Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]#[N:9])[CH:4]=[N:3][CH:2]=1.Br[CH2:11][CH:12]1[CH2:14][CH2:13]1.[H-].[Na+]>CN(C=O)C>[CH:12]1([CH2:11][CH:7]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[C:8]#[N:9])[CH2:14][CH2:13]1
Reactant: BrCC1CC1
Reactant: N#CCc1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CC1CC1)c1cncnc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 85 %

Procedure:
A solution of 2-(pyrimidin-5-yl)acetonitrile (1.8 g, 15.1 mmol) in DMF (20 mL) was degassed and (bromomethyl)cyclopropane was added (2.04 g, 15.1 mmol). The reaction mixture was cooled to −10° C., NaH was added (720 mg, 18.1 mmol, 60% in mineral oil) in portions under N2 and stirred at the same temperature for 45 mins. The reaction mixture was quenched with sat. NH4Cl and extracted with EtOAc (30 ml×3). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purification by column chromatography on silica gel (petroleum ether: EtOAc=3:1) to give 3-cyclopropyl-2-(pyrimidin-5-yl)propanenitrile (2.25 g, yield: 85%).1H NMR (CDCl3 400 MHz): δ9.22 (s, 1H), 68.78 (s, 2H), 3.80 (t, J=8 Hz, 2H), 1.98-1.92 (m, 1H), 1.83-1.79 (m, 1H), 0.87-0.83 (m, 1H), 0.61-0.59 (m, 2H), 0.21-0.13 (m, 2H).
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](Cl)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([N:50]5[CH2:51][CH2:52][N:47]([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=6)[CH2:48][CH2:49]5)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl chloride prepared in the manner of Example 23 (0.5 g) was added to a stirred mixture of N,N-diisopropylethyl amine (0.32 g), 4-(2-pyridyl)piperazine (0.39 g) and 4-(dimethylamino)pyridine (0.05 g) in dichloromethane (25 mL). After stirring overnight at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol®. and the eluate evaporated to dryness to provide the desired title compound (0.30 g) as a pale yellow amorphous solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].Cl[CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[CH2:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: ClCc1ccco1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccco2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 40 %

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-chloromethylfuran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound (40%) as a colorless solid: mp 110-112° C.; 1H NMR (300 MHz, CDCl3) δ 7.35-7.33 (m, 1H), 7.29-7.23 (m, 1H), 7.15 (d, 1H), 7.06-7.00 (m, 2H), 6.50 (s, 1H), 6.34-6.31 (m, 2H), 6.10 (s, 1H), 5.85 (dd, 2H), 4.92 (ABq, 2H), 4.79 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 177.1, 155.9, 149.0, 148.9, 142.6, 142.3, 141.8, 132.2, 128.9, 123.8, 123.5, 119.5, 110.6, 109.3, 108.7, 103.1, 101.5, 93.6, 80.4, 58.2, 37.1; MS (ES+) m/z 362.5 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[N:21]=[C:20]3[S:22][C:23]([NH2:25])=[N:24][C:19]3=[CH:18][CH:17]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:27](Cl)(=[O:29])[CH3:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[N:21]=[C:20]3[S:22][C:23]([NH:25][C:27](=[O:29])[CH3:28])=[N:24][C:19]3=[CH:18][CH:17]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(Oc2ccc3nc(N)sc3n2)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)OC(C)(C)C)ccc3F)nc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-fluorophenyl}carbamate (0.94 g, 2.5 mmol) and N,N-dimethylpyridine-4-amine (0.31 g, 2.5 mmol) in pyridine (5 mL) was added dropwise acetyl chloride (0.40 g, 5 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (1.05 g, quantitatively) as a white amorphous.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1.Cl[C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[CH:30][N:29]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][O:24][C:28]2[N:29]=[CH:30][CH:31]=[CH:32][C:33]=2[C:34]#[N:35])=[CH:25][CH:26]=1
Reactant: N#Cc1cccnc1Cl
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a mixture of 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyl alcohol (4.00 g), 2-chloro-3-cyanopyridine (2.41 g) and N,N-dimethylformamide (80 mL) was gradually added sodium hydride (60%, oil, 700 mg) under ice-cooling. After stirring the reaction mixture at room temperature for 2 hrs, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. Recrystallization from ethyl acetate-isopropyl ether gave colorless prism crystals (4.02 g, 78%) of 2-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyloxy]nicotinonitrile. melting point: 145-146° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[C:13]([O:17][C:18]([O:20]C(OC(C)(C)C)=O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][O:20][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(NOC(=O)OC(C)(C)C)nc1C
Reaction time: 18 h
Yield: 66.1 %

