Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7].C[O-].[Na+].O.[NH2:12][NH2:13]>C(O)C.O>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:12][NH2:13])[NH2:7]
Reactant: NN
Reactant: N#Cc1ccc[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NN=C(N)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1H-pyrrole-2-carbonitrile 10 g (108 mM) and sodium methoxide (1 eq) in ethanol (20 ml) and stirred for 10 min. Hydrazine hydrate (3 eq.) is then added and resulting reaction mixture is stirred at room temperature for 18 hrs. Reaction mass is then diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated under vacuum to yield desired compound.
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])[CH3:3].[CH2:25]([Mg][Cl:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1>[ClH:34].[CH3:3][N:2]([CH:4]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[OH:11])[CH3:1]
Reactant: Cl[Mg]CCc1ccccc1
Reactant: CN(C)C(c1cccc(Oc2ccccc2)c1)C1CCCCC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C(c1cccc(Oc2ccccc2)c1)C1CCCCC1(O)CCc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 45.3 %

Procedure:
2.0 g (6.2 mmole) of the 2-[dimethylamino-(3-phenoxy-phenyl)methyl]cyclohexanone prepared according to Example 34 were dissolved in 9 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 7.4 ml (9.0 mmole) of phenethylmagnesium chloride (1 M solution in tetrahydrofuran), and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and extracted three times at RT with 10 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.55 g of crude base (96.0% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times, each time with 10 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.51 g of crude base (56.8% of theory) were obtained, from which 1.31 g of 2-[dimethylamino-(3-phenoxyphenyl)methyl]-1-phenethylcyclohexanol, hydrochloride (45.2% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 120° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[CH:11].C(N)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC.[Cu]I>[CH3:9][C:4]1[CH:3]=[C:2]([C:11]#[C:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: Cc1cc(I)ccc1N
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCN
Product: Cc1cc(C#Cc2ccccc2)ccc1N

Procedure:
4-iodo-2-methylbenzenamine (24, 233 mg, 1 mmol) on reaction with ethynyl benzene (25a, 102 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 2-methyl-4-(phenylethynyl)benzenamine compound (26a) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 2-methyl-4-(phenylethynyl)benzenamine (26a, 207 mg, 1 mmol) with 2-methyl-4H-benzo[α][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h. After completion of the reaction as indicated by TLC. The reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a). Reaction of 2-methyl-3-(2-methyl-4-(phenyl ethynyl)phenyl)quinazolin-4(3H)-one (29a, 350 mg, 1 mmol) with 4-hydroxy benzaldehyde (30b, 122 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (4b) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH:30]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31]1>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:34]([NH:33][CH:30]3[CH2:32][CH2:31]3)=[O:35])[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C=NC1CC1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)NC3CC3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
108 mg (0.22 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 7A) and 22 mg (0.26 mmol, 1.2 eq.) of cyclopropyl isocyanate were reacted according to General Method 4. Yield: 64 mg (76% of theory)
Reaction SMILES: [NH:1]([C:37](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:38])[C@H:2]([C:10]([NH:12][C@H:13]([C:34]([OH:36])=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[C:24]1[C:32](=[O:33])[CH2:31][C:28]([CH3:30])([CH3:29])[CH2:27][C:25]1=[O:26])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1CCCC[CH2:55]1.N[C@H](C(N[C@H](C(O)=O)CCCCNC(=C1C(=O)CC(C)(C)CC1=O)CC(C)C)=O)CC1C=CC=CC=1.C(OC(=O)C)(=O)C>CN(C=O)C>[NH:1]([C:37]([CH3:55])=[O:38])[C@H:2]([C:10]([NH:12][C@H:13]([C:34]([OH:36])=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[C:24]1[C:25](=[O:26])[CH2:27][C:28]([CH3:29])([CH3:30])[CH2:31][C:32]1=[O:33])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)CC(NCCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Reactant: C1CCNCC1
Agent: CC(C)CC(NCCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCCNC(CC(C)C)=C1C(=O)CC(C)(C)CC1=O)C(=O)O

