Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20](=O)[O:21]C2C=CC([N+]([O-])=O)=CC=2)=[CH:15][CH:14]=1)([O-:12])=[O:11].CN1CCOCC1>C(Cl)Cl>[C:20](=[O:21])([O:19][C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=1)[O:9][CH2:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(CO)CC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 90 h
Yield: 73.6 %

Procedure:
(1-Methylpiperidin-4-yl)methanol (2.50 g, 19.3 mmol) in DCM (50 mL) was added to a solution of bis-(4-nitrophenyl)carbonate (7.06 g, 23.2 mmol) in DCM (100 mL), followed by NMM (1.70 mL, 15.5 mmol). The reaction mixture was stirred for 90 hours and then washed sequentially with aliquots of 1 M aq Na2CO3 solution until the aqueous layer was colourless. The organic layer was dried (MgSO4) and concentrated in vacuo to give (1-methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (4.18 g, 73%) as a yellow solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.C([O:21][C:22](=O)[C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)C>C(O)C>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]1[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:22](=[O:21])[C:23]([OH:32])=[C:24]1[C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1
Reactant: NCCCn1ccnc1
Reactant: O=Cc1ccccc1F
Reactant: CCOC(=O)C(=O)Cc1ccc(O)cc1
Solvent: CCO
Product: O=C1C(O)=C(c2ccc(O)cc2)C(c2ccccc2F)N1CCCn1ccnc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 2-Fluoro-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:20]=O)=[CH:14][CH:13]=1>>[I:1][C:2]1[N:3]=[CH:4][N:5]2[CH2:7][CH2:8][NH:9][CH:20]([CH2:19][CH2:18][C:15]3[CH:16]=[CH:17][C:12]([C:11]([F:10])([F:22])[F:23])=[CH:13][CH:14]=3)[C:6]=12
Reactant: NCCn1cnc(I)c1
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(CCC2NCCn3cnc(I)c32)cc1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (70 W; 130° C.; 10 bars; 10 min.) between 2-(4-iodo-imidazol-1-yl)-ethylamine (4.326 g; 18.253 mmol) and 3-(4-trifluoromethyl-phenyl)-propionaldehyde (3.690 g; 18.253 mmol) afforded 1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by FC (DCM/MeOH=25/1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]([OH:14])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][N:39]1[CH2:44][CH2:45][CH2:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:50][CH:49]=1>CN(C=O)C.C(N(C(C)C)CC)(C)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]([N:57]1[CH2:58][CH2:59][N:54]([C:51]2[CH:50]=[CH:49][C:48]([O:47][CH2:46][CH2:45][CH2:44][N:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH:38]3[CH3:37])=[CH:53][CH:52]=2)[CH2:55][CH2:56]1)=[O:14]
Reactant: Cn1cc(C(=O)O)c2cc(F)ccc21
Reactant: CC1CCCCN1CCCOc1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCCN1CCCOc1ccc(N2CCN(C(=O)c3cn(C)c4ccc(F)cc34)CC2)cc1
Reaction time: 18 h
Yield: 45.4 %

Procedure:
A solution of 5-fluoro-1-methyl-1H-indole-3-carboxylic acid (19.3 mg) and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (56 mg) in DMF (1 ml) and diisopropylethylamine (0.035 ml) was stirred for 10 min before 1-{4-[3-(2-methylpiperidin-1-yl)propoxy]phenyl}piperazine (E76b) (21.3 mg) in DMF (0.5 ml) was added. The mixture was stirred for 18 h and then concentrated under reduced pressure. The residue was purified by SPE ion exchange chromatography on an SCX-2 cartridge (1 g). The cartridge was washed with methanol (3 ml) and the product eluted with 2M ammonia in methanol (2.5 ml), to give the title compound (15 mg) LCMS RT=2.42 min, ES+ve m/z 493 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][N:2]=1.[H][H]>[Ni].C(O)C>[CH2:1]1[C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][NH:2]1
Reactant: [H][H]
Reactant: C1=NCCCC12CCCCC2
Agent: [Ni]
Solvent: CCO
Product: C1CCC2(CC1)CCCNC2
Yield: 88.1 %

