Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10](=[O:26])[C:11]2[C:16]([O:17][C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:15][CH:14]=[N:13][CH:12]=2)=[C:4]([N:27]([CH:29]2[CH2:31][CH2:30]2)[CH3:28])[CH:3]=1.[CH3:32]CCCCCC.C(OCC)(=O)C>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]([CH3:32])[C:10](=[O:26])[C:11]2[C:16]([O:17][C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:15][CH:14]=[N:13][CH:12]=2)=[C:4]([N:27]([CH:29]2[CH2:31][CH2:30]2)[CH3:28])[CH:3]=1
Reactant: CCCCCCC
Reactant: CN(c1cc(Cl)c(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl)C1CC1
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl)c1cc(F)c(Cl)cc1N(C)C1CC1

Procedure:
The title compound was prepared in analogy to Example 12, from N-[4-chloro-2-(cyclopropyl-methyl-amino)-5-fluoro-phenyl]-4-(2,5-dichloro-phenoxy)-nicotinamide and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Colorless solid (79%). MS (ESI): m/z=496.058 [M+H]+.
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([CH2:15][CH3:16])[CH:6]=1)#[N:4]>CCO>[NH2:4]/[C:3](=[N:1]/[OH:2])/[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([CH2:15][CH3:16])[CH:6]=1
Reactant: NO
Reactant: CCc1cc(C#N)ccc1NC(C)=O
Solvent: CCO
Product: CCc1cc(/C(N)=N\O)ccc1NC(C)=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Hydroxylamine (5.95 g, 90.0 mmol, 50 wt. % aq. solution) was added to a stirred solution of N-(4-cyano-2-ethylphenyl)acetamide (5.65 g, 30.0 mmol) in EtOH (70 mL), and the resulting mixture was heated to 90° C. After 2 h, the reaction mixture was cooled to rt and concentrated in vacuo to afford the title compound i-5a. m/z (ES) 222 (MH)+
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:14]=[C:13](Cl)[C:12]([N+:16]([O-:18])=[O:17])=[C:11]([Cl:19])[N:10]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21]>O>[CH3:8][C:9]1[N:10]=[C:11]([Cl:19])[C:12]([N+:16]([O-:18])=[O:17])=[C:13]([NH:23][CH:20]([CH3:22])[CH3:21])[N:14]=1
Reactant: CC(C)N
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NC(C)C)n1
Reaction time: 16 h
Yield: 73.4 %

Procedure:
30 ml of triethylamine are added to 32.5 g (0.156 mol) of 2-methyl- 4,6-dichloro-5-nitro-pyrimidine. At -18°C, 3.5 g of isopropylamine (0.16 mol) are added dropwise and the mixture is then stirred for 1 1/4 hours at this temperature. The mixture is subsequently poured on 4 liters of water, the precipitate is filtered off with suction, and washed 3 times with water. The crude product is dried at 50°C and 11 Torr for 16 hours, to yield 26.4 g of 2-methyl-4-chloro-5-nitro-isopropylamino-pyrimidine with a melting point of 69°-72°C. The pure substance (recrystallised from hexane) melts at 77°-79°C.
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[F:25][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:26])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Reactant: CC(C)N
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 74 %

Procedure:
As described for example 125, 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (160 mg, 74%), which was obtained as a white solid. MS: m/e=386.5 [M−H]−.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:37])[NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[C:27]([F:33])=[C:26]([O:34][CH2:35][CH3:36])[CH:25]=3)[CH2:19][CH2:18]2)[CH:10]=1)([CH3:7])[CH3:6])C.[Li+].[OH-].O.Cl>C1COCC1.CO>[CH2:31]([O:30][C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([O:34][CH2:35][CH3:36])[C:27]=1[F:33])[CH2:23][N:20]1[CH2:19][CH2:18][CH:17]([NH:16][C:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:38])=[O:3])=[O:37])[CH2:22][CH2:21]1)[CH3:32]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCN(Cc3cc(OCC)c(F)c(OCC)c3)CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(OC(C)(C)C(=O)O)c3)CC2)cc(OCC)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.9 %

