Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][CH2:11][CH2:10][N:9]3[CH:8]=1)=[O:6])=[N+]=[N-].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.CO>C1COCC1.[Pd]>[C:23]([O:22][C:20](=[O:19])[NH:1][CH2:4][C:5]([C:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][CH2:11][CH2:10][N:9]3[CH:8]=1)=[O:6])([CH3:26])([CH3:25])[CH3:24]
Reactant: [N-]=[N+]=NCC(=O)c1cn2c3c(cccc13)CCC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)c1cn2c3c(cccc13)CCC2

Procedure:
A solution of 2-azido-1-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethanone (4.70 g, 19.58 mmol), (BOC)2O (4.48 g, 20.56 mmol), Pd/C (10%) in THF (30 mL)/MeOH (20 mL) was shaken under H2 (60 psi) overnight. The mixture was filtered through a pad of Celite and concentrated to give a residue that was purified by silica gel column chromatography (eluent, 2/1 hex/EtOAc). [2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester was obtained as a white solid (2.82 g, 46%). M.p.=175-177° C.; 1H NMR (400 MHz, DMSO-d6) δ: 8.35 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.99 (m, 2H), 4.27 (d, J=6.0 Hz, 2H), 4.23 (t, J=6.0 Hz, 2H), 2.94 (t, J=6.4 Hz, 2H), 2.14 (m, 2H), 1.41 (s, 9H). LCMS: m/e 315.21 [M+H], 259.17 [M-56].
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40][CH2:41][C:42](=[NH:45])[NH:43][OH:44])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2].C1N=CN([C:53](N2C=NC=C2)=[O:54])C=1>C(#N)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=3)[C:22]([CH2:40][CH2:41][C:42]3[NH:45][C:53](=[O:54])[O:44][N:43]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CCC(=N)NO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Solvent: CC#N
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CCc3noc(=O)[nH]3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 60 °C
Reaction time: 25.5 h
Yield: 57.8 %

Procedure:
(2R,4S)-4-([3,5-Bis(trifluoromethyl)benzyl]-{5-[2-(N-hydroxy-carbamimidoyl)ethyl]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (140 mg) is dissolved in acetonitrile (1 ml), and thereto is added carbodiimidazole (51 mg). The mixture is heated at 60° C. and stirred for 25.5 hours. The reaction solution is cooled to room temperature, and partitioned by adding water and ethyl acetate. The organic layer is washed with saturated brine, then dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give (2R,4S)-4-([3,5-bis-(trifluoromethyl)benzyl]-{5-[2-(5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl)ethyl]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (84 mg). MS (m/z): 696 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Br)[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])([CH3:4])([CH3:3])[CH3:2].[F-:17].[K+].[K+].[Br-].Cl[C:22]([F:28])([F:27])C(OC)=O>CN(C=O)C.O.[Cu]I>[C:1]([C:5]1[CH:10]=[C:9]([C:22]([F:28])([F:17])[F:27])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])c(Br)cc1C(C)(C)C
Reactant: COC(=O)C(F)(F)Cl
Reactant: [F-]
Agent: [Cu]I
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(C(F)(F)F)cc1C(C)(C)C
Temperature: 125 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
A mixture of 1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene (867 mg, 3.0 mmol), KF (348 mg, 6 mmol), KBr (714 mg, 6 mmol), CuI (684 mg, 3.6 mmol), methyl chlorodifluoroacetate (2.2 mL, 21.0 mmol) in DMF (5 mL) was stirred at 125° C. in a sealed tube overnight, cooled to room temperature, diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO4. After removal of the solvent, the residue was purified by column chromatography (0-5% EtOAc-Hexane) to yield 1-tert-butyl-2-methoxy-5-(trifluoromethyl)-4-nitrobenzene (512 mg, 61%). 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.29 (s, 1H), 3.90 (s, 3H), 1.33 (s, 9H).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH:6]1[CH:11]=[CH:10][CH:9]=[CH:8]C=1>>[CH2:2]1[CH:1]2[CH:8]3[CH:9]=[CH:10][CH:11]([CH:5]2[CH:4]=[CH:3]1)[CH2:6]3.[CH2:3]=[CH:4][C:5](=[CH2:1])[CH3:6].[CH:5]1[CH2:4][CH:3]=[CH:2][CH:1]=1.[CH:5]1[CH2:4][CH:3]=[CH:2][CH:1]=1
Reactant: c1ccccc1
Agent: C1=CCC=C1
Product: C1=CC2C3C=CC(C3)C2C1
Product: C=CC(=C)C
Temperature: 150 °C
Yield: 72.1 %

