Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([I:20])[CH:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:2].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([I:20])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:7]([NH:6][CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])=[O:8]
Reactant: CCN(CC)CCNC(=O)c1c[nH]c2ccc(I)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCN(CC)CCNC(=O)c1cnc2ccc(I)cc2c1Cl
Temperature: 25 °C
Yield: 76 %

Procedure:
A stirred solution of compound 94 (9.00 g, 21.8 mmol) in phosphorus oxychloride (50 mL) was heated at 100° C. for 20 min. After cooling to room temperature, the solvent was evaporated under vacuum. The residue was poured into crushed ice (100 g). A 10% aqueous sodium hydrogenocarbonate solution (100 mL) and dichloromethane (100 mL) were added successively at 0° C. The mixture was stirred until the brown oil was totally dissolved. The solution was decanted and the aqueous layer was then extracted with dichloromethane (3×200 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed (Al2O3, AcOEt/cyclohexane, 9/1, v/v) to give compound 95 (7.12 g, 16.5 mmol) as a yellow solid. Yield 76%; Rf (Al2O3, AcOEt/cyclohexane, 9/1, v/v) 0.34; mp 76-78° C.: IR (KBr) ν 1329, 1477, 1558, 1636, 2798, 2966, 3300 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.01 (t, 6H, J=7.1 Hz), 2.58 (q, 4H, J=7.1 Hz), 2.70 (t, 2H, J=5.8 Hz), 3.55 (q, 2H, J=5.8 Hz), 7.39 (se, 1H), 7.73 (d, 1H, J=8.8 Hz), 7.96 (dd, 1H, J=1.8, 8.8 Hz), 8.55 (d, 1H, J=1.8 Hz), 8.93 (s, 1H); MS m/z 433 (M+2, 2), 431 (M+, 6), 417 (3), 415 (8), 317 (6), 315 (20), 289 (2), 287 (6), 189 (6), 161 (9), 128 (5), 99 (6), 86 (100), 72 (6), 56 (13).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)c1ccc(Oc2ccccn2)cc1
Yield: 73 %

