Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[CH:14])[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1.[CH2:15]([O:22][C:23](=[O:33])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)C1C=CC=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][O:22][C:23](=[O:33])/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][C:29]([C:14]#[C:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][N:4]([CH:1]3[CH2:3][CH2:2]3)[CH3:5])[CH:8]=2)=[CH:30][CH:31]=1
Reactant: C#Cc1cccc(CN(C)C2CC2)c1
Reactant: O=C(C=Cc1ccc(O)cc1)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)/C=C/c1ccc(C#Cc2cccc(CN(C)C3CC3)c2)cc1

Procedure:
Following General Procedure B and using cyclopropyl-(3-ethynyl-benzyl)-methyl-amine (Intermediate 91, 0.060 g, 0.32 mmol), methyl-4-iodo-cinnamate (Reagent 4, 0.093 g, 0.32 mmol), triethyl amine (8 mL), copper(I)iodide (0.015 g, 0.08 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.056 g, 0.08 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-15% ethyl acetate in hexane as the eluent, the title compound was obtained (0.11 g, 100%).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10](=[NH:12])[CH3:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:14](=[CH:18]OC)[C:15](=[O:17])[CH3:16].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:15]([C:14]1[N:9]([C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[C:10]([CH3:11])=[N:12][CH:18]=1)(=[O:17])[CH3:16]
Reactant: COC=C(Br)C(C)=O
Reactant: CC(=N)N[C@H](C)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)c1cnc(C)n1[C@H](C)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 26.2 g (0.162 mol) of N—((R)-1-phenylethyl)acetamidine (which was prepared in the above-mentioned Reference Example 2), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 8 hours for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluant: ethyl acetate) to give 18.7 g (yield: 76%) of 5-acetyl-2-methyl-1-((R)-1-phenylethyl)imidazole.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[C:22]3[C:23]4=[C:24]5[C:19](=[CH:20][CH:21]=3)[CH:18]=[CH:17][CH:16]=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)OC(=O)[C:4]=1[C:26]([O:28][CH3:29])=[O:27].[C:30]1([N:36]2[CH:44]=[C:43]3[C:38]([CH2:39][CH2:40][CH2:41][C:42]3=O)=[N:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[K+].Cl>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[C:22]3[C:23]4=[C:24]5[C:19](=[CH:20][CH:21]=3)[CH:18]=[CH:17][CH:16]=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)[C:41]2[CH2:40][CH2:39][C:38]3[C:43](=[CH:44][N:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:37]=3)[C:42]=2[C:4]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1c(SC)cc(-c2ccc3ccc4cccc5ccc2c3c45)oc1=O
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2ccc3ccc4cccc5ccc2c3c45)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of methyl 4-(methylthio)-2-oxo-6-(pyren-1-yl)-2H-pyran-3-carboxylate (400 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 8 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 58% of methyl 8-(methylthio)-2-phenyl-6-(pyren-1-yl)-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate. Yellow solid; mp-174-176° C.; 1H NMR (300 MHz, CDCl3) δ 2.49 (s, 3H, CH3), 2.60-2.67 (m, 2H, CH2), 2.71-2.77 (m, 2H, CH2), 4.08 (s, 3H, OCH3), 7.27-7.36 (m, 2H, ArH), 7.47 (t, J1=8.28 Hz, J2=7.50 Hz, 2H, ArH), 7.65-7.72 (m, 2H, ArH), 7.73-7.81 (m, 1H, ArH), 7.90 (d, J=7.77 Hz, 1H, ArH), 7.99-8.09 (m, 3H, ArH), 8.14 (s, 2H, ArH), 8.18-8.29 (m, 3H, ArH); MS (ESI) m/z551 (M++1).
Reaction SMILES: C(OC([N:8]([CH3:84])[C@@H:9]([CH3:83])[C:10]([NH:12][C@@H:13]([C:79]([CH3:82])([CH3:81])[CH3:80])[C:14]([N:16]1[C@H:25]([C:26]([NH:28][C@@H:29]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30](O)=[O:31])=[O:27])[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C@H:40]3[CH2:44][C@@H:43]([C:45](=[O:57])[NH:46][C@H:47]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[CH2:50][CH2:49][CH2:48]4)[N:42]([C:58](=[O:78])[C@@H:59]([NH:64][C:65](=[O:77])[C@@H:66]([N:68]([C:70](OC(C)(C)C)=O)C)[CH3:67])[C:60]([CH3:63])([CH3:62])[CH3:61])[CH2:41]3)=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])=[O:11])=O)(C)(C)C.[NH:85]1[CH2:90][CH2:89][O:88][CH2:87][CH2:86]1>>[CH3:82][C:79]([CH3:80])([CH3:81])[C@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][CH3:84])[CH3:83])[C:14]([N:16]1[C@H:25]([C:26]([NH:28][C@@H:29]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:30]([N:85]2[CH2:90][CH2:89][O:88][CH2:87][CH2:86]2)=[O:31])=[O:27])[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C@H:40]3[CH2:44][C@@H:43]([C:45](=[O:57])[NH:46][C@H:47]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[CH2:50][CH2:49][CH2:48]4)[N:42]([C:58](=[O:78])[C@@H:59]([NH:64][C:65](=[O:77])[C@@H:66]([NH:68][CH3:70])[CH3:67])[C:60]([CH3:63])([CH3:62])[CH3:61])[CH2:41]3)=[CH:21][CH:22]=2)[CH2:17]1)=[O:15]
Reactant: C1COCCN1
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1)C(C)(C)C
Yield: 36.9 %

