Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:35]=[CH:34][C:17]([C:18](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:17]2[CH:34]=[CH:35][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)CCCCCCCO
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OCCCCCCCC(=O)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 127.5 %

Procedure:
8-hydroxyoctanoic acid (100 mg, 0.59 mmol) was dissolved in 1.5 mL of pyridine. To the solution, 4,4′-dimethoxytrityl chloride (237 mg, 0.7 mmol) was added, and the mixture was stirred overnight. The completion of the reaction was confirmed by TLC. Then, the reaction solution was separated into organic and aqueous phases using methylene chloride and water. The organic phase was dried over sodium sulfate, and the solvent was then concentrated under reduced pressure. The residue was purified with a silica gel column (4 g, methylene chloride) to obtain amorphous 8-(4,4′-dimethoxytrityloxy)octanoic acid (348 mg). The obtained 8-(4,4′-dimethoxytrityloxy)octanoic acid was dissolved in 1 mL of methylene chloride. To the solution, 4-aminophenol (70.9 mg, 0.64 mmol), EDC (101.6 mg, 0.88 mmol), HOBT (79 mg, 0.886 mmol), and triethylamine (92 L) were added, and the mixture was stirred overnight. The completion of the reaction was confirmed by TLC. Then, the reaction solution was purified with a silica gel column (5 g, 30%-+50% ethyl acetate/n-hexane) to obtain the amorphous compound (148 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:19](#[N:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:8]1=[N:12][C:11]([CH3:13])=[N:10][N:9]1[C:19]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:26]
Reactant: N#Cc1ccccc1
Reactant: Cc1nc(-c2ccc(Cl)cc2)n[nH]1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc2n(n1)C(N)(c1ccccc1)c1cc(Cl)ccc1-2
Temperature: 0 °C
Yield: 49.1 %

Procedure:
2.0 g (10.3 mmol) of 3-(4-Chlorophenyl)-5-methyl-1,2,4-triazole is dissolved in 50 ml of tetrahydrofuran (THF) (freshly distilled from lithium aluminum hydride) mechanically stirred in a 250 ml round-bottom 3-necked flask equipped with a septum and nitrogen inlet and cooled in an ice bath. 13.6 ml (22.7 mmol) of n-butyllithium (1.67 mol/liter in hexane) is injected with a syringe and the mixture is stirred in the ice bath for 30 minutes. 2.12 g (20.6 mmol) of benzonitrile is added in a little THF. After stirring for 30 minutes in the ice bath and for 30 minutes at room temperature, the mixture is poured into a chilled stirred mixture of 100 ml of 2.5 M ammonium chloride and 200 ml of chloroform. The layers are separated and the aqueous layer washed with chloroform. The combined chloroform layers are washed with water and dried (Na2SO4). The chloroform is removed under vacuum and the residue is recrystallized from toluene to yield 1.5 g of the title compound, m.p. 173°-175°.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.[CH3:23][O:24][CH2:25][CH:26](O)[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH:26]([CH3:27])[CH2:25][O:24][CH3:23])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: COCC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: COCC(C)OC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Yield: 97 %

Procedure:
3.3 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetic acid and 1.8 g of 1-methoxy-2-propanol were dissolved in 50 ml of benzene, followed by addition of 0.5 g of p-toluene sulfonic acid. Then, the mixture was heated under reflux for 6 hours. After completion of the reation, 50 ml of ether was added to the reaction mixture. The resulting mixture was washed with water by the customary method and dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.9 g of 1-methyl-2-methoxyethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1ccc(F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(Cl)c1
Yield: 75.5 %

