Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:20])[CH:13]3[CH:9]2[CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12]3)[CH:5]=[CH:4][C:3]=1[NH2:21].[OH-].[Na+].[CH:24](O)=O>O>[NH3:1].[CH2:14]([N:11]1[CH2:10][CH:9]2[CH:13]([C:8]2([C:6]2[CH:5]=[CH:4][C:3]3[NH:21][CH:24]=[N:1][C:2]=3[CH:7]=2)[CH3:20])[CH2:12]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1ccc(N)c(N)c1
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCN1CC2C(C1)C2(C)c1ccc2[nH]cnc2c1
Product: N
Yield: 40 %

Procedure:
A solution of 2-amino-4-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 48, 112 mg, 0.39 mmol) in formic acid (2.0 ml) was heated under reflux for 1 h. The mixture was cooled, diluted with water (3 ml) and the pH adjusted to 10 with 5N sodium hydroxide. The aqueous layer was extracted with diethyl ether (3×5 ml) and ethyl acetate (2×5 ml). The combined organic layers were dried (MgSO4), filtered and the solvent removed in vacuo. The crude residue was purified by silica columnn chromatography eluting with ethyl acetate then ethyl acetate:methanol:ammonia solution (0.880) (80:20:1) to afford the title compound (46 mg, 40%) as a colourless oil.
Reaction SMILES: [C:1](=[S:3])=[S:2].Br[CH2:5][CH2:6]Br.[H-].[Na+].[CH2:10]([O:12][C:13]([CH2:15][C:16]([NH:18][C@@H:19]1[C:33](=[O:34])[N:21]2[CH:22]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[C:23]([CH3:26])([CH3:25])[S:24][C@H:20]12)=[O:17])=[O:14])[CH3:11]>CN(C)C=O.C1(C)C=CC=CC=1>[S:2]1[CH2:6][CH2:5][S:3][C:1]1=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[C:16]([NH:18][C@@H:19]1[C:33](=[O:34])[N:21]2[CH:22]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[C:23]([CH3:26])([CH3:25])[S:24][C@H:20]12)=[O:17]
Reactant: C=CCOC(=O)C1N2C(=O)[C@@H](NC(=O)CC(=O)OCC)[C@H]2SC1(C)C
Reactant: S=C=S
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1N2C(=O)[C@@H](NC(=O)C(C(=O)OCC)=C3SCCS3)[C@H]2SC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Carbon disulfide (1.5 mL), 1,2-dibromoethane (845 mg, 4.5 mmol) and sodium hydride, 60% (240 mg, 6 mmol) were added sequentially to a solution of allyl 6β-[(ethoxycarbonyl)acetamido]-2,2-dimethylpenam-3-carboxylate (1.11 g, 3 mmol) in 3 mL of dimethylformamide at 0° C. The reaction mixture was stirred at 0° C. for 30 min under a nitrogen atmosphere. The mixture was diluted with toluene, washed with water and saturated NaCl solution, and dried over Na2SO4. After concentration, the residue was chromatographed on silica gel with chloroform-ethyl acetate (95:5) as the eluant to give the title compound (926 mg, 65%) as yellow crystals: m.p. 116°-117° C. (ethyl acetate); IR (CHCl3) 1790, 1750, 1680 cm-1; 1 H NMR (CDCl3) δ 1.39 (3H, t, J=7Hz, CH2CH3), 1.49 and 1.66 (each 3H, s, C2 -(CH3)2), 3.32 (4H, s, SCH2CH2S), 4.30-4.40 (2H, m, CH2CH3), 4.46 (1H, s, C3 -H), 4.62-4.68 (2H, m, OCH2CH=CH2), 5.26-5.40 (2H, m OCH2CH=CH2), 5.57 (1H, d, J=4Hz, C5 -H), 5.83 (1H, dd, J=4 and 9Hz, C6 -H), 5.83-6.00 (1H, m, OCH2CH=CH2), 9.05 (1H, d, J=9Hz, NH).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C[Si]([O:15][S:16](Cl)(=[O:18])=[O:17])(C)C.[Cl:20]C(Cl)C>>[Cl:20][C:4]1[CH:5]=[C:6]2[C:10](=[CH:2][CH:3]=1)[NH:9][CH:8]=[C:7]2[S:16]([OH:18])(=[O:17])=[O:15]
Reactant: CC(Cl)Cl
Reactant: C[Si](C)(C)OS(=O)(=O)Cl
Reactant: Clc1cccc2cc[nH]c12
Product: O=S(=O)(O)c1c[nH]c2ccc(Cl)cc12
Temperature: -10 °C

