Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([NH:16][C:17]2[C:18]([N:27]3[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]3)=[C:19]3[CH2:25][CH2:24][C@@H:23]([OH:26])[C:20]3=[N:21][CH:22]=2)=[O:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=2.NC1C(C(NC2C(N3CCC[C@H](N)C3)=C3CC[C@H](O)C3=NC=2)=O)=NC2C(C=1)=CC=C(CC)C=2>>[NH2:1][C:2]1[C:3]([C:14]([NH:16][C:17]2[C:18]([N:27]3[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]3)=[C:19]3[CH2:25][CH2:24][CH:23]([OH:26])[C:20]3=[N:21][CH:22]=2)=[O:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=2
Reactant: CCc1ccc2cc(N)c(C(=O)Nc3cnc4c(c3N3CCC[C@H](N)C3)CC[C@H]4O)nc2c1
Agent: CCc1ccc2cc(N)c(C(=O)Nc3cnc4c(c3N3CCC[C@H](N)C3)CC[C@@H]4O)nc2c1
Product: CCc1ccc2cc(N)c(C(=O)Nc3cnc4c(c3N3CCC[C@H](N)C3)CCC4O)nc2c1

Procedure:
The diastereoisomers are assigned as 3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-7-ethylquinoline-2-carboxamide and 3-amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-7-ethylquinoline-2-carboxamide.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-c3cccnc3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1cncc(-c2ccc(Oc3ccc(OC[C@H]4CCCN4)cc3)cc2)c1
Yield: 95 %

Procedure:
To a solution of the product from step 3 (100 mg, 0.22 mmol) in dioxane (1 mL) was added 4 M HCl in dioxane (5 mL) at rt and the resulting residue was triturated with ether and dried under vacuum to obtain the title product (79 mg, 95%): MS; m/z 347.7 (M°H); 1H NMR (400 MHz, DMSO-d6); δ 1.72-1.77 (m, 1H), 1.90-2.00 (m, 2H), 2.11-2.15 (m, 1H), 3.21-3.24 (m, 2H), 3.89-3.91 (m, 1H), 4.15-4.19 (m, 2H), 7.05-7.13 (m, 6H), 7.83-7.86 (m, 2H), 7.94 (dd, 2H, J1=5.2 Hz, J2=8 Hz), 8.63 (d, 1H, J=7.6 Hz), 8.77 (dd, 1H, J1=5.2 Hz, J2=1.2 Hz), 9.13 (d, 2H, J=2 Hz), 9.67 (br, 3H); HPLC (UV); 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC2CCCc3c2[nH]c2ccc(Cl)cc32)cc1

Procedure:
6-Chloro-N-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one and 4-methoxyaniline in a similar manner as described in Example 13 to give 32 mg (21% yield) of a brown solid. 1H-NMR (CDCl3): δ 8.13 (s, 1H), 7.50 (d, 1H), 7.23 (dd, 1H), 7.14 (dd, 1H), 6.92-6.84 (m, 2H), 6.79-6.73 (m, 2H), 4.76 (m, 1H), 3.83 (s, 3H), 2.74 (m, 2H), 2.28 (m, 1H), 2.08 (m, 1H), 1.98-1.75 (m, 2H); MS m/z 325 (M−1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([CH:13]1[CH:18]2[CH2:19][N:15]([CH2:16][C:17]2([O:22][CH3:23])[O:20][CH3:21])[CH2:14]1)([O:11][CH3:12])=[O:10].I[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.O>C1COCC1.ClCCl>[N:26]1[CH:27]=[CH:28][N:29]=[CH:30][C:25]=1[C:13]1([C:9]([O:11][CH3:12])=[O:10])[CH:18]2[CH2:19][N:15]([CH2:16][C:17]2([O:20][CH3:21])[O:22][CH3:23])[CH2:14]1
Reactant: COC(=O)C1CN2CC1C(OC)(OC)C2
Reactant: Ic1cnccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(c2cnccn2)CN2CC1C(OC)(OC)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.3 %

