Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[I:10]I>[OH-].[Na+]>[I:10][C:5]1[C:6]([OH:8])=[N:7][C:2]([CH3:1])=[N:3][C:4]=1[CH3:9]
Reactant: II
Reactant: Cc1cc(O)nc(C)n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(C)c(I)c(O)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
The crude compound 326-1 (25.6 g) was dissolved in a 1.25 N sodium hydroxide aqueous solution (140 ml). Iodine (19.9 g) was added to the solution, and the obtained mixture was then stirred at 120° C. for 2 hours. The temperature of the reaction solution was returned to room temperature, and the reaction solution was then extracted with chloroform. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure, so as to obtain the title compound (14.5 g).
Reaction SMILES: [C:1]([N:5]([C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)[NH:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16]SC)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=[C:33]([C:37]([O:39]O)=[O:38])C=1>C(Cl)Cl>[C:1]([N:5]([C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)[NH:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][O:39][C:37](=[O:38])[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1CSC
Solvent: ClCCl
Product: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1COC(C)=O
Reaction time: 0.08 h

Procedure:
3-Methoxy-2-methylsulfanylmethyl-benzoic acid N′-tert-butyl-N′-(3,5-dimethyl-benzoyl)-hydrazide in CH2Cl2 was stirred at room temperature with 1.0 eq of m-chloroperbenzoic acid. The reaction was complete within 5 min as indicated by TLC. The reaction mixture was washed with saturated NaHCO3 and the organic layer was stripped under vacuum. The residue was mixed with 1-2 mL of 1:1 ether:hexane and the solution was removed with a pipette, leaving the product which was then dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:12][C:13]1[C:18]([NH:19][CH2:8][CH:7]=[CH:6][C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: Nc1cccnc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncccc1NCC=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 50 h
Yield: 42.2 %

Procedure:
7.71 g of p-chlorocinnamyl chloride and 13.5 g of 2,3-diaminopyridine were dissolved in 220 ml of dimethylformamide, and to the solution was added 8.6 g of potassium carbonate, and the mixture was stirred at a room temperature for 50 hours, and after adding 300 ml of water, extracted twice with 200 ml of chloroform. The extract was dried over magnesium sulfate and concentrated under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with chloroform/methanol (100:1 to 50:1), to obtain 4.52 g of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:19](=[O:20])[N:18]2[C:12]([C:13]([CH3:22])([CH3:21])[O:14][CH2:15][CH2:16][CH2:17]2)=[N:11][C:10]=1[C:23](O)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:57][CH2:58][C:59]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][C:60]=1[C:61]([NH:63][CH3:64])=[O:62].CN(C1C=CC=CN=1)C>CN(C)C=O>[F:69][C:66]1[CH:67]=[CH:68][C:59]([CH2:58][NH:57][C:23]([C:10]2[N:11]=[C:12]3[N:18]([C:19](=[O:20])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:22])=[O:24])=[C:60]([C:61](=[O:62])[NH:63][CH3:64])[CH:65]=1
Reactant: CNC(=O)c1cc(F)ccc1CN
Reactant: CC1(C)OCCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCOC2(C)C
Reaction time: 0.17 h

Procedure:
A solution of intermediate 35, 3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylic acid in anhydrous dimethylformamide (4 mL) was treated with HATU (0.278 g, 0.70 mmol) and stirred for 10 minutes. The reaction mixture was treated with 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetic acid salt (0.24 g, 0.8 mmol), followed by dimethylaminopyridine (0.121 g, 0.97 mmol), then stirred for 4 hours at 60° C. Following this, the solvent was removed in vacuo and the remaining residue dissolved in ethyl acetate (15 mL) and washed with 1.0 N HCl (15 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiO2), eluting with ethyl acetate. Fractions containing the product were pooled, concentrated to dryness and triturated with ether to provide 0.366 g of the title compound as a white glassy solid. 1H NMR (500 MHz, d6-acetone) δ ppm: 8.71-8.82 (1H, m), 7.84-7.95 (1H, br), 7.47-7.62 (4H, m), 7.27-7.40 (5H, m), 7.20 (1H, dt, J=8.5, 2.7 Hz), 5.15-5.21 (2H, br s), 4.48-4.60 (4H, m), 2.96 (2H, s), 2.94 (2H, s), 1.62-1.64 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([OH:14])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[CH2:25][C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[CH:4]([O:14][C:26](=[O:27])[CH2:25][C:18]1[C:17]([CH3:16])=[CH:22][C:21]([CH3:23])=[CH:20][C:19]=1[CH3:24])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([O:12][CH3:13])[CH2:10][CH2:11]1
Reactant: COC(=O)C(O)CC1CCN(OC)CC1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Solvent: Cc1ccccc1
Product: COC(=O)C(CC1CCN(OC)CC1)OC(=O)Cc1c(C)cc(C)cc1C

