Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5][C@H:6]1[NH:11][C@@H:10]([CH3:12])[CH2:9][N:8]([C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=O)=[CH:15][CH:14]=2)[CH2:7]1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1>C1(C)C=CC=CC=1>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH:41][C:17](=[O:19])[C:16]3[CH:15]=[CH:14][C:13]([N:8]4[CH2:9][C@H:10]([CH3:12])[NH:11][C@H:6]([CH3:5])[CH2:7]4)=[CH:23][CH:22]=3)[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: CCOC(=O)c1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4C[C@@H](C)N[C@@H](C)C4)cc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 41.1 %

Procedure:
A 2M solution of trimethylaluminium in toluene (1.875 mL, 3.75 mmol) was added dropwise to a stirred suspension of ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (0.394 g, 1.50 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.374 g, 1.5 mmol) in toluene (10 mL) at 20° C., over a period of 5 mins under nitrogen. The resulting solution was stirred at 60° C. for 5 h. The reaction mixture was cooled and the reaction quenched by diluting with acetone (100 ml) and excess damp sodium sulphite added in portions. This was stirred for 60 mins. The resulting solid filtered off, washed with 10% methanol in DCM. The filtrate was evaporated to give crude product. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (0.287 g, 41.1%) as a white solid. 1H NMR (500.13 MHz, DMSO-d6) δ 1.08 (6H, d), 2.31 (2H, t), 3.70-3.73 (2H, m), 3.78 (6H, s), 5.10 (2H, s), 5.64 (1H, s), 6.46 (1H, t), 6.62 (2H, d), 6.95-6.97 (2H, m), 7.83-7.85 (2H, m), 10.21 (1H, s), 11.09 (1H, s). MS: m/z 466 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH2:24]Br>>[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH2:24][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Fc1ccc(F)c(CBr)c1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cc(F)ccc2F)c(=O)[nH]c1=O
Yield: 53.7 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (214 mg, yield: 53.7%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([C:18]([O:21][CH3:22])([CH3:20])[CH3:19])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH2:23])[CH2:10]1.[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C@@:26]21[CH2:44][C:36]1=[N:37][CH:38]=[C:39]([C:41](O)=[O:42])[CH:40]=[C:35]1[CH2:34]2.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([C:18]([O:21][CH3:22])([CH3:19])[CH3:20])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH:23][C:41]([C:39]2[CH:40]=[C:35]3[CH2:34][C@@:26]4([C:27]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:33][C:25]4=[O:24])[CH2:44][C:36]3=[N:37][CH:38]=2)=[O:42])[CH2:10]1
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: COC(C)(C)c1cnc2n1C[C@H](c1cccc(F)c1F)C[C@@H]2N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)c1cnc2n1C[C@H](c1cccc(F)c1F)C[C@@H]2NC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reaction time: 0.75 h
Yield: 25.2 %

Procedure:
To a solution of (6S,8S)-6-(2,3-difluorophenyl)-3-(2-methoxypropan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-amine (11.0 mg, 0.034 mmol) in N,N-dimethylformamide (342 μL) were added (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (10.6 mg, 0.038 mmol), 1-hydroxy-7-azabenzotriazole (0.5 mg, 3.4 μmol), N-methylmorpholine (4.1 μL, 0.038 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.2 mg, 0.038 mmol). The mixture was stirred 45 min. Water was added, and the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) giving the title compound (5 mg). HRMS 585.2403 (M+1). 