Procedure:
A solution of 2-azaspiro-[5.5]-undec-1-ene (15 g.; 0.10 mole) and one teaspoon (3 g.) of W2 Raney nickel catalyst in absolute ethanol (300 ml.) is hydrogenated at an initial pressure of 40 psi until hydrogen uptake ceases (2 hours). The mixture is filtered through celite and the filtrate concentrated under reduced pressure. Distillation of the residual liquid yields 88% of 2-azaspiro-[5.5]-undecane (13.5 g.), b.p. 55°-57° C./0.10 mm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=3)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:28])=[CH:4][N:3]=1>O.CO.C(O)(=O)C.[Fe]>[NH2:25][C:21]1[CH:20]=[C:19]([S:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]3[C:5]([Cl:28])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:10]=2)(=[O:17])=[O:18])[CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: [Fe]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc(S(=O)(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 109.7 %

Procedure:
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}-3-nitrobenzenesulfonamide (0.5 g, 1.0 mmol) in water (0.9 mL), methanol (4.4 mL) and acetic acid (1.7 mL) was added iron (250 mg, 4.5 mmol) powder in one portion. The mixture was stirred at 0° C. for 1 h and then mixed with celite and filtered. The crude cake was washed with EtOAc. The brown filtrate was concentrated and mixed with EtOAc and NaHCO3/water. The aqueous phase was extracted once with EtOAc. The organic phases were combined and dried over Na2SO4. The volatiles were removed under vacuum to give the desired product (0.45 g, 100%). LCMS for C16H13Cl2N5O2S (M+H)+: m/z=410.0, 411.9. 1H NMR (400 MHz, DMSO-d6): δ 9.57 (s, 1H), 9.42 (s, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.29 (dd, J=7.9, 7.6 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 7.10-7.05 (m, 2H), 6.90 (dd, J=8.2, 0.9 Hz, 1H), 6.84-6.81 (m, 1H), 4.11 (s, 2H).
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]([O:14][C:15](=[O:25])[CH2:16]P(OCC)(OCC)=O)[CH3:13].[Cl-].[Li+].[F:28][C:29]([F:41])([C:37]([F:40])([F:39])[F:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=O>C(#N)C.C(OC)(C)(C)C>[CH2:12]([O:14][C:15](=[O:25])/[CH:16]=[CH:35]/[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]([F:28])([F:41])[C:37]([F:38])([F:39])[F:40])[CH3:13]
Reactant: O=CCCCCCC(F)(F)C(F)(F)F
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)/C=C/CCCCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.08 mL, 7.26 mmol) was added to a solution of (diethoxy-phosphoryl)-acetic acid ethyl ester (1.57 mL, 7.87 mmol) and lithium chloride (359 mg, 8.47 mmol) in acetonitrile (60.5 mL) at 0° C., and the mixture was stirred at 0° C. for 10 minutes. A solution of 7,7,8,8,8-pentafluoro-octanal (1.32 g, 6.05 mmol) in acetonitrile (20.5 mL) was added dropwise to the reaction solution at 0° C., and the mixture was stirred for 10 minutes. Thereafter, the reaction mixture was stirred at room temperature for one hour and diluted with methyl tert-butyl ether (300 mL). The organic layer was sequentially washed with 2 N hydrochloric acid (50 mL), H2O (50 mL) and saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (E)-9,9,10,10,10-pentafluoro-dec-2-enoic acid ethyl ester (purity 80%) as a colorless oily substance (49.7 mg, 47%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][CH:3]=1.[C:7](O)([CH3:10])([CH3:9])[CH3:8].[Cl:12]([OH:16])(=[O:15])(=[O:14])=[O:13].O1CCCC1>CCOCC>[Cl:12]([O-:16])(=[O:15])(=[O:14])=[O:13].[C:7]([N+:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1ccno1
Reactant: CC(C)(C)O
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc[n+](C(C)(C)C)o1
Product: [O-][Cl+3]([O-])([O-])[O-]
Temperature: 25 °C

