Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:26]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:8]([NH2:28])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:30]([CH3:32])[CH3:31]>>[NH2:28][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:26])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH:30]([CH3:32])[CH3:31])[CH2:22][CH2:21]1
Reactant: CC(C)I
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCCC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[5-(4-piperidinyl)pentyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28](OB(O)O)=[CH:27][C:26]=1[CH3:36])[CH3:20].C(N(CC)CC)C>ClCCl>[CH2:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:27][C:26]=1[CH3:36])[CH3:20]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCOCCOc1c(C)cc(OB(O)O)cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCCOc1c(C)cc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.4 g), 4-(2-ethoxyethoxy)-3,5-dimethylphenylboric acid (0.71 g), cupric acetate (0.27 g) and molecular sieves 4A (0.8 g) suspended in dichloromethane (15 ml) was added triethylamine (1.0 ml), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the filtrate was evaporated to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain methyl 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.39 g) as a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[CH:4]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+].O>CN(C)C=O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:2][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]([CH3:13])[C:5](=[O:14])[CH:4]=3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: Cn1c(=O)cc(CBr)c2ccccc21
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)cc(CN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc21
Yield: 64.6 %

Procedure:
A suspension of 4-bromomethyl-l-methyl-2(1H)-quinolinone (756 mg, 3 mmol), 3-(4-piperidinyl)-1H-indole (600 mg, 3 mmol) and sodium hydrogencarbonate (378 mg, 4.5 mmol) in dry dimethylformamide (5 ml) was allowed to react at 80 ° C. for 2 hours. The reaction mixture was poured into water and the separated solid was filtered off. The solid was washed with water, dried and then recrystallized from methanol/tetrahydrofuran to give the desired product (III16) (720 mg, yield 65%). Mp 228°-229 ° C. (methanol/tetrahydrofuran).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C([O-])([O-])=O.[K+].[K+].[CH3:11][O:12][C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]34[CH2:38][CH:33]5[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]5)[CH2:30]3)[CH2:36]4)[CH:23]=2)=[CH:18][CH:17]=1.O>CN(C=O)C>[CH3:11][O:12][C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:2][C:3]#[N:4])=[C:24]([C:29]34[CH2:38][CH:33]5[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]5)[CH2:30]3)[CH2:36]4)[CH:23]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1ccc(-c2ccc(OCC#N)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
Bromoacetonitrile (84 mg, 0.7 mmol), K2CO3 (166 mg, 1.2 mmol) and KI (53 mg, 0.32 mmol) were added to a solution of (E)-3-(3′-adamantan-1-yl-4′-hydroxybiphenyl-4-yl)-acrylic acid methyl ester (250 mg, 0.64 mmol) in DMF (2 ml). The mixture was stirred at RT for 3 h. Cold water was added and the solution was extracted with EtOAc. The organic layer was washed with a saturated solution of NaHCO3, water and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to obtain (E)-3-(3′-adamantan-1-yl-4′-cyanomethoxybiphenyl-4-yl)-acrylic acid methyl ester (240 mg, 88%).
Reaction SMILES: C(OC(=O)[CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:7])C.[BrH:15].[Br:16]Br>>[BrH:15].[Br:15][CH:5]([Br:16])[C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: BrBr
Reactant: CCOC(=O)CC(=O)c1cccnc1
Agent: Br
Product: O=C(c1cccnc1)C(Br)Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.6 %

Procedure:
3-(3-Pyridyl)-3-oxopropionic acid ethyl ester (1.95 g, 10.2 mmol) was added dropwise to 47% aqueous HBr solution (3.86 g) under ice-cooling. Bromine (2.2 g, 1.2 equivalent amount relative to 3-(3-pyridyl)-3-oxopropionic acid ethyl ester) was added dropwise at not more than 10° C. After stirring for 30 min, iced-water bath was removed and water (2 ml) and 47% aqueous HBr solution (4 ml) were added. The mixture was stirred at room temperature for 30 min. Furthermore, bromine (2.2 g, 1.2 equivalent amount relative to 3-(3-pyridyl)-3-oxopropionic acid ethyl ester) was added dropwise and the mixture was stirred at 65-70° C. After cooling to room temperature, the reaction mixture was filtrated to give 3.73 g of the titled compound (yield 95.2%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.CCCCCC.[Sn:17](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[CH2:26]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1nccs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazol (0.71 ml, 10 mmol) in dry THF (20 ml) was added dropwise 1.6 M-BuLi in hexane (6.9 ml, 11 mmol) under argon at -78° C. The reaction mixture was stirred at -78° C. for 0.5 hr and Bu3SnCl (3.1 ml, 11 mmol) was added dropwise. After stirring for 1 hr at -78° C. and for 1 hr at room temperature, the mixture was concentrated, triturated with water (50 ml) and extracted with diethylether (100 ml×3). The extract was washed with brine, dried and concentrated under reduced pressure to give (33) as colorless oil.(3.7 g, quant.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[C:10]([NH:25][C:26](=[O:53])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[N:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[C:41](=[O:46])[C:42]([F:45])([F:44])[F:43])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCCCC=1>O1CCOCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([NH:25][C:26](=[O:53])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[N:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[C:41](=[O:46])[C:42]([F:43])([F:44])[F:45])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4ccc(OCc5ccccc5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: C1=CCCCC1
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4ccc(O)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Yield: 95 %