Procedure:
7-Chloroindole (1.51 g, 10 mmole) was dissolved in 2 ml dichloroethane and cooled under nitrogen to −10° C. in an ice-salt-acetone bath. Trimethylsilylchlorosulfonate (1.89 g, 1.6 ml, 10 mmole) was slowly added with stirring. Upon termination of the addition, the reaction was allowed to warm to room temperature and stirred for 30 min at this temperature. The dark red solution was evaporated to dryness and the solvent was replaced with 50 ml ethyl acetate. Methanol (5 ml) was added and the solvents were removed and the residue thoroughly dried to afford the crude 5-chloro-1H-indole-3-sulfonic acid as a red oil. Step 2 7-Chloro-1H-indole-3-sulfonic acid dimethylamide
Reaction SMILES: C(O)[CH2:2][O:3][CH2:4][CH2:5][OH:6].[OH-:8].[K+].BrC(Br)=C[C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]2[O:20]CO[C:14]=12>O>[Br:19][C:17]1[CH:16]=[C:4]2[O:3][CH2:2][O:6][C:5]2=[C:13]([CH2:14][C:15]([OH:20])=[O:8])[CH:18]=1
Reactant: [OH-]
Reactant: OCCOCCO
Reactant: BrC(Br)=Cc1cc(Br)cc2c1OCO2
Agent: [K+]
Solvent: O
Product: O=C(O)Cc1cc(Br)cc2c1OCO2
Temperature: 0 °C

Procedure:
Diethylene glycol (100 ml), water (60 ml), and 85% potassium hydroxide (32 g, 0.485 mol) were added to β, β-dibromo-5-bromo-2,3-methylenedioxystyrene (42.36 g, 0.11 mol), and the mixture was heated with stirring under reflux for 2 hours. The reaction mixture was poured into ice water and extracted with toluene. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was recrystallized from ethyl acetate (80 ml) and hexane (300 ml) to give 5-bromo-2,3-methylenedioxyphenylacetic acid (25.35 g).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:15]=O.Cl>O1CCOCC1.[Cu]Cl>[C:1]1([C:7]#[C:8][CH2:15][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: C1CCNCC1
Reactant: C=O
Agent: Cl[Cu]
Agent: Cl
Solvent: C1COCCO1
Product: C(#Cc1ccccc1)CN1CCCCC1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
With stirring, a solution of phenylacetylene (10.2 g) in dioxane (10 ml), a solution of piperidine (13.3 g) in dioxane (10 ml) and copper(I) chloride (0.1 g) were added successively to a suspension of paraformaldehyde (3.6 g) in dioxane (10 ml). The mixture was heated under reflux for 6 hours, allowed to cool to 25° C. and acidified using 20% strength hydrochloric acid. The solution was washed with diethyl ether and the aqueous phase was made alkaline using 50% strength aqueous sodium hydroxide solution and extracted with diethyl ether (3×100 ml). The organic phase was dried with magnesium sulfate and concentrated completely. Distillation of the residue under reduced pressure gave an oil (13.0 g) of boiling point 95° C./0.045 mm Hg.
Reaction SMILES: Cl.Cl.[CH:3]1([N:9]([CH3:16])[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=2)=[CH:23][CH:22]=1)=[O:19].C(NC(C)C)(C)C>CN(C)C=O.O1CCCC1>[F:36][C:34]([F:35])([F:37])[C:31]1[CH:32]=[CH:33][C:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:18]([N:13]3[CH2:12][CH2:11][CH:10]([N:9]([CH:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[CH3:16])[CH2:15][CH2:14]3)=[O:19])=[CH:22][CH:23]=2)=[N:29][CH:30]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(C1CCCCC1)C1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CN(C1CCCCC1)C1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title product was prepared from cyclohexyl-methyl-piperidin-4-yl-amine, dihydrochloride and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 2 equivalent of diisopropylamine; dimethylformamide/tetrahydrofuran (2:1). The reaction mixture was evaporated to dryness and the crude product extracted with ethyl acetate from an aqueous HCl solution saturated with sodium chloride, pH 1–2. The title product was crystallized from ethyl acetate during evaporation of the solvent, filtered and dryed in vacoum (45%, white crystals). HPLC-MS m/z=478.2 (M+1), Rt: 3.10 min.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][N:7]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][N:4]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.[CH3:30][C:31]([CH3:33])=O.C[Si]([C:38]#[N:39])(C)C>CCO>[CH3:30][C:31]([NH:1][CH2:2][C@H:3]1[CH2:8][N:7]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:11])[CH2:6][CH2:5][N:4]1[C:17]1[CH:18]=[CH:19][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=1)([CH3:33])[C:38]#[N:39]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)=O
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN)cc1)C(F)(F)F
Solvent: CCO
Product: CC(C)(C#N)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 52.1 %