Procedure:
A C5 -fraction obtained from naphtha cracking was heated at 150° C. for 3 hours to convert cyclopentadiene contained therein to dicyclopentadiene, and crude dicyclopentadiene comprising 20.1% of pentanes and pentenes, 0.5% of benzene, 72.1% of dicyclopentadiene, 4.8% of isoprene-cyclopentadiene co-dimer and 2.5% of cyclopentadiene oligomer was obtained. A metallic autoclave was then charged with 100 parts by weight (1710 g) of the crude dicyclopentadiene and 4 parts by weight of tablet-like palladium hydrogenating catalyst (C31-1A: Toyo C.C.I. K. K.), and hydrogenation was carried out at a reaction temperature of 50° C. under a hydrogen pressure of 10 kg/cm2 for 12 hours while stirring. After filtering off the catalyst and distillation, 90 parts by weight of tricyclo[5.2.1.02,6 ]deca-3-ene (9,10-dihydrodicyclopentadiene) fraction were obtained. Gas chromatography showed that the composition thereof was as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][C:7]([S:15][CH3:16])=[CH:6][C:5]2=1.[CH2:17](Br)[CH:18]=[CH2:19].[C:21]1([C:32]2CCCCCCCCCC=2)[CH2:31]CCCCCCCNN=1>C(O)C>[CH2:17]([N:1]([CH2:32][CH:21]=[CH2:31])[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][C:7]([S:15][CH3:16])=[CH:6][C:5]2=1)[CH:18]=[CH2:19]
Reactant: CSc1cc2c(cn1)[nH]c1ccc(N)cc12
Reactant: C=CCBr
Reactant: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCO
Product: C=CCN(CC=C)c1ccc2[nH]c3cnc(SC)cc3c2c1

Procedure:
229 mg of 6-amino-3-methylthio-β-carboline are heated in 15 ml of ethanol (absolute) with 0.27 ml of allylbromide and 0.37 ml of diazabicycloundecene for 3 hours to 70° C. After concentration to dryness, it is dispersed in ethyl acetate/saturated sodium chloride solution. The organic phase is dried, filtered and concentrated. After trituration of the residue with diispropyl ether, 70 mg of 6-diallylamino-3-methylthio-β-carboline with a 110° C. melting point are obtained.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[S:17][C:16]2([CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:15][N:14]=1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>ClCCl>[CH3:12][C:13]1[S:17][C:16]2([CH2:22][CH2:21][N+:20]([O-:9])([CH3:23])[CH2:19][CH2:18]2)[CH2:15][N:14]=1
Reactant: CC1=NCC2(CCN(C)CC2)S1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Product: CC1=NCC2(CC[N+](C)([O-])CC2)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of m-chloroperbenzoic acid, mCPBA, (1.40 gr, 8.11 mmol) in dichloromethane (30 ml) was added gradually to a solution of AF150(S) (1.45 gr, 7.88 mmol) in dichloromethane (10 ml). The reaction was stirred at room temperature overnight. Chromatography of the reaction mixture was on a column of natural aluminum oxide (Merck)(metanol:chloroform 1/49) gave AF406 (0.75 gr) as a crystalline solid. A sample was crystallized from ethylacetate. A very hygroscopic solid was obtained. mp. 130–132° C. (145–159° C. dec.); 1H NMR (300 MHz, CDCl3) δ 1.89 (m, 2H), 2.2 (t, j=1.5 Hz, CH3C═N), 2.82 (m, 2H), 3.24 (m, 2H), 3.25 (s, CH3N+O−), 3.35 (m, 2H), 4.03 (q, j=1.5 Hz, CH2N═C) ppm; IR(CHCl3) 2947, 1636, 1448, 1153, 931, 664 cm−1; MS(EI) 200 (M+), 184, 182, 149, 141, 140, 126, 110, 109, 108, 96, 82, 70.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[N:22]/[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:7][CH:6]=1.O.Cl>O1CCCC1.CO>[F:4][C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[N:22]/[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:10]=1
Reactant: COC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCCCC(=O)O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
Lithium hydroxide monohydrate (157 mg) was added to a solution of methyl E-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate (700 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 3 hours. 1N hydrochloric acid (3.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoic acid (608 mg, yield 89%) as colorless crystals. m.p. 79-80° C.
Reaction SMILES: I[Si](C)(C)C.C[O:7][CH2:8][CH2:9][N:10]1[C:14]([CH2:15][CH2:16][C:17]2[N:27]=[C:20]3[C:21]([CH3:26])=[N:22][CH:23]=[C:24]([CH3:25])[N:19]3[N:18]=2)=[N:13][C:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:11]1.CO.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:25][C:24]1[N:19]2[N:18]=[C:17]([CH2:16][CH2:15][C:14]3[N:10]([CH2:9][CH2:8][OH:7])[N:11]=[C:12]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:13]=3)[N:27]=[C:20]2[C:21]([CH3:26])=[N:22][CH:23]=1
Reactant: COCCn1nc(-c2ccccc2)nc1CCc1nc2c(C)ncc(C)n2n1
Agent: C[Si](C)(C)I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ncc(C)n2nc(CCc3nc(-c4ccccc4)nn3CCO)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Iodotrimethylsilane (92.0 uL, 0.646 mmol) was added to a stirred solution of 2-{2-[2-(2-Methoxy-ethyl)-5-phenyl-2H-1,2,4-triazol-3-yl]ethyl}-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (61 mg, 0.16 mmol) in Chloroform (5 mL) under an atmosphere of Argon at rt. The solution was stirred at rt 4 h. More Iodotrimethylsilane (184 uL, 1.29 mmol) was added and the mixture was stirred at rt ON. MeOH (10 ml) and solid sodium sulfite (0.5 g) was added and the mixture was stirred 30 min, filtered and evaporated. The crude product was purified by silica gel chromatography (Eluent: 0-5% MeOH in EtOAc). Yield: 27 mg (46%) of the title compound as a solid. LC-MS: m/z=364.5 (MH+), tR=1.30 min, Method C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:5]([Br:7])[N:6]=1.[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17].CCOC(C)=O.CCCCCC>CN(C=O)C>[Br:1][C:2]1[S:3][C:4]([C:8]2[N:12]=[CH:11][N:10]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[N:9]=2)=[C:5]([Br:7])[N:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1nc(Br)c(-c2nnc[nH]2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(-c2sc(Br)nc2Br)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.8 %