Procedure:
By the method of Example 7, Step C, 141.4 g (0.978 mole) of 2-chloro-4-fluorotoluene, 175.8 g (0.978 mole) of N-bromosuccinimide, and 5.0 g of benzoyl peroxide in 15 liters of carbon tetrachloride were reacted, yielding 165 g of 2-chloro-4-fluorobenzyl bromide as a white solid.
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(=O)[NH:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([CH3:45])([CH3:44])[C:35]([N:37]3[CH:41]4[CH2:42][CH2:43][CH:38]3[CH2:39][CH2:40]4)=[O:36])[CH:32]=2)[NH:27][C:26]=1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[C:48]([CH3:53])[CH:47]=1)(C)(C)C>>[NH2:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([CH3:45])([CH3:44])[C:35]([N:37]3[CH:38]4[CH2:39][CH2:40][CH:41]3[CH2:42][CH2:43]4)=[O:36])[CH:32]=2)[NH:27][C:26]=1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[C:48]([CH3:53])[CH:47]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNC(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a solution of {2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (728 mg in 30 mL methylene chloride) at 0° C. was added 1.5 mL anisole followed by 10.5 mL trifluoroacetic acid and the mixture stirred at 0° C. After 2 hours, the mixture was concentrated in vacuo and the residual acid quenched by the addition of 10% ammonium hydroxide in methanol. The concentrated was then purified by flash chromatography on silica gel (methylene chloride:10% ammonium hydroxide in methanol, 95:5; then 92:8) to give the title compound (627 mg).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1csc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c12
Reactant: c1nc[nH]n1
Product: Cc1csc2nc(-n3cncn3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]([C:27]1[N:31](COCC[Si](C)(C)C)[C:30]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:29]=2[N:28]=1)(O)[C:4]1[C:12]([S:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].FC(F)(F)C(C1N(COCC[Si](C)(C)C)C2C=C(C#N)C=CC=2N=1)(O)C1C(SC)=CC(C)=C2C=1C=[CH:54][N:55]2S(C1C=CC(C)=CC=1)(=O)=O.Cl.S(Cl)(Cl)=O.CN>CN(C=O)C>[F:47][C:2]([F:46])([F:1])[C:3]([C:27]1[NH:31][C:30]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:29]=2[N:28]=1)([C:4]1[C:12]([S:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[NH:55][CH3:54]
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CNC(c1nc2cc(C#N)ccc2[nH]1)(c1c(SC)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Temperature: 60 °C

Procedure:
To a mixture of (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 14-A) (0.37 g, 0.528 mmol) was added HCl (1.25M in MeOH, 4.22 mL, 5.28 mmol) and the mixture was stirred at 60° C. After 40 minutes the mixture was cooled to room temperature and concentrated. The residue was dissolved in CHCl3 (10.56 mL), and thionyl chloride (0.385 mL, 5.28 mmol) and a few drops of DMF were added and the mixture was heated at 70° C. After 2 hours the reaction was cooled to room temperature and concentrated. The residue was dissolved in methylamine (33% in EtOH, 6.57 mL, 52.8 mmol) and stirred at room temperature. After 5 minutes the reaction was concentrated and purified directly by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 584.2 (M+H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:23]([SiH2:27][O:28][C:29]([CH3:40])([CH3:39])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:33][NH2:34])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.[F:50][C:51]([F:57])([F:56])[CH2:52][C:53](O)=[O:54]>C(Cl)Cl>[C:23]([SiH2:27][O:28][C:29]([CH3:40])([CH3:39])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:33][NH:34][C:53](=[O:54])[CH2:52][C:51]([F:57])([F:56])[F:50])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(O)CC(F)(F)F
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CNC(=O)CC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
TBTU (3.37 g, 10.5 mmol) was added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (2.00 g, 7.00 mmol), DIPEA (4.80 mL, 28.0 mmol) and 3,3,3-trifluoropropionic acid (0.927 mL, 10.5 mmol) in CH2Cl2 (70 mL). The mixture was stirred at rt for 1 h. CH2Cl2 (30 mL) was added, and the mixture was washed with aq. sat. NH4Cl (2×), aq. 1M NaOH (1×) and brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 40:60) yielded the title compound (1.80 g, 65%). LC-MS: tR=1.10 min; ES+: 396.15.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:21]([NH2:22])=[CH:20][NH:19][N:18]=1>N1C=CC=CC=1>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:21]([NH:22][C:5](=[O:7])[CH3:6])=[CH:20][NH:19][N:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Solvent: c1ccncc1
Product: CC(=O)Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
Acetic anhydride (27 μl, 0.28 mmol) was added to a solution of 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol) in pyridine (5 ml) and the reaction mixture stirred at ambient temperature for 24 h. The mixture was reduced in vacuo and the residue purified by flash column chromatography [SiO2, EtOAc-petrol (1:2.5, 2:1)] to give N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide as a brown crystalline solid (29 mg, 48%). (LC/MS: Rt 1.70, [M+H]+ 241.64).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][N:13]([C:14]([C:16]4[C:17]([CH3:21])=[N:18][O:19][CH:20]=4)=[O:15])[C:7]3([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:6][N:5]2[CH:30]=1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:31]1([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[O:10])[N:8]4[CH2:11][CH2:12][N:13]([C:14]([C:16]5[C:17]([CH3:21])=[N:18][O:19][CH:20]=5)=[O:15])[C:7]4([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:6][N:5]3[CH:30]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc(C23Cn4cc(N)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(C23Cn4cc(NC5CCCCC5)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1