Procedure:
1 kg. of 5-methylisoxazole and 892 g. of t-butanol were stirred under nitrogen at 0° C. and 6.37 kg. of 60% perchloric acid were slowly added over a 2 1/2 hour period with vigorous stirring at 0°-5° C. The resulting suspension was allowed to warm to room temperature and stirred overnight. The reaction mixture was then slowly added to a mixture of 20 l. of tetrahydrofuran and 10 l. of ether at 0°-10° C. over a 2 hr. period with stirring. The mixture was then cooled to -5° C. and stirred for an additional 2 hrs. The product (1.821 kg.) was washed well with ether, m.p. 120°-122° C. A second crop (171 g.) was obtained from the mother liquor, m.p. 118°-121° C.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=1.Cl>C1COCC1.CCCCCC.O1CCOCC1>[CH3:4][O:3][P:2]([CH2:1][C:15]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=1)=[O:14])(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1ccc(F)c(C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1ccc(F)c(C)c1)OC
Reaction time: 0.75 h

Procedure:
To a mixture of 19.2 g (155 mmol) dimethyl methylphosphonate in 150 mL THF at −70° C. was added 97 mL (155 mmol) 1.6M n-BuLi in hexane. The mixture was stirred for 45 min and a solution of 11.8 g (70 mmol) 4-fluoro-3-methyl-benzoic acid methyl ester in 15 mL THF was added. After 15 min at −70° C. the mixture was allowed to warm to 0° C. and neutralized with 4N HCl in dioxane. The mixture was diluted with 500 mL THF to obtain [2-(4-fluoro-3-methyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester. 6 mmol [2-(4-fluoro-3-methyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester in THF was stirred together with 0.5 g (4.6 mmol) pyrimidine-5-carboxaldehyde and 1.65 g Cs2CO3 for 16 h at room temperature. The mixture was diluted with NH4Cl aq. and ethyl acetate. The organic layer was separated, dried with MgSO4 and evaporated to dryness. The residue was used crude in the consecutive step.
Reaction SMILES: COC(OC)N(C)C.[N+:9]([C:12](=[C:16]1[NH:21][CH2:20][CH2:19][CH2:18][S:17]1)[C:13](=[O:15])C)([O-:11])=[O:10]>C(Cl)(Cl)Cl.CO.C(Cl)Cl>[N+:9]([C:12](=[C:16]1[NH:21][CH2:20][CH2:19][CH2:18][S:17]1)[CH:13]=[O:15])([O-:11])=[O:10]
Reactant: CC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Agent: COC(OC)N(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=CC(=C1NCCCS1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.95 g of N,N-dimethyl formamide dimethyl acetal in 25 ml of chloroform was added dropwise at room temperature to a mixture of 8.0 g of 2 b in 50 ml of chloroform and the mixture was stirred for one hour at room temperature, then was heated to reflux and stirred for 12.5 hours. The solvent then was evaporated under reduced pressure to give a mushy solid, which was passed through fluorosil, using methylene chloride, then methanol, as eluents. The resulting material then was passed through fluorosil using a 99:1 mixture of methylene chloride and methanol as eluent to give 21 as a yellow solid, m.p.: 171°-172°.
Reaction SMILES: [Br:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[S:14][C:10]=3[CH:9]=2)=[C:4]([N+:23]([O-])=O)[CH:3]=1.CC(O)=O.CO>CCO.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:23])[C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[S:14][C:10]=3[CH:9]=2)=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c([N+](=O)[O-])cc1Br
Agent: [Zn]
Solvent: CO
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
To a stirred suspension of 4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (212 mg, 0.5 mmol) from Step 1 of this Example in EtOH (4 mL) and HOAc (2 mL) at 0° C. under argon was added zinc powder (160 mg, 2.4 mmol) in one portion. After 1.5 h at 0° C., MeOH (5 mL), additional HOAc (2 mL), and zinc powder (160 mg, 2.4 mmol) were added. The mixture was allowed to warm to rt and stirred for 18 h. The mixture was filtered and the filtrate was cooled to 0° C. The pH of the filtrate was adjusted to pH˜9 by addition of solid Na2CO3. The mixture was then partitioned between EtOAc (150 mL) and water (100 mL). The EtOAc layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc to afford 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (120 mg, 61%). LCMS (ESI) m/z 410 and 412 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25]>CN(C=O)C.CCOC(C)=O>[CH2:1]([NH:8][C:9](=[O:12])[CH2:10][NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)NCc1ccccc1
Reactant: Nc1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(F)cc1F)NCc1ccccc1
Temperature: 100 °C
Reaction time: 40 h