Procedure:
5-Benzyloxy-3-{4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoylamino}-indazole-1-carboxylic acid tert-butyl ester (2.3 g, 3.13 mmol) in dioxane (46 mL) was treated with cyclohexene (18 mL) and 10% Pd/C (1.6 g). The mixture was stirred at reflux temperature. After 1.5 hs it was filtered over a celite funnel and washed with dioxane. Evaporation of the solvent left a solid that was washed with Et2O. After drying at 45° C. under vacuum, 1.92 g of title compound in 95% yield were obtained.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[C:10]=1[CH3:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[C:1]([C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([CH3:19])[C:16]([O:18][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:17])[C:10]=1[CH3:20])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 62.7 %

Procedure:
In 5 ml of methylene chloride was dissoved 2-(3-benzoyl-2,5-dimethylpyrrol-1-yl)propionic acid (500 mg, 1.85 mmoles), and 257 μl (1.85 mmoles) of triethylamine was added. The mixture was stirred at -15° C. for 5 minutes. Isobutyl chloroformate (243 μl, 1.85 mmoles) was added to the solution, and the mixture stirred at -15° C. for 10 minutes. Then, 190 μl (1.85 mmoles) of benzyl alcohol was added. The mixture was stirred at room temperature for 20 hours, and 50 ml of methylene chloride was added. The organic layer was washed with water, dilute hydrochloric acid and an aqueous solution of sodium hydrogen carbonate in this order, dried, and concentrated to afford 543 mg of a crude product. The product was chromatographed on a column of silica gel using benzene/ethyl acetate as an eluent to afford compound (720)(421 mg, 1.16 mmoles, 63%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=3)[N:12]([CH3:23])[C:11](=[O:24])[C:10]=12)=[O:5])[CH3:2].[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:25])[N:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=3)[N:12]([CH3:23])[C:11](=[O:24])[C:10]=12)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncn2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Yield: 39.5 %

Procedure:
To a solution of 5-methyl-4-oxo-7-trifluoromethyl-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (3.9 g) in carbon tetrachloride (250 ml) was added N-bromosuccinimide (20 g). The mixture was stirred vigorously and was refluxed for 18 hours. After removal of solvent under water aspirator vacuum the residue was chromatographed via a short silica gel dry column (chloroform as eluant). The product was isolated out as an off-white solid (1.9 g, 39% yield). Recrystallized from acetonitrile, m.p. 205°-207° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[C:20]([OH:34])[CH:19]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:9]([O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])=[C:20]([O:34][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Oc1ccc(C(=O)OCc2ccccc2)c(O)c1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Benzyl bromide (0.80 mL) was added to a mixture of benzyl 4-benzoyloxy-2-hydroxybenzoate (2.23 g) and cesium carbonate (2.29 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was stirred at 50° C. for 3 hrs, and water was added. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure liquid silica gel column chromatography (eluent: n-hexane/ethyl acetate=6/1) to afford benzyl 4-benzoyloxy-2-benzyloxybenzoate (2.87 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11](=O)[C:10]([CH3:14])([CH3:13])[C:9]2[C:4](=[C:5]3[CH2:27][CH2:26][CH2:25][C:6]3=[C:7]([C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][CH:19]=[N:20]4)[CH:8]=2)[NH:3]1.[CH3:29]C1C(C2C=C3C(=C4CCCC=24)NC(C)(C)C(=C)C3(C)C)=C(C)ON=1>>[CH3:1][C:2]1([CH3:28])[C:11](=[CH2:29])[C:10]([CH3:14])([CH3:13])[C:9]2[C:4](=[C:5]3[CH2:27][CH2:26][CH2:25][C:6]3=[C:7]([C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][CH:19]=[N:20]4)[CH:8]=2)[NH:3]1
Reactant: C=C1C(C)(C)Nc2c(cc(-c3c(C)noc3C)c3c2CCC3)C1(C)C
Reactant: CC1(C)Nc2c(cc(-c3cccc4ncccc34)c3c2CCC3)C(C)(C)C1=O
Product: C=C1C(C)(C)Nc2c(cc(-c3cccc4ncccc34)c3c2CCC3)C1(C)C
Yield: 21 %