Procedure:
4'-Hydroxyacetophenone was condensed with 2-bromopyridine by Ullmann reaction to obtain 4'-(pyridine-2-yloxy)acetophenone (yield 73%). This was converted to Mannich base with dimethylamine hydrochloride and paraformaldehyde (yield 56%), which was then cyclized by reacting with 1-ethoxycarbonylmethylpyridinium chloride and ammonium acetate in N,N-dimethyl formamide, (as described in Synthesis (1976), pages 1-24) to obtain 6-[4-(pyridine-2-yloxy)phenyl]-2-pyridone (yield 32%).
Reaction SMILES: [C:1]([CH2:3][C@@:4]1([C:30]([O:32]C)=O)[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15]CC3C=CC=CC=3)=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])#[N:2]>CO.[Ni]>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C@H:6]2[CH2:7][CH2:8][C@:4]3([CH2:3][CH2:1][NH:2][C:30]3=[O:32])[N:5]2[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@]1(CC#N)CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@]12CCNC2=O
Reaction time: 14 h
Yield: 67.8 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-2-(cyanomethyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1,2-pyrrolidinedicarboxylate (D24, 2.7 g, 5.99 mmol): in methanol (50 ml) was added Raney Nickel (slurry in water) and the mixture was stirred under a hydrogen atmosphere (7 atmospheres) for 14 hours. The catalyst was filtered off, the solvent removed under reduced pressure, and the solid residue was treated with toluene (3×20 ml) and dried under vacuum. The dry white solid obtained was refluxed in methanol (40 ml) for five hours until cyclization was complete. The solvent was removed under reduced pressure and the crude material purified by chromatography on silica gel using dichloromethane/methanol (95:5 to 90:10) to afford the title compound as a white solid (1.35 g, 68%); Rt (HPLC): 3.91 min; R (dichloromethane:methanol=9:1): 0.41; MS: (ES/+) m/z: 665 [2M+Na+], 355 [M+Na+]; C18H24N2O4 requires 332; 1H NMR (400 MHz, DMSO-d6) δ(ppm): 9.11 (s, 1H); 7.76 and 7.66 (s, s, 1H); 7.43 (dd, 2H); 6.66 (dd, 2H); 4.81-4.70 (m, 1H); 3.29-3.20 (m, 1H); 3.19-3.09 (m, 1H); 2.47-2.20 (m, 2H); 2.08-1.85 (m, 2H); 1.84-1.74 (m, 1H); 1.68-1.52 (m, 1H); 1.33 and 1.08 (s, s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:8][CH2:7][C:6]([CH3:11])([CH:9]=O)[CH2:5][CH2:4]1.Cl.[NH2:21][OH:22]>C(O)C>[CH3:1][N:2]([CH3:19])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:8][CH2:7][C:6]([CH3:11])([CH:9]=[N:21][OH:22])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(C)(C=O)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CN(C)C1(c2cccc(F)c2)CCC(C)(C=NO)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the title compound of step 2 (1.38 g, 5.53 mmol) and hydroxylamine hydrochloride (576 mg, 8.3 mmol) in abs. ethanol (20 mL) were mixed with Amberlyst A 21 (3.9 g) and stirred for 16 h at RT. The ion exchanger was filtered off, the solution concentrated to low volume and the residue made alkaline with 1N NaOH. The aqueous phase was extracted with ethyl acetate, dried over Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[CH2:12]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[CH:4]=[O:5])[CH3:13]
Reactant: O=Cc1c(O)cccc1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cccc(F)c1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-fluoro-6-hydroxybenzaldehyde (2.500 g; 17.80 mmol), iodoethane (5.566 g; 35.70 mmol), and K2CO3 (2.959 g; 21.40 mmol) in anh. DMF (50 ml) was heated to 80° C., under nitrogen, for 2 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-ethoxy-6-fluorobenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.66 min.; [M+H]+: 169.14 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=O.C(O)(=O)C.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:16][C:18]3[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH3:28])[CH3:29])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(C)S(=O)(=O)c1ccc(C=O)cc1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (100 mg, 410 μmol) in MeOH (5 mL) was added 4-formyl-N,N-dimethyl-benzenesulfonamide (96.1 mg, 451 μmol) followed by acetic acid (36.7 mg, 35 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (65.7 mg, 615 μmol) was added and the stirring was continued for 5 days. The reaction mixture was poured into 0.1N HCl solution (25 ml) to give a suspension, and the suspension was filtered to give an off white solid as desired product (119 mg, 66% yield). MS +m/z: 441 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11]C)=[O:10])=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[O:27])=[CH:21][CH:20]=2)[N:3]=1.[OH-].[Na+].CCOCC.Cl>C1COCC1>[CH3:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[O:27])=[CH:23][CH:24]=2)[N:3]=1
Reactant: COC(=O)Cc1c(C)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(N2CCCC2)c1CC(=O)O
Temperature: 60 °C
Reaction time: 13 h
Yield: 31.2 %

Procedure:
A solution of methyl {4-methyl-2-[4-(2-naphthoylamino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}acetate (0.018 g, 0.04 mmol) in THF (1 mL) at room temperature was treated with 1N NaOH (0.5 mL) and the resulting biphasic mixture was stirred at 60° C. for 13 hours. After cooling to room temperature, Et2O was added and the organic layer siphoned off. The remaining aqueous layer was acidified with 6N HCl and the separated solids were collected by suction, rinsed with water, and dried under high vacuum for 4 hours to give {4-methyl-2-[4-(2-naphthoyl-amino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}acetic acid (0.006 g, 37% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][CH2:5][CH:6]=[O:7].[O:12]=[C:13]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17]>C(Cl)(Cl)Cl>[CH2:4]([C@H:5]1[C@@H:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[C:13]([C:20]2[CH:21]=[CH:22][C:23]([Br:26])=[CH:24][CH:25]=2)[O:12][C:6]1=[O:7])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: COC(=O)/C=C/C(=O)c1ccc(Br)cc1
Reactant: O=CCCc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C=C(c2ccc(Br)cc2)OC(=O)[C@H]1Cc1ccccc1
Yield: 80 %