Procedure:
To the deprotected Lys-resin sample was added Fmoc-Phe (8.8 mg, 33.2 μmol) in DCM/DMF and 1,3-diisopropylcarbodiimide (DIC) (3 μL, 20 μmol). The coupling reaction was continued for 2 h and ninhydrin tests gave negative amino group readings. The Fmoc-Phe-Lys(ivDde) on resin was then treated with photogenerated piperidine as described above. Upon completion of the reaction, the resin was washed with DCM/DMF. Capping of the NH2-Phe-Lys(ivDde)-resin was carried out for 1 h with acetic anhydride (470 μL, 5 mmol) and TEA (700 μL, 5 mmol) in 1.5 mL DMF to give Ac-Phe-Lys(ivDde)-resin.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[NH:15][N:16]=[C:17]([CH3:19])[CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Cl)nc3ccccc23)[nH]n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,4-dichloroquinazoline (12.69 g, 63 mmol) and 3-amino-5-methylpyrazole (6.18 g, 63 mmol) in ethanol (220 mL) is added triethylamine (8.13 mL, 63 mmol) and the reaction mixture is stirred for 3 hours at room temperature. The pale yellow precipitate is then collected by filtration, washed with cold ethanol and dried under vacuum to give (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[C:4]([Br:12])[C:3]=1[OH:13].[C:14]([CH:16]1[CH2:18][CH2:17]1)#[CH:15]>N1C=CC=CC=1>[Br:12][C:4]1[C:3]2[O:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[CH:15][C:2]=2[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=1
Reactant: CS(=O)(=O)c1cc(Br)c(O)c(Br)c1
Reactant: C#CC1CC1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1cc(Br)c2oc(C3CC3)cc2c1
Temperature: 130 °C
Yield: 49 %

Procedure:
To a solution of 2,6-dibromo-4-methylsulfonylphenol (1 g, 3.30 mmol) in pyridine (40 mL) was added ethynylcyclopropane (240 mg, 3.64 mmol) and Cu2O (260 mg, 1.82 mmol). The reaction mixture was degassed with N2. The mixture was heated to 130° C. for 3 hours. It was then concentrated and purified by column chromatography (PE to PE/EA=3/1) to give the title product (510 mg, 53%) as a gray solid. 1H NMR (CDCl3, 400 MHz) δ 7.99 (s, 1H), 7.93 (s, 1H), 6.52 (s, 1H), 3.07 (s, 3H), 2.13-2.11 (m, 1H), 1.13-1.05 (m, 4H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:13][CH2:12]3)=[CH:4][C:3]=2[O:2]1.[Cl:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=2)=[N:42][CH:43]=1>>[ClH:36].[ClH:36].[ClH:36].[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=5)[CH:19]=4)[CH2:13][CH2:12]3)[CH2:37][C:38]3[CH:39]=[CH:40][C:41]([C:44]4[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=4)=[N:42][CH:43]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)OCO5)CC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2ccc(CCl)cn2)cc(OC)c1OC
Product: COc1cc(-c2ccc(CN(c3ccc4c(c3)OCO4)C3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)cn2)cc(OC)c1OC
Product: Cl

Procedure:
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl) pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1>O1CCCC1>[C:26]1([CH3:29])[CH:27]=[CH:28][C:23]([NH:22][C:15]([C:9]2[C:10]3[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4][C:5]=3[CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[C:8]=2[CH3:18])=[O:16])=[CH:24][CH:25]=1
Reactant: Cc1ccc(N)cc1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Solvent: C1CCOC1
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Nc3ccc(C)cc3)c2nc1OC

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and p-toluidine 180 mg (1.68 mmol). Reaction was carried out in refluxing tetrahydrofuran for 50 hours, and the crude product was eluted through a flash column (7:3 hexanes:ethyl acetate), 200 mg (65%), mp 214-215° C.; 1H NMR (CDCl3): δ 8.33 (s, 1H), 7.69 (d, 2H, J=8.3 Hz), 7.65 (s, 1H), 7.15 (d, 2H, J=8.3 Hz), 4.17 (s, 3H), 4.03 (s, 3H), 2.58 (s, 3H), 2.32 (s, 3H); MS (APCI): m/z 383 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>O.CO.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[CH:8][CH:9]=1
Reactant: N#CCCCc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#CCCCc1ccc(N)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of compound 82 (2.67 g, 14 mmol), NH4Cl (11.2 g, 210 mmol) and Iron Powder (7.8 g, 140 mmol) in water (90 mL) and CH3OH (90 mL) was stirred at 90° C. for 1 h. After cooling, the reaction mixture was filtered and the solid was washed by DCM. The filtrates were separated, and the organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 83 (1.85 g, 83%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.90 (d, 2H, J=8.1 Hz), 6.58 (d, 2H, J=8.1 Hz), 3.30 (br s, 2H), 2.59 (t, 2H, J=7.4 Hz), 2.22 (t, 2H, J=7.4 Hz), 1.80-1.90 (m, 2H).
Reaction SMILES: C([O:4][C:5]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1)([CH3:9])[CH2:6][CH2:7][OH:8])(=O)C.[OH-].[K+].CO.O>C(Cl)(Cl)Cl>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([C:5]([OH:4])([CH3:9])[CH2:6][CH2:7][OH:8])=[CH:11][CH:12]=1
Reactant: CC(=O)OC(C)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
3.20 g. of 3-acetoxy-3-(2',4'-difluoro-4-biphenylyl)butan-1-ol and 2 g. of KOH in 50 ml. of methanol are heated under reflux for 2 hours. Water and chloroform are added and the reaction mixture is worked up to give 3(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, m.p. 82°-84°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-:14].[K+].[K+].[CH3:19][C:20]([CH3:22])=[O:21]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:19][C@@H:20]([OH:21])[CH2:22][OH:14])=[CH:10][CH:11]=1
Reactant: OCCCCc1ccc(O)cc1
Reactant: CC(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: OCCCCc1ccc(OC[C@@H](O)CO)cc1

