Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([C:7]#[N:8])[NH:2]2.[CH2:9]([O:16][C:17]([NH:19][C@@H:20]([C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][C:26]([OH:34])([CH2:27]3)[CH2:25]1)[CH2:31]2)[C:21](O)=[O:22])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:7]([C@@H:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[N:2]1[C:21](=[O:22])[C@@H:20]([NH:19][C:17](=[O:18])[O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][C:26]([OH:34])([CH2:27]3)[CH2:25]1)[CH2:31]2)#[N:8]
Reactant: N#C[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: O=C(N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2)OCc1ccccc1
Product: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(=O)OCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
Path A: (1S,3S,5S)-2-Azabicyclo[3.1.0]hexane-3-carbonitrile or its salts of formula-XIII can be coupled with (2S)-2-{[(benzyloxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid of formula-XIV to give benzyl N-[(1S)-2-[(1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxo-ethyl]carbamate of Formula-XI in a suitable solvent, for example, tetrahydrofuran, N,N-dimethyl formamide, 1,4-dioxane or ethyl acetate using a coupling agent, for example, 1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-(3′-dimethyl amino propyl)carbodiimide (EDAC), 1-propane phosphonic acid cyclic anhydride or N-[(dimethylamino)-1H-1,2,3-trizole[4,5-b]pyridylmethylene]-N-methylmethanaminium hexafluoro phosphate N-oxide (HATU) and optionally, a catalyst, for example, 1-hydroxybenzotriazole (HOBT) or 7-aza-hydroxylbenzotriazole (HOAt) and optionally, with a base, for example, N,N-dimethylamino pyridine (DMAP), triethylamine, N,N-diisopropylethylamine or N-methyl morpholine.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[CH:12]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[OH:13])=[C:4](F)[CH:3]=1.[H-].[Na+]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][N:7]3[CH:11]=[CH:10][CH:9]=[C:8]3[CH:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[O:13][C:4]=2[CH:3]=1
Reactant: CN1CCC(C(O)c2cccn2Cc2ccc(Cl)cc2F)CC1
Agent: [H-]
Agent: [Na+]
Product: CN1CCC(C2Oc3cc(Cl)ccc3Cn3cccc32)CC1
Temperature: 80 °C

Procedure:
A mixture of [1-(4-chloro-2-fluorobenzyl)-2-pyrryl][(1-methyl)piperidin-4-yl]methanol (0.65 g, 0.002 mole) and sodium hydride (50% in oil, 0.12 g, 0.0023 mole, washed once with hexane) in 25 ml 20% DMF/benzene was heated at 80° C. for seven hours.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:23])=[C:12]3[CH:18]=[C:17]([C:19]#[C:20][CH2:21][OH:22])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([OH:36])=[O:35]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:18]=[C:17]([C:19]#[C:20][CH2:21][OH:22])[S:16][C:13]=3[N:14]([CH2:33][C:34]([OH:36])=[O:35])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C#CCO)cc2c1O
Reactant: O=C(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(3-hydroxy-1-propynyl)-thieno[2,3-b]pyridine-5-carboxamide (Example No. 5) (0.250 g) in DMF (3 mL) is added K2CO3 (0.278 g) and bromoacetic acid (0.279 g). The reaction is heated to 100° C. and stirred for 18 h. An additional 0.200 g of bromoacetic acid is added and the reaction is stirred for an additional 18 h. The reaction mixture is concentrated in vacuo, and the resulting residue is dissolved in 10% NaOH and washed with CH2Cl2. The aqueous layer is acidified with conc. HCl and the resulting precipitate is filtered. This material is recrystallized 3 times from methanol to yield 0.068 g (24%) of the title compound as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6](=[O:9])[CH2:7]Br.[C:15]([OH:18])(=[O:17])[CH3:16]>>[C:15]([O:18][CH2:7][C:6]([C:5]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:9])(=[O:17])[CH3:16]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: CC(=O)O
Product: COc1ccc(C(=O)COC(C)=O)cc1OC