Procedure:
A mixture of N-benzyl-2-chloroacetamide (700 mg—obtained as described for intermediate 1), DIPEA (0.76 mL) and 2,4-difluoro-aniline (0.4 mL) in anhydrous DMF (5 mL) was stirred at 100° C. for 40 hours under a Nitrogen atmosphere. Then, more DIPEA (0.2 mL) was added and the mixture was heated to 100° C. for further 4 hours. After cooling to room temperature, the solution was diluted with AcOEt and washed with water and ice. The separated aqueous phase was extracted with further AcOEt (3×20 mL). The combined organic extracts were dried and concentrated in vacuo. The residue was purified by flash chromatography (CH/AcOEt 7:3) to give the title compound (600 mg) as a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([N:13]1[C:21]2[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH:15]2[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][CH:14]12)#[CH:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:27][N:24]1[CH2:25][CH2:26][C:14]2[N:13]([C:11]#[C:12][C:2]3[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=3)[N:8]([CH3:10])[CH3:9])[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: C#CN1c2ccc(C)cc2C2CN(C)CCC21
Reactant: CN(C)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2cccc(N(C)C)c2)CCN(C)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
(3-Bromo-phenyl)-dimethylamine (100 mg, 0.5 mmol), 5-ethynyl-2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido[4,3-b]indole (123 mg, 0.5 mmol), dichlorobis(triphenylphosphine)palladium(II) (17 mg, 0.25 mmol) and TBAF.3H2O (275 mg, 1.5 mmol) were mixed and stirred at 80° C. for 30 min under nitrogen. The progress of reaction was monitored by TLC and LCMS. The mixture was cooled to RT, water was added, and extracted with EtOAc. The organic layer was washed with water (1×10 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography using silica gel (100-200 mesh), neutralizing the silica gel with aq. Ammonia, and using 0-2% MeOH:DCM as eluent. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.50 (d, 1H), 7.30 (m, 1H), 7.18 (d, 2H), 7.05 (d, 2H), 6.90 (m, 1H), 4.78 (m, 1H), 4.10 (m, 1H), 3.90 (m, 1H), 3.40 (m, 2H), 3.20 (m, 1H), 3.0 (s, 9H), 2.42 (s, 3H),
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([CH3:6])[CH3:5].[C:7]([N:15]=[C:16]=[S:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[C:7]([NH:15][C:16]([N:2]([CH3:1])[CH2:3][CH:4]([CH3:6])[CH3:5])=[S:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CNCC(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)CN(C)C(=S)NC(=O)c1ccccc1
Reaction time: 0.75 h
Yield: 100.1 %

