Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]3[CH:25]=[C:26]([C:30]4[N:31]=[CH:32][N:33]([CH2:35][CH2:36][O:37]C)[CH:34]=4)[CH:27]=[C:28]([CH3:29])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]3[CH:25]=[C:26]([C:30]4[N:31]=[CH:32][N:33]([CH2:35][CH2:36][OH:37])[CH:34]=4)[CH:27]=[C:28]([CH3:29])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: COCCn1cnc(-c2cc(C)c3nc(C4CC4)n(Cc4ccc(-c5ccccc5C(=O)O)cc4)c3c2)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc(-c2cn(CCO)cn2)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
A solution of 500 mg (1.0 mMol) of 4'-[(2-cyclopropyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid and 1.5 g (6.0 mMol) of boron tribromide in 50 ml of methylene chloride is stirred for 16 hours at ambient temperature, then mixed with about 30 ml of water and stirred vigorously for another 10 minutes. This mixture is evaporated to dryness and the residue is refluxed in about 40 ml of ethanol for 10 minutes. The mixture is evaporated to dryness once more, the residue is dissolved in about 30 ml of 2N ammonia solution and this solution is adjusted to pH 5-6 with 2N acetic acid. The crude product precipitated is suction filtered and purified by column chromatography (80 g silica gel; eluant:methylene chloride/methanol=4:1).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH3:13][N:14]([CH3:27])[CH2:15][CH2:16][O:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>>[CH3:13][N:14]([CH3:27])[CH2:15][CH2:16][O:17][N:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CN(C)CCONCc1ccc(F)cc1
Product: CN(C)CCON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 30 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with O-(2-dimethylamino-ethyl)-N-(4-fluorobenzyl)-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (30% yield): mp 95-96° C. (ether-hexane). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 1.70 (6H, s, CH3), 2.16 (6H, s, NCH3), 2.44 (2H, t, J=5.3 Hz, CH2), 3.97 (2H, t, J=5.3 Hz, CH2), 4.79 (2H, s, NCH2), 6.52 (1H, s, CH), 7.18 (2H, m, aromatics), 7.34 (2H, m, aromatics). Anal. calcd for C18H23FN2O5: C, 59.00; H, 6.32; N, 7.64. Found: C, 58.73; H, 6.13; N, 7.40.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([F:57])[C:45]=1[O:46][Si](C(C)C)(C(C)C)C(C)C)[CH2:5][CH:6]([CH:16]=[CH:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([F:57])[C:45]=1[OH:46])[CH2:5][CH:6]([CH:16]=[CH:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:37][CH:38]=2)=[CH:29][CH:28]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCCCC(C=Cc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC(C=Cc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Cc1cc(F)c(O)c(F)c1
Temperature: 25 °C

Procedure:
720 mg (0.89 mmol) of ethyl 6-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)-8-[5-fluoro-2-(4′-trifluoromethylbiphenyl-4-ylmethoxy)phenyl]oct-7-enoate are introduced into 15 ml of THF at 0° C. under argon, 1.77 ml (1.77 mmol) of a 1 M solution of tetra-n-butylammonium fluoride in THF are added, and the mixture is stirred at room temperature until reaction is complete. All the volatile components are removed in vacuo. The resulting crude product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:1). 400 mg (68% of theory) of the title compound are obtained as an E/Z mixture (2:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CC(O)=O.[Rh]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C@@H:15]1[CH2:24][CH2:23][C@H:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@@H](OC[C@@H]2CCCN2C(=O)OC(C)(C)C)CC1
Reaction time: 36 h

Procedure:
A mixture of methyl 4-(1-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methoxybenzoate (1.0 g, 2.9 mmol) and 5% Rh on alumina (500 mg) in EtOH (10.0 ml) and AcOH (1.0 ml) was hydrogenated at room temperature at 5 atm for 36 hr. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (6:1, v/v) as eluent to give methyl cis-4-[(1-tert-butoxycarbonyl-(2S)-pyrrolidinyl) methoxy]cyclohexanecarboxylate (900 mg, 89%) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.46 (s, 9H), 1.46–2.00 (m, 12H), 2.34 (m, 1H), 3.20–3.55 (m, 5H), 3.67 (s, 3H), 3.84–3.92 (m, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14](=[O:16])[CH3:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[S:9][C:10]([C:14](=[O:16])[CH3:15])=[C:11]([CH3:13])[N:12]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: C1=CCCCC1
Reactant: CC(=O)c1sc(-c2ccc(I)cc2)nc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1sc(-c2ccc(C3=CCCCC3)cc2)nc1C
Temperature: 80 °C
Yield: 39 %