1H NMR (400 MHz, DMSO): δ 11.12 (s, 1H); 9.08 (d, J=8.5 Hz, 1H); 8.89 (d, J=2.0 Hz, 1H); 8.12 (d, J=1.9 Hz, 1H); 8.09 (dd, J=5.3, 1.6 Hz, 1H); 7.47 (dd, J=7.3, 1.6 Hz, 1H); 7.41−7.38 (m, 1H); 7.33−7.25 (m, 2H); 6.93 (dd, J=7.3, 5.3 Hz, 1H); 6.83 (s, 1H); 5.50−5.43 (m, 1H); 4.48 (dd, J=11.9, 4.0 Hz, 1H); 3.88 (d, J=11.9 Hz, 1H); 3.40 (d, J=16.6 Hz, 2H); 3.31 (m, 2H); 2.98 (s, 3H); 2.67 (q, J=1.9 Hz, 1H); 2.34−2.31 (m, 2H); 1.51−1.43 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[C:26]([C:37]([F:40])([F:39])[F:38])[CH:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([F:41])[C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9]C(C)(C)C)=[O:8].[ClH:42]>O1CCOCC1>[ClH:42].[F:41][C:15]1[CH:16]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[C:26]([C:37]([F:38])([F:40])[F:39])[CH:25]=3)[O:21][N:20]=2)[CH:18]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3cc(F)c(CN(C)CC(=O)OC(C)(C)C)c(F)c3)no2)cc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccc(-c2nc(-c3cc(F)c(CN(C)CC(=O)O)c(F)c3)no2)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To tert-butyl 2-((2,6-difluoro-4-(5-(2′-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)(methyl)amino)acetate (0.101 g, 0.18 mmol) was added a 4N solution of HCl in dioxane (4.5 mL) and the reaction mixture stirred at 70° C. for 1 hour. The reaction mixture was allowed to cool and the solvent evaporated in vacuo. The residue was triturated with ACN to afford the title compound (0.087 g, 87%). 1H NMR (DMSO-d6, 400 MHz) δ 8.60 (1H, d, J=1.7 Hz), 8.55 (1H, dd, J=8.0, 1.7 Hz), 7.98 (2H, d, J=7.7 Hz), 7.72 (1H, d, J=8.0 Hz), 7.45-7.38 (2H, m), 7.33 (1H, ddd, J=7.6, 6.5, 2.3 Hz), 7.20 (1H, d, J=7.6 Hz), 4.51 (2H, br s), 4.15 (2H, br s), 2.81 (3H, br s), 2.06 (3H, br s). LC/MS (Method A): 518 (M+H)+. HPLC (Method F) Rt 3.38 min (Purity: 99.5%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=1)=[O:9].O1[CH2:42][CH2:41]OCC1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12]([N:11]2[CH2:42][CH2:41][N:7]([CH3:6])[CH2:8][CH2:10]2)[N:11]=1)=[O:9]
Reactant: C1COCCO1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(S(C)(=O)=O)ncc1-c1ccccc1Cl
Product: CN1CCN(c2ncc(-c3ccccc3Cl)c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)CC1
Reaction time: 16 h
Yield: 179.7 %

Procedure:
To a solution of 0.40 g (0.72 mmol) 5-(2-chloro-phenyl)-2-methylsulfonyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml dioxan 0.20 ml (1.81 mmol) 1-methyl-piperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml H2O. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) to give 0.37 g (89%) 5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a white foam, MS (ISP): 572.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:10]=[C:9](I)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[F:14][C:15]1([F:23])[C@H:19]([OH:20])[C@H:18]([CH3:21])[NH:17][C:16]1=[O:22].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:10]=[C:9]([N:17]2[C@@H:18]([CH3:21])[C@@H:19]([OH:20])[C:15]([F:23])([F:14])[C:16]2=[O:22])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: C[C@@H]1NC(=O)C(F)(F)[C@@H]1O
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@H]1[C@@H](O)C(F)(F)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using 2-trifluoromethyl-4-iodobenzonitrile (1.64 g), (4R,5S)-3,3-difluoro-4-hydroxy-5-methylpyrrolidin-2-one (1.00 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (488 mg), tris(dibenzylideneacetone)dipalladium(0) (303 mg) and cesium carbonate (2.54 g), and in the same manner as in Reference Example 18, the title compound was obtained as a colorless solid (yield: 84.7 mg, 5%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1.C(OCC)(=O)C.CCCCCC.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2nc[nH]n2)ccc1Br
Reactant: C1=COCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Temperature: 70 °C
Yield: 42 %

Procedure:
