Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.Cl.[NH2:46][OH:47].C(=O)([O-])[O-].[K+].[K+]>CCO>[OH:47]/[N:46]=[CH:1]/[C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=C(C)[C@@H]1CC[C@]2(/C=N/O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (200 mg, 0.334 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (186 mg, 2.67 mmol) and potassium carbonate (369 mg, 2.67 mmol) and the mixture was stirred overnight at room temperature. LC/MS showed the mass of the expected product. The mixture was diluted with 7 mL of sat. NaHCO3 and was extracted with dichloromethane (3×7 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product as an off white foam (˜100%) was used in the next step with no additional purification. LCMS: m/e 614.53 (MH+), 3.82 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.90 (2H, m, J=8.3 Hz), 7.60 (1H, s), 7.19 (2H, m, J=8.3 Hz), 5.23-5.35 (1H, m), 4.76 (1H, d, J=1.8 Hz), 4.64 (1H, s), 2.56 (1H, td, J=11.0, 5.4 Hz), 2.05-2.19 (1H, m), 1.92-2.05 (2H, m), 1.83-1.92 (2H, m), 1.64-1.82 (7H, m), 1.58-1.64 (9H, m), 1.38-1.57 (9H, m), 1.22-1.31 (2H, m), 1.10-1.20 (2H, m), 1.07 (3H, s), 1.04 (3H, s), 0.97-1.01 (3H, m), 0.85-0.97 (6H, m)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.Cl.[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1)[CH3:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:41][CH2:40][CH2:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][N:30]([CH3:31])[CH3:29])=[CH:34][CH:35]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: CN(C)Cc1ccc(CCN)cc1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(CN(C)C)cc4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirred suspension of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.10 g, 0.28 mmol), 2-(4-((dimethylamino)methyl)phenyl)ethanamine dihydrochloride (0.056 g, 0.31 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.13 g, 0.34 mmol) in N,N-dimethylformamide (1.4 mL) at ambient temperature was added N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). The resulting solution was stirred at ambient temperature for 60 minutes, then partitioned between water (15 mL) and ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 90/10 chloroform/(90/10 methanol/concentrated ammonium hydroxide), to afford methyl 6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a colorless film (0.083 g, 57% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[CH3:12][O:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:30](=[O:37])[C:31]#[C:32][C:33]([OH:36])([CH3:35])[CH3:34])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2I)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:31](=[C:32](\[C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)/[C:33]([OH:36])([CH3:35])[CH3:34])/[C:30]2=[O:37])[CH:16]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)(C)O)c2ccccc2I)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(C#N)cc3)C(C)(C)O)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-cyano-phenylboronic acid (commercially available) and 3-{[(4-hydroxy-4-methyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (400 MHz, DMSO-d6) δppm 1.33 (s, 6H) 3.85 (s, 3H) 5.15 (s, 2H) 5.35 (d, J=7.83 Hz, 1H) 6.68 (t, J=7.71 Hz, 1H) 7.03 (d, J=7.83 Hz, 1H) 7.15 (t, J=7.71 Hz, 1H) 7.48-7.55 (m, 1H) 7.52 (d, J=7.58 Hz, 3H) 7.62 (d, J=7.83 Hz, 1H) 7.89 (d, J=7.83 Hz, 1H) 7.99 (s, 1H) 8.05 (d, J=8.34 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[C:13]3[C:26](=[O:32])[C:27]([O:29]CC)=[O:28])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+]>C1COCC1.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[C:13]3[C:26](=[O:32])[C:27]([OH:29])=[O:28])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(C(C)=O)cc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(-c2ccc3c(c2)c(C(=O)C(=O)O)cn3Cc2ccccc2)cc1