Procedure:
A mixture of 2-hydroxy-3-(1-methoxy-piperidin-4-yl)-propionic acid methyl ester (700 mg, 3.5 mmol) and (2,4,6-trimethyl-phenyl)-acetyl chloride (700 mg, 3.6 mmol) in 10 ml of toluene was refluxed for 6 h. Then, the reaction mixture was concentrated under vacuum to dryness and the residue was purified by column chromatography on silica gel. Yield: 520 mg of 3-(1-methoxy-piperidin-4-yl)-2-[2-(2,4,6-trimethyl-phenyl)-acetoxy]-propionic acid methyl ester (title compound P3.12) as a oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([N:22]=[N+]=[N-])=[CH:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH3:2]>CC1C=CC(C)=CC=1>[CH2:1]([O:3][C:4]([C:5]1[NH:22][C:11]2[CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[O:8][C:7]=2[CH:6]=1)=[O:25])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(-c2cccc(C(F)(F)F)c2)o1)N=[N+]=[N-]
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)c1cc2oc(-c3cccc(C(F)(F)F)c3)cc2[nH]1
Yield: 96 %

Procedure:
The isolated 2-azido-3-[5-(3-trifluoromethyl-phenyl)-furan-2-yl]-acrylic acid ethyl ester was heated to 125° C. in p-xylene (5 ml) for 1 hour. The solvent was thereafter evaporated under reduced pressure to give 39.6 mg (96% yield) of 2-(3-trifluoromethyl-phenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester as a brownish solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[O-:12][C:13]#[N:14].[K+].C(O)(=O)C.[OH-].[Na+]>O>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:14][C:13](=[O:12])[NH:1]2)=[CH:7][CH:8]=1
Reactant: N#C[O-]
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2ccc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
To a mixture of 2-amino-4-fluorobenzoic acid (4.0 g, 26 mmol) and potassium cyanate (3.5 g, 43 mmol) in water (200 mL) was added acetic acid (3 mL, 45 mmol) and the mixture was stirred at room temperature for about 5 h. To the mixture was added NaOH (15 g, 375 mmol) and it was stirred for another 1 h. The mixture was filtered and the solid was mixed in hot water, and it was adjusted to pH=5˜6 by addition of acetic acid. The mixture was filtered and washed with water, dried to give the title compound (3.0 g, 65% yield) as gray solid. MS: m/z 181.1 [M+H]+
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][C:4]=1[C:5]([O:7]C)=O.[NH2:16][CH2:17][C:18]1[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=1[CH3:24]>CO>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][N:16]1[CH2:2][C:3]2[C:4](=[CH:9][C:10]([O:13][CH2:14][CH3:15])=[CH:11][CH:12]=2)[C:5]1=[O:7]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCOc1ccc(CBr)c(C(=O)OC)c1
Solvent: CO
Product: CCOc1ccc2c(c1)C(=O)N(Cc1c(C)cc(C)[nH]c1=O)C2
Temperature: 80 °C
Yield: 4.5 %