Procedure:
To a solution of 7-amino-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]-pyrazin-5-one (33 mg, 0.081 mmol) in CH2Cl2 (0.5 mL) was added cyclohexanone (9 μL, 0.081 mmol), acetic acid (7 μL, 0.12 mmol) followed by sodium triacetoxyborohydride (26 mg, 0.12 mmol). After stirring the mixture for three further hours, cyclohexanone (20 μL, 0.18 mmol) was added followed by the addition of additional acetic acid (20 μL, 0.34 mmol). The mixture was quenched with a saturated aqueous solution of NaHCO3. Additional CH2Cl2 (3 mL) was added and the organic layer separated, the aqueous layer was further extracted with CH2Cl2 (3 mL). The organic layers were combined dried (Na2SO4), filtrated, concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4, gradient 0-10% MeOH in EtOAc) and reverse phase chromatography (Biotage SP4, 12 g C18 cartridge; gradient ACN in water). The compound 7-(cyclohexylamino)-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (112) was isolated as a solid (1.6 mg, yield 1%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH2:39][NH2:40]>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:40][CH2:39][CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[Cl:31])[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccccc1Cl
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccccc3Cl)n2)c1

Procedure:
Intermediate 4 was coupled to 2-(2-chloro-phenyl)-ethylamine following procedure F and the resulting product deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 474. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.8 (m, 1H) 8.18 (m, 4H) 7.6 (m, 6H) 4.45 (s, 2H) 3.95 (m, 2H) 3.4 (m, 2H) 3.18 (m, 4H) 3.0 (m, 2H) 2.9 (s, 3H) 1.75 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=1)=[O:5])[CH3:2]>CCO.CC(O)=O.O=[Pt]=O>[C:4]([OH:5])(=[O:3])[CH3:6].[CH2:15]([O:14][C:12]([CH:10]1[CH2:11][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][NH:8][CH2:9]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cncc(C(=O)OCC)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CNCC(C(=O)OCC)C1

Procedure:
Hydrogenate pyridine-3,5-dicarboxylic acid diethyl ester (13.4 g, 60.0 mmol) in EtOH (100 mL) and HOAc (35 mL) with PtO2 (2.7 g, cat.) overnight at room temperature and 60 psi. Filter through celite and concentrated to dryness. Partition between sat. aq NaHCO3 and CHCl3. Extract 3× with CHCl3. Wash with sat. aq NaHCO3, wash with brine, dry over Na2SO4, filter and concentrate to dryness. MS(IS) 231.1 (M+2); Carried on without further purification.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](/[CH:53]=[CH:54]/[CH2:55][C:56](O)=[O:57])=[CH:49][CH:48]=2)[C:43]([CH3:59])=[CH:42][C:41]=1[O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.C(Cl)(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:48]=[CH:49][C:50](/[CH:53]=[CH:54]/[CH2:55][C:56]([NH:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71])=[O:57])=[CH:51][CH:52]=2)[C:43]([CH3:59])=[CH:42][C:41]=1[O:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CC(=O)NC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a chloroform solution (2.2 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-3-carboxyprop-1-en-1-yl]benzyl]-4-methylphenyl]-D-glucitol (200 mg, 0.223 mmol) were added 2-amino-2-methyl-1-propanol (40 mg, 0.446 mmol), 1-hydroxy benzotriazole (33 mg, 0.245 mmol) and WSC (60 mg, 0.312 mmol), and the mixture was stirred overnight at room temperature. To the reaction solution was added water, and the resulting mixture was extracted with chloroform. The organic layer was washed with brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1 to 1:2) to obtain the title compound (120 mg, 56%) as an orange-yellow oily compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[CH:30]=O>>[CH3:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[CH2:30][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Cn1c(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)nc2ccccc21