3-Bromo-2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridine (0.7 g, 2.93 mmol) and 3,4-dihydro-2H-pyran (0.493 g, 5.86 mmol) were dissolved in tetrahydrofuran (20 mL). TFA (3.34 mg, 0.029 mmol) was added and the resulting solution was heated to 70° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered and poured into a separatory funnel containing water and ethyl acetate. The organic layer was concentrated under reduced pressure. Flash chromatography (0-60% ethyl acetate in hexane) gave the desired product as a white solid (0.40 g, 1.23 mmol, 42% yield). MS (ESI) m/z 325.1 [M+2]+. Alternate approach: 3-Bromo-2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridine (1 equiv), 3,4-dihydro-2H-pyran (2 equiv) and methanesulfonic acid (0.08 equiv) were combined in tetrahydrofuran (8×vol). The solution was heated and stirred at 68° C. for 3.5 h then cooled to room temperature. Triethylamine (0.4 equiv) was added and the resulting solution was concentrated under reduced pressure to an oil. The oil was treated with acetonitrile and concentrated under reduced pressure iteratively until a solid was obtained. The solid was dissolved in acetonitrile and treated with water. The suspension was filtered and the solids were collected and dried. The crude product was slurried in hexanes, filtered and dried to give the purified title compound as a light pink solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15].N(C(OC(C)C)=O)=NC(OC(C)C)=O.FC1C=CC([N+]([O-])=O)=CC=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCOc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=[N+]([O-])c1ccc(F)c(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COCCO
Product: COCCOc1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
1-Fluoro-2-(2-methoxyethoxy)-4-nitrobenzene. Diisopropyl azodicarboxylate (1.356 mL, 7.00 mmol) was added dropwise to a stirred solution of 2-fluoro-5-nitrophenol (1.00 g, 6.37 mmol), triphenylphosphine (1.837 g, 7.00 mmol), and 2-methoxyethanol (0.533 g, 7.00 mmol) in tetrahydrofuran (10 mL) cooled with a water bath. The resulting dark red mixture was stirred at room temperature under nitrogen for 1.5 h. The resulting mixture was purified using flash chromatography (Biotage) (0-30% ethyl acetate in hexane). Fractions containing the desired product were combined and washed twice with water and once with brine. The organics were dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator nearly to dryness. The residue was diluted with cold hexane. Solids were collected by vacuum filtration, washed with cold hexane, and dried under high vacuum to give the desired product (0.865 g, 4.02 mmol, 63% yield) as slightly yellow needles. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.01 (dd, J=2.73, 7.42 Hz, 1H), 7.91 (ddd, J=2.73, 3.90, 8.98 Hz, 1H), 7.54 (dd, J=8.98, 10.93 Hz, 1H), 4.31-4.39 (m, 2H), 3.67-3.76 (m, 2H), 3.32 (s, 3H); MS (ESI) m/z 216.3 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([O:12][CH:13]([C@@H:15]2[C@@H:18]([CH2:19][CH:20]=[O:21])[NH:17][C:16]2=[O:22])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO.C(O)(=O)C>[OH:21][CH2:20][CH2:19][C@H:18]1[NH:17][C:16](=[O:22])[C@@H:15]1[CH:13]([O:12][C:10]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:24][CH:23]=1)=[O:11])[CH3:14]
Reactant: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CCO
Yield: 62.1 %

Procedure:
(3S,4R)-3-[(1RS)-1-(p-Nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-(2-oxoethyl)azetidine (8 mg) was dissolved in methanol (0.8 ml) and sodium borohydride (2 mg) was added at 0° C. The mixture was then stirred for 30 minutes at the same temperature and acetic acid (3 drops) was added. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, and brine, dried over magnesium sulfate and evaporated. The residue was purified by preparative thin layer chromatography (silica gel) developing with benzene: acetone (1:1) to give (3S,4R)-4-(2-hydroxyethyl)-3-[(1RS)-1-(p-nitrobenzyloxycarbonyloxy)-ethyl]-2-oxoazetidine (5 mg).