Procedure:
Following the procedure of Example 1,5 grams of 3,4-dimethoxyphenacyl bromide are reacted with 5 grams of acetic acid to obtain 3,4-dimethoxyphenacyl acetate, m.p. 82°-84° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14]C)=[CH:10][C:11]=2[CH3:13])[C:6]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:5]1)[CH2:2][CH3:3].Cl.N1C=CC=CC=1>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[CH:10][C:11]=2[CH3:13])[C:6]([CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[CH:5]1)[CH2:2][CH3:3]
Reactant: CCCn1cc(C2CCN(C)CC2)c2cc(OC)cc(C)c21
Agent: Cl
Solvent: c1ccncc1
Product: CCCn1cc(C2CCN(C)CC2)c2cc(O)cc(C)c21
Yield: 87.1 %

Procedure:
By a method similar to PREPARATION 8, using 1-propyl-5-methoxy-7-methyl-3-(1-methylpiperdin-4-yl)-1H-indole (1.24 g) and pyridine hydrochloride (25 g) to afford 1.03 g (87%) of the title compound: mass spectrum (ion spray): m/z=287 (M+1); Calculated for C18H26N2O.0.4 H2O: C, 73.63; H, 9.34; N, 9.23. Found: C, 73.70; H, 9.34; N, 9.33.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[CH2:9][O:8][C:7]=2[CH:23]=1.S(Cl)([Cl:26])=O.N1C=CC=CC=1>ClCCl>[Cl:26][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[CH2:9][O:8][C:7]=2[CH:23]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C=C1c2ccccc2COc2cc(CO)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C=C1c2ccccc2COc2cc(CCl)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 1-b (6.58 g) was dissolved in 200 ml of dichloromethane, and 6.2 ml of thionyl chloride and 6.9 ml of pyridine were added to the solution. The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The obtained product was unstable and immediately subjected to the subsequent reaction without purification.
Reaction SMILES: C[O-].[Na+].[NH:4]1[CH:11]=[CH:10][C:8](=[S:9])[NH:7][C:5]1=[O:6].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:9][C:8]2[CH:10]=[CH:11][NH:4][C:5](=[O:6])[N:7]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=c1[nH]ccc(=S)[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1nc(SCc2ccc(Cl)cc2)cc[nH]1
Yield: 67.3 %

Procedure:
Sodium methoxide (0.057 g, 1.050 mmol) was added to a mixture of 4-thiouracil (0.128 g, 1.0 mmol) and 1-(bromomethyl)-4-chlorobenzene (0.216 g, 1.05 mmol) in 1 mL MeOH. After stirring the reaction at RT overnight, the reaction mixture was concentrated, partitioned between EtOAc and sat. NH4Cl. The organic phase was dried (MgSO4), concentrated and the residue was subjected to ISCO flash chromatography (silica gel/methylene chloride to 80:20 methylene chloride-MeOH gradient) to afford 4-(4-chlorobenzylthio)pyrimidin-2(1H)-one 2A (0.17 g, 0.673 mmol, 67% yield) as a light yellow solid. 1H NMR (400 MHz, methanol-D) δ 7.58 (1H, d, J=6.78 Hz), 7.43 (2H, d, J=8.53 Hz), 7.30 (2H, d, J=8.53 Hz), 6.39 (1H, d, J=6.78 Hz), 4.44 (2H, s).
Reaction SMILES: [Na:1].CC1(C)COC(C[O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)=[O:19])[C:12]=2[CH3:29])OC1.[CH2:31]1[O:35][CH2:34][O:33][CH:32]1[CH2:36]O>>[Na:1].[O:35]1[CH2:31][CH:32]([CH2:36][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)=[O:19])[C:12]=2[CH3:29])[O:33][CH2:34]1
Reactant: OCC1COCO1
Reactant: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: [Na]
Product: Cc1c(OCC2COCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1

