Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:28])([F:27])[F:26])=[C:6]([CH:24]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=O)=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=[O:8].[NH2:29][CH2:30][CH:31]([NH2:35])[CH2:32][CH2:33][CH3:34]>O=P(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:28])([F:27])[F:26])=[C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]4[NH:35][CH:31]([CH2:32][CH2:33][CH3:34])[CH2:30][N:29]=4)=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[O:8])[CH:24]=1
Reactant: CCCC(N)CN
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCC1CN=C(c2ccc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)nc2)N1
Temperature: 25 °C
Yield: 9 %

Procedure:
To a stirred solution of 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]nicotinic acid (0.509 g, 1.281 mmol) in POCl3(10 mL) was added dropwise 1,2-diaminopentane (3.50 g, 34.0 mmol). The resulting mixture was stirred at reflux for 16 h and then allowed to cool to ambient temperature and concentrated. The residue was taken up in saturated NaHCO3 and extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by chromatography to afford the title compound in 9% yield (0.052 g). 1H NMR (300 MHz, CDCl3) δ 9.09 (d, J=2.2 Hz, 1H), 8.56 (dd, J=2.2, 9.2 Hz, 1H), 7.74 (dd, J=5.1, 8.8 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.10 (dd, J=2.4, 8.0 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 4.32-3.49 (m, 9H), 1.92-0.75 (m, 9H). MS (ES+) m/z 464 (M+1).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CCO>[F:9][CH:8]([F:10])[CH2:7][N:6]1[C:2]([N:14]2[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]2)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]1
Reactant: OC1CCCNCC1
Reactant: O=[N+]([O-])c1cnn(CC(F)F)c1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnn(CC(F)F)c1N1CCCC(O)CC1
Yield: 62.1 %

Procedure:
A solution of 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (470 mg, 2.22 mmol), azepan-4-ol (281 mg, 2.44 mmol) and DIPEA (1 mL) in EtOH (3 mL) was heated at 155° C. in the microwave for 5 hr. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give 1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-ol as a pale orange gum (400 mg). This gum (390 mg, 1.35 mmol) was dissolved in MeOH (25 mL) and treated with ammonium formate (340 mg, 5.38 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 85° C. for 4 hr. After standing at room temperature overnight more ammonium formate (205 mg, 3.25 mmol) and 10% palladium on carbon (50 mg) were added to the reaction mixture which was then heated at 85° C. for 1 hr. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between DCM (30 mL) and water (20 mL). The organic layer was passed through a phase separation cartridge and the solvent was removed under reduced pressure to afford 1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-ol as an orange oil (265 mg, 42% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.17 (s, 1H), 6.27-5.91 (m, 1H), 4.39-4.23 (m, 2H), 4.16-4.04 (m, 1H), 3.30-3.11 (m, 4H), 2.60 (br s, 3H), 2.55 (s, 2H), 2.08-1.81 (m, 3H), 1.80-1.71 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:17][NH2:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH:18][CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN
Reactant: O=CC1(c2ccc(F)c(Cl)c2)CCCCC1
Product: CNCC1(c2ccc(F)c(Cl)c2)CCCCC1
Yield: 55 %