Procedure:
Following procedures analogous to those described for the preparation of Example 42, (S)-2-((S)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-7-((3R,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)-3-phenylpropanoic acid (Compound B of Example 41, 25 mg, 0.021 mmol) and morpholine (Aldrich, 3 mg, 0.032 mmol) were converted to the title compound (8 mg, 37% over 2 steps). MS (ESI+) m/z 1032.7 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]([CH:21]([CH2:27][CH2:28][CH2:29]Cl)[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.ClC1C=CC=CC=1>O>[C:14]1([C:13]2[N:1]([CH2:2][CH2:3][C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[NH:6][CH:5]=3)[CH2:29][CH2:28][CH2:27][C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(CCCCl)C(=O)c1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O
Solvent: Clc1ccccc1
Product: CCOC(=O)C1=C(c2ccccc2)N(CCc2c[nH]c3ccccc23)CCC1

Procedure:
0.273 g. (0.0017 mole) of tryptamine are added to a solution of 0.229 g. (0.00085 mole) of (±)-ethyl 2-benzoyl-5-chloro-valerate prepared according to Example 29 in 5 ml. of chlorobenzene, and the reaction mixture is heated on an oil bath of 150° C. for 5 hours, with stirring, while the water formed is allowed to distill off slowly together with chlorobenzene. After cooling the precipitate is filtered off, washed with chlorobenzene, and the combined chlorobenzene solution is evaporated from a bath of 40° C. on a rotating evaporator. The title compound is obtained by subjecting the residue to column chromatography on 40 g. of silica gel (Geduran Si 60, 0.063-0.200 mm.) using toluene containing 10% of diethyl amine as an eluting agent.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C:17]1[CH:25]=[CH:24][C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=1)=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[NH:26](C(OC(C)(C)C)=O)[C@@H:27]([C:32](O)=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:26][C@@H:27]([C:32]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[CH:24][CH:25]=1)=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N=C(N)NCCC[C@H](NC(=O)CN)C(=O)Nc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](N)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 107.6 %