Procedure:
A suspension of ethyl-2-amino-4-methyl-thiazole-5-carboxylate (18.6 g, 100 mmol), di-t-butyldicarbonate (26.2 g, 120 mmol) and 4-dimethylaminopyridine (800 mg, 6.55 mmol) in dry tetrahydrofuran (300 mL) was stirred under nitrogen for 18 h. The solvent was evaporated in vacuo. The residue was suspended in dichloromethane (1 L) and filtered through a pad of celite. The filtrate was washed with 1 N aqueous HCl solution (300 mL, 2×), water and brine, dried (MgSO4), and concentrated in vacuo. The residue was triturated with hexanes. The solid was filtered and dried in vacuo to obtain the title compound (20 g, 72%) as a tan solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([NH:5][C@@H:6]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=1)=O)[C:7]([OH:9])=[O:8])=[O:4].C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]([F:22])([F:23])[C:3]([NH:5][C@@H:6]([CH2:10][CH2:11][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: [H][H]
Reactant: CCCc1ccc(C(=O)C[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCc1ccc(CC[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Reaction time: 48 h
Yield: 93.1 %

Procedure:
A solution of N-trifluoroacetyl-α-(S)-(2-(4-n-propylphenyl)-2-oxoethyl)glycine 6 (140 mg, 0.43 mmol) in ethyl acetate (10 mL) containing acetic acid (0.25 mL) and 10% palladium on carbon (10 mg) was stirred under one atmosphere of hydrogen gas. After two days, the catalyst was filtered off and fresh catalyst was added and the reaction stirred under hydrogen overnight. The mixture was filtered and the solvent evaporated in vacuo to yield the product 7 (127 mg, 93% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:24])[CH:11]([NH:16]C(OC(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH:8]2[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:24])[C@@H:11]([NH2:16])[CH2:12][CH2:13][CH2:14][CH2:15][C@H:8]2[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC2CCCCC(NC(=O)OC(C)(C)C)C(=O)N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CC[C@@H]2CCCC[C@H](N)C(=O)N21
Reaction time: 2 h

Procedure:
6-tert-butoxycarbonylamino-5-oxo-decahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid methyl ester, 17, (272 mg, 0.8 mmol) is dissolved in dichloromethane (5 mL) and treated trifluroacetic acid (5 mL). The solution is stirred for two hours then the solvent removed in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].Cl>C1(C)C=CC=CC=1.CS(C)=O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])[CH:19]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 115 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a distillation device and a dropping funnel and having an inner volume of 500 ml were charged 11.0 g (0.2 mol) of sodium methoxide and 30 ml of dimethyl sulfoxide under argon atmosphere, and the temperature of the mixture was raised to 110 to 120° C. while stirring, then, 27.0 g (0.2 mol) of dimethyl malonate with a purity of 98% was gradually added dropwise to the mixture over 30 minutes, and the resulting mixture was stirred for 2 hours while removing methanol under reduced pressure of 0.010 to 0.013 MPa. Subsequently, the mixture was cooled to 100° C. under the same pressure, 16.2 g (0.1 mol) of 2,4-difluoronitrobenzene with a purity of 98% was gradually added dropwise to the mixture over 30 minutes, and the mixture was further reacted at the same pressure and the same temperature for one hour. After completion of the reaction, the mixture was cooled to room temperature, 100 ml of toluene was added to the mixture and 40 ml (0.2 mol) of 5 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 50 ml of water and 50 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. This organic layer was analyzed (absolute quantitative method) by high performance liquid chromatography, it can be found that 20.6 g (yield: 76%) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate was formed.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.Cl>C(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[C:16]1[CH:21]=[CH:22][C:13]([NH:12][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A solution of methanesulfonyl chloride (15.2 g, 132 mmol) in methylene chloride (50 mL) was added dropwise to a stirring slurry of pyridine (41.8 g, 529 mmol) and methyl 4-aminobenzoate (20.0 g, 132 mmol) in methylene chloride (110 mL) cooled by a dry ice/acetone bath. The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was added to 400 mL of 4% aqueous HCl solution and the solid that formed was collected by filtration. The orange solid was recrystallized from methanol to give 28.8 g (91.5%) of an orange-pink solid, mp 147°-150° C.
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])C1C=CC=CC=1.S(=O)(=O)(O)O.[H][H]>[Pt]=O.C(O)(=O)C>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[N:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[OH:8]
Reactant: Clc1cccc(Cl)c1N=C1NCCN1OCc1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: ON1CCNC1=Nc1c(Cl)cccc1Cl