Procedure:
The same procedure as in the steps (1c) to (1g) of Example 1 was repeated using glycerol formal (1.76 ml, 20.3 mmol) to obtain the title compound (87 mg, 0.22 mmol) as a beige solid.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:14])[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>C(Cl)Cl>[Br:1][CH2:2][CH:3]([O:14][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1)[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6]
Reactant: CCOC(=O)CNC(=O)CC(O)CBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CC(CBr)OC1CCCCO1
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 1 g ethyl 2-(4-bromo-3-hydroxybutanamido)acetate in 30 ml methylene chloride are added 100 mg pyridinium p-toluenesulphonate and 1 ml dihydropyran. Stirring is continued for 3 h at ambient temperature, the solvent is evaporated in vacuo and the residue chromatographed on silica, eluting with ether. A pale straw-coloured oil is obtained in 91% yield, Rf 0.5 (silica gel plates, thickness 0.25 mm eluent ethyl acetate).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[N:9]=[C:10]([I:11])[C:3]=12.[F:13][CH:14]1[CH2:17][NH:16][CH2:15]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:13][CH:14]1[CH2:17][N:16]([C:2]2[N:7]=[CH:6][N:5]=[C:4]3[N:8]([CH3:12])[N:9]=[C:10]([I:11])[C:3]=23)[CH2:15]1
Reactant: Cn1nc(I)c2c(Cl)ncnc21
Reactant: FC1CNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(I)c2c(N3CC(F)C3)ncnc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (C9) (2.00 g, 6.79 mmol), 3-fluoroazetidine (833 mg, 7.46 mmol), saturated aqueous sodium bicarbonate solution (30 mL), and tetrahydrofuran (40 mL) were combined and allowed to stir at room temperature for 18 hours. After removal of volatiles in vacuo, the residue was diluted with water. Filtration provided the product as a tan solid. Yield: 1.91 g, 5.73 mmol, 84%. LCMS m/z 334.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 3.91 (s, 3H), 4.47-4.63 (m, 2H), 4.75-4.90 (m, 2H), 5.44-5.64 (m, 1H, JHF=58.0 Hz), 8.31 (s, 1H).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C:8]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:11]#[N:12])[C:9]#[N:10]>C(O)=O>[C:11]([C:8]([C:9]#[N:10])([CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:7][CH2:6][CH:2]=[O:1])#[N:12]
Reactant: N#CC(C#N)(CCOCCc1ccccc1)CCC1OCCO1
Solvent: O=CO
Product: N#CC(C#N)(CCC=O)CCOCCc1ccccc1
Yield: 70 %

Procedure:
The material from step c) (0.500 g) was dissolved in 80% formic acid (5 ml) and left to stand at room temperature until TLC analysis indicated that the reaction had gone to completion (17 hours). The reaction mixture was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The combined organic extracts were washed with aqueous sodium bicarbonate solution and brine, dried and evaporated to yield the subtitled compound as a colourless oil (0.349 g, 70%). This was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[N:4][CH:5]=[CH:6][N:7]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:16][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(NNc1nccnc1Cl)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(NNc1ncc(Br)nc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
A 500 mL round bottom flask was charged with N′-(3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide (7.76 g, 32.3 mmol) and CHCl3 (200 mL). To the above solution was added N-bromosuccinimide (8.63 g, 48.5 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 h. Reaction progress was monitored by TLC (EtOAc/petroleum ether=1:2). Work-up: the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 20% EtOAc in petroleum ether, to afford 2.97 g (29%) of the product as a light yellow solid.
Reaction SMILES: [F:1][C:2](=[C:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)=[CH:29][CH:28]=1>CS(C)=O.C(N(CC)CC)C.O>[F:1][C:2]([C:3]1[CH:19]=[CH:18][CH:17]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][N:8]=2)[CH:4]=1)=[C:20]1[CH2:25][CH2:24][N:23]([C:34]([NH:33][C:30]2[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=2)=[O:35])[CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Oc2ccccc2)cn1
Reactant: FC(=C1CCNCC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)N2CCC(=C(F)c3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)cn1
Reaction time: 12 h
Yield: 59.3 %