Procedure:
To a stirring solution of N-methylisobutylamine (3.21 g, 36.8 mmol, 4.45 mL) in 40 mL of CHCl3 was added benzoyl isothiocyanate (6.0 g, 36.8 mmol, 4.95 mL). After stirring for 45 min, the solution was concentrated to yield the title compound as a pale yellow solid (9.22 g, 100%). 1HNMR (400 MHz, CDCl3; 2:1 mixture of rotamers) δ 7.86 (d, 2 H), 7.60 (t, 1 H), 7.50 (t, 2 H), 3.90 (d, 2 H), 3.44 (s, 3 H), 3.41 (d, 2 H), 3.27 (s, 3 H), 2.35-2.32 (m, 1 H), 2.13 (m, 1 H), 1.06 (d, 6 H), 0.90 (d, 6 H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[C:14]([C:17]1[CH:21]=[C:20]([CH2:22][OH:23])[O:19][N:18]=1)(=[O:16])[NH2:15].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:23][CH2:22][C:20]1[O:19][N:18]=[C:17]([C:14](=[O:16])[NH2:15])[CH:21]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1cc(CO)on1
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
2.84 g (14.07 mmol) of 4-nitrophenyl chloroformate are added in small portions to a solution, cooled to approximately 0° C., of 2.00 g (14.07 mmol) of 3-carbamoylisoxazol-5-ylmethanol, 1.71 ml (21.11 mmol) of pyridine and 0.17 g (1.41 mmol) of N,N-dimethylaminopyridine in 15 ml of dichloromethane. The medium is kept stirred at 0° C. for 1 hour and then at ambient temperature for 1 hour. The precipitate formed is filtered off and then copiously rinsed with diisopropyl ether. After drying under vacuum at approximately 60° C., 3.12 g (72%) of the expected product are obtained in the form of a white solid used as is in the following stage.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH:40]1[CH2:42][CH2:41]1)(=O)=O.[CH3:45][O:46][C:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1B(O)O)=[O:48].COC(C1C=CC(B(O)O)=CC=1)=O>>[CH:40]1([N:11]2[C:12]3[C:8](=[C:7]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=4[C:47]([O:46][CH3:45])=[O:48])[CH:15]=[C:14]([C:16]([N:18]4[CH2:19][CH2:20][C:21]5([CH2:32][C:31](=[O:33])[C:30]6[C:25](=[CH:26][CH:27]=[C:28]([C:34]7[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=7)[CH:29]=6)[O:24]5)[CH2:22][CH2:23]4)=[O:17])[CH:13]=3)[CH:9]=[CH:10]2)[CH2:41][CH2:42]1
Reactant: COC(=O)c1ccccc1B(O)O
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(OS(=O)(=O)C(F)(F)F)c5ccn(C6CC6)c5c4)CC2)O3)cn1
Agent: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccccc1-c1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cnn(C)c4)ccc2O3)cc2c1ccn2C1CC1

Procedure:
The intended compound was produced according to the procedure described in Example 28-1 but using 1-cyclopropyl-6-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}-1H-indol-4-yl trifluoromethanesulfonate and [2-(methoxycarbonyl)phenyl]boronic acid in place of 8-cyclopropyl-2-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}quinolin-4-yl trifluoromethanesulfonate and [4-(methoxycarbonyl)phenyl]boronic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].C(#N)C>C(Cl)Cl>[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Clc1ccccc1CNCCCOc1cccc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2-chlorobenzylamine and acetonitrile essentially as described above in example 48 except that the crude product is dissolve in DCM and purified by using a step gradient of 50% ethyl acetate in heptane, to 100% ethyl acetate. Purity by LC/MS (APCI)=98%, [M+H]+=399.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Oc1ccccc1Cl
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1COc1ccccc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
A mixture of methyl 2-(bromoethyl)-5-chlorobenzoate (100 mg, 0.38 mmol), 2-chlorophenol (43 μL, 0.42 mmol) and potassium carbonate (105 mg, 0.76 mmol) in N,N-dimethylforamide (2 mL) was stirred at room temperature for 3 h and at 50° C. for 4 hours. Water (5 mL) was added and the mixture was extracted with diethyl ether (15 mL×2). The combined organic extracts were washed with brine (15 mL) and dried (sodium sulfate). After removal of solvent, the residue was purified by pTLC eluting with hexane/ethyl acetate (9/1) to afford 103 mg (87%) of the title compound:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)[NH2:6].N1C=CC=CC=1.Cl.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:20]1([S:26]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[C:3]([O:2][CH3:1])=[O:12])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloroanthranilic acid methyl ester (400 mg;. prepared in Reference Example 1.) and pyridine (0.87 ml) in methylene chloride, benzenesulfonylchloride (0.33 ml) was added at 0° C. The solution was stirred overnight at room temperature. The reaction mixture was poured into diluted HCl and extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (hexane-AcOEt) to give the title compound (664 mg) having the following physical data.