Procedure:
To a solution of methyl 2-(bromomethyl)-5-ethoxybenzoate (134c, 0.636 g, 2.33 mmol) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (Cpd V, 0.390 g, 2.56 mmol) in MeOH (20 mL) was added TEA (0.258 g, 2.56 mmol) at room temperature. The resulting mixture was heated at 80° C. for 12 hours. The reaction mixture was concentrated under vacuum to give the crude product, which was purified by column chromatography (CH2Cl2/MeOH=20:1) and then re-crystallized from MeOH (15 mL) to give the title compound (Example 134, 32.6 mg, 4.4%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.39-7.37 (m, 1H), 7.25 (s, 1H), 7.24-7.14 (m, 1H), 6.09 (s, 1H), 4.73 (s, 2H), 4.33 (s, 2H), 4.09-4.07 (q, 2H), 2.30 (s, 3H), 2.24 (s, 3H), 1.43-1.40 (t, 3H); MS 313.0 [M+1].
Reaction SMILES: [CH2:1]([C:5]1([CH2:30][CH2:31][CH2:32][CH3:33])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[N:18]=2)[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].[OH-].[Na+:35]>C(#N)C>[CH2:1]([C:5]1([CH2:30][CH2:31][CH2:32][CH3:33])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([O-:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:27])(=[O:28])[N:18]=2)[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].[Na+:35]
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2cc(F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C([O-])c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 104.4 %

Procedure:
A solution of compound of Example 18H (33 mg, 0.07 mmol) in acetonitrile (3 mL) and treated with sodium hydroxide solution (1.0 N, 10 μL, 0.07 mmol) followed by stirring at ambient temperature for 20 min. The solution was frozen and lyophilized to afford the title compound (36 mg, 70% overall yield) as a fluffy white solid. 1H NMR (300 MHz, DMSO-d6): 60.52 (d, J=6.25 Hz, 2 H) 0.66 (t, J=7.35 Hz, 6 H) 0.85 (m, 2 H) 1.04 (m, 4 H) 1.68 (m, 2 H) 2.11 (m, 2 H) 7.30 (m, 3 H) 7.53 (m, 2 H) 7.69 (m, 2 H) 15.31 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[S-:10][C:11]#[N:12].[NH4+].BrBr>CC(O)=O>[Br:1][C:2]1[C:3]([F:9])=[CH:4][C:5]2[N:6]=[C:11]([NH2:12])[S:10][C:7]=2[CH:8]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Br)c(F)c1
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2cc(F)c(Br)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of 4-bromo-3-fluoro-aniline (3.68 g, 19.37 mmol) in glacial AcOH (40 mL) was added ammonium thiocyanate (2.95 g, 38.74 mmol). When the reaction mixture was almost clear, it was placed in a cold water bath and a solution of bromine (3.1 g, 19.37 mmol) in glacial AcOH (10 mL) was added dropwise over a 10 min period. The reaction mixture was stirred at room temperature for 1 h, then it was concentrated in vacuo. The residue was partitioned between 1 N aqueous KOH and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-70% ethyl acetate/hexane afforded 2.73 g of 6-bromo-5-fluoro-benzothiazol-2-ylamine as a light yellow solid (57% yield): 1H NMR (DMSO-d6) δ 7.29 (d, 1H), 7.78 (broad s, 2H), 7.99 (d, 1H); MS (m/z) 247, 249 [M+H+]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19]CCC[CH:15]([N:20]([CH3:30])[C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO>C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:14][CH:15]([N:20]([CH3:30])[C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:19]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CN(c1ncnc2[nH]ccc12)C1CCCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Solvent: ClCCl
Solvent: CO
Product: CN(c1ncnc2[nH]ccc12)C1CN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Yield: 23 %