Procedure:
Lithium diisopropylamide (3.7 ml of a 1.5M solution in THF, 5.58 mmol) was added dropwise to a solution of 3-carbomethoxy-5,5-dimethoxy-1-azabicyclo[2.2.1]heptane (1 g, 4.7 mmol) in THF (40 ml), at -78° C., and stirred for 2 h. A solution of 2-iodopyrazine (1.15 g, 5.58 mmol) in THF (5 ml) was added, at -78° C., stirred for 1 h, and then warmed to room temperature and stirred for 16 h. Water (25 ml) and dichloromethane (70 ml) were added and the aqueous extracted with dichloromethane (3×100 ml). The combined extracts were dried (Na2SO4), evaporated, and the crude product chromatographed through silica-gel using dichloromethane/methanol (92:8) as eluant to give the title compound as a yellow liquid (0.1 g); (Found: M+ =293.1378; C14H19N3O4 requires M+ =293.1376); m/e 293 (M+); δ (360 MHz, CDCl3) 2.34 (1H, d, J=16 Hz, CH of CH2N); 2.82 (1H, s, CH-bridgehead); 3.05 (1H, dd, J=4.3 and 14.6 Hz, CH of CH2 --N); 3.18 (3H, s, OMe); 3.20 (1H, dd, J=3.3 and 8.5 Hz, CH of CH2 --N); 3.28 (1H, d, J=12.7 Hz, CH of CH2 --N); 3.34 (3H, s, OMe); 3.59 (3H, s, CO2Me); 3.67 (1H, d, J=10.8 Hz, CH of CH2 --N); 3.91 (1H, dd, J=3 and 12.7 Hz, CH of CH2 --N); 8.45 (1H, d, J=3.7 Hz, pyrazine-H); 8.51 (1H, dd, J=2.5 and 3.7 Hz, pyrazine-H); 8.58 (1H, d, J=2.5 Hz, pyrazine-H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.Cl.Cl.[CH:17]1([N:23]2[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:17]1([N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:2]3[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=3)[CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N[C@@H]1CCN(C2CCCCC2)C1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C3CCCCC3)C2)cn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (416 mg) in DMF (10 mL) was added (3R)-1-cyclohexyl-3-pyrrolidinamine dihydrochloride (849 mg) and K2CO3 (1.35 g). After stirring for 2 hours at 120° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)-1-cyclohexyl-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (318 mg).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[O:3][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:5]#[CH:6].[CH2:14]([SnH:18]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])/[CH:6]=[CH:5]/[CH:4]([O:3][Si:2]([CH3:12])([CH3:13])[CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:24][CH2:25][CH3:26]
Reactant: C#CC(CCCCC)O[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Product: CCCCCC(/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C

Procedure:
Under an argon atmosphere, 3-trimethylsilyloxy-1-octyne (47, 2.00 g, 10.08 mmol) and tributyltin hydride (2.70 mL, 10.18 mmol) were irradiated with a 275 W GE sunlamp, without solvent, for 4 h to produce 49: 1H NMR (CDCl3) δ 6.04 (d, J=18.9 Hz, 1H), 5.93 (dd, J1 =18.9 Hz, J2 =5.4 Hz, 1H), 4.04 (q, J1 =6.5 Hz, J2 =5.6 Hz, 1H), 1.52, 1.34 (2m, 26H), 0.91 (m, 12H), 0.11 (s, 9H). 1H NMR analysis revealed that 49 was only ca. 85% pure. Other isomers, presumed to be the cis-vinyl-stannane and the regioisomeric vinylstannane, could be clearly seen in the vinyl region of the NMR spectrum. The production of these impurities in this reaction has been previously described.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:16]([OH:17])[CH2:15][CH2:14][C@@H:13]3[C@H:9]2[CH2:10][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]3)=[CH:4][CH:3]=1.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](Cl)=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:25][C:26]([F:40])([F:41])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1)[C:30]([O:17][C@H:16]1[CH2:15][CH2:14][C@@H:13]2[C@@H:9]([CH2:10][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]2)[C@@H:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:31]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H](O)[C@@H](c3ccc(F)cc3)[C@@H]2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H](OC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4.75 g (14.0 mmol) of the intermediate of step B in dry methylene chloride under nitrogen atmosphere at RT was added 4.71 g (17.0 mmol) of 3,5-bis(trifluoromethyl)-benzoyl chloride, 2.4 mL (17.3 mmol) TEA and a catalytic amount of DMAP. The resulting mixture was stirred at RT for 2 hr then transferred to a separatory funnel, washed with saturated. aq. NaHCO3 and brine. The combined organic layers dried over magnesium sulfate, filtered and the solvent evaporated under vacuum to afford the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ: 8.63 (1H, s), 8.19 (2H, s), 7.25 (2H, m), 7.00 (2H, m), 5.22 (1H, m), 3.59–3.33 (2H, m), 3.30–3.20 (2H, m), 2.83 (1H, t,J=12.7 Hz), 2.62 (1H, m), 2.43 (1H, m), 2.20 (1H, m), 2.02 (1H, m), 1.90–1.70 (2H, m), 1.55, 1.47 (9H, two singlets).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[I-].[K+].[N:13]1[NH:14][N:15]=[N:16][C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:14]2[N:15]=[N:16][C:17]([C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)=[N:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1cccc(-c2nn[nH]n2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nnc(-c3cccc(O)c3)n2)cc1
Temperature: 65 °C

