCl3, 400 MHz): 8.07 (br s, 1H), 7.73 and 7.66 (A and B of AB quartet, J=8.41 Hz, 4H), 7.50 (dd, J=8.41, 2.35 Hz, 1H), 7.14 (dt, J=8.61, 2.54 Hz, 1H), 6.64 (t, J=4.70 Hz, 1H), 4.56 (s, 2H), 4.16 (t, J=6.85 Hz, 2H), 3.80-3.67 (m, 7H), 3.53 (q, J=5.48 Hz, 2H), 3.03 (br m, 2H), 2.98 (t, J=5.67 Hz, 2H), 2.90 (s, 3H), 2.60 (t, J=5.87 Hz, 2H), 2.38 (br m, 4H), 2.12 (br m, 4H), 1.86-1.73 (br m, 3H).
Reaction SMILES: [CH2:1]([CH:8]1[C:14](=[O:15])[N:13]2[CH:9]1[CH2:10][CH:11]=[C:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([SH:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([CH:8]1[C:14](=[O:15])[N:13]2[CH:9]1[CH2:10][CH:11]([S:28][CH2:26][CH3:27])[CH:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)C1=CCC2C(Cc3ccccc3)C(=O)N12
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSC1CC2C(Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl 6-benzyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (138) (0.420 g) was dissolved in dry dimethylformamide (5 ml) and treated with ethanethiol (0.12 ml) and potassium carbonate (0.087 g). It was stirred at ambient temperature for 1 hour and the solvent was then distilled off under high vacuum. The residue was partitioned between ethyl acetate and brine, and the ethyl acetate solution was dried over sodium sulphate and concentrated. The residue was carefully chromatographed on a column of silica gel 60 (<230 mesh) eluting with ethyl acetate/60°-80° petroleum ether 3:7 to give three diastereoisomers of benzyl 6-benzyl-3-ethylthio-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate as gums. The first compound in increasing order of polarity was the 2α, 3α-isomer (139) (0.054 g); νmax (CHCl3) 2950, 1765 and 1745 sh; τ(CDCl3) 2.6-2.9 (10H, m, phenyls), 4.86 (2H, s, OCH2), 5.59 (1H, d J 5 Hz, C2-H), 6.1-6.5 (2H, m, C3-Hand C5-H), 6.6-7.2 (3H, m, C6-H), 7.50 (2H, q J 7 Hz, SCH2), 7.55 (1H, dt J 14 and 7 Hz, C4-H), 8.41 (1H, dt J 14 and 7 Hz, C4-H) and 8.84 (3H, t J 7 Hz, CH3); (M+ at m/e 395.1554. C23H25NO3S requires 395.1553). Next was the 2α, 3β-isomer (98) (0.260 g); νmax (CHCl3) 2960, 1765 and 1750 sh cm-1 ; τ(CDCl3) 2.6-2.9 (10H, m, phenyls), 4.87 (2H, s, OCH2), 5.26 (1H, d, J 7 Hz, C2-H), 6.10 (1H, td, J 51/2 & 21/2 Hz, C5-H), 6.52 (1H, td J9 and 7 Hz, C3-H), 6.7-7.2 (3H, m, C6-H, C8-H2), 7.47 (2H, q, J7 Hz, SCH2), 7.89 (2H, dd J9 and 51/2 Hz, C4-H2) and 8.85 (3H, t J7 Hz, CH3); (M+ at m/e 395.1553. C23H25NO3S requires 395.1553). Lastly was obtained the 2β, 3α -isomer (140) (0.112 g); νmax (CHCl3) 2960, 1770 and 1745 cm-1 ; τ(CDCl3) 2.6-2.9 (10H, m, phenyls), 4.82 (2H, s, OCH2), 5.94 (1H, d J8 Hz, C2-H), 6.2-7.2 (5H, m, C3-H, C5-H, C6-H and C8-H2), 7.51 (2H, d J7 Hz, SCH2), 7.83 (1H, dt J12 and 6 Hz, C4-H), 8.10 (1H, td J12 and 9 Hz, C4-H) and 8.86 (3H, t J7 Hz, CH3); (M30 at m/e 394/1560. C23H25NO3S requires 395.1553).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:14]1([CH:13]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.1 %