Procedure:
[5-(4-Acetylphenyl)-1-benzyl-1H-indol-3-yl](oxo)acetic acid was prepared from ethyl [5-(4-acetylphenyl)-1-benzyl-1H-indol-3-yl](oxo)acetate (0.225 g, 0.529 mmol), and potassium hydroxide (0.104 g, 1.85 mmol) in THF (7 mL) and water (7 mL) according to the procedure described in Step 4 of Example 5. After drying for 15 hours at 96° C., the title compound was obtained as a tan solid (0.166 g, 79%), mp: 213-214° C. (dec.). Mass spectrum (−APCI, [M−H]−) m/z 396; 1HNMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.5 (d, 1H, J=1.7 Hz), 8.05 (d, 2H, J=8.3 Hz), 7.8 (d, 2H, J=8.3 Hz), 7.7 (d, 1H, J=8.8 Hz), 7.65 (dd, 1H, J=8.7 Hz and 1.6 Hz), 7.25-7.4 (m, 5H), 5.65 (s, 2H), and 2.6 ppm (s, 3H). Elemental Analysis for C25H19NO4.0.50 H2O: Calculated: C, 73.87; H, 4.96; N, 3.45. Found: C, 73.54; H, 4.64; N, 3.32.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.[NH2:28][CH2:29][C:30]1([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:28][CH2:29][C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCC1(O)CCCCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(C(=O)NCC2(O)CCCCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 18.2 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate(18 mg, 0.050 mmol) described in example 92, 1-(aminomethyl)cyclohexanol hydrochloride (110 mg, 0.66 mmol) and triethylamine (0.28 mL, 1.98 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(1-hydroxycyclohexyl)methyl]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (4 mg, 18% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.46 (br s, 1 H), 8.55 (s, 1 H), 7.38 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.94 (m, 2 H), 4.12 (s, 2 H), 3.58 (s, 3 H), 3.48 (d, J=5.6 Hz, 2 H), 1.62-1.49 (m, 1 H); MS m/z 440 (M+1).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.[N:58]1[CH:63]=[CH:62][CH:61]=[C:60]([S:64](Cl)(=[O:66])=[O:65])[CH:59]=1>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:64]([C:60]3[CH:59]=[N:58][CH:63]=[CH:62][CH:61]=3)(=[O:66])=[O:65])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.291 mmol) and 3-pyridinesulfonyl chloride (94 mL, 0.430 mmol), the title compound was obtained as a tan solid (34 mg, 24% yield). MS (ESI): 485.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O.CN(C=O)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:5]([OH:6])[CH2:4][CH2:3][C:2]([F:9])([F:8])[F:1])=[CH:19][CH:18]=1
Reactant: Brc1ccccc1
Reactant: O=C(O)CCC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: OC(CCC(F)(F)F)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4,4,4-trifluorobutanoic acid (1.0 g), oxalyl dichloride (0.820 mL) and bromobenzene (3.71 mL) was added DMF (0.008 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added aluminum chloride (1.408 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water at 0° C., the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a mixture of the residue, ethanol (15 mL) and THF (5 mL) was added sodium borohydride (0.266 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water at 0° C., the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.49 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:30])=[C:17]([S:19]([NH:22][Si](C(C)(C)C)(C)C)(=[O:21])=[O:20])[CH:18]=3)=[O:12])=[CH:8][CH:9]=2)[N:4]([Si](C(C)(C)C)(C)C)[CH:3]=1.[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.O>[Cl:30][C:16]1[CH:15]=[CH:14][C:13]([C:11]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:3][NH:4]3)=[CH:9][CH:8]=2)=[O:12])=[CH:18][C:17]=1[S:19]([NH2:22])(=[O:21])=[O:20]
Reactant: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1cc(C(=O)c2ccc3c(Br)cn([Si](C)(C)C(C)(C)C)c3c2)ccc1Cl
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)c2ccc3c(-c4ccccc4)c[nH]c3c2)ccc1Cl
Temperature: 130 °C

Procedure:
To a mixture of 0.1 g of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide, 0.039 g of phenylboronic acid and 0.025 g of 1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II)-dichloromethane complex in dimethoxyethane (3.6 mL) is added 0.099 g of tri-potassium phosphate in water (1.2 mL). The solution is heated to 130° C. for 5 minutes (microwave irradiation). The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water, dried (magnesium sulfate) and concentrated to 0.094 g of crude product. Purification via flash chromatography on silica gel (98:2 methylene chloride/methanol) afforded 2-chloro-5-(3-phenyl-1H-indole-6-carbonyl)-benzenesulfonamide as a tan powder. MS (m/z): 409 (M−1); Rf 0.22 (95:5:0.5 methylene chloride/methanol/ammonium hydroxide).
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: NCc1ccccc1
Reactant: CC(C)CCc1cccc(C(=O)O)c1
Product: CC(C)CCc1cccc(C(=O)NCc2ccccc2)c1
Yield: 74.9 %