Procedure:
0.54 g (1.0 mmol) of 2-{3-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylcarbamoyl]-phenoxy}-2-methyl-propionic acid ethyl ester (example 50k) was reacted with 1.0 mL of LiOH/water (1.0 molar) in 15 mL of THF/MeOH (2:1) at 0° C. and subsequent temperature increase to rt. After 5 h, the reaction mixture was poured into crashed ice, the pH was adjusted to ˜7.0 with aq. HCl (1N) and the reaction mixture was extracted twice with MeCl2; the organic phases were washed with water, dried over MgSO4, filtered and evaporated i.V. The crude product was purified by chromatography (silicagel, eluent:gradient of MeCl2/MeOH) to yield 0.135 g of the title compound as colorless solid. MS: 503.1 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Br-].C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24](=O)[CH2:25]C>O>[CH2:25]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[CH:24]=[CH2:23]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: C=CCOc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
A reaction mixture obtained by adding 20 g of 4-cyano-4′-hydroxybiphenyl, 20 g of ally bromide and 25 g of potassium carbonate to 250 mL of butanone was refluxed for 7 hours. Water was added to the reaction mixture, which was then separated. An organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain a residue, which was purified by silica gel column chromatography using toluene as an elusion solvent and then subjected to recrystallization from ethanol to obtain 22 g of 4-allyloxy-4′-cyanobiphenyl.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1C(=O)N(C)CCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:42][O:43][C:44]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:45]=1[CH2:46]Br.C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:46][C:45]2[CH:48]=[CH:49][C:50]([O:52][CH3:53])=[CH:51][C:44]=2[O:43][CH3:42])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(CBr)c(OC)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)c(OC)c1
Reaction time: 0.25 h

Procedure:
A solution of 3.57 g (11.7 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [Example 2b)] in 12 ml of abs. THF and 2.35 ml of DMPU (1.65 equivalents) is cooled down to -75° C., under argon, and is treated dropwise, at an internal temperature of less than -70° C. and over a period of 30 min, with 22.9 ml (1.96 equivalents) of a 1M solution of lithium bis(trimethylsilyl)amide in THF (Aldrich, Steinheim, FRG). After a further 15 min, 25 ml of a toluene solution containing approximately 1 equivalent of 2,4-dimethoxybenzyl bromide is added dropwise to this mixture, over the space of 20 min, and this mixture is allowed to react at -70° C. for 2 h. 4.36 ml of propionic acid and 4.36 ml of water are then added to this solution and the temperature is allowed to rise to 0° C. The reaction mixture is diluted with 200 ml of (cold) ethyl acetate and stirred up for 5 min with 60 ml of (cold) 10% citric acid. After that, the phases are separated. The organic phase is washed, in succession, with saline, sat. sodium bicarbonate solution and with saline once again, dried over Na2SO4 and concentrated. The title compound is isolated by flash chromatography on silica gel (E). TLC Rf (E)=0.24. FAB-MS (M+H)+ =455. HPLC tRet =16.85 min (gradient II). IR(CH2Cl2)=inter alia 3429, 1769, 1712, 1613 and 1506 cm-1. 1H-NMR(CDCl3)=inter alia 7.34-7.10/m (5H); 6.98/d (1H); 6.45-6.29/m (2H); 4.31/txd (1H); 3.78 and 3.71/each s (each 3H); 3.08 and 2.66/each dxd (each 1H); 1.35/s (9H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH2:6][C:7]1[CH:12]=[C:11]([NH:13][CH2:14][CH3:15])[C:10]([C:16]#[N:17])=[C:9]([Cl:18])[N+:8]=1[CH2:19][CH3:20]>>[Cl-:18].[NH2:6][C:7]1[CH:12]=[C:11]([NH:13][CH2:14][CH3:15])[C:10]([C:16]#[N:17])=[C:9]([N:1]=[N+:2]=[N-:3])[N+:8]=1[CH2:19][CH3:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CCNc1cc(N)[n+](CC)c(Cl)c1C#N
Agent: [Cl-]
Agent: [Na+]
Product: CCNc1cc(N)[n+](CC)c(N=[N+]=[N-])c1C#N
Reaction time: 2 h
Yield: 74.7 %