Procedure:
A solution of 4-iodophenylthiazole 4i (100 mg, 0.3 mmol) in dry DMF (5 mL) was charged with Pd(OAc)2 (5 mg), cyclohexene (1 mL) and triethylamine (0.5 mL). The reaction mixture was heated at 80° C. for 5 h. The reaction mixture was quenched with distilled water (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was separated and dried over anhydrous Na2SO4. After evaporation of solvent under reduced pressure, the oily residue was collected and purified by silica gel flash chromatography, using hexane-ethyl acetate (9:1), to yield faint yellowish oil (35 mg, 39%). 1H NMR (CDCl3) δ 7.90 (d, J=8.1 Hz, 2 H), 7.29 (d, J=8.1 Hz, 2 H), 5.76 (m, 2 H), 2.80 (m, 1 H), 2.77 (s, 3 H), 2.55 (s, 3 H), 2.27-1.24 (m, 6 H); 13C NMR (CDCl3) δ 190.45, 169.54, 159.46, 150.94, 130.84, 130.63, 128.42, 127.60, 126.97, 126.33, 40.06, 32.98, 30.73, 29.40, 25.59, 18.45; CIMS m/z (rel intensity) 298 (MH+, 100); HRMS (EI), m/z 297.1189 M+, calcd for C18H19NOS 297.1187.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:39](=[O:56])[C:40]2[CH:45]=[CH:44][N:43]([CH3:46])[C:42](=[O:47])[C:41]=2[O:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:39](=[O:56])[C:40]4[CH:45]=[CH:44][N:43]([CH3:46])[C:42](=[O:47])[C:41]=4[O:48][C:49]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: Cn1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1=O
Product: Cn1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1=O
Yield: 41 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-7-methyl-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione was reacted to give the title compound (25.2 mg, 41%) as a colourless gum. LCMS (Method B): RT=4.49 min, [M+Na]+=521.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@H:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[CH2:8]1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][S:2]([O:6][C@H:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.7 %

Procedure:
MsCl (6.61 mL, 85 mmol) was added dropwise at 0° C. to a solution of (2R,4S)-1-tert-butyl 2-methyl 4-hydroxypiperidine-1,2-dicarboxylate (21 g, 81 mmol) and DMAP (100 mg, 0.81 mmol) in pyridine (50 mL). The mixture was stirred at room temperature for 5 hours and then was concentrated under reduced pressure to remove most solvent. Brine (200 mL) was added and extracted with ethyl acetate (2×200 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give title compound 26.7 g (98%) as colorless oil. LC-MS: 338.1 (t=1.9 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:40]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:14]([Cl:40])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC1Cc2c(nc[nH]c2=O)CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CC1Cc2c(Cl)ncnc2CN1C(=O)OC(C)(C)C

Procedure:
A solution of (±)-6-methyl-4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester, (7.5 g, 28.3 mmol), triphenylphosphine (14.8 g, 56.5 mmol) and carbon tetrachloride (8.2 mL, 85 mmol) in 1,2-DCE (100 mL) is heated at 80° C. for 6 h. At that time the solution is concentrated in vacuo and the residue is separated via FCC (5-60% EtOAc/heptane) to give the title compound. MS (ESI) m/z 284.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[CH:9][N:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[C:4]=2[N:5]=[N:6][CH:7]=1.[CH2:15]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:16]>>[CH:11]1([N:8]2[C:4]3[N:5]=[N:6][CH:7]=[C:2]([C:28]4[CH:27]=[C:26]([C:23]5[CH:24]=[CH:25][C:20]([S:17]([CH2:15][CH3:16])(=[O:18])=[O:19])=[CH:21][CH:22]=5)[C:31]([F:32])=[CH:30][CH:29]=4)[C:3]=3[N:10]=[CH:9]2)[CH2:14][CH2:13][CH2:12]1
Reactant: Clc1cnnc2c1ncn2C1CCC1
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2F)cc1
Product: CCS(=O)(=O)c1ccc(-c2cc(-c3cnnc4c3ncn4C3CCC3)ccc2F)cc1
Yield: 10 %