Procedure:
Using preparation method 1, 96B (288 mg, 1.5 mmol) was reacted with benzylamine (240 μL, 236 mg, 2.2 mmol). Purification by flash chromatography on SiO2 using CH2Cl2/hexanes 50:50 then CH2Cl2 100% afforded white crystals (316 mg, 74%). NMR 1H (ppm, CDCl3): 7.62 (s, 1H), 7.56-7.53 (m, 1H), 7.36-7.27 (m, 7H), 6.35 (br. s, 1H), 4.64 (d, J3=5.7 Hz, 2H), 2.66-2.60 (m, 2H), 1.64-1.46 (m, 3H), 0.92 (d, J3=6.3 Hz, 6H).
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][CH:4]([C:3](=[O:9])[CH2:2][CH3:1])[C:5](=[O:8])[CH2:6][CH3:7])[CH3:11]
Reactant: CCOC(=O)CBr
Reactant: CCC(=O)CC(=O)CC
Product: CCOC(=O)CC(C(=O)CC)C(=O)CC

Procedure:
By a method analogous to that described in Example 34, 3,5-heptane dione was reacted with bromoacetic acid-ethyl ester to form 3,3-dipropionyl-propionic acid-ethyl ester, which was further reacted with phenylhydrazine to produce 3,5-diethyl-1-phenyl-pyrazol-4-acetic acid-ethyl ester which was saponified to form the free acid. Obtained was 3,5-diethyl-1-phenyl-pyrazol-4-acetic acid having a melting point of 129°-130° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+]([O-])=O)[C:4]=1[C:12]#[N:13])#[N:2].[C:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH:19]1[OH:25])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:25][CH:19]2[CH:20]([CH3:24])[CH2:21][CH2:22][CH2:23][CH:18]2[C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]=1[C:12]#[N:13])#[N:2]
Reactant: CC1CCCC(C(C)(C)C)C1O
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Product: CC1CCCC(C(C)(C)C)C1Oc1cccc(C#N)c1C#N
Yield: 50 %

Procedure:
As in Synthesis Example 1 but using 1.73 grams of 1,2-dicyano-3-nitrobenzene and 3.40 grams of 2-t-butyl-6-methylcyclohexanol, there was obtained 1.48 grams of 1,2-dicyano-3-(2-t-butyl-6-methylcyclohexyloxy)benzene (yield of 50%). Next, as in Synthesis Example 1 but using 1.48 grams of this benzene compound and 0.42 gram of BBr3, there was obtained 1.1 grams of the end product (yield 68%, mp 154°-155° C.).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].Cl(O)(=O)(=O)=O.C([O-])(O)=O.[Na+].C(O[C:24]([CH3:27])([CH3:26])[CH3:25])(=O)C>>[C:24]([O:8][C:7]([C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1)=[O:9])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
30.0 g of L-pyroglutamic acid 133 (232 mmol) was suspended in 500 ml of tert-butyl acetate and added with 12 ml of 60% perchloric acid. After stirring for 15 h at RT, the resulting clear solution was cooled to 0° C. and adjusted to a pH value of 4-5 by adding 30.0 g of solid NaHCO3. After removing the solid by filtration, the filtrate was concentrated to dryness, thereby obtaining 25.4 g (136 mmol, 58%) of the tert-butyl ester 206 as a white solid that was reacted without further purification. An analytical sample was obtained by column chromatography over silica gel (eluant: EE).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:11]CN(CC)CC.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[CH3:11][NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: CCN(CC)CC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CN[C@H]1CCc2ccccc21
Reaction time: 72 h
Yield: 76.9 %

