Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[F:19][C:20]([F:31])([F:30])[C:21]([F:29])([F:28])[C:22]([F:27])([F:26])[C:23](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:6][C:5]2[NH:17][C:23]([C:22]([F:26])([F:27])[C:21]([F:28])([F:29])[C:20]([F:31])([F:30])[F:19])=[N:18][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2ccc(Cl)cc2Cl)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Product: FC(F)(F)C(F)(F)C(F)(F)c1nc2cc(Cl)c(Oc3ccc(Cl)cc3Cl)cc2[nH]1
Yield: 47 %

Procedure:
To a solution of 4,5-dichloro-2-nitroaniline (20 g, 96.61 mmol) in DMSO (200 ml) was added 2,4-dichlorophenol (15.8 g, 96.93 mmol) and potassium carbonate (26.7 g, 193.18 mmol). The resulting solution was stirred overnight at 90° C. and then quenched by the addition of water (1000 ml). The resulting solution was extracted with ethyl acetate (3×500 ml) and the organic layers combined and dried over anhydrous magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(2,4-dichlorophenoxy)-2-nitroaniline as a yellow solid (23 g, 71%). Next, the 4-chloro-5-(2,4-dichlorophenoxy)-2-nitroaniline (22 g, 65.96 mmol) was added to ethanol (200 ml) and hydrogen chloride (16 ml, 197.9 mmol). This was followed by the addition of Zn powder (21.4 g, 395.8 mmol) at room temperature in portions. The resulting solution was stirred for 4 h at 85° C. and then concentrated under vacuum. The residue was dissolved in water (500 ml), adjusted pH to 8 with aqueous sodium bicarbonate and extracted with ethyl acetate (4×200 ml). The combined organic layers were dried and concentrated under reduce pressure to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to afford 4-chloro-5-(2,4-dichlorophenoxy)benzene-1,2-diamine as a red oil (15 g, 75%). Finally, a solution of 4-chloro-5-(2,4-dichlorophenoxy)benzene-1,2-diamine (14 g, 46.12 mmol) in heptafluorobutanoic acid (150 ml) was stirred overnight at 80° C. in an oil bath. The reaction was then quenched by the addition of water (400 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 2%˜10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-dichlorophenoxy)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a white solid (10.4705 g, 47%).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[C:13]2[N:14]([CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1.[OH-].[NH4+]>O>[Cl:11][C:12]1[C:13]2[N:14]([C:18]([CH:3]=[O:4])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2cn3cccc(Cl)c3n2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccc(F)cc2)nc2c(Cl)cccn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
N,N-Dimethylformamide (10 mL) was cooled to 0° C. and treated with phosphorous oxychloride (1.0 mL, 11 mmol). After the addition was complete, the mixture was warmed to room temperature and stirred for 10 minutes. To this was added 8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine (1.15 g, 4.7 mmol) and the resulting solution was stirred overnight. Water was added to the reaction. The mixture was neutralized to pH 7 with ammonium hydroxide. The aqueous phase was extracted with dichloromethane (3×50 mL). The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from acetonitrile to give 8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine-3-carbaldehyde (1.1 g, 85%) as a white solid. 1H NMR (CDCl3): δ 10.05 (s, 1H), 9.60 (d, 1H), 7.86 (q, 2H), 7.65 (d, 1H), 7.23 (t, 2H), 7.08 (t, 1H); 19F NMR (CDCl3) δ −110.8; MS m/z 275 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f24) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C@@H:3]([C:15]([N:17]1[CH2:22][C@@H:21]2[CH2:23][C@H:18]1[CH2:19][N:20]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])[NH:4]C(OCC1C=CC=CC=1)=O>CO.[Pd]>[CH3:1][C:2]([CH3:32])([CH3:31])[C@@H:3]([C:15]([N:17]1[CH2:22][C@@H:21]2[CH2:23][C@H:18]1[CH2:19][N:20]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])[NH2:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@H](N)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl (1S,4S)-5-(3-methyl-N-{[(phenylmethyl)oxy]carbonyl}-L-valyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (31.6 g, 71 mmol) in MeOH (600 mL) was added Pd/C (12 g). The mixture was stirred for 18 h at room temperature under an atmosphere of H2 (40 psi). The reaction mixture was then filtered and the organic layer was concentrated to yield the crude product. LCMS (m/z): 312.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-:25]#N.[K+]>C(O)C#C>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][C:20]#[CH:25])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: C#CCO
Agent: [K+]
Product: C#CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
A mixture of 6.92 g (0.02 mol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 100 ml of propargyl alcohol and 0.4 g of potassium cyanide is heated to boiling under reflux for 4 hours, 75 ml of the solvent are then removed by distillation, 75 ml of propargyl alcohol are added to the mixture and the resulting mixture is heated to boiling under reflux for a further 16 hours. The mixture is concentrated, 25 ml of water are added to the residue and the mixture obtained is extracted three times with 25 ml of chloroform each time, the chloroform solution is dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate. By recrystallization from ethyl acetate there is obtained 2-propynyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 213°-214°.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[O:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[O:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: CCN
Reactant: CSC(=C[N+](=O)[O-])NCCCSc1ncco1
Product: CCNC(=C[N+](=O)[O-])NCCCSc1ncco1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[3-(2-oxazolylthio)propylamino]ethylene (see Example 19 (iv) with ethylamine by the procedure of Example 8(ii) gives the title product.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[C:10]#[N:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH2:10][NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1c(NC2CCCCC2)cccc1-c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1c(NC2CCCCC2)cccc1-c1ccccc1
Temperature: 25 °C