Procedure:
A suspension of 4-methoxybenzylchloride (0.26 mL, 1.94 mmol) (Aldrich), potassium iodide (0.31 g, 1.85 mmol) (Aldrich), 3-(2H-tetrazol-5-yl)-phenol (0.3 g, 1.85 mmol) (from Example 25 supra), potassium carbonate (0.38 g, 2.78 mmol) and 18-crown-6 (24.0 mg, 0.09 mmol) (Aldrich) in N,N-dimethylformamide (15 mL) was heated at 65° C. for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 5-40% ethyl acetate in hexanes to give 3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenol. (Yield 0.38 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1N.N([O-])=O.[Na+].[BrH:17]>O.CCOC(C)=O>[Br:17][C:3]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([CH3:9])=[CH:8][C:2]=1[F:1]
Reactant: Br
Reactant: Cc1cc(F)c(N)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
2-Fluoro-4-methyl-5-nitro-aniline (1.85 g, 10.90 mmol) was suspended in concentrated hydrobromic acid (22 mL) and cooled to 0° C. Solution of sodium nitrite (0.83 g, 12.00 mmol) in water (3.6 mL) was added dropwise while maintaining the temperature at 0˜5° C. After stirring for 15 min, the mixture was filtered through a cotton pad and slowly poured into a solution of cuprous oxide (2.60 g, 17.5 mmol) and concentrated hydrobromic acid (20 mL) at 0° C. After stirring overnight, the reaction mixture was diluted with EtOAc, washed with 10% aq NaOH and 5% aq Na2S2O5 successively, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate:hexane; 2:98) to afford 1-Bromo-2-fluoro-4-methyl-5-nitro-benzene as a colorless oil (2.30 g, 91%). 1H NMR (CDCl3, 400 MHz,): 2.59 (s, 3H), 7.11 (d, J=8.4 Hz, 1H), 8.24 (d, J=6.3 Hz, 1H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[C:42]1[CH:50]=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH:50]([C:42]1[NH:41][C:49]2[C:44]([CH:43]=1)=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2ccccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCC=Cc1cc2ccccc2[nH]1
Reaction time: 0.5 h