Procedure:
0.8 gms (.012 mole) of sodium azide was added to an aqueous solution containing 2.6 gms (.01 mole) of 2-amino-6-chloro-5-cyano-1-ethyl-4-ethylamino pyridinium chloride (compound 2 - Table 1) left for 2 hours at room temperature and then cooled. 2.0 gms (70% yield) of 2-amino-6-azido-5-cyano-1-ethyl-4-ethylamino pyridinium chloride crystallised out (MPt 164° - 165°C).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.N[C:20]([NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:24])=[O:21]>N1C=CC=CC=1>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:20]([NH:22][C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][CH:29]=[CH:28]3)=[O:24])=[O:21])[CH2:7][CH2:6]1
Reactant: NC(=O)NC(=O)c1ccc2ncccc2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Solvent: c1ccncc1
Product: O=C(NC(=O)c1ccc2ncccc2c1)NC1CCN(Cc2ccc3ccccc3c2)CC1
Reaction time: 8 h
Yield: 13.6 %

Procedure:
A suspension of 4-amino-1-(2-naphthalenylmethyl)piperidine (1.4 g, 5.83 mmol) and N-aminocarbonyl-6-quinolinecarboxamide (1.08 g, 5.02 mmol) in pyridine (7 cm3) was refluxed for 7 hours. The mixture was left at room temperature overnight then more 4-amino-1-(2-naphthalenylmethyl)piperidine (0.3 g, 1.4 mmol) was added and refluxing was continued for 5 hours. Undissolved solid was filtered off from the hot mixture and the filtrate was diluted with water (8 cm3) and filtered again. The filtrate was further diluted with water and cooled in ice. The deposited solid was collected and dried (0.46 g,) then recrystallised from ethanol (50 cm3) to give 0.30 g of the title compound, m.p. 211°-13° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)N>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Reactant: Cc1ccc(Oc2ccc(N)cc2Cl)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCO)c34)cc2Cl)cn1
Yield: 52.1 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (800 mg, 3.58 mmol) and 3-chloro-4-[(6-methylpyridin-3-yl)oxy]aniline (925 mg, 3.94 mmol) to give the title compound as a white solid (770 mg, 52%); NMR Spectrum: 2.45 (s, 3H), 3.81 (br t, 2H), 4.34 (t, 2H), 5.13 (br s, 1H), 7.21 (d, 1H), 7.26 (s, 1H), 7.27 (s, 1H), 7.71 (dd, 1H), 8.10 (d, 1H) 8.21 (s, 1H), 8.34 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 413 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1>O.C(O)C.[Fe]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[CH2:5][S:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1
Reactant: Cc1cc(C)cc(CSc2ccc([N+](=O)[O-])cc2)c1
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)cc(CSc2ccc(N)cc2)c1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A mixture of 4-(3,5-dimethyl-benzylsulfanyl)-nitrobenzene (0.35 g, 1.28 mmol) calcium chloride (0.071 g, 0.64 mmol) and iron powder (−325 mesh) (0.573 g, 10.3 mmol) in 4 ml water and 17 ml ethanol was heated at reflux under nitrogen for 4.5 h. The reaction mixture was then cooled to room temperature, filtered through Celite and the filtrate was concentrated under reduced pressure. The residual oil was purified by column chromatography, eluting with 9:1 hexane/ethyl acetate to yield the title compound as a yellowish oil (0.29 g, 91% yield). MS: 244.3 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:38])=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(CO)ccc1NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(CBr)ccc1NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
The compound (1.035 g) obtained in Example 518 was dissolved in methylene chloride (20 ml) and to the solution, triphenylphosphine (1.38 g) and carbon tetrabromide (1.74 g) were successively added under ice cooling. The reaction mixture was stirred for 30 min under ice cooling, then stirred at room temperature for 30 min and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=5:1) to give 476.6 mg of the titled compound (yield, 36%).
Reaction SMILES: CC([O-])(C)C.[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>C1COCC1.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:17]1([C:14](=[O:16])[CH2:15][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1ccccc1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
Pd(OAc)2 (2.3 mg, 0.010 mmol), tri-t-butylphosphine (2.1 mg, 0.010 mmol) and NaOtBu (211 mg, 2.20 mmol) were suspended in 1 mL of THF in a screw-capped vial. The vial was sealed with a cap containing a PTFE septum and removed from the dry box. Bromobenzene (157 mg, 1.00 mmol) and acetophenone (132 mg, 1.10 mmol) were added to the reaction mixture by syringe. The reaction mixture was stirred at 25° C. and monitored by GC analysis. The crude reaction was diluted with ether and washed with 1N HCl, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc=95/5) to give 188 mg (96%) of 1,2-Diphenyl-1-ethanone: 1H NMR: (CDCl3) δ 8.02 (d, J=7.1 Hz, 2H), 7.58-7.26 (m, 8H), 4.31 (s, 2H); 13C{1H} NMR: (CDCl3) δ 197.52, 136.79, 134.67, 133.09, 129.54, 129.50, 128.64, 128.62, 126.88, 45.50.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(OC)nc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(OC)nc2)cc1)C(=O)O
Yield: 62.7 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(2-methoxypyridine-5-carbonylamino)ethoxy]phenyl]propionate (500 mg), which is the product of Example 51, was reacted with aqueous sodium hydroxide solution (1N, 4.00 ml) and the reaction mixture was treated to give the title compound (293 mg) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[CH:42]=[N:41][C:40](OS(C(F)(F)F)(=O)=O)=[CH:39]2.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:40]4[N:41]=[CH:42][C:43]5[C:38]([CH:39]=4)=[CH:37][C:36]([CH3:35])=[CH:45][CH:44]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc2cnc(OS(=O)(=O)C(F)(F)F)cc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc2cnc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)cc2c1
Temperature: 105 °C