Procedure:
A similar procedure was used as describe for the synthesis of 2-(3,5-dichloro-phenylamino)-1-{3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-azepan-1-yl}-ethanone to give a residue that was subjected to column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (10 mg, 23%) the titled compound. 1H NMR (DMSO-d6, 400 MHz): 11.88 (bs, 1H), 8.18 (s, 1H), 7.22 (d, J=4.0 Hz, 1H), 6.66 (s, 2H), 6.60 (s, 1H), 6.50-6.22 (m, 1H), 5.58-5.42 (m, 1H), 4.54 (t, J=8.0 Hz, 2H), 4.40-4.28 (m, 1H), 4.24 (t, J=8.0 Hz, 1H), 4.16-4.08 (m, 1H), 3.36 (s, 3H) 3.80 (d, J=2.0 Hz, 1H). LC-MS: m/z [M+1]=405.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([CH2:17][CH2:18][O:19][CH3:20])[N:5]=2.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1>>[CH3:20][O:19][CH2:18][CH2:17][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([NH:21][C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[NH:3]2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:7]=1
Reactant: COCCc1nc(N2CCOCC2)c2nc(Br)[nH]c2n1
Reactant: Cc1cccc(N)c1
Product: COCCc1nc(N2CCOCC2)c2nc(Nc3cccc(C)c3)[nH]c2n1
Temperature: 190 °C
Yield: 81 %

Procedure:
A suspension of 8-bromo-2-(2-methoxy-ethyl)-6-morpholin-4-yl-9H-purine (0.42 g, 1.2 mmol) in m-toluidine (0.5 mL, 3.8 eq) in a tightly stoppered flask was heated at 190° C. for 15 minutes. Column chromatography afforded [2-(2-methoxy-ethyl)-6-morpholin-4-yl-9H-purin-8-yl]-m-tolyl-amine (0.36 g, 81%) as an off-white solid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11](NC(C)CCl)(=[O:13])[CH3:12]>>[OH:13][CH2:11][CH2:12][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)NC(C)CCl
Reactant: c1ccc2c(c1)CCCN2
Product: OCCN1CCCc2ccccc21

Procedure:
N-(2-Acetamidopropyl)-1,2,3,4-tetrahydroquinoline was obtained in an analogous way by reacting 1,2,3,4-tetrahydroquinoline with 2-acetamidopropyl chloride.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH:7](=O)[CH2:8][CH3:9].O.S(=O)(=O)(O)O.[CH2:17]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]([CH3:20])[CH3:19]>>[CH3:19][CH:18]([CH3:20])[CH2:17][N:21]([CH:7]=[CH:8][CH3:9])[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CCC=O
Reactant: CC(C)CNCC(C)C
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Product: CC=CN(CC(C)C)CC(C)C
Temperature: 12.5 °C
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
To a suspension of magnesium sulfate (15.1 g) in diisobutylamine (107.3 g) was added dropwise propionaldehyde (24.8 g) at 0-10° C. under a nitrogen atmosphere, and it was stirred at 10-15° C. for 1.5 hours. After ice-cooling, water (90 ml) was added and it was stirred to dissolve the magnesium sulfate. After the removal of the aqueous layer, to the organic layer obtained was added an 8% (w/v) aqueous sulfuric acid solution (300 ml) at 0-5° C. and then stirred for 10 minutes. The aqueous layer was, then, removed again, a 0.5% (w/v) aqueous sodium hydroxide solution (90 ml) was added to the organic layer at 0-5° C., and stirred for 10 minutes. After stirring, the aqueous layer was removed to afford the title compound (57.0 g, yield: 76%, purity: 96.7%) as a colorless oil.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[N:33]=[C:32]([C:34]([OH:36])=[O:35])[CH:31]=[CH:30][CH:29]=2)[CH2:24][CH:23]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:43].C(OCC)(=O)C.C(OC(C)C)(C)C>C(OCC)(=O)C>[ClH:43].[C:11]1([C@H:9]([NH:8][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[C:32]([C:34]([OH:36])=[O:35])[CH:31]=[CH:30][CH:29]=3)[CH2:24][CH:23]2[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2cccc(C(=O)O)n2)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](NCC1CCN(c2cccc(C(=O)O)n2)CC1c1ccccc1)c1cccc2ccccc12
Reaction time: 2 h