Procedure:
The title compound was synthesized from 1-(3-chloro-4-fluorophenyl)-cyclohexanecarbaldehyde and methyl amine using General Procedure H1 and was obtained in 55% yield. LCMS Rt=7.73 min, m/z=256 (M+1). 1H NMR (CDCl3, δ): 7.37 (dd, J=2.4, 7.1 Hz, 1H), 7.22 (ddd, J=2.4, 4.6, 8.7 Hz, 1H), 7.09 (t, J=8.7 Hz, 1H), 2.58 (s, 2H), 2.29 (s, 3H), 2.0 (m, 2H), 1.7-1.2 (m, 8H). 13C NMR (CDCl3, δ, mult): 157.4(0), 154.9(0), 142.9(0), 129.2(1), 126.8(1), 126.7(1), 120.8(0), 120.6(0), 116.3(1), 116.1(1), 64.2(2), 42.1(0), 37.3(3), 34.6(2), 26.4(2), 22.1(2).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:26]=[CH:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17](=[O:27])[C:16]=3[CH:15]=2)[CH2:9]1)(OC(C)(C)C)=O.O.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>CCOC(C)=O>[C:29]1([CH3:39])[CH:30]=[CH:31][C:32]([S:35]([OH:38])(=[O:36])=[O:37])=[CH:33][CH:34]=1.[NH:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:26]=[CH:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17](=[O:27])[C:16]=3[CH:15]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc3c(c2)C(=O)c2ccccc2-3)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2ccccc2-c2ccc(O[C@H]3CCNC3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A solution of 2-[(S)-N-Boc-pyrrolidin-3-yloxy]-fluoren-9-one (315 mg, 0.863 mmol; Example 4A) and p-toluenesulfonic acid monohydrate (165 mg, 0.868 mmol; Aldrich) in EtOAc (15 mL) was heated to reflux. A precipitate began to form after about 30 min of heating. After 18 h, the mixture was cooled to room temperature and the yellow crystals were collected by filtration to afford the title compound (334 mg, 0.763 mmol; 88% yield): 1H NMR (300 MHz, CD3OD) δ ppm 7.67-7.73 (m, J=8 Hz, 2H), 7.55-7.63 (m, 3H), 7.52 (dt, J=7, 1 Hz, 1H), 7.27 (dt, J=7, 1 Hz, 1H), 7.20-7.24 (m, J=5, 3 Hz, 3H), 7.14 (dd, J=8, 3 Hz, 1H), 5.24-5.30 (m, 1H), 3.44-3.63 (m, 4H), 2.29-2.39 (m, 5H); MS (DCl/NH3) m/z 266 (M+H)+; Anal. C17H15NO2.C7H8O3S: C, H, N.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][C:10]([OH:18])([C:12]#[C:13][Si](C)(C)C)[CH2:9][CH2:8][O:7]1)=O)C.[NH3:19]>CO>[C:12]([C:10]1([OH:18])[CH2:9][CH2:8][O:7][CH:6]([C:4]([NH2:19])=[O:3])[CH2:11]1)#[CH:13]
Reactant: N
Reactant: CCOC(=O)C1CC(O)(C#C[Si](C)(C)C)CCO1
Solvent: CO
Product: C#CC1(O)CCOC(C(N)=O)C1
Reaction time: 0.17 h
Yield: 97 %

Procedure:
4-Hydroxy-4-trimethylsilanylethynyl-tetrahydro-pyran-2-carboxylic acid ethyl ester (2.50 g, 9.25 mmol) was dissolved in MeOH (20 mL) in a pressure reaction tube and NH3 gas was passed through the solution for 10 minutes with stirring. The tube was tightly capped and the reaction was stirred for 3 days. After solvent removal, 1.53 g (97%) of yellow oil was obtained: 1H NMR (CD3OD) δ 1.48 (t, 1H), 1.70 (td, 1H), 1.85 (d, 1H), 2.30 (d, 1H), 3.04 (s, 1H), 3.29 (s, 1H), 3.71(t, 1H), 3.98 (d, 1H), 4.06 (dt, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1>O1CCCC1>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][CH2:11]2)=[S:27])=[CH:21][CH:20]=1
Reactant: Cc1ccc(N=C=S)cc1
Reactant: NCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=S)NCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-1-piperazineethanamine (0.01 mol) and 4-methyl-1-isothiocyanatobenzene (0.01 mol) in tetrahydrofuran (300 ml) was stirred at room temperature for 1 hour. The solvent was evaporated. The residue was recrystallized from DIPE. The precipitate was filtered off and dried. The product was used without further purification, yielding 4.2 g N-(4-methylphenyl)-N'-[2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl]thiourea (interm. 6).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:14](O)=O>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:14]([C:13]3[CH:17]=[CH:18][C:19]([CH3:20])=[C:11]([CH3:10])[CH:12]=3)[O:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: Nc1ccc(Br)cc1O
Product: Cc1ccc(-c2nc3ccc(Br)cc3o2)cc1C