Procedure:
Prepared according to the general procedure from 2-chloro-hydrocinnamaldehyde and (E)-methyl 4-oxo-4-(4-bromophenyl)but-2-enoate using 0.5 mol % 1 as the catalyst in 80% yield as a 6:1 mixture of diastereomers (white solid). [α]D20 (c 1.23, CHCl3)=+112.1; mp=139-141° C.; 1H NMR (400 MHz, CDCl3) δ 7.53-7.47 (m, 4H), 7.35-7.25 (m, 5H), 7.19-7.17 (m, 2H), 5.81 (d, 1H, J=7.1 Hz), 5.74* (d, 1H, J=5.6 Hz), 4.23 (q, 2H, J=7.0 Hz), 4.13* (q, 2H, J=7.2 Hz), 3.55 (dd, 1H, J=14.4, 4.7 Hz), 3.40-3.35* (m, 1H), 3.27-3.24* (m. 1H), 3.25 (dd, 1H, J=7.1, 5.8 Hz), 3.14* (dd, 1H, J=13.8, 5.7 Hz), 3.03-2.97 (m, 1H), 2.91* (dd, 1H, J=13.8, 8.8 Hz), 2.77 (dd, 1H, J=14.3, 10.0 Hz), 1.30 (t, 3H, J=7.0 Hz), 1.24* (t, 3H, J=7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 170.2, 168.7, 151.7, 138.1, 131.9, 130.9, 1294, 129.2, 129.0, 127.4, 127.1, 126.5, 124.0, 98.7, 96.7, 66.1, 62.1, 61.9, 42.8, 42.2, 41.5, 40.7, 35.5, 33.3, 15.5, 14.3, 14.2; IR (thin film) ν 3087, 3027, 2980, 1778, 1731, 1489, 1455, 1176, 1069, 1009 cm−1; HRMS (ESI) calcd for C21H19BrO4 [M+Na]+ 437.0358, found 437.0359; 99% ee (3S,4S)-isomer as determined by HPLC (AD-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=57.6 min, tr (3R,4R)=25.4 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:16])([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:50]1(=[O:60])[NH:54][C:53](=[O:55])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][N:54]2[C:50](=[O:60])[C:51]3[C:52](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:53]2=[O:55])([F:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
After dissolving 4-fluoro-4-(hydroxymethyl)piperidinecarboxylic acid tert-butyl ester (4.26 g, 18.3 mmol) in THF (183 mL), the solution was cooled to 0° C. Triphenylphosphine (7.19 g, 27.4 mmol) and DIAD (diisopropyl azodicarboxylate) (5.39 mL, 27.4 mmol) were then added to the solution. After stirring for 20 minutes, phthalimide (4.03 g, 27.4 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated, and the crude product was crudely purified by silica gel column chromatography (20% AcOEt/hexane) to obtain 4-[(1,3-dioxoisoindolin-2-yl)methyl]-4-fluoropiperidinecarboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:18][CH2:19][CH3:20])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]=1[CH3:7].C([Sn](CCCC)(CCCC)[C:26]1[N:30]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[N:29]=[CH:28][CH:27]=1)CCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:19]([O:18][C:4]1[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]([CH3:7])=[C:2]([C:26]2[N:30]([C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[N:29]=[CH:28][CH:27]=2)[N:3]=1)[CH3:20]
Reactant: CCOc1nc(Br)c(C)n1-c1cccc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOc1nc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n1-c1cccc(C(F)(F)F)c1
Temperature: 94 °C

Procedure:
A solution of 4-bromo-2-ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazole (3.14 g, 9 mmol) and 4-(5-tributylstannyl-pyrazol-1-yl)-benzonitrile (see WO2014009425A1, which is incorporated herein by reference in its entierty) (6.19 g, 13.5 mmol) in 1,4-dioxane (45 mL) was degassed by bubbling argon through the solution for 5 minutes. Tetrakis(triphenylphosphine)palladium(O) (0.52 g, 0.45 mmol) was added and after a further period of degassing the mixture was heated at 94° C. under an argon atmosphere during 17 h. The mixture was cooled to RT and filtered through a 50 g flash SCX 2 cartridge. The cartridge was eluted with DCM, 10% methanol in DCM then a 1:1 mixture of 2M ammonia in methanol and DCM. Concentration of the appropriate fractions in vacuo afforded the crude product. This was triturated with cyclohexane and dried in vacuo to afford the title compound (3.01 g).
Reaction SMILES: [CH3:1][N:2]([O:17][CH3:18])[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([N+:13]([O-])=O)[CH:5]=1>[Pd].O1CCCC1.C(O)C>[CH3:1][N:2]([O:17][CH3:18])[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:13])[CH:5]=1
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(N)c(N)c1
Reaction time: 6 h
Yield: 97.1 %