Procedure:
To a solution of 2-(3-(fluoro(piperidin-4-ylidene)methyl)phenoxy)-5-(trifluoromethyl)pyridine (110 mg, 0.312 mmol) and phenyl 6-methylpyridin-3-ylcarbamate (71.2 mg, 0.312 mmol) in DMSO (5 mL) under a N2 atmosphere was added 5 drops of triethyl amine and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water several times to remove the excess DMSO. The title compound was crystallized from hexane and diethyl ether to give the pure title compound (90 mg). 1H NMR (500 MHz, CDCl3): δ 2.5 (brs, 2H), 2.6 (brs, 2H), 2.8 (s, 3H), 3.7 (brs, 2H), 3.8 (brs, 2H), 7.0 (d, 1H, J=7.5 Hz), 7.1-7.3 (m, 3H), 7.4 (m, 2H), 7.9 (d, 1H, J=7.5 Hz), 8.4 (s, 1H), 9.0 (d, 1H, J=8.5 Hz), 9.4 (s, 1H), 9.8 (s, 1H); 13C NMR (125 MHz, CDCl3): 22.6, 25.6, 27.8, 44.2, 44.4, 53.4, 111.6, 114.1, 114.3, 121.4, 122.0, 123.8, 125.3, 129.7, 130.0, 133.8, 134.7, 136.9, 138.7, 145.4, 151.8, 153.0, 154.6, 165.4; m/z (487.4 M+ H+); HPLC: 98.9%; MP: 158-160° C.
Reaction SMILES: [C:1]([O:5]CC)(=O)[CH:2]=[CH2:3].[CH3:8][N:9]([CH3:15])[CH2:10][CH2:11][CH2:12][NH:13][CH3:14].[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C(OCC)(=O)C.CCOCC>[CH3:8][N:9]([CH3:15])[CH2:10][CH2:11][CH2:12][N:13]([CH3:14])[CH2:3][CH2:2][CH2:1][OH:5]
Reactant: CNCCCN(C)C
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(C)CCCN(C)CCCO
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under stirring, 15 g. ethyl acrylate was added to 11.6 g. N,N,N'-trimethyl-propane-1,3-diamine. Stirring was continued 8 hours at room temperature and the mixture was then heated to 80° C. for 16 hours before stripping the solvent in vacuo. The residue was dissolved in 75 ml. ether and added to a slurry of 2.1 g. LiAlH4 in 100 ml. of ether. This mixture was refluxed 2 hours. After cooling, ethyl acetate and then aqueous HCl were added and the mixture was stirred one hour. The clear, two-phase system was separated. The organic layer was dried over MgSO4, filtered, stripped of solvent, and the residue was distilled at 70°-75° C./0.4 mm, producing pure N,N,N'-trimethyl-N'-(3-hydroxypropyl)propane-1,3-diamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:17][C:18]3[N:28]=[C:21]4[N:22]=[C:23](C)[CH:24]=[C:25](C)[N:20]4[N:19]=3)[C:12](=[O:29])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:35]1([C:38]#[N:39])[CH2:37][CH2:36]1.Cl[C:41]1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC.ClC1C=NC2N(N=C(C=O)N=2)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:17][C:18]3[N:28]=[C:21]4[N:22]=[CH:23][C:24]([CH3:41])=[CH:25][N:20]4[N:19]=3)[C:12](=[O:29])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:35]1([C:38]#[N:39])[CH2:37][CH2:36]1
Reactant: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C5(C#N)CC5)c(Cl)c4)(C4CCCC4)OC3=O)nc2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: O=Cc1nc2ncc(Cl)cn2n1
Product: Cc1cnc2nc(CC3=C(O)CC(CCc4ccc(C5(C#N)CC5)c(Cl)c4)(C4CCCC4)OC3=O)nn2c1