Procedure:
The product of example 1b above, 2-cyclohexylamino-6-phenylbenzonitrile, (0.095 g, 0.34 mmol) was dissolved in dry tetrahydrofuran (20 mL) and stirred under argon at room temperature. Lithium aluminum hydride (0.136 g, 3.4 mmol) was added and the mixture heated to reflux under argon for 9 hours. The reaction mixture was cooled to room temperature and anhydrous sodium sulfate was added followed by the addition of a freshly prepared saturated solution of anhydrous sodium sulfate. The solvent was evaporated and the residue triturated with ethyl acetate, filtered and evaporated. Flash chromatography on silica gel eluted with 0-2% methanol in methylene chloride followed by recrystallization from ethyl acetate/hexane gave the title compound as a white crystalline solid. mp 95-96° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[CH3:19][NH2:20]>>[CH3:15][C:14]1[C:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:20][CH3:19])[CH:18]=[CH:17][C:6]=3[N:7]=2)=[C:11]([NH2:16])[NH:12][N:13]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Reactant: CN
Product: CNCc1ccc2nc(-c3c(C)n[nH]c3N)sc2c1

Procedure:
The title compound (1.6 mg) was prepared starting from 18 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess methylamine. MS (m/z, ES+): 274.1 (M+1, 100%), 243.1 (M-CH3NH, 60%).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32](Br)[CH:33]=[CH2:34]>>[CH2:34]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([N:13]3[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:15][CH2:14]3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[CH:33]=[CH2:32]
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Reactant: C=CCBr
Product: C=CCN1Cc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc2C1=O
Yield: 93 %

Procedure:
In the same manner as in Example 51, the title compound (51 mg) was prepared from the compound (50 mg) obtained in Example 50 and allyl bromide (22 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[N:10]([CH3:14])[N:11]=[CH:12][CH:13]=2)[CH:7]=1>[Pd].CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]([CH3:14])[N:11]=[CH:12][CH:13]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: Cn1nccc1Nc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1nccc1Nc1cc(F)ccc1N
Temperature: 20 °C
Reaction time: 5 h
Yield: 75.2 %

Procedure:
A mixture of (5-fluoro-2-nitrophenyl)-(2-methyl-2H-pyrazol-3-yl)-amine (0.96 g, 4.06 mmol) and 10% palladium on carbon (0.20 g) in EtOAc (40 mL) was stirred under an atmosphere of hydrogen at atmospheric pressure and 20° C. for 5 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo to give the title compound as a white solid (0.63 g, 88%). LCMS (Method C): RT 1.88 min [M+H]+ 207.0
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([O:27][CH:28]([F:30])[F:29])[C:11]([N:18]3[CH2:22][CH2:21][C@@H:20]([C:23]([NH2:26])([CH3:25])[CH3:24])[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:31]2[CH2:33][CH2:32]2)[C:7]=1[S:34](C)(=O)=O)=[O:5])[CH3:2].O.[SH-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([O:27][CH:28]([F:29])[F:30])[C:11]([N:18]3[CH2:22][CH2:21][C@@H:20]([C:23]([NH2:26])([CH3:25])[CH3:24])[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:31]2[CH2:33][CH2:32]2)[C:7]=1[SH:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(S(C)(=O)=O)n(C2CC2)c2c(OC(F)F)c(N3CC[C@@H](C(C)(C)N)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(S)n(C2CC2)c2c(OC(F)F)c(N3CC[C@@H](C(C)(C)N)C3)c(F)cc2c1=O

Procedure:
Compound 14 (1.6 g, 2.93 mmol) is dissolved in DMF (40 mL) under an atmosphere of argon. Sodium hydrosulfide hydrate crystals (Aldrich, 72.6% by titration, 330 mg, 5.88 mmol) are added to this solution. The resulting mixture is sparged slowly with argon for 30 min. The progress of the reaction is monitored by HPLC-MS, and judged to be complete (≦2% of 14 remains) after 5 h. Excess sodium hydrosulfide is quenched upon addition of aq. HCl (4.5 mL, 4 N). The resulting orange solution (pH ˜2) is sparged with argon (30 min) to remove the generated hydrogen sulfide. DMF is removed under reduced pressure to give orange oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH3:22])=[CH:16][C:15]=2[O:23][CH3:24])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[OH:5][CH2:4][C:3]1[CH:8]=[CH:9][C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH3:22])=[CH:16][C:15]=2[O:23][CH3:24])=[CH:11][C:2]=1[OH:1]
Reactant: CCCc1ccc(OCc2ccc(C(=O)OC)c(O)c2)c(OC)c1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCc1ccc(OCc2ccc(CO)c(O)c2)c(OC)c1
Reaction time: 3 h
Yield: 89.3 %

Procedure:
Methyl 2-hydroxy-4-[(2-methoxy-4-propylphenoxy)methyl]benzoate (300 mg) was dissolved in THF (15 mL). To the reaction liquid was added LAH (103.4 mg) at 0° C., followed by warming from 0° C. to 25° C. and then stirring for 3 hours. To the reaction liquid was added a saturated aqueous Rochelle salt solution (30 mL), followed by extraction with EtOAc (30 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain 2-(hydroxymethyl)-5-[(2-methoxy-4-propylphenoxy)methyl]phenol (245.2 mg) as a white solid.
Reaction SMILES: C1COCC1.I[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][C:25]#[CH:26])([CH3:19])([CH3:18])[CH3:17]>[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.C(N(CC)CC)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][C:25]#[C:26][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C#CCCNC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC#Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a mixture of anhydrous THF and triethylamine (20 mL, 1/1) were sequentially added 1-iodo-4-nitrobenzene (2.0 g, 8.032 mmol) and copper(I)iodide (0.31 g, 1.606 mmol). The mixture was stirred at room temperature for 15 min. The flask was evacuated and re-filled with argon four times to ensure no oxygen remained. The catalyst, dichlorobis(triphenylphosphine)-palladium(II) (0.56 g, 0.803 mmol) was added into the mixture under argon protection, followed by dropwise addition of but-3-ynyl-carbamic acid tert-butyl ester (1.62 g, 9-638 mmol). The newly formed reaction mixture was further stirred at room temperature overnight. The solid in the reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was re-dissolved in methylene chloride and purified by column chromatography, eluting with a mixture of ethyl acetate (0-10%) and hexanes (100-90%) to afford 2.08 g (89%) of the product 51 as an orange solid. 1H NMR (CDCl3) δ 1.46 (s, 9H), 2.66 (t, J=6.5 Hz, 2H), 3.36-3.43 (m, 2H), 4.86 (br s, 1H), 7.53 (d, J=8.7 Hz, 2H), 8.16 (d, J=8.7 Hz, 2H). m/z (APCI)=291 [Cl5H18N2O4+H]+, 191 [Cl5H18N2O4−Boc+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([CH3:23])[CH:3]=1.N1C=CC=CC=1.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl.O.C(Cl)Cl>[Cl:30][C:31]1[N:36]=[CH:35][C:34]([S:37]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@@H:11]([CH3:22])[CH2:10]3)=[C:4]([CH3:23])[CH:3]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: Cc1cc(N)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(Cl)nc2)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 106.8 %

Procedure:
D7 (100 mg, 0.31 mmol) in dry DCM (1.05 mL) and pyridine (0.30 mL, 3.8 mmol) was stirred to 0° C. under argon and 6-chloro-3-pyridinesulfonyl chloride (60 mg, 0.28 mmol) in dry DCM (1.05 mL) added dropwise. The reaction mixture was stirred under argon and allowed to warm to room temperature. After 17 h, the reaction mixture was diluted with water/DCM. The aqueous layer was extracted with DCM, the organic layer dried (Na2SO4) and solvent removed under vacuum. The product was purified by column chromatography (Biotage Horizon 40+S) eluting with petroleum ether/Et2O to afford the title compound as a colourless oil (148 mg). MS (ES+): MH+ 495.1/497.1.
Reaction SMILES: [I-].[CH3:2][C:3]1[C:4]2[N:5]([C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:7][N+:8]=1[CH3:9].O.[BH4-].[Na+].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO.C(O)C>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:2][CH:3]1[N:8]([CH3:9])[CH2:7][CH2:6][N:5]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=[C:4]12
Reactant: CC1=[N+](C)CCn2c1ccc2-c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [I-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC1c2ccc(-c3ccccc3)n2CCN1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
3,4-Dihydro-1,2-dimethyl-6-phenylpyrrolo[1,2-a]pyrazinium iodide (0.4 g) was dissolved in 20 ml of methanol and 0.5 ml of water under argon and, after the addition of 0.2 g of sodium borohydride, stirred at room temperature for 15 minutes. The methanol was removed in a vacuum and the residue was stirred briefly with 50 ml of methylene chloride and 20 ml of 10% ammonia solution. The aqueous phase was extracted twice with 20 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 0.2 g of yellow oil, was taken up in a 25-fold amount of ethanol, treated with 2 equivalents of a saturated solution of fumaric acid in ethanol, concentrated to 2 ml and boiled with 5 ml of ethyl acetate. There was obtained 0.2 g (51%) of 1,2,3,4-tetrahydro-1,2-dimethyl-6-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt. 127° -128° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH2:30][CH2:31][CH:32]=O)[CH:22]=1)([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[N:9]=[CH:8]2)[OH:4].C(O)(=O)C.[NH:40]1[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[F:34][C:2]([F:1])([F:35])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[N:9]=[CH:8]2)([C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH2:30][CH2:31][CH2:32][N:40]2[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]2)[CH:22]=1)[OH:4]
Reactant: O=CCCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccccc21
Reactant: OCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: OCC1CCN(CCCn2cc(C(O)(c3ccc4c(cnn4-c4ccc(F)cc4)c3)C(F)(F)F)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a chilled (0° C.) solution of 100 mg (0.21 mmol) of 3-(3-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}indol-1-yl)propionaldehyde (prepared according to methods described in Examples 34 and 35) in dichloroethane was added 160 mg (2.6 mmol) acetic acid and 300 mg (2.6 mmol) 4-piperidinemethanol. The solution was warmed to room temperature, stirred for 30 minutes, and 0.1 g (0.5 mmol) of sodium triacetoxyborohydride was added. The solution was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate, the aqueous layer was separated and the organic layers were combined and washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to afford 42 mg (34.8%) of the title compound. MS m/z 581.6 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([CH2:24]O)[S:22][CH:23]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:51]1[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([CH2:24][N:51]4[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]4)[S:22][CH:23]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(-c2noc(-c3ccc(Cc4ccccc4)cc3)n2)cs1
Reactant: CCOC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2cc(-c3noc(-c4ccc(Cc5ccccc5)cc4)n3)cs2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using {4-[5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (95 mg, 0.27 mmol) that was obtained in Example 6 (6a), carbon tetrabromide (0.18 g, 0.54 mmol), triphenylphosphine (0.14 g, 0.54 mmol), ethyl 3-azetidinecarboxylate hydrochloride (67 mg, 0.41 mmol), and N,N-diisopropylethylamine (0.12 ml, 0.68 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (6:4) as the developing solvent to afford the title compound (84 mg) in a yield of 68% as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.CO.[BH4-].[Na+]>>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1
Reactant: Cc1ncc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ncc(CO)cn1
Reaction time: 0.5 h

Procedure:
A solution of 2-methylpyrimidine-5-carbaldehyde (7.5 g, 0.058 mol) in methanol (370 mL, 9.1 mol) was cooled to 0° C. and treated with sodium tetrahydroborate (3.4 g, 0.090 mol). After 30 min, the reaction was quenched with eq H2O (200 mL) and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to give the title compound as a yellow solid.