Reaction SMILES: [CH3:1][CH:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[NH:3]1.Cl[C:14]([O:16][C:17]([CH3:19])=[CH2:18])=[O:15]>N1C=CC=CC=1>[C:17]([O:16][C:14]([N:3]1[C:4]2[C:9](=[CH:8][N:7]=[CH:6][CH:5]=2)[NH:10][C:11](=[O:12])[CH:2]1[CH3:1])=[O:15])([CH3:19])=[CH2:18]
Reactant: CC1Nc2ccncc2NC1=O
Reactant: C=C(C)OC(=O)Cl
Solvent: c1ccncc1
Product: C=C(C)OC(=O)N1c2ccncc2NC(=O)C1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
(2RS)-2-Methyl-1,2-dihydro-1,4,6-triazanaphthalen-3(4H)-one (A. Albert, G. B. Barlin J. Chem. Soc. 1963, 5156) (570 mg, 3.5 mmol) was dissolved in 30 ml of anhydrous pyridine and cooled in an ice bath. 0.42 ml (3.8 mmol) of isopropenyl chloroformate was added dropwise, and the mixture was subsequently stirred at room temperature overnight. Concentration, chromatography on silica gel (ethyl acetate/methanol=20:1) and crystallization (pentane/diethyl ether) resulted in 100 mg (12%) of the desired product of melting point 170°-171° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(N(CC)CC)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.[Cu]I.CN(C=O)C>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: Oc1ccc(I)cc1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(O)cc2)c1)c1ccccc1
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a degassed solution of 1.3 mL DMF at room temperature containing (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (63 mg, 0.22 mmol), 4-iodophenol (121 mg, 0.55 mmol), and triethylamine (0.09 mL, 0.66 mmol) was added dichlorobis(triphenylphosphine)palladium(II) (15 mg, 0.022 mmol) and copper(I)iodide (4 mg, 0.022 mmol). After proceeding for 1 hour the reaction was partitioned between EtOAc and H2O. The mixture was filtered to remove an insoluble brown precipitate and the EtOAc layer was washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown film was chromatographed eluting with CHCl3/EtOAc to give a yellow solid which was recrystallized from CHCl3/hexane to give the title compound as an off-white solid (38 mg, 45%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1csc2nc(-c3cnccn3)nc(Cl)c12
Product: Cc1csc2nc(-c3cnccn3)nc(NCc3ccc(F)cc3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(4-fluorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1>C1COCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:20]2[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(N)c1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(Nc2ncc(C#N)s2)c1
Reaction time: 0.25 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (8-5, 5.94 g, 24.9 mmol) was dissolved in 50 mL anhydrous THF under N2. NaH (60% suspension, 2.99 g, 74.8 mmol, 3 equiv) was added (vigorous bubbling occurs) and the resulting mixture was stirred for 15 min. 2-Chloro-thiazole-5-carbonitrile (4.32 g, 29.9 mmol) was added and the reaction was heated to reflux. After 2 h the reaction was cooled and was quenched by the addition of water. The THF was removed in vacuo and the resulting aqueous solution was adjusted to pH=7 by the addition of 1M HCl (aq). The resulting precipitate was filtered and washed with water to provide reasonably pure desired product. 1H NMR (CDCl3) δ10.32 (bs, 1H), 8.33 (d, 1H, J=5.3 Hz), 7.99 (s, 1H), 6.96 (s, 1H), 6.91 (d, 1H, J=5.3 Hz), 4.78 (s, 2H), 0.98 (s, 9H), 0.16 (s, 6H)
Reaction SMILES: C=O.S(=O)(=O)(O)O.[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])([OH:20])[C:12]1=[O:27])[CH:9]=[CH2:10].[C:28]([O-])(=[O:30])C.[Na+]>C(O)(=O)C.O>[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:28][OH:30])=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]([N:24]([CH3:25])[CH3:26])=[O:23])([OH:20])[C:12]1=[O:27])[CH:9]=[CH2:10]