Procedure:
To the solution of 3-(2,4-dibromo-1,3-thiazol-5-yl)-4H-1,2,4-triazole (1.16 g, 3.74 mmol) in dry DMF (5.0 mL) at 0° C. was added portionwise sodium hydride (60%, 0.180 g, 4.49 mmol). The ice bath was removed, mixture was stirred for 5 min. at ambient temperature and cooled with ice bath. SEM chloride (0.795 mL, 4.49 mmol) in dry DMF (2.0 mL) was added dropwise and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with ice-water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, evaporated to give a crude oil. Chromatograph in a silica column using EtOAc/hexane (0/100 to 20/80) afforded white solid product (1.10 g, 67%). LCMS: (FA) ES+ 441. 1H NMR (400 MHz, d1-chloroform) 8.29 (s, 1H), 5.54 (s, 2H), 3.71 (t, J=8.28 Hz, 2H), 0.95 (t, J=8.28 Hz, 2H), 50.00 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:11]([Br:12])=[C:10]([CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4]1(C)O[CH:7]2[CH:6]=[CH:5]1.[CH2:16]([OH:21])C(F)(F)F.[CH3:22][OH:23]>>[Br:1][C:2]1[C:3]([CH3:4])=[C:8]2[C:9](=[C:10]([CH3:13])[C:11]=1[Br:12])[C@H:22]([OH:23])[C@@H:5]([O:21][CH3:16])[CH:6]=[CH:7]2
Reactant: OCC(F)(F)F
Reactant: CO
Reactant: Cc1cc2c(c(Br)c1Br)C1(C)C=CC2O1
Product: CO[C@H]1C=Cc2c(C)c(Br)c(Br)c(C)c2[C@@H]1O
Yield: 79 %