Procedure:
Using 2,2,4,4-tetramethyl-6-(quinolin-5-yl)-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one obtained in Example instead of 6-(3,5-dimethylisoxazol-4-yl)-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one of Example 23 and according to a similar method, the title compound (13 mg, 21%) was obtained.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2](C)=[CH2:3].[C:8](OC)(=O)[CH:9]=[CH2:10].[C:14](#[N:17])[CH:15]=[CH2:16].[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:14](#[N:17])[CH:15]=[CH2:16].[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[CH:2]=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: C=CC(=O)OC
Solvent: C=Cc1ccccc1
Solvent: C=CC#N
Product: C=CC(=O)OCCCC

Procedure:
Polymerization was conducted in the same manner as in Production Example 16 excepting that 36 parts of methyl methacrylate and 2 parts of methyl acrylate used in graft polymerization was changed to 10 parts of acrylonitrile and 28 parts of styrene, obtaining graft copolymer latex obtained by graft-polymerizing acrylonitrile and styrene to butyl acrylate rubber.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:10]=[C:9]([CH2:11][N:12]2[CH2:16][CH2:15][N:14]([C@@H:17]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([O:20]C(C)(C)C)=[O:19])[C:13]2=[O:29])[CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].FC(F)(F)C(O)=O>O>[OH:1][C:2]([C:5]1[N:10]=[C:9]([CH2:11][N:12]2[CH2:16][CH2:15][N:14]([C@@H:17]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([OH:20])=[O:19])[C:13]2=[O:29])[CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2cccc(C(C)(C)O)n2)C1=O)C(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)c1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 224.2 %

Procedure:
The product of Example 50-5 (61 g, 150.6 mmol) at 25° C. was treated with 90% trifluoroacetic acid in water (300 mL). The reaction was stirred at 25° C. for 5 hours and concentrated to give 118 g of residue. The residue was loaded on 600 g of silica gel, eluted with 4 L of 5% methanol in dichloromethane, then with 4 L of 10% methanol in dichloromethane. The desired fractions were combined and concentrated to give 100 g of crude material. The crude material was crystallized from diethyl ether (350 mL) to afford 54 g of the trifluoroacetic acid salt of the title compound, 77% yield. 1H NMR (CDCl3): δ ppm 1.10 (s, 9 H,) 1.63 (s, 6 H), 3.48 (m, 2 H), 3.65 (m, 1 H), 3.87 (m, 1H), 4.33 (s, 1 H), 4.78 (q, 2 H), 7.54 (d, 1 H), 7.61 (d, 1 H), 8.12 (t, 1 H), 9.2(w, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]#[N:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1.C(N(CC)CC)C>C(O)CCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]#[N:16])[CH2:14][CH2:13][N:12]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: N#CC1(c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: N#CC1(c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 79.7 %

Procedure:
A solution of 4-(4-chlorophenyl)piperidine-4-carbonitrile hydrochloride (0.055 g, 0.2155 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.033 g, 0.2155 mmol) and triethylamine (0.150 ml, 1.0775 mmol) in n-butanol (2.0 ml) was heated to 100° C. for 2 days. Concentration and trituration with methanol (3 ml) gave a white solid (0.058 g, 80%). LC-MS (LCT2) m/z 338 [M+H+], Rt 6.17 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][F:26])[C@H:9]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.CO.[Pd]>[F:26][CH2:25][CH2:24][N:8]([C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCF)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCF)[C@H]1CCNC1
Reaction time: 2 h