Procedure:
Following the procedures of Preparation Ic, a reaction mixture comprising (i) 910 mg (1.57 mmol) of H-Gly-L-Arg-pNA.2H-TFA, (ii) 363 mg (1.57 mmol) of Boc-D-Leu-OH, (iii) 1.2 ml of DIEA and (iv) 695 mg (1.57 mmol) of Bop is reacted in DMF and the reaction mixture is kept at RT for 2 h, with stirring. After evaporation to dryness under vacuum, the evaporation residue is chromatographed on silica gel using a CHCl3 /MeOH/AcOH gradient (20/3/1 to 10/3/1 v/v) as the eluent. The homogeneous fractions collected are pooled and the eluent is evaporated off. Lyophilization gives 785 mg (yield: 80%) of the expected product in pure form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:21])[CH2:16][C:17]([NH:19][NH2:20])=[O:18])[CH2:11][CH2:10]1.[CH2:22]1[CH2:27][CH2:26][CH:25]([CH2:28][N:29]=[C:30]=[O:31])[CH2:24][CH2:23]1.CCOC(C)=O>C1(C)C=CC=CC=1>[CH:25]1([CH2:28][NH:29][C:30]([NH:20][NH:19][C:17](=[O:18])[CH2:16][CH:15]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)[CH3:21])=[O:31])[CH2:26][CH2:27][CH2:22][CH2:23][CH2:24]1
Reactant: COc1ccccc1N1CCN(C(C)CC(=O)NN)CC1
Reactant: O=C=NCC1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(C(C)CC(=O)NNC(=O)NCC2CCCCC2)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 3-[4-(2-methoxyphenyl)piperazin-1-yl]butanohydrazide D12 (0.5 g, 1.71 mmol) in anhydrous toluene (7 mL), cyclohexanemethyl isocyanate (0.25 g, 1.80 mmol) was added dropwise at room temperature, the mixture was heated at 100° C. and stirred for 10 min. The solution was allowed to cool slowly to room temperature, AcOEt (15 mL) was added and the organic phase was washed with water (2×10 mL), dried over MgSO4 and evaporated under reduced pressure to afford 0.909 g N-(cyclohexylmethyl)-2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]butanoyl}hydrazinecarboxamide D13 as an orange oil. The product containing little toluene was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]2[C:31]([OH:33])=O)[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.O[N:40]1C2C=CC=CC=2N=N1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19][C@H:18]2[C:31]([NH2:40])=[O:33])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A 3 L round bottom flask was charged with (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (75.5 g, 0.158 mol), EDC*HCl (33.5 g, 0.175 mol), 1-hydroxybenzotriazole (23.6 g, 0.175 mol), and dichloromethane (1 L). The reaction was stirred at room temperature for 2 h, during which time it changed from a white suspension to a clear solution. Ammonia (gas) was bubbled into the solution until the pH was strongly basic (paper) and the reaction was stirred for 10 min; this ammonia addition was repeated and the reaction was stirred for an additional 10 min. Water was added. The organic phase was washed with sat. NaHCO3, NaH2PO4, and brine before being concentrated in vacuo. The residue was slurried with acetonitrile (0.5 L) and then concentrated in to give (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxamide as a white solid (75.9 g, ˜100%), which was used in the next step without further purification. LC/MS for primary peak: [M-Boc+H]+=375.3; [M±H]+=475.4; [M-tBu+H]+=419.3. 1H-NMR (400 MHz, d4-MeOH): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.25 (m, 2H), 3.70 (m, 1H), 3.6 (m, 1H), 3.45 (m, 1H), 2.91 (m, 1H), 2.38 (m, 1H), 2.12 (m, 1H), 1.9-2.05 (m, 2H), 1.65-1.9 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-:18])[C:3]=1[C:8]#[N:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccnc1C#N
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methylpyridine-2-carbonitrile (10 g, 85 mmol) was taken up in DCM (180 mL) and mCPBA (20.9 g, 93 mmol) was added. The resulting mixture was stirred at room temperature overnight. Additional mcpba (9.49 g, 42 mmol) was added and stirring continued at room temperature for 24 hours. Saturated aqueous NaHCO3 and the resulting mixture was extracted with EtOAc (3×), followed by 20% MeOH—CHCl3 (2×). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-20% MeOH/EtOAc) gave the title compound as a white solid.
Reaction SMILES: C([N:8](C(OCC1C=CC=CC=1)=O)[C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][C:24]([F:27])([F:26])[CH3:25])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][C:24]([F:27])([F:26])[CH3:25]
Reactant: CC(F)(F)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(F)(F)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Yield: 93.8 %

Procedure:
The same operation as in Example (90d) was performed using tert-butyl cis(±)-4-{benzyl[(benzyloxy)carbonyl]amino}-3-(2,2-difluoropropoxy)piperidine-1-carboxylate obtained in Example (128c) (1.31 g, 2.5 mmol), 10% Pd/C (wet, 0.4 g), ammonium formate (0.95 g, 15 mmol) and methanol (20 mL), to obtain 0.69 g of the title compound as a colorless oily substance (64%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH2:17][OH:18])=[N:6][CH:7]=[C:8]([N:10]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11]2)[N:9]=1.I[CH3:20].O>CS(C)=O.C(OCC)(=O)C.CCCCCCC>[Cl:3][C:4]1[C:5]([CH2:17][O:18][CH3:20])=[N:6][CH:7]=[C:8]([N:10]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11]2)[N:9]=1
Reactant: CI
Reactant: Cc1cc(C)n(-c2cnc(CO)c(Cl)n2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COCc1ncc(-n2nc(C)cc2C)nc1Cl
Reaction time: 0.25 h
Yield: 31.3 %