Procedure:
Add 18.0 g of 10% weight Pd/C catalyst to a solution of N-[methyl] N-[methoxy] 3,4-dinitrobenzamide (182 g, 0.712 moles) in 900 mL tetrahydrofuran and 900 mL ethanol under a nitrogen atmosphere. Hydrogenate at room temperature for 6 hours under 60 p.s.i. Filter the mixture through Celite® and concentrate the filtrate under reduced pressure. Suspend the residue in 500 mL dichloromethane, concentrate under reduced pressure and dry the residue under reduced pressure to provide 135 g (97%) of the desired compound.
Reaction SMILES: C(OC(NC[C@H]1CC[C@H]([C:16]([NH:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH2:21])=O)CC1)=O)(C)(C)C.[ClH:30].O1CCOC[CH2:32]1>O1CCOCC1>[ClH:30].[CH3:32][N:18]([CH3:16])[C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH2:21]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)[C@@H](N)Cc2ccccc2)CC1
Reactant: C1COCCO1
Agent: Cl
Product: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the compounds (I) (19.15 g) was added dry 1,4-dioxane (50 ml) and 4N hydrogen chloride/1,4-dioxane solution (250 ml), and the mixture was stirred under room temperature for 2 hours. The solvent was removed under a reduced pressure and toluene was added and reevaporated to give L-phenylalanine 4-carbamoylanilide hydrochloride (II) quantitatively as a white powder. On the other hand, trans-4-(t-butoxycarbonylaminomethyl)cyclohexylcarboxylic acid (13.36 g) was dissolved in dry tetrahydrofuran (500 ml), and triethylamine (7.80 ml) was added under ice-cooling, followed by stirring at the same temperature for 10 minutes. Subsequently, a solution of ethyl chlorocarbonate (5.64 g) in dry tetrahydrofuran (50 ml) was added dropwise under ice-cooling for 3 minutes, and the mixture was again stirred at the same temperature for 20 minutes. The above mixture was added to the suspension of the hydrochloride (II) previously obtained and triethylamine (8.53 ml) in N,N-dimethylformamide (150 ml) under ice-cooling, followed by stirring at the same temperature for 2 hours, and under room temperature for 6 hours. Ice-water (1.4 liter) was added and the insolubles were collected by filtration, thoroughly washed with water, and further washed with 10% aqueous citric acid, water 5% aqueous sodium hydrogen carbonate, followed by washing with water at 40° to 50° C., and drying, to give N-[4-trans-(t-butoxycarbonylaminomethyl)cyclohexylcarbonyl]-L-phenylalanine 4-carbamoylanilide (III) (24.63 g). The structure was confirmed by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:22])[C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[Cl:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>>[Cl:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:22][C:13]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[C:2]([Cl:1])[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1)=[O:27]
Reactant: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2N)CC1
Reactant: O=C(O)c1cccnc1Cl
Product: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2NC(=O)c2cccnc2Cl)CC1
Yield: 25 %

Procedure:
The desired compound was prepared according to Method A from 6-chloro-7-(4-methyl-piperazin-1-yl)-8-amino-9H-β-carboline and 2-chloro-nicotinic acid in 25% yield.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([NH:47][C:48](=[O:50])[CH3:49])[CH:43]=[CH:44][C:45]=1[F:46]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:46][C:45]1[C:40]([C:33]2[CH:32]=[CH:31][C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)[CH:3]([CH3:4])[CH3:5])=[CH:35][CH:34]=2)=[CH:41][C:42]([NH:47][C:48](=[O:50])[CH3:49])=[CH:43][CH:44]=1
Reactant: CC(=O)Nc1ccc(F)c(Br)c1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)Nc1ccc(F)c(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 33.4 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.19 g), N-(3-bromo-4-fluorophenyl)acetamide (990 mg) and tetrakis(triphenylphosphine)palladium(0) (0.21 g), the title compound (870 mg) was obtained as a pale-yellow amorphous powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[CH3:18][C:19]1([CH3:30])[C:23]2([CH3:29])[C:24]([O:26][C:27](=O)[CH:20]1[CH2:21][CH2:22]2)=[O:25]>>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[C:27](=[O:26])[CH:20]3[C:19]([CH3:18])([CH3:30])[C:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]2=[O:25])[CH2:11][CH2:10]1
Reactant: CC12CCC(C(=O)OC1=O)C2(C)C
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Product: CC12CCC(C(=O)N(CCCCN3CCN(c4ncccn4)CC3)C1=O)C2(C)C
Yield: 17 %