Procedure:
To a suspension of decyl-triphenyl-phosphonium bromide in THF was added NaHMDS in THF and the mixture was stirred for 30 minutes. A solution of 1H-indole-2-carbaldehyde was added to the reaction mixture and stirred for 3 hours. The reaction mixture was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [OH:1][C:2]([C:10]1[CH:11]=[C:12]([O:16][Si](C(C)(C)C)(C)C)[CH:13]=[CH:14][CH:15]=1)([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[CH2:3][CH3:4].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:1][C:2]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[CH2:3][CH3:4]
Reactant: CCC(O)(c1cccc(O[Si](C)(C)C(C)(C)C)c1)c1nccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)(c1cccc(O)c1)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of compound from Step 2 (5.57 g, 15.96 mmol) in THF (40 mL) them was added n-Bu4NF 1M in THF (18 mL); the mixture was stirred at r.t. for 30 min., then H2O (10 mL) was added. The mixture was concentrated to a small volume, the residue extracted with EtOAc, the extract washed twice with brine, dried and evaporated to a residue which was chromatographed on silica gel, eluting with a 1:1 mixture of EtOAc and hexane, to afford the title product as a white solid (2.59 g) m.p. 145°-146° C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:23][C:24]1[N:25]=[CH:26][C:27]([CH2:30][NH2:31])=[N:28][CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(#N)C>[CH3:23][C:24]1[N:25]=[CH:26][C:27]([CH2:30][NH:31][C:13]([C:10]2[CH:11]=[C:12]3[C:7]([CH:6]=[N:5][N:4]3[CH:1]([CH3:2])[CH3:3])=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH:9]=2)=[O:15])=[N:28][CH:29]=1
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc3c2cnn3C(C)C)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CC#N
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc3c2cnn3C(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a solution of 1-isopropyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (0.24 g, 0.814 mmol) in acetonitril was added C-(5-methyl-pyrazin-2-yl)-methylamine (0.12 g, 0.976 mmol), EDCI (0.23 g, 1.22 mmol), HOBt (0.16 g, 1.22 mmol), and NMM (0.45 mL, 4.07 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography gave 0.144 g (44%) of 1-isopropyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide MS (M+H)=401.
Reaction SMILES: [C:1]([C:4]([C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)(C(=O)C)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]([CH:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:27])=[CH:24][CH:23]=1)#[N:26]
Reactant: CCOC(=O)CCCCCC(C(C)=O)(C(C)=O)C(=O)c1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCCCC(C(C)=O)C(=O)c1ccc(C#N)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
Ethyl 7-acetyl-7-(4-cyanobenzoyl)-8-oxononanoate (3.5 g) was dissolved in trifluoroacetic acid (12.6 ml) and the mixture was stirred at 20° C. for 15 minutes. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, aqueous sodium bicarbonate and brine, dried over MgSO4 (magnesium sulfate), and evaporated to give ethyl 7-(4-cyanobenzoyl)-8-oxononanoate (2.25 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8]O)=[CH:5][CH:4]=1.CO.[H][H]>[Pd]>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1
Reactant: ON=Cc1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCc1ccc(C(F)(F)F)cc1
Yield: 87.6 %

Procedure:
The second step of the process of the present invention was conducted as follows. At first, a 100 ml autoclave equipped with an electromagnetic stirrer was charged with 5.00 g (26 mmol) of 4-trifluoromethylbenzaldehyde oxime, 50 ml of 2M-ammoniacal methanol solution (containing 100 mmol of ammonia), and 0.25 g of a catalyst (i.e., a carbon powder (50% wet) carrying thereon 5% palladium), followed by introduction of hydrogen to have an inside pressure of 1 MPa. Then, the reaction mixture was stirred, while the reaction temperature was maintained at 20° C. and while hydrogen was gradually introduced into the autoclave in a manner to maintain the total pressure at 1 MPa. After conducting the reaction for 2 hr, the reaction was stopped, followed by removing the catalyst by filtration. As a result of analyzing the obtained reaction liquid by gas chromatography, 4-trifluoromethylbenzylamine was formed at a yield of 87.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@@H:8]1[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1.[Br:23][C:24]1[N:29]=[C:28]([C:30](O)=[O:31])[CH:27]=[CH:26][C:25]=1[F:33]>CCOC(C)=O>[Br:23][C:24]1[N:29]=[C:28]([C:30]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C@@H:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)=[O:31])[CH:27]=[CH:26][C:25]=1[F:33]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C[C@H](c2ccncc2N)C1
Reactant: O=C(O)c1ccc(F)c(Br)n1
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C[C@H](c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C1

Procedure:
Following Method 9, tert-butyl (1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexylcarbamate and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, tert-butyl (1S,3R,5S)-3-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-5-methylcyclohexylcarbamate was obtained. LCMS (m/z): 507.1/509.1 (MH+), Rt=0.90 min.
Reaction SMILES: [CH3:1][CH:2]1[C:14](=[O:15])[C:5]2=[CH:6][C:7]3CCCC[C:12]=3[CH:13]=[C:4]2[CH2:3]1.[CH:16]1C=CC=CC=1>>[CH2:1]([CH:2]1[CH2:3][C:4]2[C:5](=[CH:6][CH:7]=[CH:12][CH:13]=2)[C:14]1=[O:15])[CH3:16]
Reactant: CC1Cc2cc3c(cc2C1=O)CCCC3
Reactant: c1ccccc1
Product: CCC1Cc2ccccc2C1=O