Procedure:
Prepared according to the method described for Example 26 using 4-chloro-7-cyclobutyl-7H-imidazo[4,5-c]pyridazine (Preparation 99) and 2-(4′-ethylsulfonyl-6-fluorobiphenyl-3-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Preparation 48) to afford the title compound as an off white solid in 10% yield, 10 mg.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1)(=[O:5])=[O:4].[OH-].[Na+].C([OH:23])C.OO>O>[CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([C:10]([NH2:11])=[O:23])=[C:8]([C:14]([F:15])([F:17])[F:16])[CH:7]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(C(N)=O)c(C(F)(F)F)c1
Temperature: 40 °C

Procedure:
A mixture of 4-(N,N-dimethylsulphamoyl)-2-trifluoromethylbenzonitrile (2.78 g), sodium hydroxide (130 mg) and ethanol was heated to 40° C. Hydrogen peroxide (7 ml of 30% solution) was then added and the mixture heated at 40° C. for 3 hours. After cooling the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue recrystallised from ethyl acetate/toluene to give 4-(N,N-dimethylsulphamoyl)-2-trifluoromethylbenzamide (1.39 g) as a white solid, m.p. 149°-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH2:10][NH2:11])=[N:6][CH:7]=1.[C:12](C1NC=CN=1)(C1NC=CN=1)=[O:13]>O1CCCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][C:12]2=[O:13])=[N:4][CH:3]=1
Reactant: NCCNc1ncc(Br)cn1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=C1NCCN1c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N1-(5-Bromopyrimidin-2-yl)ethane-1,2-diamine (100 mg) was added to a solution of carbonyl diimidazole (30 mg) in tetrahydrofuran (5 mL) at 0° C. The reaction mixture was stirred under nitrogen at room temperature for 1 h. The formed solution was concentrated to give an oil, which was purified by preparative TLC to afford the title compound. Yield: 13 mg (12% of theory).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:33]#[C:34][Si](C)(C)C)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[C:33]([C:4]1[CH:3]=[C:2]([F:1])[CH:32]=[CH:31][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:30])[CH3:29])=[O:9])#[CH:34]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#C[Si](C)(C)C)c(OCc1ccccc1)c2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 22 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A solution of intermediate 178, N-(4-fluoro-2-(2-(trimethylsilyl)ethynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.150 g, 0.28 mmol) in methanol (5 ml) was treated with potassium carbonate (0.120 g, 0.84 mmol) and the resulting mixture stirred at 22° C. for one hour. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.129 g (100% yield) of the title material as a light yellow solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.64 (6H, s, 2×CH3), 3.31 (1H, s, CH), 4.04 (4H, m, 2×CH2), 4.69 (2H, d, J=6.6 Hz, NCH2), 5.31 (2H, s, OCH2), 7.04 (1H, m, aromatic), 7.21 (1H, dd, J=2.6 Hz and J=9.1 Hz, aromatic), 7.32-7.42 (3H, m, aromatics), 7.40 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 7.52-7.54 (2H, m, aromatics), 8.00 (1H, broad t, NH). HRMS (ESI+) calculated for C26H25FN3O4 [M+H]: 462.1829; found: 462.1822.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][CH:24]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[CH3:25])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:32][C:33]([CH3:35])=O>CO.[Pd]>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][CH:24]([CH:26]5[CH2:31][CH2:30][N:29]([CH:33]([CH3:35])[CH3:32])[CH2:28][CH2:27]5)[CH3:25])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CCNCC1
Agent: [Pd]
Solvent: CO
Product: CC(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