Procedure:
To a flame dried round bottom flask, [Rh(COD)Cl]2 (1.5 mg, 0.0029 mmol), (R)-(S)-PPF-PtBu2 (3.2 mg, 0.0059 mmol) and 26 (195 mg, 0.59 mmol) were added followed by addition of trifluoroethanol (1.0 mL) and methanol (1.0 mL). The mixture was heated to reflux for 20 hours. The solvents were then removed in vacuo. The resulting solid was purified by flash chromatography (50% ethyl acetate in hexanes) to give 29 as a white crystalline solid (171.6 mg, 79%). The ee was determined to be 97% using HPLC analysis on a CHIRALCEL OD column, λ=486 nm. Retention times in 4% isopropanol in hexanes were 16.8 min (major) and 19.3 min. Rf=0.39 on silica gel (50% ethyl acetate:hexanes); mp 114-116° (Et2O); [α]25D=−197.1° (c=10.0, CHCl3); IR (KBr, cm−1) 3349(s), 2901 (m), 1700(w), 1532 (w), 1404(m), 1258 (m), 1081 (s), 936 (s); 1H NMR (400 MHz, CDCl3) δ 6.96-6.93 (1H, m), 6.23-6.19 (1H, m), 4.89 (1H, s), 3.96-3.90 (1H, m), 3.38-3.35 (3H, m), 2.61-2.57 (3H, m), 2.54 (3H, s), 1.82-1.54 (1H, m); 13C NMR (400 MHz, CDCl3) δ 137.3, 134.4, 133.2, 129.7, 129.5, 129.0, 128.1, 125.3, 75.3, 66.6, 56.6, 21.0, 20.6. HRMS calcd for C13H16O2Br2 (M+): 361.9518. Found: 361.9335.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH3:23]>>[CH2:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)[CH3:23]
Reactant: CCc1ccccc1Br
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: CCc1ccccc1C#Cc1ccc(CCC(=O)OC)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.51 mmol) and 1-bromo-2-ethylbenzene (0.10 mL, 0.73 mmol) according to the general procedure IF to give 130 mg (87%) of a clear oil after purification by flash chromatography (SiO2, EtOAc:PE, 1:7): Rf=0.28 (EtOAc:PE, 1:4); 1H NMR (CDCl3) δ 7.50-7.48 (m, 1H), 7.46-7.44 (m, 2H), 7.26-7.22 (m, 2H), 7.20-7.14 (m, 3H), 3.67 (s, 3H), 2.96 (t, J=7.8 Hz, 2H), 2.88 (q, J=7.2 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.29 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3) δ 173.2, 146.3, 140.9, 132.2, 131.8, 128.6, 128.5, 128.1, 125.8, 122.5, 121.7, 92.9, 88.0, 51.8, 35.6, 31.0, 27.9, 14.9; ESI-MS m/z 315.1 (M+Na+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)=[CH:12][CH:13]=2)=[O:29])=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(-n2ccc3ccccc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The titled compound can be synthesized from indole, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)-phenyl isocyanate by using the same techniques as in Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:46][CH3:47]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH2:46][CH3:47])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCc2ccc(OCc3ccccc3)cc2O1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C1(CC)CCc2ccc(OCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a 320 ml anhydrous THF solution of ethyl 7-benzyloxychromane-2-carboxyate 14.6 g (46.6 mmol) were added hexamethylphosphoramide (10.5 ml, 60.4 mmol). Upon cooling in a dry ice-acetone bath, sodium bis(trimethylsilyl)amide (1.0M/THF) (60.5 ml, 60.5 mmol) was added via syringe over 15 min period. The resulting orange solution was stirred at that temperature for 30 min before iodoethane (18.6 ml , 233 mmol) was added via syringe. The reaction was slowly warmed to rt and stirred overnight. The solvent was removed under reduced pressure, and the residue was diluted with AcOEt and aqueous NU4Cl (NH4Cl 7.2 g/200 ml water). The organic layer was separated, and the aqueous layer was extracted with AcOEt twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel eluting with 7.5% EtOAc/hexanes to give the title compound 15.2 g (96%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CC[N:13]([CH:17]([CH3:19])[CH3:18])C(C)C.O.CN1[C:26](=[O:27])CCC1>>[CH2:19]1[CH:26]([OH:27])[CH2:18][CH:17]1[NH:13][C:2]1[S:3][C:4]2[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: Clc1nc2ccccc2s1
Reactant: CN1CCCC1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Product: OC1CC(Nc2nc3ccccc3s2)C1
Temperature: 180 °C
Yield: 73 %

Procedure:
A mixture of (1S,3S)-3-aminocyclobutanol hydrochloride (120 mg, 0.98 mmol, 1.0 eqv), 2-chloro-benzothiazole (purchased from ALDRICH™) (169 mg, 1 mmol, 1.02 eqv) and DIEA (286 mg, 2 mmol, 2.04 eqv) in NMP (2 mL) was heated to 180° C. for 2 hours in microwave. To the reaction mixture was added water, and the residue was extracted with EtOAc (30 mL). The combined organic layer was washed with brine and dried over Na2SO4. The organic layers were concentrated and purified by column chromatography on silica gel to give (1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutanol (160 mg, 0.72 mmol, yield 73%). ESI-MS (M+1): 221 calc. for C11H12N2OS 221.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([CH2:16]O)=[CH:14][N:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:12]=2)=[O:10])=[CH:4][CH:3]=1.CS([Cl:29])(=O)=O.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([CH2:16][Cl:29])=[CH:14][N:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(Br)nc1)c1nn(-c2ccc(Cl)cc2)cc1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)nc1)c1nn(-c2ccc(Cl)cc2)cc1CCl
Temperature: 25 °C