Procedure:
To a solution of 75 mg of the crude 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]pyridine-2-carboxylic acid in 2.0 mL of ethyl acetate was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 2 hours. To the reaction mixture was added diisopropylether, and the resulting precipitate was then collected by filtration, and dried under reduced pressure to obtain 50 mg of 6-[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]pyridine-2-carboxylic acid hydrochloride as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][Mg]I.[Mg].CI>C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: C[Mg]I
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: CC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-bromo-2-fluorobenzaldehyde (5 g, 24.62 mmol) in diethyl ether (10 ml) was added to an ice-cold solution of methylmagnesium iodide prepared from magnesium (1.7 g, 73.88 mmol) and methyliodide (4.58 ml, 73.88 mmol) in diethyl ether (50 ml). The mixture was warmed stirred at RT. for 12 h, and cooled to 0° C., quenched with dil. 6N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as red colour liquid (5 g, 94%). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.40 (t, J=8.2 Hz, 1H), 7.30 (dd, J=8.3, 1.7 Hz, 1H), 7.21 (dd, J=9.9, 1.9 Hz, 1H), 5.17 (q, J=6.4 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]1[N:9]=[C:8]([CH2:10][N:11]2[C:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:19][C:15]=3[C:14](=[O:26])[N:13]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:12]2=[O:33])[O:7][N:6]=1.[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:13]5[C:14](=[O:26])[C:15]6[S:19][C:18]([C:20]7[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=7)=[CH:17][C:16]=6[N:11]([CH2:10][C:8]6[O:7][N:6]=[C:5]([CH2:4][O:3][CH3:2])[N:9]=6)[C:12]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: COCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(COC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-6-phenyl-3-piperidin-4-ylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (148 mg; compound B40) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (120 mg; compound C10) and HBTU (126 mg) in DCM (8 ml) in the presence of DIPEA (155 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 1/1.5 to 0/1 (v/v)] as a solid.
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[C:13]2[C:18]([CH:19]=1)=[C:17]([Br:20])[CH:16]=[CH:15][CH:14]=2)=O)C1C=CC=CC=1.[OH-].[Na+].C(Cl)(=O)C(Cl)=O.[NH3:37]>>[Br:20][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[CH:19]=[C:11]([C:9]([NH2:37])=[O:8])[N:12]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1
Reactant: O=C(OCc1ccccc1)c1cc2c(Br)cccc2n1Cc1cccc(F)c1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1cc2c(Br)cccc2n1Cc1cccc(F)c1

Procedure:
4-Bromo-1-(3-fluoro-benzyl)-1H-indole-2-carboxylic acid amide was prepared from 4-bromo-1-(3-fluoro-benzyl)-1H-indole-2-carboxylic acid benzyl ester by hydrolysis with ethanolic NaOH, followed by treatment with oxalyl chloride and then ammonia, as described in steps 3 and 4 of Example 1 MS: 348 (M+H)+.
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].[CH2:21]([N:23]1[CH:27]=[N:26][C:25]([NH2:28])=[N:24]1)[CH3:22]>>[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:28][C:25]2[N:26]=[CH:27][N:23]([CH2:21][CH3:22])[N:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CCn1cnc(N)n1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CCn1cnc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)n1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-ethyl-1H-1,2,4-triazol-3-amine (11.2 mg, 0.12 mmol). The title compound was obtained as a solid (8.9 mg, 20% yield). MS m/z: 466.95, 468.95 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:15])([CH3:14])[CH:12]=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F-].[K+].[CH3:18][N+:19]([O-:21])=[O:20]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:15])([CH3:14])[CH:12]([OH:13])[CH2:18][N+:19]([O-:21])=[O:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C)(C)C=O)cc1OC
Reactant: C[N+](=O)[O-]
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C(C)(C)C(O)C[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a solution of 2-(3,4-dimethoxyphenyl)-2-methylpropanal (1.0 g, 4.8 mmol) in EtOH (30 mL) were added KF (335 mg, 5.8 mmol) and CH3NO2 (1.56 mL, 28.8 mmol). The resulting mixture was stirred overnight at room temperature. The solution was concentrated, diluted with EtOAc, and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated to give 3-(3,4-dimethoxyphenyl)-3-methyl-1-nitrobutan-2-ol (1.25 g, 97%). 1H NMR (400 MHz, CDCl3) δ 6.91-6.84 (m, 3H), 4.44 (m, 1H), 4.24 (d, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 2.38 (d, 1H), 1.40 (s, 3H), 1.38 (s, 3H).