A mixture of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-piperidin-4-ylethoxy)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (211 mg, 0.50 mmol), acetone (6 mL) and 10% Pd/C (150 mg) in MeOH (2 mL) was stirred under an atmosphere of H2 at RT for 16 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, on a gradient 10-90%, 0.1% HCO2H acetonitrile/water) to afford 143 (161 mg, 69%). LCMS: RT 3.08 [M+H]+ 465.4. 1H NMR (DMSO, 400 MHz): δ 8.29 (1H, d, J=8.96 Hz), 8.23 (1H, s), 7.90 (1H, d, J=0.64 Hz), 7.85 (1H, s), 6.77 (1H, dd, J=8.99, 2.54 Hz), 6.57 (1H, d, J=2.51 Hz), 5.93-5.85 (1H, m), 4.48 (4H, s), 4.38-4.31 (1H, m), 2.97 (2H, d, J=11.01 Hz), 2.87-2.86 (1H, m), 2.30 (2H, t, J=11.50 Hz), 1.84 (1H, d, J=12.83 Hz), 1.67-1.63 (2H, m), 1.47 (6H, d, J=6.60 Hz), 1.44-1.29 (1H, m), 1.21 (3H, d, J=6.10 Hz), 1.03 (6H, d, J=6.56 Hz)
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10]1)=O)(C)(C)C.[ClH:22].CCOCC>CO>[ClH:21].[ClH:22].[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a methanol solution (80 mL) of the 3-[(tert-butoxycarbonyl)amino]-1-(4-chlorobenzyl)pyrrolidine (6.38 g, 20.5 mmol), was added 1 M HCl-Et2O (100 mL). The resulting mixture was stirred at 25° C. for 15 hours. The solvent was removed under reduced pressure to provide a solid, which was purified by recrystallization (methanol/acetonitrile=1:2, 130 mL) to thereby afford 3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride (4.939 g, 85%) as a white powder. 1H NMR (d6-DMSO, 300 MHz) δ 3.15 (br, 1H), 3.3-3.75 (br-m, 4H), 3.9 (br, 1H), 4.05 (br, 1H), 4.44 (br, 1H), 4.54 (br, 1H), 7.5-7.7 (m, 4H), 8.45 (br, 1H), 8.60 (br, 1H); the purity was determined by RPLC/MS (>99%). ESI/MS m/e 211.0 (M++H, C11H16ClN2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[O:4].[CH2:19]([N:23]=[C:24]=[O:25])[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:19]([NH:23][C:24]([NH:18][S:15]([CH2:14][C:6]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4])(=[O:17])=[O:16])=[O:25])[CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CS(N)(=O)=O
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)Cc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 7.7 g of the product from Example 4, 3.5 g of n-butyl isocyanate, and 4.8 g anhydrous potassium carbonate in 100 ml of methyl ethyl ketone was stirred at reflux temperature for 4 hours. After cooling to room temperature, the reaction mixture was concentrated to approximately one-third volume and diluted with 150 ml of water. The resulting solid was collected by filtration and washed with one portion of water and one portion of n-butyl chloride. The yield of N-[(n-butyl)aminocarbonyl]-2-(methoxycarbonyl)-6-nitrophenylmethanesulfonamide, m.p. 144°-150°, was 9.1 g as a tan solid; IR(nujol): 1725, 1665 cm-1, NMR (CDCl3 /DMSO-d6): δ 0.6-1.7 (7H, m), 2.9-3.4 (2H, m), 4.0 (3H, s, CO2CH3), 5.7 (2H, s, --CH2 --), 7.4-8.3 (3H, m), 10.5 (1H, br s, NH).
Reaction SMILES: [OH-].[K+].[ClH:3].C[O:5][C:6](=[O:23])[CH2:7][CH:8]1[CH2:13][CH2:12][C:11]([N:20]([CH3:22])[CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.Cl>C(O)C.CCOCC>[ClH:3].[CH3:22][N:20]([CH3:21])[C:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13][CH:8]([CH2:7][C:6]([OH:23])=[O:5])[CH2:9][CH2:10]1
Reactant: COC(=O)CC1CCC(c2ccccc2)(N(C)C)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
1.7 M KOH (70.5 ml, 120 mmol) was added to a solution of (4-dimethylamino-4-phenylcyclohexyl)acetic acid methyl ester hydrochloride (1.79 g, 5.77 mmol) in ethanol (80 ml). The mixture was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was taken up in water. The aqueous phase was extracted with ether, and 5.5 M hydrochloric acid (23.6 ml, 130 mmol) was added. After concentration of the aqueous phase, the residue was extracted with ethanol, the potassium chloride which remained was separated off and the filtrate was concentrated. The product was thereby obtained as a colourless, oily compound in a yield of 95% (1.62 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:27](O)=[O:28])[NH:24][C:25]=1[CH3:26].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Cl:20][C:21]1[N:22]=[C:23]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:28])[NH:24][C:25]=1[CH3:26]
Reactant: Cc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1cnc(N2CC[C@H](N)[C@H](OC)C2)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(C)[nH]3)[C@H](OC)C2)s1
Yield: 19.7 %