Procedure:
To mixture of N-(6-bromopyridin-3-yl)-1-(4-chlorophenyl)-4-(hydroxymethyl)-1H-pyrazole-3-carboxamide (330 mg, 0.810 mmol) in CH2Cl2 (15 mL) at RT was added methanesulfonyl chloride (0.101 mL, 1.295 mmol) and DIEA (0.283 mL, 1.619 mmol). The resulting mixture was stirred at room temperature over a weekend. The reaction mixture was diluted with H2O, stirred for 5 min and subjected to filtration. The solid collected was dried under vacuum to give Example 17D (340 mg, (99%) as a beige solid. 1H NMR (CDCl3) δ 4.98 (s, 2H), 7.44-7.53 (m, 2H), 7.61-7.72 (m. 2H), 8.06 (s, 1H), 8.20-8.28 (s, 2H), 8.53 (s, 1H), 8.79 (s, 1H). LCMS, [M+H]+=426.9.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:41])[NH:24][C:25]3[S:26][C:27]4[CH2:33][C@@H:32]([NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])[CH2:31][CH2:30][C:28]=4[N:29]=3)[CH:18]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].C([O-])([O-])=[O:43].[K+].[K+]>CO.O>[F:37][C:36]([F:39])([F:38])[C:35]([OH:40])=[O:43].[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:41])[NH:24][C:25]3[S:26][C:27]4[CH2:33][C@@H:32]([NH2:34])[CH2:31][CH2:30][C:28]=4[N:29]=3)[CH:18]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(NC(=O)N2CCC[C@@H]2c2cccc(C(=O)Nc3nc4c(s3)C[C@@H](NC(=O)C(F)(F)F)CC4)c2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#Cc1cccc(NC(=O)N2CCC[C@@H]2c2cccc(C(=O)Nc3nc4c(s3)C[C@@H](N)CC4)c2)c1
Product: O=C(O)C(F)(F)F
Yield: 39.1 %

Procedure:
To a stifling solution of crude (R)-2-{3-[(S)-6-(2,2,2-trifluoro-acetylamino)-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl]-phenyl}-pyrrolidine-1-carboxylic acid (3-cyano-phenyl)-amide (87 mg, 0.149 mmol) in MeOH (5 mL) and water (1 mL) at room temperature add anhydrous K2CO3 (200 mg, 1.447 mmol) and stir the reaction at 65° C. for 18 h. Remove the solvent in vacuo and dry the solid residue in vacuo. Suspend in DMF and filter off the K2CO3. Dilute with water and quench with TFA (0.5 mL). Purify the solution by reverse phase prep HPLC (10% to 90% CH3CN/water). Pool and concentrate fractions containing product and dry in vacuo to afford the title compound as a solid (35 mg). MS, electrospray 487.5 (M+H), rt 1.26 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[C:15]([C:23]([NH2:25])=[O:24])=[N:16][CH:17]=[CH:18][C:19]=1[CH2:20][CH2:21][CH3:22]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[C:15]([C:23]([NH2:25])=[O:24])=[N:16][CH:17]=[CH:18][C:19]=1[CH2:20][CH2:21][CH3:22])=[O:7])[CH3:2]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: CCCc1ccnc(C(N)=O)c1N
Solvent: c1ccncc1
Product: CCCc1ccnc(C(N)=O)c1NC(=O)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
2-Ethoxybenzoyl chloride (2.96 g, 0.016 mol) was added dropwise to a stirred solution of 3-amino-4-n-propylpridine-2-carboxamide (Preparation 6; 1.43 g, 0.008 mol) in pyridine (40 ml) at 0° C. The mixture was stirred at ambient temperature for 4 hours and then the solvent evaporated under vacuum. The residue was dissolved in dichloromethane (100 ml), the solution washed with saturated aqueous sodium carbonate solution (100 ml) and the aqueous phase then washed with dichloromethane (2×25 ml). The combined organic extracts were dried (MgSO4) and evaporated under vacuum, then the residue purified by chromatography on silica gel (15 g), using a methanol in dichloromethane elution gradient (0-3% methanol), followed by crystallisation from ethyl acetate to give the product as a light brown solid (1.36 g, 60%), 129°-131° C. Found: C,66.29; H,6.53; N,12.78. C18H21N3O3 requires C,66.04; H,6.47; N,12.84%.