Procedure:
8.4 g. of 1-benzyloxy-2-[(2,6-dichlorophenyl)imino]imidazolidine in 30 ml. of glacial acetic acid and 2.5 ml. of concentrated sulfuric acid are hydrogenated under normal pressure in the presence of 300 mg. of platinum oxide. After the uptake of hydrogen has ended, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in water and the solution is rendered alkaline with sodium carbonate. The precipitate which has formed is filtered off, washed with a little water and dried in vacuo, whereupon 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine, m.p. 215°-216°, is obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=[CH:11][N:5]2[N:4]=1.[O:21]1CCCC1.OO.[OH-].[Na+].O>>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[C:9]([OH:21])[CH:10]=[CH:11][N:5]2[N:4]=1
Reactant: CSc1ncc2c(B3OC(C)(C)C(C)(C)O3)ccn2n1
Reactant: C1CCOC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ncc2c(O)ccn2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 1-Neck round-bottom flask, 2-Methylsulfanyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrolo[2,1-f][1,2,4]triazine (1.80 g, 6.18 mmol), Tetrahydrofuran (100 mL, 1000 mmol), and 50% aq. Hydrogen peroxide (1:1, Hydrogen peroxide:Water, 6.00 mL, 97.9 mmol) were added and stirred at room temperature for 2 hours. 19.10 M of Sodium hydroxide in Water (6.00 mL, 115 mmol) was added at 0° C. Vigorous gas evolution was observed for 15 minutes. The reaction was quenched with saturated sodium thiosulfate (100 mL). The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as eluant (0 to 100% EtOAc). The collected fractions afforded 2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-5-ol a yellow solid (1.00 g, 89%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:11](=[O:25])[CH:10]=1)C1C=CC=CC=1>[Pd].C1COCC1.CO>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[C:11](=[O:25])[CH:10]=1
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A stirring suspension of 4-(benzyloxy)-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (3.0 g, 8.44 mmol) and palladium on activated carbon (1.63 g, 10 wt. %, wet, Aldrich) in THF (150 mL) and methanol (250 mL) was placed under hydrogen (balloon) for 1 h. The resulting mixture was purged with nitrogen and then diluted with THF (150 mL) and methanol (50 mL). After stirring under nitrogen for 30 min, the mixture was filtered through a pad of CELITE® 545 filter aid and the filtrate was evaporated under reduced pressure to give 2.28 g crude product as a dark greenish solid. MS (ESI) 266 (M+H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:34][C:35]1[N:36]=[N:37][CH:38]=[CH:39][N:40]=1>N1C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:34][C:35]2[N:36]=[N:37][CH:38]=[CH:39][N:40]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccnn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: O=C(Nc1nccnn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 8 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 400 mg, 1.40 mmol) in dry pyridine (5 mL) was treated with 1,3-dicyclohexylcarbodiimide (316 mg, 1.53 mmol). The reaction mixture was stirred at 25° C. for 3.5 h and then treated with 3-amino-1,2,4-triazine (296 mg, 3.08 mmol) and an additional amount of pyridine (1 mL). The reaction mixture was warmed at 100° C. for 20 h. The reaction mixture was concentrated in vacuo to remove pyridine. The resulting residue was diluted with ethyl acetate then filtered. The filtrate was washed with a 1N aqueous hydrochloric acid solution and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,2,4]triazin-3-yl-propionamide (40.9 mg, 8%) as a yellow-orange solid: mp 81-83° C.; EI-HRMS m/e calcd for C17H18Cl2N4O (M+) 364.0858, found 364.0857.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:14][CH:12]([CH2:13]2)[O:11][C:10](=[O:15])[NH:9]3)=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:24](=[O:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CCCCCC>[C:26]1([CH2:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]34[CH2:14][CH:12]([CH2:13]3)[O:11][C:10](=[O:15])[NH:9]4)=[CH:4][CH:3]=2)=[O:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CON(C)C(=O)Cc1ccccc1
Reactant: O=C1NC2(c3ccc(Br)cc3)CC(C2)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1NC2(c3ccc(C(=O)Cc4ccccc4)cc3)CC(C2)O1