Procedure:
A solution of tryptamine (15 g, 94.0 mmol) and benzaldehyde (10.9 g, 1.1 equiv.) in DCM (800 mL) was treated with TFA (15 mL, 2 equiv.). The resulting mixture was stirred at rt for one day and then neutralized to pH 7 with a saturated aqueous solution of sodium carbonate. After filtration and concentration to dryness the residue was recrystallized from 2-propanol to give the title compound (11.0 g, 47%) as white crystals. MP: 175-177° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:9][C:8]([C:23]2[N:24]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([CH:32]=O)=[CH:27][CH:26]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:41].[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:17])[CH3:18])=[CH:9][C:8]([C:23]2[N:24]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([CH2:32][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:27][CH:26]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:41]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCC3)ccc21
Yield: 65.5 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-5-[3-(tert-butyldimethylsiloxy)propoxy]-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (71.8 mg, 0.120 mmol) was dissolved in acetonitrile (2.5 mL), and the solution was treated with pyrrolidine (0.100 mL, 1.198 mmol), acetic acid (0.069 mL, 1.198 mmol) and sodium triacetoxyborohydride (76.3 mg, 0.360 mmol), followed by purification by flash column chromatography (chloroform/methanol=19/1, 4/1) to obtain 4-chloro-5-[3-(tert-butyldimethylsiloxy)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone (51.4 mg, yield 66%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:19])[CH2:12][NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:5][C:4]=1[C:20]#[N:21]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:19])[CH2:12][NH:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[CH:5][C:4]=1[C:20]#[N:21]
Reactant: N#Cc1cc(C(=O)CNC2CCCC2)cc(C#N)c1N
Agent: Cl
Product: N#Cc1cc(C(O)CNC2CCCC2)cc(C#N)c1N

Procedure:
m.p. of the hydrochloride: 214°-216° C., was prepared from 4'-amino-2-cyclopentylamino-3',5'-dicyano-acetophenone analogous to Example 48.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH:10]=2)[C:5]([Cl:22])=[CH:4][N:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI.O>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH:10]=2)[C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Nc2cccc(OC3CCCCO3)c2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC#N
Product: CN(c1cccc(OC2CCCCO2)c1)c1nc(Cl)ncc1Cl
Temperature: 70 °C
Yield: 60 %

Procedure:
A solution of 2,5-dichloro-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine (110 mg, 0.32 mmol) in acetonitrile (3 mL) was treated with potassium carbonate (89 mg, 0.65 mmol) followed by methyl iodide (60 μL, 0.97 mmol) and heated at 70° C. for 16 h. The reaction mixture was treated with additional methyl iodide (60 μL, 0.97 mmol) and heated at 70° C. for 11 h. The reaction mixture was cooled to 25° C., poured into water (30 mL), and extracted with ethyl acetate (50 mL). The organic layer was separated and washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude oil. This material was purified by flash column chromatography to give the desired product (68 mg, 59%) as a clear oil. LCMS for C16H18Cl2N3O2 (M+H)+: m/z=354.0, 356.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:23]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([O:19][C:18](=[O:20])[CH2:17][O:16][C:15]2[CH:14]=[CH:13][C:12]([C:10](=[O:11])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:22][CH:21]=2)[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(OCC(=O)O)cc1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)NCC(=O)c1ccc(OCC(=O)OC2CCN(C(=O)OCc3ccccc3)CC2)cc1

Procedure:
The compound of example 1f was treated with 4-hydroxy-piperidine-1-carboxylic acid benzyl ester in the presence of DCC as described in the procedure of example 5a to obtain the title compound. The crude material was purified using flash chromatography (silica gel, 5% CH3CN in chloroform). Yield, 73%; analysis: C28H34N2O8 requires: C, 63.87; H, 6.51; N, 5.32; found: C, 64.13; H, 6.78; N, 5.02%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([C:12]#[N:13])=[N:9]2)=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([C:12]#[N:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(-c3ccccc3)cc(C#N)nc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-c2ccccc2)c2ccc(CBr)cc2n1
Temperature: 25 °C

Procedure:
A solution of 7-methyl-4-phenylquinoline-2-carbonitrile (11.2 g, 41.7 mmol), N-bromo-succinimide (12.2 g, 68.6 mmol) and AIBN (2,2′-azobisisobutyronitrile) (200 mg) in carbon tetrachloride (200 mL) was heated at reflux overnight. The reaction was cooled to ambient temperature and the solid residue was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluting with 5% ethyl acetate in hexane) to give the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.30 (s, 1H), 8.06 (d, 1H), 7.90 (s, 1H), 7.87 (d, 1H), 7.6-7.7 (m, 5H), 4.95 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([OH:13])(=O)=[O:11].S(Cl)(Cl)(=O)=O.S(Cl)(Cl)=O.[CH3:23][NH2:24]>ClC(Cl)C.O>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH:24][CH3:23])(=[O:13])=[O:11]
Reactant: CN
Reactant: Cc1cc(N)c(S(=O)(=O)O)cc1Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CNS(=O)(=O)c1cc(Cl)c(C)cc1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-chloro-4-methyl-benzenesulfonic acid (3.0 g, 1.35 mmol) in dichloroethane (10 mL) is added sulfuryl chloride (4.4 mL, 3.83 mmol) and stirred at 60° C. After one hour, thionyl chloride (1.3 mL) is added and the mixture is further stirred at 100° C. for 7.0 hours. The mixture is poured into iced water and extracted with ether three times. The organic layer is washed with water and then brine, dried over sodium sulfate, and evaporated in vacuo. 1H-NMR (δ, ppm): 2.35 (s, 3H), 6.68 (s, 1H), 7.75 (s, 1H). This substituted sulfonyl chloride is reacted with a suitable amine. On reaction e.g. with methylamine, 2-amino-5-chloro-4,N-dimethylbenzenesulfonamide is formed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([C:23](OC)=[O:24])[C:19]([F:22])([F:21])[F:20])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:34][NH2:35]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([C:23]([NH:35][CH3:34])=[O:24])[C:19]([F:20])([F:21])[F:22])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)C(OC(=O)N1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)C(F)(F)F
Solvent: C1CCOC1
Product: CNC(=O)C(OC(=O)N1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.4 %