Procedure:
Sodium hydride (60% in mineral oil, 18 mg, 0.45 mmol) was added to a solution of [3-chloro-5-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl]methanol (102 mg, 0.43 mmol) in dimethyl sulfoxide (4 mL) and stirred for 15 minutes. Iodomethane (29 μL, 0.74 mmol) was added and the mixture was stirred at room temperature for 30 minutes and at 50° C. for 30 minutes. Sodium hydride (60% in mineral oil, 50 mg) and iodomethane (200 μL) was added and the mixture was stirred at 50° C. for 30 minutes. After cooling down water was added and a brown solid formed. Filtration followed by re-dissolvation in ethyl acetate, wash with brine, drying over sodium sulphate, filtration and evaporation gave the crude material. Flash chromatography (ethyl acetate/heptane as eluent) gave 3-chloro-5-(3,5-dimethyl-pyrazol-1-yl)-2-methoxymethyl-pyrazine (34 mg, 32%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:42])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH:32]5[CH2:36][CH2:35][O:34][CH2:33]5)=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:37]([O:39]CC)=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:42])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH:32]5[CH2:36][CH2:35][O:34][CH2:33]5)=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:37]([OH:39])=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(OC3CCOC3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3cc(OC4CCOC4)ccc3c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
To a solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylate (0.240 g, 0.424 mmol) in tetrahydrofuran (12 mL) and methanol (4 mL) at room temperature was added a solution of lithium hydroxide hydrate (0.071 g, 1.696 mmol) in water (2 mL). The resulting mixture was stirred at room temperature for 1.5 hr, and then concentrated under vacuum to almost dryness. To the residue was added water (8 mL), and the mixture was neutralized with 1N HCl to pH 4-5. The insoluble product (0.195 g, 0.363 mmol, 86% yield) was collected as a beige solid by suction filtration and dried over Drierite under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[Cl:40][C:41]1[CH:42]=[N:43][NH:44][CH:45]=1.N1C=CC=CC=1>O>[CH3:1][O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:43]3[CH:42]=[C:41]([Cl:40])[CH:45]=[N:44]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1cn[nH]c1
Solvent: O
Solvent: c1ccncc1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cc(Cl)cn2)cc1
Temperature: 50 °C
Yield: 97.4 %

Procedure:
A mixture of {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid methyl ester (0.14 g), 4-chloro-1H-pyrazole (0.053 g), cuprous acetate (0.093 g) and pyridine (3 mL) was heated at 50° C. for 116 hours. The mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated under reduced pressure. Purification of the residue by column chromatography silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 7:3 by volume) gave title compound as a colourless oil (0.13 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:12])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)[CH3:2].[C:13]([NH:17][OH:18])([CH3:16])([CH3:15])[CH3:14]>>[CH2:1]([O:3][C:4]1[C:5]([OH:12])=[C:6]([CH:7]=[N+:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[O-:18])[CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(C)(C)NO
Reactant: CCOc1cccc(C=O)c1O
Product: CCOc1cccc(C=[N+]([O-])C(C)(C)C)c1O

Procedure:
The title compound was prepared according to the procedure described in Example 13 using 3-ethoxy-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 36.4% yield as a yellow crystalline solid, m.p. 91.9° C. (Rf=0.25 on a silica gel plate using 1:1 EtOAc/hexanes as an eluant).
Reaction SMILES: C([O:3][C:4]1(OCC)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@H:6]([CH2:18][N:19]2[C:23](=[O:24])[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[CH2:5]1)C.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.O>[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@H:6]([CH2:18][N:19]2[C:23](=[O:24])[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[CH2:5]1
Reactant: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@H](CN2C(=O)c3ccccc3C2=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@@H](c1ccccc1)N1CCC(=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Reaction time: 2 h
Yield: 96.9 %

Procedure:
4,4-Diethoxy-1-(1-(S)-phenyl-ethyl)-2-(S)-phthalimidomethyl-piperidine (4.0 g, 9.2 mmol) was dissolved in a mixture of trifluoroacetic acid/water (9:1) (100 ml) at 0° C. and stirred for 2 hours at this temperature. The mixture was basified with half saturated aqueous sodium carbonate, extracted with ethyl acetate and dried (MgSO4) for 2 hours and filtered. The solvent was removed in vacuo and the residue was left in a vacuum own at 40° C. for two days, which afforded 3.23 g (98%) of 4-oxo-1-((S)-1-phenyl-ethyl)-2-(S)-phthalimidomethyl-piperidine as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:26].[I-]>N.CCO>[NH2:26][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:10]2)[N:12]=1
Reactant: CSC1=NC2(CC(C3CCCCC3)Oc3ccc(Br)cc32)C(=O)N1C
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(C3CCCCC3)Oc3ccc(Br)cc32)N=C1N
Yield: 57.4 %

Procedure:
A solution of 6-bromo-2-cyclohexyl-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (170 mg, 0.40 mmol), NH4I (117 mg, 0.80 mmol) in a solution of NH3/EtOH (10 mL, 1.5 N) was heated at 120° C. in a 40 mL test tube under microwave reactor for 3 hrs. After cooling, the mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-cyclohexy-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (90 mg, 57%).