Procedure:
A solution of 5-(4-bromo-phenyl)-2-oxa-4-aza-bicyclo[3.1.1]heptan-3-one (prepared according to WO2009/148916, 4 g) in dry THF (60 mL) was cooled to −78° C. and treated with n-BuLi (6.56 mL of a 2.5M solution in hexane) and stirred for 30 minutes at this temperature before addition of further n-BuLi (13.1 mL of a 2.5M solution in hexane). Stirring was continued at this temperature for 30 minutes before a solution of N-methoxy-N-methyl-benzeneacetamide (prepared according to US6407119B1, 4.6 g) in THF (10 mL) was added. After 10 minutes the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with EtOAc and the combined organic phases washed with brine, filtered and concentrated. The residue was triturated with hexane/EtOAc to give the title compound which was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][S:17](O)(=[O:19])=[O:18]>ClCCl>[C:13]([NH:12][C@@H:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:1]1[CH:6]=[CH:5][C:4]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:3][CH:2]=1)(=[O:15])[CH3:14]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)NC1CCCC1c1ccccc1
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCC[C@H]1c1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C

Procedure:
4.7 g of the crude product of example 2a were dissolved in 90 ml of dichloromethane. To this mixture 5.4 ml of chloro sulfonic acid were added drop by drop under stirring at room temperature. The reaction mixture was heated at 50° C. for 1 hour and, after cooling to room temperature, triturated with 70 ml of ice water. After separating the organic layer was dried over sodium sulfate and evaporated to dryness yielding 4.4 g of the crude product.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[CH3:13]>C(O)(=O)C>[Br:1][CH2:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([F:3])=[C:5]([CH3:13])[CH:6]=1)=[O:12]
Reactant: CC(=O)c1ccc(F)c(C)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(C(=O)CBr)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.67 mL bromine was added to 2 g 1-(4-fluoro-3-methyl-phenyl)-ethanone in 10 mL conc. acetic acid. The reaction was stirred 3 h at RT. The mixture was added to ice water. The precipitate was filtered, washed with water and dried to give 2.7 g desired product. Rt: 1.10 min (method A), (M+H)+: 231
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12](=O)[CH3:13])[CH:8]=[C:9]([CH3:11])[CH:10]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:13])[CH:8]=[C:9]([CH3:11])[CH:10]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(C)cc(OCC(F)F)c1
Product: Cc1cc(OCC(F)F)cc(C(C)N[S@](=O)C(C)(C)C)c1
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (0.97 g, colorless oil) from 1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanone (0.85 g, 3.9 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[CH3:12][C:13](O)([C:15]#[N:16])[CH3:14].S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13]([C:15]#[N:16])([CH3:14])[CH3:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)(O)C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(NC(C)(C)C#N)cc1
Yield: 92 %

Procedure:
A mixture of 4-aminobenzoic acid methyl ester (0.32 g, 2.12 mmol), acetonecyanohydrin (3 ml) and sodium sulfate (1 g) was refluxed for 15 hours. After filtration to remove the sodium sulfate, the filtrate was washed with brine and extracted with ethyl acetate. The organic layer was concentrated and chromatographed (dichloromethane:acetone, 60:40) to yield 4-[(cyanodimethylmethyl)-amino]-benzoic acid methyl ester (49b) (0.398 g, 1.95 mmol, 92%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: Cc1nc(NC(=O)c2ccccc2C(F)(F)F)sc1C(=O)NCc1ccccc1
Yield: 36 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-trifluoromethylbenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 36% yield; 1H NMR (CDCl3, 300 MHz) δ 7.79-7.26 (m, 10H), 5.94 (s, br, 1H), 4.59 (d, J=5.8 Hz, 2H), 2.22 (s, 3H); MS (ES+) m/z 420.0 (M+1).