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 3,4-dimethyl-benzoic acid.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14](=O)[C:8]=2[CH:7]=[CH:6][N:5]=1>C(N(CC)CC)C>[OH:3][N:2]=[C:14]1[C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]1
Reactant: NO
Reactant: O=c1ccccc2cnccc12
Agent: Cl
Solvent: CCN(CC)CC
Product: ON=c1ccccc2cnccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Hydroxylamine hydrochloride (2.20 g, 0.317 mole) was added to a stirred mixture of cyclohepta[1,2-c]pyridin5-one and triethylamine (15.00 ml) and the resulting yellow solution was stirred overnight at its reflux temperature. The pale yellow solution was cooled to room temperature, then concentrated by solvent evaporation to a pasty yellow solid. The solid was dissolved in a mixture of water and diethyl ether (1:1, ~700ml) and the yellow Et2O layer was separated and extracted with water (2X, 500 ml), washed with brine, then dried (MgSO4). Filtration through celite followed by concentration of the filtrate gave 2.30g (53%) of a yellow solid, which after trituration with hexane and recrystallization from aqueous ethanol, gave the desired product, m.p. 164°-167° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[CH2:12][N:11]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[C:37]([NH:38]C(=O)OCC3C=CC=CC=3)=[CH:36][C:35]3[C:30](=[CH:31][C:32]([C:49]4[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH:54]=4)=[CH:33][CH:34]=3)[N:29]=2)=[O:27])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:38][C:37]1[C:28]([C:26]([NH:25][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:19]=2[N:11]2[CH2:12][C@H:13]([C:15]([F:18])([F:16])[F:17])[CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]2)=[O:27])=[N:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[C:32]([CH:49]1[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH2:54]1)[CH:31]=2
Reactant: [H][H]
Reactant: CN1CC=C(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)Nc4cnccc4N4C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C4)nc3c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(c2ccc3cc(N)c(C(=O)Nc4cnccc4N4C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C4)nc3c2)CC1
Yield: 79.7 %

Procedure:
A mixture of benzyl [2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl]carbamate (0.010 g, 0.013 mmol) in 1.5 mL of MeOH was hydrogenated in the presence of 10% Pd on carbon (3.5 mg) under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl [(3S,5R)-1-[3-({[3-amino-7-(1-methylpiperidin-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.0065 g, 79%). LCMS calc. for C32H41F3N7O3 [M+H]+: m/z=628.3. found: 628.3.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[O:12])=[CH:9][N:8]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+:27].[OH-]>O1CCOCC1>[NH2:27][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[O:12])=[CH:9][N:8]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [NH4+]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1cn(C2CCCC2)c2ncnc(Cl)c12
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(C(=O)c1cccc([N+](=O)[O-])c1)cn2C1CCCC1
Yield: 97 %

Procedure:
A solution of (4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-nitro-phenyl)-methanone (11.3 g, 30.5 mmol) and NH4OH (200 mL) in 1,4-Dioxane (300 mL) was heated to 50° C. in a pressure reactor. After 2 h the reaction was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated to afford the title compound as a yellow solid (10.37 g, 97%). MS: 352.1 (MH+); HPLC Rf: 5.56 min. (HPLC method 4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14](=[O:33])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:33])[CH2:15][C:16]1[CH:17]=[C:18]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=[O:8])[C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:12]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cc(Br)ccc1I
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 5-bromo-2-iodo-benzaldehyde and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.[CH:44]([O:47][C:48]1[N:53]=[CH:52][C:51]([C@@H:54]([NH2:56])[CH3:55])=[CH:50][CH:49]=1)([CH3:46])[CH3:45]>CN(C=O)C>[CH:44]([O:47][C:48]1[N:53]=[CH:52][C:51]([C@@H:54]([NH:56][C:10]([C@H:8]2[CH2:9][C@@H:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:12])[CH3:55])=[CH:50][CH:49]=1)([CH3:46])[CH3:45]
Reactant: CC(C)Oc1ccc([C@H](C)N)cn1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trans-2-phenyl-1-cyclopropanecarboxylic acid IM46 (0.590 g, 3.64 mmol) was dissolved in DMF (15.0 mL). N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.38 g, 3.63 mmol) was added. Triethylamine (1.10 mL, 7.89 mmol) was then added and the mixture was stirred for 15 minutes at room temperature. This mixture was added drop wise to a solution of (S)-1-(6-isopropoxy-pyridin-3-yl)-ethylamine IM24 (0.655 g, 3.63 mmol) dissolved in DMF (15.0 mL) over 2 minutes. The mixture was stirred at room temperature over night. The mixture was evaporated to dryness. The residue was transferred to a silica gel column and eluded with EtOAc/heptanes 1:1 to give Compound 1 as a solid. This solid was dissolved in EtOAc (50 mL) and to this solution was slowly added heptanes (50 mL). The mixture was concentrated to approx. 25 mL in vacuo and this solution was cooled in an ice/water bath. A white precipitate formed. The solids was collected by filtration and dried in vacuo to give the title compound as colorless crystals (0.794 g, 67%). LC-MS (m/z) 325.4 (MH+), tR=1.51 min (method A). 1H NMR (500 MHz, DMSO) δ 8.57-8.50 (m, 1H), 8.06 (br s, 1H), 7.65-7.57 (m, 1H), 7.30-7.24 (m, 2H), 7.20-7.14 (m, 1H), 7.10 (d, J=7.5 Hz, 2H), 6.69 (d, J=8.5 Hz, 1H), 5.25-5.16 (m, 1H), 4.98-4.88 (m, 1H), 2.24-2.15 (m, 1H), 1.94-1.88 (m, 1H), 1.41-1.32 (m, 4H), 1.26 (d, J=6.2 Hz, 6H), 1.20 (ddd, J=8.5, 6.1, 4.1 Hz, 1H). Diastereomeric excess >95% based on 1H NMR.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([C:37](O)=[O:38])=[CH:36][C:31]=2[O:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37]([C:35]5[CH:34]=[CH:33][C:32]6[O:28][CH2:29][O:30][C:31]=6[CH:36]=5)=[O:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc2c(c1)OCO2