Procedure:
To a solution of (S)-(+)-1-aminoindan (176 mg, 1.29 mmol) in THF (10.0 mL) was added Et3N (0.200 mL, 1.43 mmol) followed by di-tert-butyldicarbonate (286 mg, 1.31 mmol). The mixture was stirred under an atmosphere of nitrogen for 3 days, concentrated, diluted with DCM (100 mL), and washed with 0.1 N aq hydrochloric acid (50.0 mL) and aq NaCl. The organic layer was dried (MgSO4), filtered and concentrated. The tan solid was taken up in tetrahydrofuran (10.0 mL) and to this was added with a 1.00 M solution of lithium aluminum hydride (1.0 M in THF, 5.80 mL). The mixture was heated at reflux for 6 hours, quenched with water (0.300 mL), 15% aq NaOH solution (0.300 mL) and water (0.900 mL). This was stirred for 10 minutes, filtered through celite, diluted with EtOAc (100 mL), dried (MgSO4), filtered and concentrated. The residue was purified via flash chromatography (0 to 100% EtOAc/hexanes to 10% MeOH/DCM) to afford the title compound as a black solid (146 mg, 77%).
Reaction SMILES: F[C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(OC(N1CCC(OC2C=C3C(=CC=2)C=NC=C3)CC1)=O)(C)(C)C>>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:2]2[C:3]([N+:12]([O-:14])=[O:13])=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[CH:5]3)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=[N+]([O-])c1c(F)ccc2cnccc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2[N+](=O)[O-])CC1

Procedure:
90 mg (0.47 mmol) 6-Fluoro-5-nitro-isoquinoline (152) were treated with 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester following the method described for the preparation of compound 154.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([NH:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:36])[CH3:35]
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccnc2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccnc2)cc1
Yield: 92.3 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-pyridyl)benzamide (150.0 mg, 0.335 mmol) and acetic anhydride (0.038 ml, 0.40 mmol), the procedure of Inventive Example 94 was repeated to obtain 151.0 mg (95.6%) of the title compound in a colorless amorphous form.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.CS(O[CH:20]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH3:21])(=O)=O.C(O)(=O)C>CN(C)C(=O)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH:20]([CH3:21])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:9][CH:8]=1
Reactant: CC(COc1ccc(Cl)cc1)OS(C)(=O)=O
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: COC(=O)Cc1ccc(OC(C)COc2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
To a suspension of 8.0 g of sodium hydride (60% dispersion in oil) (washed with hexane) in 190 ml of N,N-dimethylacetamide is added dropwise 35.2 g of methyl p-hydroxyphenylacetate in 60 ml of N,N-dimethylacetamide. The mixture is stirred at room temperature for one hour and at 50° C. for 20 minutes. To the mixture is added dropwise 53 g of 3-(p-chlorophenoxy)propan-2-ol O-methanesulfonate in 100 ml of N,N-dimethylacetamide. The mixture is stirred and heated at 100° C. for 18 hours. After pouring into 2 liters of ice-water containing 6 ml of acetic acid and chilling in an ice bath for 2 hours, the mixture is filtered and the solid washed with water. The damp waxy product is dissolved in dichloromethane and the solution dried (MgSO4). The solvent is removed under reduced pressure to give 52.6 g of product as an oil. The oil is crystallized from hexane and recrystallized from methanol to give the product as white crystals, mp 84°- 85° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@:10]([CH2:14][NH2:15])([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([N:28]([CH3:36])[C:29](=[O:35])[C@@H:30]3[CH2:34][C@@H:31]32)=[CH:26][C:25]=1[CH:37]=O.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@:10]([CH2:14][NH:15][CH2:37][C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][C:24]=3[O:23][CH3:22])[C@H:31]3[CH2:34][C@H:30]3[C:29](=[O:35])[N:28]4[CH3:36])([CH2:11]2)[C@@H:9]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@]2(CN)[C@@H]1c1ccccc1
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)[C@@H]1C[C@H]21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1CNC[C@@]13C[C@@H]1CN(C(=O)OC(C)(C)C)[C@H]3c1ccccc1)N(C)C(=O)[C@@H]1C[C@H]21
Reaction time: 3 h
Yield: 104.5 %

Procedure:
Racemic Intermediate 21, one enantiomer being (1R,2S,5S)-1-aminomethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.055 g, 0.19 mmol) was combined with (1aR,7bS)-6-methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde (0.046 g, 0.20 mmol) in methylene chloride (3 mL) and the mixture was stirred for 3.0 hours. APCI mass spec showed complete imine formation (m+1: 503). Methanol (1.0 mL) and sodium triacetoxyborohydride (0.053 g, 0.25 mmol) were added and the reaction allowed to stir for 16 hours. The solvent was removed at reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution and methylene chloride, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a white foam (0.10 g, quantitative crude yield). This material was used without further purification.