Procedure:
To a solution of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (53.7 mg, 0.114 mmol), trifluoromethanesulfonic acid 6-methylisoquinolin-3-yl ester (35.0 mg, 0.120 mmol), and PS-PPh3-Pd (0.10 mmol/g loading; 76 mg, 0.0076 mmol; Argonaut) in 1,4-dioxane (2.0 mL, 25 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (75.6 mg, 0.232 mmol) in H2O (0.60 mL, 33 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 105° C. for 30 minutes. The resin was filtered off and washed with DCM. The combined filtrate and washings were washed with 1M NaOH, water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC [20×20 cm plate, 500 μm layer of silica gel, eluting with 3.5% MeOH in DCM (3×)]. Material from the main band was collected and dried in vacuo overnight to give the title compound as a yellow glassy solid. 1H NMR (400 MHz, CDCl3): δ=9.22 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.94 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.77 (d, J=0.4 Hz, 1H), 7.67 (brs, 1H), 7.66 (s, 1H), 7.46 (dd, J=8.4, 1.6 Hz, 1H), 6.43 (brs, 2H), 4.38-4.19 (m, 3H), 2.92 (brt, J=11.0 Hz, 2H), 2.58 (s, 3H), 2.19 (brdd, J=2.0, 12.4 Hz, 2H), 1.98 (dq, J=4.4, 12.0 Hz, 2H), 1.49 (s, 9H). MS(ES+): m/z=485.19 (100) [MH+], 429.13 (7) [MH+-isobutene]. HPLC: tR=2.71 min (polar—5 min, ZQ2).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5](=[S:27])[NH:6][NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1>CO>[F:23][C:22]([F:25])([F:24])[C:18]1[CH:17]=[C:16]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[NH:4][C:5](=[S:27])[NH:6][N:7]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: NC(=S)NNC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1cccc(Nc2ccccc2-c2n[nH]c(=S)[nH]2)c1
Yield: 59.7 %