Procedure:
To a suspension of 5% Pd/C (1.4 g, 2.2 mmol) in ethanol (12 mL) was added slowly a solution of (S)-benzyl 3-(tert-butoxycarbonyl(2-fluoroethyl)amino)pyrrolidine-1-carboxylate (2.44 g, 21.6 mmol) in methanol (5 mL). The mixture was evacuated and backfilled with nitrogen and then evacuated and backfilled with hydrogen, then stirred under a hydrogen atmosphere for 2 hours. The suspension was filtered through a pad of Celite and washed with a methanol (50 ml). The filtrate was concentrated under reduced pressure to afford (S)-tert-butyl 2-fluoroethyl(pyrrolidin-3-yl)carbamate. To a solution of (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (0.97 g, 2.82 mmol) in anhydrous THF (5 mL) was added (S)-tert-butyl 2-fluoroethyl(pyrrolidin-3-yl)carbamate (0.92 g, 3.95 mmol) and K2CO3 (0.59 g, 4.23 mmol). The resulting mixture was heated with stirring at 50° C. for 18 hours. After cooling to ambient temperature the mixture was partitioned between water (12 mL) and ethyl acetate (30 mL). The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure and the residue obtained purified by column chromatography (Biotage 25M; 10% ethyl acetate:hexanes) to afford tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-yl(2-fluoroethyl)carbamate (0.58 g, 48%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][CH3:19])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:18]([CH:15]1[CH2:14][CH2:13][N:12]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:17][CH2:16]1)[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CNC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
0.2 mole of acetyl chloride is slowly added to a solution containing 0.2 mole of N-[1-(benzyl)-4-piperidyl]-N-methylamine, 0.2 mole of triethylamine and 500 cm3 of methylene chloride. The mixture is left in contact for 2 hours, evaporated, taken up in ether and then washed with water. After evaporation, an oil which corresponds to the expected compound is obtained:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C@:9]([NH2:16])([CH3:15])[C:10]([F:14])([F:13])[CH2:11][OH:12])=[O:5])[CH3:2].[N:17]#[C:18]Br.C(#N)C>C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C@:9]1([CH3:15])[C:10]([F:14])([F:13])[CH2:11][O:12][C:18]([NH2:17])=[N:16]1)=[O:5])[CH3:2]
Reactant: N#CBr
Reactant: CCOC(=O)[C@H]1C[C@@H]1[C@@](C)(N)C(F)(F)CO
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)[C@H]1C[C@@H]1[C@@]1(C)N=C(N)OCC1(F)F
Temperature: 75 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
A mixture of (1S,2S)-rel-2-((R)-1-amino-2,2-difluoro-3-hydroxy-1-methyl-propyl)-cyclopropane-carboxylic acid ethyl ester (542 mg, 2.28 mmol) and cyanogen bromide in acetonitrile (5M; 685 μl, 3.43 mmol) in ethanol (14 ml) was heated at 75° C. for 7 hours. In order to complete the reaction another volume of cyanogen bromide in acetonitrile (5M; 228 μl, 1.14 mmol, Eq: 0.50) was added and heating continued at 75° C. for 6 hours, and again cyanogen bromide in acetonitrile (228 μl, 1.14 mmol, Eq: 0.50) was added and heating continued at 75° C. for 24 hours. For the workup, the solution was evaporated, the residual oil was washed once with a solution of sodium carbonate (2M) and twice with ethyl acetate, then dried over sodium sulphate, filtered and concentrated at reduced pressure. The light yellow oil (731 mg) was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent. The (1S,2S)-rel-2-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropanecarboxylic acid ethyl ester (404 mg, 67% yield) was obtained as a colorless oil. MS (ISP): m/z=263.2 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([C:26](Cl)=[O:27])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:26]([C:24]4[CH:23]=[CH:22][C:21]5[O:16][CH2:17][CH2:18][O:19][C:20]=5[CH:25]=4)=[O:27])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)c1ccc2c(c1)OCCO2
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc2c(c1)OCCO2

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 2,3-dihydro-1,4-benzodioxine-6-carbonyl chloride (74 mg; 0.37 mmol; 1.5 eq.) as a white powder (34 mg, 37%). HPLC, Rt: 3.17 min. (purity 81.5%). LC/MS, M+(ESI): 363.0.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][N:10]=2)=[N:6][C@@H:5]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[C:4]=1[C:25]([O:27][CH3:28])=[O:26].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CO.O>[Cl:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C@H:5]1[C:4]([C:25]([O:27][CH3:28])=[O:26])=[C:3]([CH2:2][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][N:10]=2)=[N:6]1
Reactant: COC(=O)C1=C(CBr)NC(c2ncc(F)cc2F)=N[C@H]1c1ccc(F)cc1Cl
Reactant: C1CCNCC1
Solvent: O
Solvent: CO
Product: COC(=O)C1=C(CN2CCCCC2)NC(c2ncc(F)cc2F)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 100 mg of freshly prepared methyl (R)-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridyl)-1,4-dihydropyrimidine-5-carboxylate from Example XIII in 0.5 ml of methanol is mixed with 5 equivalents of piperidine and stirred at room temperature for 30 minutes. The solution is diluted with water and extracted with ethyl acetate.