Procedure:
To 4-(4-Hydroxy-butyl)-phenol (32.7 g, 197 mmol) in acetone (600 ml) is added potassium carbonate (40.8 g, 295 mmol) followed by (S)-glycidolgg (13.7 ml, 207 mmol). The mixture is heated at reflux overnight. Further potassium carbonate (20 g) is added, followed by (S)-glycidolgg (5 g) and the mixture is heated at reflux for 72 hours. The suspension is cooled, filtered and the filtrate concentrated in vacuo. The residue is partitioned between EtOAc (500 ml) and 5% citric acid solution (500 ml). The organics are separated, dried (MgSO4) and concentrated in vacuo to give (S)-3-[4-(4-Hydroxy-butyl)-phenoxy]-propane-1,2-diol as a brown oil; 1H NMR (CDCl3): 1.56-1.74 (4H, m), 2.20 (1H, t, J=2.46 Hz), 2.61 (2H, t, J=7.6 Hz), 3.68 (2H, t, J=6.2 Hz), 3.78 (1H, dd, J=5.4 and 11.5 Hz), 3.86 (1H, dd, J=3.9 and 11.5 Hz), 4.0-4.16 (3H, m), 6.85 (2H, d, J=8.6 Hz), 7.12 (2H, d, J=8.6 Hz).
Reaction SMILES: O=C(Cl)OC(Cl)(Cl)Cl.[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1[NH:20][CH2:21][C:22]1[C:23]([NH:30][CH3:31])=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=1.CCN(CC)CC.[C:39]([O-:42])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1[N:20]1[CH2:21][C:22]2[C:23](=[N:24][C:25]([S:28][CH3:29])=[N:26][CH:27]=2)[N:30]([CH3:31])[C:39]1=[O:42]
Reactant: CNc1nc(SC)ncc1CNc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1cc([N+](=O)[O-])c(F)cc1Cl)C2
Temperature: 50 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of diphosgene (2.1 mL, 6.8 mmol) in anhydrous dioxane (30 mL) was added a solution of 5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (2.2 g, 6.2 mmol) and Et3N (1.32 g, 13 mmol) in anhydrous dioxane (30 mL) at 0° C. After complete addition, the resulting mixture was stirred at 50° C. overnight. Water was added and the mixture was basified with saturated Na2CO3 solution. The mixture was concentrated in vacuo and the residue was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residual solid was washed with ether and dried to afford 3-(2-chloro-4-fluoro-5-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.4 g, 59%). 1H NMR (400 MHz, DMSO-d6): δ 8.53 (d, J=8 Hz, 1 H), 8.26 (s, 1 H), 8.08 (d, J=12 Hz, 1 H), 4.82 (d, J=16 Hz, 1 H), 4.57 (d, J=16 Hz, 1 H), 3.29 (s, 3 H), 2.50 (s, 3 H); MS (ESI) m/z: 384.1[M+H]+.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[C:48]([C:52]1[NH:56][N:55]=[C:54]([CH2:57][NH2:58])[CH:53]=1)([CH3:51])([CH3:50])[CH3:49]>>[C:48]([C:52]1[NH:56][N:55]=[C:54]([CH2:57][NH:58][C:41]([C:39]2[S:40][C:36]([N:33]3[CH2:34][CH2:35][N:31]([CH2:30][C:29]4[CH:46]=[CH:47][C:26]([F:25])=[CH:27][CH:28]=4)[C:32]3=[O:45])=[CH:37][C:38]=2[CH3:44])=[O:42])[CH:53]=1)([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)c1cc(CN)n[nH]1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cc(C(C)(C)C)[nH]n1
Yield: 41 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (5-tert-butyl-1H-pyrazol-3-yl)methanamine, the title compound was obtained as a colorless solid in 41% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.99 (m, 2H), 6.42 (t, J=5.4 Hz, 1H), 6.10 (s, 1H), 6.05 (s, 1H), 4.55 (d, J=5.4 Hz, 2H), 4.42 (s, 2H), 3.83-3.75 (m, 2H), 3.47-3.39 (m, 2 H), 2.49 (s, 3H), 1.32 (s, 9H); MS (ES+) m/z 470.2 (M+1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:21]=[CH:20][C:11]([CH:12]=[C:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1.[NH2:22][CH2:23][C@H:24]([OH:34])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[OH:34][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:21]=[CH:20][C:11]([CH:12]=[C:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:2][CH2:7]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: O=C1NC(=O)C(=Cc2ccc(N3CCCCC3=O)cc2)S1
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)cc4)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 36) and 4-[(2S)-3-amino-2-hydroxy-propoxy]-phenol (which was obtained in Example 5) according to the procedure of Example 73 as a pale yellowish solid; mp >208° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.60 (m, 2H), 1.90-2.05 (m, 2H), 2.70-3.50 (m, 5H), 3.80-4.10 (m, 5H), 6.90 (d, J=6.7 Hz, 2 H), 6.77 (d, J=6.7 Hz, 2H), 7.02 (d, J=8.9 Hz, 2H), 7.35 (s, 1H), 7.39 (d, J=8.9 Hz, 2H), 8.95 (brs, 1H); MS (ES) m/z: 469.9 (MH+); HRMS Calcd. for C24H28N305S(M+): 469.1671. Found: 469.1648.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].C[O:33][C:34](=[O:42])[CH2:35]P(OC)(OC)=O.CC([O-])(C)C.[K+]>C1COCC1>[CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=[CH:35][C:34]([OH:42])=[O:33])[CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:6])[CH3:7])(=[O:4])=[O:3]
Reactant: CC(C)(c1cc(-c2cccc(-c3cccc(C=O)c3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: COC(=O)CP(=O)(OC)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(c1cc(-c2cccc(-c3cccc(C=CC(=O)O)c3)c2)c2ncccc2c1)S(C)(=O)=O