Procedure:
A 5-mL vial was charged with 2-(4-((2S)-2-(aminomethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.0521 g, 0.116 mmol, Example 192, Step 2), acetone (10 μL, 0.14 mmol) and EtOH (1 mL). The reaction mixture was cooled to 0° C. and stirred for 35 min. Trimethylsilyl cyanide (46.3 μL, 0.348 mmol, Sigma-Aldrich, St. Louis, Mo.) was added drop wise at 0° C. The mixture was slowly allowed to warm up to room temperature and stirred for 12 h. The solvent was removed and the remaining white residue was dissolved into EtOAc and passed through a pad of silica gel rinsing with EtOAc as eluent. The solvent was removed and the crude product was purified by column chromatography (10 g of silica gel, 50 to 100% EtOAc in hexanes) to afford 2-methyl-2-((((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)amino)propanenitrile (0.0312 g) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[S:4][C:3]=1[C:14](OC)=O.C(O)(=O)C.[CH:22]([NH2:24])=N.C(N)=[O:26]>>[N+:11]([C:10]1[C:5]2[S:4](=[O:26])[C:3]3[CH:14]=[N:24][CH:22]=[N:1][C:2]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:13])=[O:12]
Reactant: N=CN
Reactant: NC=O
Reactant: COC(=O)c1sc2c([N+](=O)[O-])cccc2c1N
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2c1S(=O)c1cncnc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-amino-7-nitrobenzothiophene-2-carboxylate (242 mg, 0.96 mmol) and formamidine acetate (0.51 g, 4.9 mmol) was heated up to 185° C. when 1.5 mL formamide was added to the reaction. After 1 hour at 185° C., the reaction was cooled to 25° C. The solid was collected and washed with water then dried. 6-Nitrobenzothieno [3,2-d]pyrimidone was isolated as a yellow solid (161.5 mg, 68%).
Reaction SMILES: [CH3:1][C:2]([CH3:31])=[C:3]([N:8]1[C@H:11](SC)[C@@H:10]([C@H:14]([O:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[CH3:15])[C:9]1=[O:30])[C:4]([O:6][CH3:7])=[O:5].[Cl:32]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:32][CH:11]1[N:8]([C:3](=[C:2]([CH3:31])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])[C:9](=[O:30])[C@@H:10]1[C@H:14]([O:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])[CH3:15]
Reactant: ClCl
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C1Cl
Temperature: 0 °C