Procedure:
The title compound, white solid (107 mg, 89%), MS (ISP) m/z=479.3 [(M+H)+], mp 243.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and benzo[1,3]dioxole-5-carboxylic acid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[S:15][CH:16]=[CH:17][C:18]=1[C:19]#[N:20].[H-].[Na+]>C1COCC1>[F:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([NH:13][C:14]2[S:15][CH:16]=[CH:17][C:18]=2[C:19]#[N:20])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: N#Cc1ccsc1N
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccsc1Nc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.6 %

Procedure:
Combine 2,4,5-trifluoro-nitrobenzene (5.00 g, 24.24 mmol), 2-aminothiophene-3-carbonitrile (3.51 g, 28.24 mmol), and anhydrous THF (30.0 ml). Cool the mixture to 10° and then slowly add NaH (2.26 g, 56.47 mmol, 60% dispersion in mineral oil) while keeping the temperature less than 10°. Warm the mixture to ambient temperature after NaH addition is complete. Stir the mixture at ambient temperature for 24 hours and then pour it onto ice chips. Extract the aqueous with ethyl acetate and then wash (brine), dry (sodium sulfate), and reduce the organic to residue. Purify the residue on silica gel using hexanes/dichloromethane (35:65) to give 4.06 g (51%) of the title compound as a red solid: mass spectrum (ion spray): m/z=280.0 (M−1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:9]=[CH:8][N:7]=1
Reactant: CCOC(=O)COc1ccc(CN(CCOC)c2nccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of ethyl {4-[((2-methoxyethyl){4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]-2-methylphenoxy}acetate (80 mg, 0.16 mmol) in methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was added 2M sodium hydroxide (1.5 mL). The resulting mixture was stirred at room temperature for 1 h. The solvents were removed in vacuo and the residue was diluted with water (10 mL) acidified with 2M HCl and extracted ethyl acetate (2×30 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo, to afford the title compound as a cream solid (72 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]([NH:17][C:18]([C:20]1[C:32]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][CH:26]=[CH:25][C:24]=3[C:23]=2[N:22]([CH2:33][C:34]([F:37])([F:36])[F:35])[CH:21]=1)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[NH2:7][CH2:8][C@@H:9]([NH:17][C:18]([C:20]1[C:32]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][CH:26]=[CH:25][C:24]=3[C:23]=2[N:22]([CH2:33][C:34]([F:37])([F:36])[F:35])[CH:21]=1)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1)NC(=O)c1cn(CC(F)(F)F)c2c1CCc1cnccc1-2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NC[C@H](Cc1ccccc1)NC(=O)c1cn(CC(F)(F)F)c2c1CCc1cnccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of tert-butyl[(2S)-3-phenyl-2-({[1-(2,2,2-trifluoroethyl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinolin-3-yl]carbonyl}amino)propyl]carbamate L8 (0.38 mmol) in dry dioxane (20 mL), 4M HCl in dioxane (5 mL) was added. The reaction mixture was stirred at rt overnight. The solvent was removed and the residue dissolved with DCM and washed with aq NaHCO3. The organic layer was dried (Na2SO4) and concentrated. Purification by chromatography on silica gel (eluant: DCM/MeOH 19:1) gave, after trituration with diethylether, the title compound (75% yield). ESI (+) MS: m/z 429 (MH+). 1H-NMR: 4.06-4.18 (m, 1H), 5.32 (q, J=8.98, 2H), 7.18 (m, 1H), 7.48 (d, J=5.24, 1H), 7.57 (s, 1H), 7.71 (d, J=8.41, 1H), 8.38 (d, J=5.24, 1H), 8.40 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([C:12]([O:14]CC)=[O:13])[O:4][N:3]=1.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([C:12]([OH:14])=[O:13])[O:4][N:3]=1
Reactant: CCOC(=O)c1onc(C)c1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(C)noc1C(=O)O
Reaction time: 16 h