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1-methylbenzimidazole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(1-methylbenzimidazol-2-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.C1CCCCC1.S(=O)(=O)(O)O.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH:40]=[C:39]([C:44]([O:46][CH3:47])=[O:45])[CH:38]=[CH:37]3)=[CH:30][CH:29]=1>C(O)C>[C:5]12([C:29]3[CH:30]=[C:31]([C:34]4[CH:35]=[C:36]5[C:41](=[CH:42][CH:43]=4)[CH:40]=[C:39]([C:44]([O:46][CH3:47])=[O:45])[CH:38]=[CH:37]5)[CH:32]=[CH:33][C:28]=3[O:27][CH3:26])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: COC(=O)c1ccc2cc(-c3ccc(OC)cc3)ccc2c1
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Solvent: CCO
Product: COC(=O)c1ccc2cc(-c3ccc(OC)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Reaction time: 2 h
Yield: 68.5 %

Procedure:
In a 100 ml three-necked flask, are placed 1 g of 1-acetoxyadamantane and 50 ml of cyclohexane in a nitrogen environment. After total dissolution, 0.25 g of concentrated sulfuric acid is added drop by drop and 1 g of methyl 6-(4-methoxyphenyl)-2-naphthoate is added slowly. After leaving in vigorous agitation for 48 hours, 20 ml of denatured ethanol are added and the mixture is agitated for 2 hours. The solid obtained is filtered with sintered glass and washed abundantly with water until neutrality is reached. After drying at 30° C. for 24 hours in a vacuum oven, 1 g of desired raw product was obtained (Melting point: 221°-227° C.).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]=[C:12]2[CH3:15])=[CH:7][CH:6]=1.Cl>CO>[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH:12]2[CH3:15])=[CH:7][CH:6]=1
Reactant: COc1ccc2c(c1)C(C)=NCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)C(C)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Sodium borohydride (3.81 g, 100.8 mmol) was slowly added at 0° C. to a solution of 7-methoxy-1-methyl-3,4-dihydroisoquinoline (14.72 g, 84 mmol) prepared in Step 2 in anhydrous methanol (100 ml). The reaction mixture was stirred overnight at room temperature. 1N hydrochloric acid was added to the reaction mixture, which was concentrated under reduced pressure, basified with potassium hydroxide, and then extracted with dichloromethane. The organic layer washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 11.01 g of the titled compound as brown oil. (Yield: 74%) The product was used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([NH:22]C(OC(C)(C)C)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][CH:16]([CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(Cc1cccc(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(N)Cc1cccc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 84.8 %

Procedure:
159 (850 mg) was dissolved in 4 ml of DCM and 4 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated to afford 160 as a white solid (540 mg, 86%), 1H NMR (DMSO): δ 1.26 (t, 3H, J=6.5 Hz), 1.89 (5, 2H), 2.89 (dd, 1H, J=6.5 Hz), 5.21 (s, 2H), 6.90 (d, 1H, J=7.6 Hz), 6.99 (s, 2H), 7.32 (t, 1H, J=7.8 Hz), 7.47 (m, 1H), 7.53 (t, 2H, J=7.0 Hz), 7.58 (d, 2H, J=7.6 Hz).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C=O)C>[CH3:15][N:14]([CH3:16])[CH:13]=[C:8]([C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: N#CCc1ccncc1
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C=C(C#N)c1ccncc1
Temperature: 110 °C

Procedure:
To a solution of 4-pyridylacetonitrile hydrochloride (155 mg, 1 mmol) in DMF (0.5 mL) was added dimethylformamide dimethylacetal (2 mL) and triethylamine (0.15 mL, 1.1 eq). The mixture was heated at 110° C. for 9 hours and then concentrated to give 3-dimethylamino-2-pyridin-4-ylacrylonitrile (3, Ar=4-Py) as dark brown crystals and used for the next step without further purification.