Procedure:
To a solution of methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)-ethyl}-2-oxoazetidin-1-yl]but-2-enoate (481 mg) in dichloromethane (5 ml) was added a solution of chlorine (83 mg) in carbon tetrachloride (0.65 ml) at -78° C. The solution was allowed to warm to 0° C. during 45 minutes and evaporated in vacuo. The residue was chromatographed on silica gel (12 g) eluting with 10-33% ethyl acetate in hexane to give methyl 2-[(3S)-4-chloro-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)-ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate [a mixture (55:45) of (4R) isomer and (4S) isomer] (394 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C([Li])(C)(C)C.CN(C)[CH:27]=[O:28]>O1CCCC1>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[N:6]=[CH:7][C:2]([CH:27]=[O:28])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccc(CNc2ccc(Br)cn2)cc1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=Cc1ccc(NCc2ccc(C(F)(F)F)cc2)nc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a solution of (5-bromo-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine (17, 3.55 g, 0.0107 mol, commercially available, or prepared as described in Example 10) in tetrahydrofuran (150 mL) was added tert-butyllithium (13.2 mL, 1.70M in pentane, 0.0224 mol) slowly under an atmosphere of nitrogen at −78° C. over 10 minutes. The reaction mixture was stirred at −78° C. for 90 minutes. N,N-Dimethylformamide (2.2 mL, 0.028 mol) was added slowly into the reaction mixture. The reaction mixture was stirred at −78° C. for 2 hours, then allowed to warm to room temperature. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a light yellow solid (18, 1.67 g, 56%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][C:34]=1[O:35][C:36](=[O:38])[CH3:37])[C:8]([O:10][CH2:11][C:12]1[CH2:19][S:18][CH:17]2[N:14]([C:15](=[O:28])[CH:16]2[NH:20]C(OC(C)(C)C)=O)[C:13]=1[C:29]([OH:31])=[O:30])=[O:9])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][C:34]=1[O:35][C:36](=[O:38])[CH3:37])[C:8]([O:10][CH2:11][C:12]1[CH2:19][S:18][C@H:17]2[N:14]([C:15](=[O:28])[C@H:16]2[NH2:20])[C:13]=1[C:29]([OH:31])=[O:30])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)OCC2=C(C(=O)O)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)cc1OC(C)=O
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc(C(=O)OCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)cc1OC(C)=O
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a magnetically stirred 500 mL flask under argon at room temperature (about 23° C.) was added 25.69 g of (6R-trans)-3-[[[3,4-bis(acetyloxy)-benzoyl]oxy]methyl-7-[[1,1dimethylethoxycarbonyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 250 mL of methylene chloride. This was followed by the addition of 25 mL of anisole and 250 mL of trifluoroacetic acid. Stirring was continued for 3 hours and then the solvents removed in vacuo. To the oil residue was added 200 mL of ethyl acetate and stirred for 20 minutes causing precipitation. 650 mL of anhydrous ether was added to this suspension and stirred for 10 minutes. The mixture was filtered on a Buchner funnel and dried under high vacuum to give 20.25 g (76.9%) of the named product.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.C[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([C:23]2[N:24]([CH:28](S(OC)(=O)=O)[CH3:29])[CH:25]=[CH:26][CH:27]=2)[CH:22]=1>CN(C)C=O.O>[CH3:1][C:25]1[N:24]([CH2:28][CH2:29][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[C:23]([C:21]2[CH:22]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)C(C)n1cccc1-c1cccc(C)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2)n1CCOc1ccc(C=O)cc1
Reaction time: 4 h

Procedure:
To a suspension of potassium carbonate (16.43 g) in dimethyl formamide (50 mL), 4-hydroxy benzaldehyde (4.37 g) was added and warmed to 90° C. to 95° C. To the solution, methyl 1-[5-methyl phenyl-1H-pyrrol-1yl]ethane sulfonate (10 g) (compound no. 41) dissolved in dimethyl formamide (50 mL) was added within 30 min and the reaction was continued for further 4 hours. The reaction mixture was diluted with water (100 mL) and was extracted with ethyl acetate (3×100 mL), washed with water (3×100 mL), brine (200 mL), and was dried over sodium sulfate. The solvent was evaporated under reduced pressure, to yield the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][C:17]1[N:18]=[C:19]([C:25]2S[CH:27]=[CH:28][CH:29]=2)S[C:21]=1[C:22](=O)[CH3:23].[NH3:30]>>[CH3:16][C@@H:17]1[CH2:21][CH2:22][CH2:23][N:18]1[CH2:19][CH2:25][C:29]1[CH:9]=[C:10]2[C:13](=[CH:27][CH:28]=1)[N:30]=[C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=1)[CH:14]=[CH:11]2
Reactant: N
Reactant: CC(=O)c1ccc(N2CCCCC2)cc1
Reactant: CC(=O)c1sc(-c2cccs2)nc1C
Product: C[C@@H]1CCCN1CCc1ccc2nc(-c3ccc(N4CCCCC4)cc3)ccc2c1