Reactant: C=CCN1C(=O)C(O)(CC(=O)N(C)C)c2ccccc21
Reactant: CC(=O)[O-]
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCN1C(=O)C(O)(CC(=O)N(C)C)c2cc(CO)ccc21
Temperature: 80 °C
Yield: 113 %

Procedure:
To a suspension of para-formaldehyde (36.2 g, 1.13 mol) in 150 ml of glacial acetic acid, sulfuric acid (22.2 g, 0.226 mol) is added and the mixture heated at 80° C., until a clear solution has been formed. To this, during 45 minutes a solution of 2-(1-allyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (example 26) (62 g, 226 mmol) in a mixture of glacial acetic acid (350 mL) and water (10 mL) is added. The red reaction mixture is stirred for another hour at 80° C., and by then all of the starting material is consumed (HPLC). Sodium acetate (46.3 g, 564 mmol) is added, and after stirring for 5 minutes an orange suspension forms. The solvent is removed on the rotavapor, and to the residue water (about 250 mL) is added. Extraction with chloroform (2×200 mL), drying the organic layer and removal of the solvent leaves the crude title product (77.7 g, quant.) as a red oil. After chromatographic purification white crystals, mp=125° C. 1H-NMR (CDCl3, 300 MHz) δ 2.71, 2.94 (AB, 2H, 2J=16.1 Hz, CH2CONMe2); 2.83, 2.84 (2 s, 3H each, N(CH3)2); 4.19, 4.25 (ABAtlyl, 2H, 2J=16.4 Hz, 3J=5.3 Hz, NCH2); 4.47 (s, 2H, CH2OH); 5.12 (dd, 1H, 2J=1.2 Hz, 3J=10.3 Hz, cis CH═CH2), 5.51 (dd, 1H, 3J=17.3 Hz, trans CH═CH2); 5.75 (ddtr, 1H, CH═CH2); 6.21 (br s, 1H, OH); 6.70 (d, 1H, 3J=7.9 Hz, H-7); 7.15 (dd, 1H, 4J=1.5 Hz, H-6); 7.37 (d, 1H, H-4). 13C-NMR (CDCl3, 75 MHz) δ 35.71, 37.84 (N(CH3)2); 38.87 (CH2CONMe2); 42.67 (NCH2); 64.80 (CH2OH); 74.46 (C-3); 109.36 (C-7); 117.73 (CH═CH2); 123.43 (C-4); 128.63 (C-6); 131.00 (C-9); 131.33 (CH═CH2); 136.35 (C-5); 141.89 (C-8); 170.53 (C-11); 176.36 (C-2).
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:27])[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[Cl:26])[CH2:14][CH2:13]1)=[O:11])(C)(C)C>O1CCOCC1>[ClH:25].[NH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:27])[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[Cl:26])[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
Saturated HCl in 1,4-dioxane (1.0 mL) was added to a stirred solution of {2-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (280 mg, 0.67 mmol) in 1,4-dioxane (1.0 mL) at ambient temperature. The mixture was stirred at room temperature for 15 minutes then concentrated. The resulting solid was washed with diethyl ether to afford 2-amino-1-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-ethanone hydrochloride as a solid in 78.9% yield. LC-MS purity: 94.019%
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Mg].[CH2:11]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:22][CH2:21][C:20]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)([OH:23])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: [Mg]
Product: OC1(c2cc(F)cc(F)c2)CCN(Cc2ccccc2)C1

Procedure:
Preparation according to Preparation 1: 1-Bromo-3,5-difluorobenzene (2.0 g, 10.3 mmol), magnesium turnings (0.25 g, 10.3 mmol), 1-benzylpyrrolidin-3-one (1.65 g, 9.3 mmol). Purification using flash chromatography on silica gel (ethyl acetate/isooctane, 1:4 to 1:1). Yield: 0.81 g. MS m/z (rel. intensity, 70 eV) 289 (M+, 2), 198 (26), 133 (32), 132 (23), 91 (bp). The enantiomers were separated by HPLC on Kromasil 5-Cellucoat (heptane/2-propanol/diethyl amine, 99:1:0.1): (+)-enantiomer (0.23 g). [α]D=+28.3° (methanol). MS m/z (rel. intensity, 70 eV) 289 (M+, 5), 198 (48), 133 (48), 132 (37), 91 (bp). (−)-enantiomer (0.35 g). [α]D=−28.1° (methanol). MS m/z (rel. intensity, 70 eV) 289 (M+, 9), 198 (58), 133 (48), 132 (40), 91 (bp).