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (5d) (0.21 g, 0.73 mmol), 4-chloro-5-methyl-1H-imidazole-2-carboxylic acid obtained in Example (5c) (0.10 g, 0.64 mmol), WSC hydrochloride (0.27 g, 1.41 mmol) and DMAP (10 mg, 0.083 mmol), to obtain 54 mg of the title compound as a pale yellow solid (20%).
Reaction SMILES: [OH:1][C:2]1[C:10]([NH2:11])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH:12]([O-])([O-])OCC>>[NH:8]1[C:9]2[C:10]3[N:11]=[CH:12][O:1][C:2]=3[CH:3]=[CH:4][C:5]=2[CH:6]=[N:7]1
Reactant: Nc1c(O)ccc2cn[nH]c12
Reactant: CCOC([O-])[O-]
Product: c1nc2c(ccc3cn[nH]c32)o1

Procedure:
A 0.40 g of 6-hydroxy-7-aminoindazole was mixed with 10 ml of ethyl orthoformate and heated under reflux for 2 hours. After cooling of the reaction solution, the solvent was evaporated under a reduced pressure and the residue was purified by a silica gel column chromatography to give 0.31 g of 1H-pyrazolo[3,4-e]benzoxazole.
Reaction SMILES: C(OC([N:8]1[CH2:27][CH2:26][N:11]2[C:12](=[O:25])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])=O)(C)(C)C.[ClH:28]>CCOCC.O>[ClH:28].[C:19]([C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:25])[N:11]3[CH2:26][CH2:27][NH:8][CH2:9][C@H:10]32)=[C:14]([C:21]([F:23])([F:24])[F:22])[CH:15]=1)#[CH:20]
Reactant: C#Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: C#Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-ethynyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (27 mg, 0.8 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 22 mg of a white solid. MS (ESI) 281 (M−Cl).
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:11](OC(=O)C)[CH:10]=[CH:9][C@H:8]([C:16](=[NH:19])[NH:17][OH:18])[O:7]1)(=O)C.[CH2:20]([O:22][C:23]([C:25]#[C:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])[CH3:21]>CCO>[OH:4][CH2:5][C@H:6]1[O:7][C@@H:8]([C:16](=[NH:19])[NH:17][O:18]/[C:26](=[CH:25]/[C:23]([O:22][CH2:20][CH3:21])=[O:24])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:9][CH2:10][CH2:11]1
Reactant: CC(=O)OC[C@H]1O[C@@H](C(=N)NO)C=C[C@@H]1OC(C)=O
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)/C=C(/ONC(=N)[C@H]1CCC[C@@H](CO)O1)C(=O)OCC
Temperature: 60 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To ((2R,3S,6R)-3-acetoxy-6-(N-hydroxycarbamimidoyl)-3,6-dihydro-2H-pyran-2-yl)methyl acetate (2.33 g, 13.4 mmol) in EtOH (15 mL) was added diethylacetylenedicarboxylate (3.20 mL, 20.1 mmol) and the reaction mixture was stirred at 60° C. for 3 h. The solvent was removed in vacuo to afford 2.40 g (52% yield) of the title compound as an amber oil. LCMS (+ESI, M+H+) m/z 345.