Procedure:
To a stirring solution of 1,1,1-trifluoro-3-methoxy-3-oxopropan-2-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate (6h) (41 mg, 0.081 mmol) in THF (2 mL) was added methyl amine (0.81 mL, 0.81 mmol, 1.0M in THF). After stirring the reaction mixture for 24 h at room temperature, the reaction was quenched by the addition of aqueous 1N HCl (5 mL) and extracted with dichloromethane (3×, 25 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by SiO2 preparative TLC (50% EtOAc/hexanes) to give the title compound as a colorless oil (30 mg, 73%): 1H NMR 600 MHz (CDCl3) δ 7.31 (d, J=8.50 Hz, 4H), 7.27 (d, J=8.52 Hz, 4H), 6.05 (bs, 1H), 5.48 (q, J=7.10 Hz, 1H), 4.24 (s, 1H), 3.66-3.51 (m, 3H), 3.46 (dd, J=4.67, 15.51 Hz, 1H), 2.89 (d, J=4.90 Hz, 3H), 2.45 (d, J=8.91 Hz, 2H), 2.34 (t, J=16.23 Hz, 2H); HRMS m/z calc'd for [M+H]+ C22H22Cl2F3N3O3: 504.1063. found 504.1065.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CN(OC)[C:9]([C@@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][CH3:13])=[O:10]>CCOCC>[CH:9]([C@@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][CH3:13])=[O:10]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of LiAlH4 (0.453 g, 11.9 mmol) in Et2O (20 mL) at 0° C. was added dropwise a solution of 1,1-dimethylethyl ((1S)-1-{[methyl(methyloxy)amino]carbonyl}-propyl)carbamate (2.67 g, 10.8 mmol) in Et2O (15 mL). The reaction mixture was stirred for 30 min at 0° C. and quenched with EtOAc (6.5 mL) followed by 5% aq. potassium bisulfate (6.5 mL). The reaction mixture was washed with 1 M aq. HCl (3×10 mL), saturated aq. NaHCO3 (3×10 mL), and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a clear, colorless oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Br)[CH3:13]>CN(C=O)C>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH3:13]
Reactant: CCOC(CBr)OCC
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(C=O)cc1)OCC
Temperature: 27.5 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a stirred suspension of sodium hydride (2.5 g, 100 mmol, 98%) in DMF (100 mL) was added a solution of 4-hydroxy benzaldehyde (10.0 g, 82 mmol) in DMF (100 mL) slowly dropwise at 25-30° C. and stirred for 30 min at 25-30° C. 2,2-diethoxy-1-bromoethane (19.7 g, 100 mmol) was added to the reaction mixture. The reaction mixture was immersed in a preheated oil bath at 60° C. and stirring was continued for 48 h at 60° C. The reaction mixture was cooled to room temperatures, quenched with water (200 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by column chromatography using EtOAc:pet. ether (1:2) as eluent to yield the title compound (12.65 g, 58%) as a brown coloured liquid.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=[O:28])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[F:48][C:49]([F:61])([F:60])[O:50][C:51]1[CH:59]=[CH:58][C:54](C(Cl)=O)=[CH:53][CH:52]=1>C(Cl)Cl.O>[CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:28])[C:54]4[CH:53]=[CH:52][C:51]([O:50][C:49]([F:48])([F:60])[F:61])=[CH:59][CH:58]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(COc2ccc(N3CCN(C(=O)c4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
Tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]-piperazine-1-carboxylate prepared in Example 148 (300 mg, 0.65 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (5 ml) was added followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and added methylene chloride (10 ml), triethylamine (2 ml) and 4-trifluoromethoxybenzoyl chloride (0.15 ml, 0.98 mmol). The reaction mixture was stirred at room temperature for 1 hour, then poured into water, and extracted with methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and crystallized from methylene chloride-diisopropyl ether to afford (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxybenzoyl)piperazin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (263 mg, yield 74%) as a white powder.