Procedure:
Sodium methoxide (548.0 mg, 10.5 mmol) is added to a solution of 2-[(3-trifluoromethylphenyl)amino]-benzoic acid, 2-(aminothioxomethyl)hydrazide (1.023 g, 2.89 mmol) in 50 ml of methanol and the mixture is heated at reflux under a nitrogen atmosphere. Additional amounts of sodium methoxide (548.0 mg and 250.0 mg) are added after heating at reflux for one and two days. The volatiles are removed in vacuo and the residue dissolved in water. The aqueous solution is acidified to pH 4-5 with 1N hydrochloric acid. The resultant pale yellow solid is collected to give 934.1 mg. The solid is chromatographed, eluting with hexane:ethyl acetate (1:2) to give 580.0 mg (59%) of 5-[2-[(3-trifluoromethylphenyl)amino]phenyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione, mp 275°-279° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C:14]2([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(#N)C.C(N(CC)C)C>C(=O)=O>[C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1=NC2(c3cccs3)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Agent: CCN(C)CC
Agent: O=C=O
Solvent: CO
Solvent: CC#N
Product: O=C(NC1=N[C@@]2(c3cccs3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Yield: 46.5 %

Procedure:
Racemic benzyl 2-benzamido-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (34 g, 63 mmol) is chirally purified by SFC (Column: Chiralpak IC (5 j), 2×250 mm; eluent: 40% methanol/acetonitrile (8/2) with 0.2% diethylmethyl amine) in CO2; flow: 65 mL/min at UV 260 nm). The second eluting isomer is the title compound (14 g, 42%, >98% ee): [α]D20=−30 (C=1.0, methanol), ES/MS (m/e) 478 (M+H).
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6][C@@H:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])/[CH:3]=[O:4].CC1[C@@H]2C(C)(C)[C@@H](C2)CC=1>>[CH3:1]/[C:2](=[CH:5]\[CH2:6][C@@H:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])/[CH2:3][OH:4]
Reactant: CC1=CC[C@@H](C/C=C(\C)C=O)C1(C)C
Agent: CC1=CC[C@@H]2C[C@H]1C2(C)C
Product: CC1=CC[C@@H](C/C=C(\C)CO)C1(C)C
Yield: 80 %

Procedure:
(E)-(S)-2-Methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-2-buten-1-al synthesized from (1R,5R)-α-pinene having an optical purity of 97% e.e. (available from Aldrich) was hydrogenated in the same manner as in Example 1 to obtain 3.08 g (yield 80%) of the title compound. The chemical purity of the product was found to be 98% by GC.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:9][C:8](=O)[CH:7]=[CH:6][N:5]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:15])=O>>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([Cl:15])[CH:7]=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nccc(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: COCc1nccc(Cl)n1
Temperature: 0 °C

Procedure:
A mixture of 2-methoxymethyl-4-pyrimidone (1.73 g) and phosphorus oxychloride (20 ml) were heated together under reflux for 30 minutes. The mixture was stripped, ice/water added and the pH raised to 14 (NaOH). The solution was extracted with chloroform, the extracts dried (MgSO4) and stripped to give 2-methoxymethyl-4-chloropyrimidine (1.72 g) as an oil which was used without further purification.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: NCCCc1ccccc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCCCc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 78.1 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 3-phenylpropylamine (0.47 g, 3.5 mmol) was added. The mixture was stirred at room temperature for 50 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.67 g, 2.5 mmol, yield: 80%) as colorless needles.