Procedure:
2-Ethyl-indan-1-one is prepared from benzene following analogous procedures to those used for 2-methyl-2,3,5,6,7,8-hexahydro-cyclopenta[b]naphthalen-1-one.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH:12]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]1[CH2:25][C:26](OCC)=[O:27])([CH3:14])[CH3:13]>O>[CH:12]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]1[CH2:25][C:26]([NH:10][C:9]([NH2:11])=[NH:8])=[O:27])([CH3:14])[CH3:13]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2ccccc2C(=O)N1C(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CC(C)N1C(=O)c2ccccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 20 h
Yield: 6.8 %

Procedure:
N-[(2-Isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 1.5 g of potassium tert-butoxide, 1.3 g of guanidinium chloride and 0.7 g of ethyl (2-isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, followed by addition of 30 cm3 of water. The aqueous phase is extracted with 3 times 50 cm3 of ethyl acetate and is then concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 45° C. The residue is taken up in water, triturated and filtered. The solid is taken up in a mixture of dichloromethane/methanol (90/10 by volume) and filtered, and the filtrate is purified by chromatography under argon pressure (60 kPa), on a column of silica gel (particle size 15-40 μm), eluting with a dichloromethane/methanol mixture (90/10 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.05 g of N-[(2-isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is thus obtained in the form of a white solid. Mass spectrum EI: m/e 274 (M+), m/e 187, m/e 132. Infrared spectrum (KBr): 3412; 1974; 1667; 1603; 1531; 1367 and 698 cm−1.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][CH:4]=[N:3]1.C(#N)C.C1COCC1.C[Si](C)(C)[O:18][C:19]([CH:21]=[CH2:22])=[CH2:20]>ClCCl.Cl.[Cl-].[Cl-].[Zn+2]>[CH3:1][C:2]1([CH3:7])[N:3]2[CH:4]([CH2:20][C:19](=[O:18])[CH2:21][CH2:22]2)[CH2:5][CH2:6]1
Reactant: CC1(C)CCC=N1
Reactant: C=CC(=C)O[Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: CC1(C)CCC2CC(=O)CCN21
Temperature: 60 °C
Yield: 10.9 %

Procedure:
3,4-Dihydro-2,2-dimethyl-2H-pyrrole (900 mg, 9.3 mmol) was added to acetonitrile (90 ml) in a 250 ml round bottom flask, fitted with water condenser. ZnCl2 (0.5M) in THF (23 ml, 11.6 mmol) was added to the solution and warmed to 60° C. 2-(Trimethylsiloxy)-1,3-butadiene (2.6 g, mmol, 18.4 mmol) was added to the mixture and heated at 90° C. overnight. The solution was cooled to room temperature and diluted with dichloromethane (90 ml) and 1N HCl (90 ml). The two layers were separated, the aqueous layer was basified with NH3 (28%) in H2O, and extracted with dichloromethane. The organic layer was washed with brine and dried with Na2SO4. Solid was removed by filtration and mother liquor was concentrated in vacuo to give 250 mg brown color oil. This oil was further purified by column chromatography (100% ethyl acetate to 95% ethyl acetate: 5% methanol) to give a light yellow oil (170 mg, 11% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20]C(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.[CH2:34]([O:36][C:37](=[O:43])/[CH:38]=[CH:39]/C(O)=O)[CH3:35].CCN=C=NCCCN(C)C.Cl.Cl>CO.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])/[CH:39]=[CH:38]/[C:37]([O:36][CH2:34][CH3:35])=[O:43])[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Reactant: CCOC(=O)/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/C(=O)N1CC[C@H](NC(=O)c2nc(Cl)c(CC)[nH]2)[C@H](OC)C1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1g) (133 mg, 0.34 mmol) was dissolved in methanol (2 mL). A 4 N hydrochloric acid/ethyl acetate solution (4 mL) was added, and the mixture was stirred at 70° C. for 30 minutes. Following concentration under reduced pressure, the residue was dissolved in DMA (5 mL). Fumaric acid monoethyl ester (54.42 mg, 0.38 mmol), WSC hydrochloride (197.41 mg, 1.03 mmol) and DMAP (41.94 mg, 0.34 mmol) were added, and the mixture was stirred at room temperature overnight. Dilute hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate.