Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]([NH:9][C:10]([C:12]1[C:13]2[CH2:14][C@@H:15]3[CH2:27][C@@H:16]3[C:17]=2[N:18]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=2)[N:19]=1)=[O:11])([CH2:7][F:8])[CH2:5][F:6].[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CO>[F:8][CH2:7][C:4]([NH:9][C:10]([C:12]1[C:13]2[CH2:14][C@@H:15]3[CH2:27][C@@H:16]3[C:17]=2[N:18]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=2)[N:19]=1)=[O:11])([CH2:5][F:6])[CH2:3][OH:2]
Reactant: COC(=O)C(CF)(CF)NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NC(CO)(CF)CF)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 23 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 2-{[(1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-3-fluoro-2-fluoromethyl-propionic acid methyl ester (130 mg, 0.316 mmol) in THF (2 mL) and MeOH (0.200 mL) was added sodium borohydride (23.94 mg, 0.633 mmol). The reaction was stirred at 23° C. for 2 h. Saturated aqueous NaHCO3 (15 mL) was added. The mixture was extracted with dichloromethane (3×15 mL). The combined organic extracts were dried (MgSO4), filtered, then concentrated. The residue was purified by silica gel flash chromatography to give the title compound (106 mg) as a white solid. LCMS m/z=383.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.46 (td, J=4.6, 3.5 Hz, 1H), 1.27 (td, J=8.0, 4.9 Hz, 1H), 2.25-2.31 (m, 1H), 2.80-2.85 (m, 1H), 2.89 (d, J=16.9 Hz, 1H), 2.99 (dd, J=16.6, 6.3 Hz, 1H), 3.96 (d, J=5.9 Hz, 2H), 4.25 (t, J=6.8 Hz, 1H), 4.55-4.84 (m, 4H), 7.23 (dd, J=5.3, 1.8 Hz, 1H), 7.27 (s, 1H), 7.92 (d, J=1.6 Hz, 1H), 8.36 (d, J=5.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][NH2:30])[CH:26]=[N:27][CH:28]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH2:29][C:25]2[CH:26]=[N:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cncc(CN)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COc1cncc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (28 mg, 0.08 mmol) and (5-methoxypyridin-3-yl)methanamine (13.8 mg, 0.1 mmol). The title compound was obtained as a solid (20 mg, 43% yield). MS m/z: 470.98, 472.98 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[O:24][C:25]([C:28]([O:30]C)=[O:29])=[CH:26][CH:27]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[O:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)o1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)o1

Procedure:
Hydrolysis of (S)-2-[4-(5-Methoxycarbonyl-furan-2-yl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (0.350 g, 0.77 mmol) with NaOH (1M, 2 mL, 2 mmol) gave (S)-2-[4-(5-Carboxy-furan-2-yl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester; MS: 442.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2C=C[C:15](O[Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.CC1(C)CC=C(O[S:52](C(F)(F)F)(=O)=O)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2>>[CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[S:52][CH:15]=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 250.0 mg (0.52 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 186.8 mg (1.37 mmol) of zinc chloride 37.1 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2-lithiothiophene (prepared by the addition of 65.9 mg (0.69 ml, 1.03 mmol) of n-butyllithium (1.5M solution in hexane) to a cold solution (−78° C.) of 86.5 mg (1.03 mmol) of thiophene in 1.0 ml of THF). PMR (CDCl3): δ 1.33 (6H, s), 1.36 (3H, t, J=7.1 Hz), 2.38 (2H, d, J=4.7 Hz), 4.34 (2H, q, J=7.2 Hz), 6.25 (1H, t, J=4.7 Hz), 7.13 (2H, m), 7.47 (4H, m), 7.62 (2H, d, J=8.5 Hz), 8.00 (2H, d, J=8.5 Hz).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]cc(I)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a suspension of 2-Bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine (290 mg, 0.895 mmol) in THF (5 ml) was added NaH (60%, 43 mg, 1.08 mmol) in one portion at 0° C. The resulting mixture was stirred for 20 minutes before a solution of para-toluenesulfonyl chloride (188 mg, 0.98 mmol) in THF (2 mL) was added. The reaction mixture was then stirred at room temperature for 3 hours. Solvents were removed and the resulting dark brown residue washed with aqueous KOH, water and dried to afford the title compound (423 mg, 99% yield) as a light brown solid. 1H-NMR (500 MHz, d6-DMSO) δ 8.60 (d, 11.5 Hz, 1H), 7.99 (d, 11.5 Hz, 2H), 7.44 (d, 7.5 Hz, 2H), 2.34 (s, 3H). MS: m/z 477.8/479.8 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:19][C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:21])([F:22])[F:10])=[CH:17][CH:16]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and p-(trifluoromethyl)acetophenone, 3-(4-chlorophenyl)-1-(4-(trifluoromethyl)-phenyl)prop-2-en-1-one was obtained as beige coloured solid.
Reaction SMILES: [Si](O[CH2:9][C@@H:10]1[O:21][C@H:11]1[CH2:12]OCC1C=CC=CC=1)(C(C)(C)C)(C)C.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][Mg]Br)[CH:23]=1>>[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:12][CH:11]([OH:21])[CH2:10][CH3:9])[CH:23]=1
Reactant: Cc1cccc(C[Mg]Br)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H]1COCc1ccccc1
Product: CCC(O)CCc1cccc(C)c1

Procedure:
325 mg of (2S,3S)-4-benzyloxy-2,3-epoxy-1-butanol tert-butyldimethylsilyl ether obtained in Example 53. was subjected to Grignard reaction in the same manner as in Example 53 by using 3-tolylmethyl magnesium bromide (0.8M diethyl ether solution). The product was purificated by silica gel column chromatography to obtain 210 mg of (2R,3R)-4-benzyloxy-1-tert-butyldimethylsilyloxy-3-(3-tolylmethyl-2-butanol as colorless oily substance.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10][N:9]1NC(CC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)NC(=O)[C@@H]1CN(NC(=O)OC(C)(C)C)CCN1NC(=O)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H]1CN(NC(=O)OC(C)(C)C)CCN1
Reaction time: 2 h

Procedure:
To 1.20 g (2.86 mmol) of N-t-butyl-4-(1,1-dimethyl-ethoxy-carbonylamino)-1-(phenylmethylcarbonyl-amino)piperazine-2(S)-carboxamide and 1.1 g (0.086 mmol) of 10% Pd/C was added 15 mL of methanol. The vessel was charged with hydrogen and the reaction stirred for 2 hours, filtered through celite and washed with ethanol. The solvents were removed in vacuo to provide the title product as a foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29]>>[CH:19]1([CH2:18][O:17][C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][C:12]([C:13]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]3[OH:29])=[O:15])=[CH:11][N:10]=2)[CH2:21][CH2:20]1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 5d, using 5-(4-fluorophenyl)-6-cyclopropylmethoxy-nicotinic acid and (1R,2R)-2-amino-cyclohexanol as starting materials, MS (ISP) 385.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:20]
Reactant: COC(=O)c1cccnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-methylpyridine-3-carboxylate (10 g, 66.2 mmol) was taken up in DCM (140 mL) and mCPBA (16.31 g, 72.8 mmol) was added. The resulting solution was stirred at room temperature overnight. The reaction mixture was purified directly by silica gel chromatography (0-20% MeOH/EtOAc) to afford the title compound as a beige solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[C:19]2[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][C:18]3=2)[C:11](=[O:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37]>CO.CCOCC>[ClH:37].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[C:19]2[CH2:25][NH:26][CH2:27][CH2:28][C:18]3=2)[C:11](=[O:36])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc31)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc31)CCNC2
Reaction time: 1 h
Yield: 98 %

Procedure:
tert-Butyl 6-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (0.340 g, 0.70 mmol) was dissolved in MeOH (5 mL) and 2 N HCl in ether (15 mL) was added. After stirring for 1 h, the liquid was decanted off and the resultant solid was filtered and washed with ether (3×). This provided the title compound (267 mg, 98%) as a light yellow solid: mp 290-300° C.; 1H NMR (500 MHz, CD3OD) δ 7.66 (d, J=7.5 Hz, 1H), 7.57-7.52 (m, 2H), 7.46 (d, J=7.7 Hz, 2H), 7.41 (overlapping dd, J=7.3 Hz, 2H), 7.36 (d, J=7.5 Hz, 1H), 7.19 (dd, J=8.6, 2.0 Hz, 1H), 6.42 (dd, J=7.5, 2.7 Hz, 1H), 6.22 (d, J=2.6 Hz, 1H), 5.22 (s, 2H), 4.55 (s, 2H), 3.75 (s, 3H), 3.58 (t, J=6.0 Hz, 2H), 3.10 (t, J=6.0 Hz, 2H); ESI MS m/z 386 [M+H]+; HPLC (Method B) 98.8% (AUC), tR=12.8 min.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CO>[CH3:6][O:7][C:8]1[CH:13]=[C:12]([CH:11]=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[NH2:14]
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccccn1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COc1cc(N)ccc1-c1ccccn1
Temperature: 25 °C

Procedure:
Tin(II) chloride dihydrate (6.77 g, 30.0 mmol) and 2-(2-methoxy-4-nitrophenyl)pyridine (2.30 g, 10.0 mmol) were combined in MeOH (100 mL) and stirred at reflux for 18 h. The reaction mixture was then cooled to RT and concentrated in vacuo. The residue was then partitioned with EtOAc (200 mL) and 1N aqueous NaOH (100 mL). The aqueous layer was washed with EtOAc (3×75 mL), and the combined EtOAc layers were back-extracted with H2O (100 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by SiO2 chromatography, eluting with 2:1 EtOAc:hexanes to afford 3-methoxy4-pyridin-2-ylaniline as an amber oil. 1H-NMR (CDCl3, 300 MHz) δ 8.63 (m, 1H), 7.78 (d, 1H), 7.57-7.67 (m, 2H), 7.04-7.13 (m, 1H), 6.34-6.41(dd, 1H), 6.26 (d, 1H), 3.72-3.92 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[C:11]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([F:1])[CH:3]=1)=[O:16]
Reactant: Nc1ccc(F)c(F)c1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ccc(F)c(F)c1

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 3,4-difluoroaniline and methyl chlorooxoacetate.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C)(=O)=O)=[CH:13][CH:12]=[N:11][C:10]=2[O:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])=[CH:13][CH:12]=[N:11][C:10]=2[O:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)nccc2c1OS(C)(=O)=O
Reactant: Cc1ccccc1N
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OC)nccc2c1Nc1ccccc1C
Yield: 56 %

Procedure:
3-Butyryl-4-methanesulfonyloxy-8-methoxy-1,7-naphthyridine (259 mg) and o-toluidine (0.17 ml) were dissolved into 7 ml of acetonitrile, and the solution was extracted with chloroform, and the organic phase was washed with water and then saturated sodium bicarbonate. After drying, and concentration under reduced pressure, the resulting residue was subjected to silica gel column chromatography using a mixture of hexane:ethyl acetate (1:1) as an eluant to give yellow titled compound (150 mg, 56%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CC(C)=O.C(OCC)(=O)C>[Cl:7][C:8]1[C:9]([N:23]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[S:24]([CH3:27])(=[O:26])=[O:25])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2
Reactant: COC(=O)CBr
Reactant: COc1nc2cc(Cl)c(Cl)c(NS(C)(=O)=O)c2nc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)CN(c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Yield: 79.7 %

Procedure:
Anhydrous potassium carbonate (1.60 g, 11.2 mmol) was added to a suspension of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-methanesulphonamide (see Preparation 3, 3.0 g, 9.4 mmol) in acetone (70 ml) with stirring. The mixture was heated at reflux for 15 minutes, cooled, and methyl bromoacetate (1.8 ml, 18.7 mmol) was added. The mixture was then heated at reflux for 2 h, cooled, diluted with ethyl acetate (300 ml) and washed with water (2×100 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/ethyl acetate) to give the title compound as a white solid (3.177 g, 80%).
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][CH:10]1[CH2:24][OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH2:1]([N:8]([CH3:26])[C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][C@H:10]1[CH2:24][O:25][S:35]([CH3:34])(=[O:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1ccccc1)C1CCN(CCc2ccc(F)cc2)CC1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1COS(C)(=O)=O
Reaction time: 1.75 h
Yield: 108.8 %

Procedure:
A solution of -{4-(benzyl-methyl-amino)-1-[2-(4-fluorophenyl)-ethyl]-piperidin-3-yl}-methanol (105 mg, 294 μmol) and triethylamine (62 μL, 442 μmol) in dichloromethane (1 mL) was stirred on an ice bath and treated with a solution of methanesulfonyl chloride (25 μL, 320 μmol) in dichloromethane (0.5 mL). After 1.75 hours, the mixture was concentrated and the residue was dissolved in ethyl acetate. The suspension was filtered, the solid was rinsed with ethyl acetate, and the filtrate was concentrated under vacuum to provide a yellowish gum (139 mg) which was used without purification. 1H NMR (300 MHz, CDCl3) δ7.32 (m, 5H), 7.17 (m, 2H), 6.99 (t, J=9 Hz, 2H), 4.57 (dd, J=10, 3 Hz, 1H), 4.29 (m, 1H), 3.72 (d, J=13 Hz, 1H), 3.50 (d, J=13 Hz, 1H), 3.4-3.1 (m, 2H), 3.00 (s, 3H), 2.83 (m, 2H), 2.70 (m, 2H), 2.48 (m, 1H), 2.35 (m, 1H), 2.22 (s, 3H), 2.07 (m, 2H), 2.0-1.7 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2cccnn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1ccc(-c2cccnn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridazin-3-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 471 [M+1]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([S:29][CH3:30])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].N[N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([S:29][CH3:30])=[N:23][C:24]=2[N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)(=[O:3])[CH3:2]
Reactant: NN1CCCCC1
Reactant: CSc1nc(Cl)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSc1nc(N2CCCCC2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.6 %

Procedure:
The above 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methylthio-9H-purine (1.83 g, 3.9 mmol) was dissolved in dioxan (40 ml) followed by 1-aminopiperidine (0.59 g, 5.85 mmol) and triethyl-amine (1.63 ml, 11.7 mmol). The reaction mixture was stirred at ambient temperature for 18 h, evaporated and purified by flash chromatography on silica gel. Elution initially with dichloromethane, followed by dichloromethane/methanol (100/1) provided 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-2-methylthio-6-(1-piperidinyl)-9H-purine (1.24 g, 59%) as a foam. This compound was dissolved in methanolic ammonia (10 ml) and the solution was stirred at room temperature for 18 h, evaporated and purified by flash chromatography on silica gel. Elution initially with dichloromethane, followed by dichloromethane/methanol (19/1) gave 2-methylthio-N-(1-piperidinyl) adenosine (0.67 g, 55%) as a foam, 1H NMR (DMSO-d6) δ 2.51 (3H, s, --SCH3), 3.50-3.56 (1H, m, H-5'a), 3.62-3.68 (1H, m, H-5'b) 3.92 (1H, q, H-4'), 4.15 (1H, q, H-3'), 4.50 (1H, q, H-2'), 5.03 (1H, t, 5'-0H), 5.18, 5.44 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 8.24 (1H, s, H-8), 8.84 (1H, s, N--H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[C:20]([F:23])[CH:19]=[CH:18][CH:17]=3)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)(=O)=O.[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.[Li+].[Cl-]>CN(C=O)C.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>[Cl:13][C:10]1[N:9]=[C:8]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[C:20]([F:23])[CH:19]=[CH:18][CH:17]=3)[C:7]([CH:26]=[CH2:27])=[CH:12][N:11]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1cnc(Cl)nc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1cnc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 72494.7 %

Procedure:
To a mixture of 2-chloro-4-(4-fluoro-1H-indol-2-yl)pyrimidin-5-yl trifluoromethanesulfonate (500 mg, 1.26 mmol), tributyl(vinyl)stannane (400 mg, 1.26 mmol) and anhydrous LiCl (150 mg, 3.54 mmol) in DMF (5 mL), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol) was added under N2 protection. The reaction mixture was stirred at 60° C. for 1 h. Then it was concentrated in vacuo, and the residue was purified by column chromatography (PE:EA=10:1) to give the product of 2-(2-chloro-5-vinylpyrimidin-4-yl)-4-fluoro-1H-indole (250 g, yield: 72.3%). 1H-NMR (DMSO-d6, 400 MHz) δ 12.21 (br s, 1H), 8.85 (s, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.21˜7.27 (m, 1H), 7.08˜7.20 (m, 2H), 6.87 (dd, J=10.4, 7.6 Hz, 1H), 6.01 (dd, J=17.6, 1.2 Hz, 1H), 5.72 (dd, J=11.2, 1.2 Hz, 1H). MS (M+H)+: 274/276.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:7][C:6]1[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: O=c1nc(Nc2ccc(C(F)(F)F)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: O=c1c2cccnc2sc(=Nc2ccc(C(F)(F)F)cc2)n1Cc1ccccc1

Procedure:
The reaction procedure of Example 11 was followed except that 646 mg of 2-(4-trifluoromethylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 18 mg of lithium hydride and 0.24 ml of benzyl bromide were used. As a result, 630 mg of 3-benzyl-2-[(4-trifluoromethylphenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: II.[CH:3]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH:8]1[CH:4]2[C:5](=[O:14])[CH2:6][C:7]1=[O:13].[CH3:15]O>>[CH3:15][O:14][C:5]1[CH:4]2[CH:8]([CH:9]3[O:12][CH:3]2[CH2:11][CH2:10]3)[C:7](=[O:13])[CH:6]=1
Reactant: O=C1CC(=O)C2C3CCC(O3)C12
Reactant: CO
Agent: II
Product: COC1=CC(=O)C2C3CCC(O3)C12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iodine (0.10 g, 0.38 mmol) is added to a solution of (1RS,2SR,6RS,7SR)-10-oxa-tricyclo[5.2.1.02,6]decane-3,5-dione (2.1 g, 12.65 mmol) in methanol (50 ml) and the reaction mixture is stirred for 2 hours at room temperature. The solvent is then removed under reduced pressure, dichloromethane is added and the organic layer is washed with saturated aqueous sodium thiosulfate solution, water and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give (1RS,2SR,6RS,7SR)-5-methoxy-10-oxatricyclo[5.2.1.02,6]dec-4-en-3-one and used without further purification in the next step.