Procedure:
65 g of diethyl 3-methylisoxazole-4,5-dicarboxylate, dissolved in 100 ml of ethanol, are added dropwise to 18.9 g of potassium hydroxide in 100 ml of water at room temperature. After 16 hours, the mixture is poured onto 300 ml of water and extracted with ether, and the aqueous phase is acidified with concentration hydrochloric acid. Extracting with dichloromethane and evaporating down give 3-methyl-4-ethoxycarbonylisoxazole-5-carboxylic acid as colorless crystals of melting point 54°-58° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:29]I.CCOC(C)=O>C(Cl)(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:10]([I:29])=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: II
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccccc2)cc1OC1CCCC1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cc(I)c([C@H](Cc2ccncc2)c2ccccc2)cc1OC1CCCC1
Yield: 90.3 %

Procedure:
From (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl] pyridine (made as described in International Patent Specification No. WO 94/14742) (1.82 g, 4.88 mmol) in CHCl3 (50 ml)m, silver triflate (1.26 g, 4.88 mmol) and iodine (1.24 g, 4.88 mmol). Chromatography (SiO2 ;EtOAc) afforded the title compound (2.2 g) as a colourless gum. (Found C, 59.23; H, 5.32; N, 2.67. C23H26NO2 l requires C, 60.13; H, 5.25; N, 2.81) δH (CDCl3) 1.5-1.9 (8H, m,CH2)4), 3.25 (1H, d, J 5 Hz, CH2 pyridine), 3.27 (1H, d, J 5 Hz, CH2 pyridine), 3.74 (3H, s, OCH3), 4.6-4.7 (1H, m, OCH), 4.64 (1H, t, J 8 Hz, CH phenyl), 6.74 (1H, s, C6H2), 7.01 (2H, d, J 5 Hz, H3, H5 pyridine), 7.24 (1H, s, C6 H2), 7.25-7.4 (5H, m, C6H5), and 8.39 (2H, d, J 5 Hz, H2, H6 pyridine). m/z 500 (M+, 100%), 406 (25) and 212 (14).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH:23]([CH3:25])[CH3:24])[CH:16]=1)[CH2:5][C:6]1[NH:10][N:9]=[N:8][N:7]=1.B(F)(F)F.S(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:23]([CH3:24])[CH3:25])[CH:16]=1)[CH2:5][C:6]1[NH:10][N:9]=[N:8][N:7]=1
Reactant: COc1ccc(Oc2c(Cl)cc(Cc3nnn[nH]3)cc2Cl)cc1C(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: CC(C)c1cc(Oc2c(Cl)cc(Cc3nnn[nH]3)cc2Cl)ccc1O

Procedure:
A reaction mixture of 3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)-benzyltetrazole (60 mg), BF3.Me2S (0.5 ml) and CH2Cl2 (6 ml) was stirred at room temperature over night. The yield after purification was quantitative.