Procedure:
The title compound was prepared from 2.47 g (10.4 mmol) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine and 1.89 g (10.3 mmol) of dl-camphoric anhydride, substantially according to the procedure of Example 1. This afforded 0.7 g of product, mp 94°-97° C. (17% yield).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[CH2:7]([Li])[CH2:8][CH2:9][CH3:10]>CCOCC>[CH:1]1([C:4]([CH2:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH2:3][CH2:2]1
Reactant: [Li]CCCC
Reactant: O=C(O)C1CC1
Solvent: CCOCC
Product: CCCCC(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vigorously-stirred solution of 31.0 g of cyclopropanecarboxylic acid in 330 ml of ether is added a solution of n-butyllithium (784 mmoles) in ca. 750 ml. of 2:1 ether-hexane during 1 hour at 5°-10° C. The resulting suspension is diluted with 300 ml of ether and stirred at room temperature for 2 hours and at reflux for 2 hours. The mixture is cooled and poured into several portions of 1:1 ice--4 N hydrochloric acid. The ethereal phases are combined and washed with brine, soeium carbonate solution, and brine. The extract is dried over magnesium sulfate and concentrated. The residue is distilled to provide a liquid, b.p. 102°-104° C. (80 mm), pmr spectrum (CDCl3):δ2.55 (triplet--CH2CO--).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]#[N:13])[CH:5]=[N:4][CH:3]=[N:2]1>[Pd].C(O)C>[N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][NH2:13])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: N#Cc1ccccc1-n1cncn1
Agent: [Pd]
Solvent: CCO
Product: NCc1ccccc1-n1cncn1

Procedure:
A solution of 2-(1,2,4-triazol-1-yl)cyanobenzene (508 mg, 2.99 mmol) and 25% by weight of palladium on carbon, 10% catalyst (134 mg) in ethanol (75 ml) was placed on a PARR hydrogenation Apparatus under a hydrogen atmosphere at 55 psi. overnight. The mixture was filtered through celite and concentrated to give 2-(1,2,4-triazol-1-yl)-benzylamine; 1H NMR (CD3OD) δ 8.80 (s, 1H), 8.22 (s, 1H), 7.64–7.43 (m, 4H), 3.66 (s, 2H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:10])[CH2:4][CH2:3]1.CN.[B-][C:23]#[N:24].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:23][NH:24][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:10])[CH2:4][CH2:3]1
Reactant: O=C1CCC(NC(=O)c2ccc3[nH]ncc3c2)CC1
Reactant: [B-]C#N
Agent: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CNC1CCC(NC(=O)c2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Acetic acid (0.096 ml) was added to a solution of the N-(4-oxocyclohexyl)-1H-indazole-5-carboxamide (40.0 mg, 0.155 mmol) obtained in Example 160 in methanol (1.2 ml), and the resulting solution was maintained at room temperature for 30 minutes. To this solution was added a 40% aqueous methylamine solution (60.0 mg, 0.777 mmol), and the resulting mixture was maintained at room temperature for another 2 hours. Then, a solution of sodium cyanotrihydroborate (48.7 mg, 0.777 mmol) in methanol (0.6 ml) was added dropwise thereto, and the resulting mixture was stirred for 22 hours while being maintained at room temperature. A 1N aqueous sodium hydroxide solution (0.8 ml) was added to the reaction solution, and the resulting mixture was stirred while being maintained at room temperature, and was then concentrated to dryness. The resulting crude product residue was purified by a silica gel column chromatography (eluent: chloroform/methanol/aqueous ammonia=10/1/0.1) to obtain N-[4-(methylamino)cyclohexyl]-1H-indazole-5-carboxamide (an isomer having a lower polarity) (12.2 mg, 29%) and N-[4-(methylamino)cyclohexyl]-1H-indazole-5-carboxamide (an isomer having a higher polarity) (28.3 mg, 67%).