Procedure:
The title compound was prepared using the procedure described in Example 1G using 1-(4-piperidin-1-yl-phenyl)-ethanone for 1-(4-methyl-2-thiophen-2-yl-thiazol-5-yl)-ethanone. 1H NMR (300 MHz, CDCl3) δ 1.14 (d, J=5.42 Hz, 3H), 1.70 (m, 10H), 2.24 (m, 1H), 2.39 (m, 2H), 3.01 (m, 2H), 3.14 (m, 1H), 3.29 (m, 5H), 7.04 (d, J=8.81 Hz, 2H), 7.56 (dd, J=8.48, 2.03 Hz, 1H), 7.59 (s, 1H), 7.80 (d, J=8.48 Hz, 1H), 8.01–8.10 (m, 4H); MS (DCI-NH3) [M+H]+ at 400.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[C:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:30]([O:29][C:27]([N:34]1[CH2:39][CH2:38][N:37]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[NH:26][C:12]4[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH3:19])[C:11]=4[CH:10]=3)=[CH:5][CH:4]=2)[CH2:36][CH2:35]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CCl)cc3)cc12)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12)c1ccccc1
Temperature: 65 °C

Procedure:
A mixture of 1.6 g (4 mmol) [6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine (for the preparation see Example 9, Step 9.3 of WO 03/013541 A1) in 50 ml DMF is treated with 1.56 g (8.4 mmol) N—BOC-piperazine and 2.76 g (20 mmol) anhydrous potassium carbonate and the mixture heated to 65° C. for 1 hour. The reaction mixture is cooled and the inorganic salts removed by filtration (Hyflo Super Cel®; Fluka, Buchs, Switzerland). The DMF is evaporated under reduced pressure and the residue purified through flash chromatography using first dichloromethane/ethanol 95:5 and then dichloromethane/ethanol 9:1. The title compound is obtained as a solid; m.p. 244-246° C.; MS-ES+: (M+H)+=513; TLC Rf(dichloromethane/ethanol 9:1) 0.46.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].N1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C1(C=O)CCCC1.Cl>N1C=CC=CC=1>[CH:9]1(/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)CC(=O)O
Reactant: C1CCNCC1
Agent: Cl
Agent: O=CC1CCCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/C1CCCC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of malonic acid (1.06 g, 10.2 mol) in pyridine (1.25 mL) was added piperidine (0.15 mL) and cyclopentanecarbaldehyde (1.00 g, 10.2 mmol). The mixture was heated to 40° C. for 2 hours, followed by stirring at room temperature for 16 hours. The mixture was then cooled in an ice bath and 2N HCl was added to acidify. The product was extracted with ether. The ether extract was washed with aq. HCl and brine, dried over sodium sulfate, filtered, and the solvent was removed in vacuo to afford the product (1.30 g, 77%), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:39])[NH:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH3:32])[CH3:31])[CH:23]=1.[C:40](Cl)(=[O:42])[CH3:41]>N1C=CC=CC=1>[C:40]([NH:1][C:2]1[C:7]2[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:39])[NH:29][C:30]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([CH3:32])[CH3:31])[CH:23]=1)(=[O:42])[CH3:41]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)c(N)c12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)c(NC(C)=O)c12
Reaction time: 2 h
Yield: 34 %

Procedure:
4-amino-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide (20 mg, 0.038 mmol) was diluted in pyridine (1 mL) and treated with excess acetyl chloride (10 μL). The reaction was allowed to stir for 2 hours. The mixture was concentrated and diluted with MeOH (1 mL). The product began to crash out, it was sonicated and filtered and washed with MeOH to afford the titled compound (8 mg, 34%). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.41 (1H, s), 8.43 (1H, s), 8.31-8.38 (1H, m), 7.88-7.92 (1H, m), 7.82-7.87 (2H, m), 7.80 (1H, d, J=7.63 Hz), 7.71 (1H, d, J=8.55 Hz), 7.54-7.60 (1H, m), 7.43-7.49 (2H, m), 7.36-7.43 (5H, m), 7.28 (2H, t, J=7.78 Hz), 7.17 (1H, t, J=7.32 Hz), 2.76 (3H, d), 1.79 (3H, s), 1.69 (6H, s). LC-MS retention time 1.42 min; m/z 564 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=12.00 min, purity=96%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=11.26 min, purity=95%.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27](=O)[CH3:28].[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:27]([C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH3:28])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: CC(=O)c1ncccn1
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CC(Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1)c1ncccn1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 1-pyrimidin-2-yl-ethanone using decaborane yielded a mixture of epimers of the title compound as a yellow waxy solid. MS (ESI): m/z=385.2 [M+H]+.