Procedure:
To a solution of 3′-[6-(1-methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-biphenyl-3-carbaldehyde from Step 1 (1.0 eq.) and (dimethoxy-phosphoryl)-acetic acid methyl ester (1.1 eq.) in THF (0.1M) was added t-BuOK (1.1 eq.; 1.0M in THF). The final mixture was stirred 3 h at rt, poured in saturated aqueous NH4 Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (CH2Cl2:EtOAc; 9:1) afforded the corresponding methyl ester of the title compound as a yellow solid. To a solution of the methyl ester in THF: MeOH (4:1), aqueous NaOH (3.0 eq.) was added. The final mixture was stirred 4 h at rt, neutralized with AcOH, poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a white solid.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][CH2:6][C@H:5]1[NH:12][C:13](=[O:21])[O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][C@H:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][CH2:6][C@H:5]1[NH:12][C:13](=[O:21])[O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: [H][H]
Reactant: CC1(C)C[C@H](N=[N+]=[N-])[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Agent: [Pd]
Solvent: CO
Product: CC1(C)C[C@H](N)[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Yield: 124.8 %

Procedure:
A mixture of 2-(trimethylsilyl)ethyl (3S,4S)-4-azido-6,6-dimethyl-tetrahydro-2H-pyran-3-ylcarbamate (510 mg, 1.25 mmol), 10% palladium on carbon (50 mg) in methanol (10 mL) was stirred at room temperature under 1 atm hydrogen atmosphere (hydrogen balloon) overnight. After that, the mixture was filtered through a pad of celite. The filtrate was concentrated to get the title compound (450 mg, crude) as a brown oil, which was used directly for the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O-:28].[Na+]>CO>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([O:28][CH3:27])=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(CNc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Yield: 81.4 %

Procedure:
A mixture of 6-benzyl-N-((6-chloropyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (2.5 g, 6.8 mmol), MeOH (5 mL), and 15% wt. sodium methoxide solution (10 g, 48 mmol) in MeOH was subjected to microwave irradiation at 150° C. for 60 min. The mixture was concentrated in vacuo and the residue was treated with water (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column (MeOH/CH2Cl2: 0-15%) to yield a yellow solid (2.0 g, 79%).