Procedure:
The title compound was prepared analogously to Example B(97) (where 1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione in that example and 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in place of the 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in that example. 1H NMR (400 MHz, CDCl3) δ: 1.38-1.42 (m, 2H), 1.47-1.73 (m, 8H), 1.73-1.77 (m, 2H), 2.01-2.21 (m, 2H)), 2.39-2.50 (m, 1H), 2.56 (d, J=16 Hz, 1H), 2.63-2.69 (m, 2H), 2.80 (d, J=16 Hz, 1H), 3.3 (s, 3H), 3.75 (d, J=16 Hz, 1H), 3.85 (d, J=16 Hz, 1H), 7.29 (dd, J=8, 1.6 Hz, 1H), 7.43-7.45 (m, 2H), 8.74 (d, J=2.3 Hz, 1H), 9.01 (dd, J=2.3, 1.1 Hz, 1H), 10.9 (s, 1H). C29H30ClN5O3.0.25: C, 64.68; H, 6.08; N, 13.00. Found: C, 64.78; H, 5.74; N, 12.65. MS (ESI): 532.2(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.Br[C:24]1[C:33]2[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C:28]=2[CH:27]=[N:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[C:33]3[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C:28]=3[CH:27]=[N:26][CH:25]=2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(Cl)c21
Product: CCC(=O)NC1CCCc2c(-c3cc(Cl)c4c(c3)CCC(=O)N4C)cncc21
Yield: 63 %

Procedure:
In analogy to the procedure described for the preparation of example 28, 8-chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-8) and (rac)-N-(4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-yl)-propionamide (intermediate B-1) were used to give the title compound as a white solid in 63% yield. MS: 398.3 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[CH2:12][N:13]([CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1C(OC(C)(C)C)=O)[CH2:14][CH:15]([CH3:17])[CH3:16].[C:35]([OH:44])(=[O:43])[C@@H:36]([C@H:38]([C:40]([OH:42])=[O:41])[OH:39])[OH:37].C1CCCCC1>ClCCl>[C:40]([C@@H:38]([C@H:36]([C:35]([OH:44])=[O:43])[OH:37])[OH:39])([OH:42])=[O:41].[CH3:16][CH:15]([CH3:17])[CH2:14][N:13]([CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)[CH2:12][C:11]1[CH:10]=[C:9]([Cl:8])[CH:33]=[C:32]([Cl:34])[CH:31]=1
Reactant: CC(C)CN(Cc1cc(Cl)cc(Cl)c1)C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(C)CN(Cc1cc(Cl)cc(Cl)c1)C[C@@H]1CCCN1
Reaction time: 2 h
Yield: 33 %

Procedure:
Trifluoroacetic acid (1.5 ml, 15 mol, 10 eq) is added to a solution of tert-butyl (2S)-2-{[(3,5-dichlorobenzyl)(isobutyl)amino]methyl}pyrrolidine-1-carboxylate (0.611 g, 1.5 mmol, 1 eq) in dichloromethane (5 ml). After 16 hours if not complete by LCMS add an additional portion of trifluoroacetic acid (1.5 ml, 15 mol, 10 eq). After 72 hrs the solvent is removed in vacuo, methanol is added to the residue and the solution is loaded onto a SCX-2 (5 g) column. The column is washed with methanol (10 ml) and then the basic material is eluted with 2M ammonia in methanol (10 ml) and the solvent is removed in vacuo. The residue is dissolved in isopropanol (5 ml) and L-tartaric acid (1 eq) is added. The solution is heated to dissolve, then cooled and is left to stand in a fridge for 2 hrs, if no crystals have formed cyclohexane is added and the surface is scratched with a glass rod. The solid formed is filtered and dried in a vacuum oven at 60° C. for 16 hrs to give the N-(2-methylpropyl)-N-{[3,5-dichlorophenyl]-methyl}-(2S)-pyrrolidine-2-yl-methylamine L-Tartrate (0.23 g, 33%). 1H NMR (300 MHz, CD3OH) δH: 7.26 (3H, s) 4.29 (2H, s, tartrate) 3.44-3.78 (3H, m) 3.06-3.30 (4H, m) 2.42-2.71 (2H, m) 2.00-2.19 (3H, m) 1.83-1.99 (2H, m) 1.65-1.81 (1H, m) 1.46-1.64 (1H, m) 0.79 (6H, dd, J=6.5 and 3.2), LCMS: Rt=3.52 (12 min method) [M+H]=315.4.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([C:14]([NH:16][C@H:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:39]>C(N(CC)CC)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([C:14]([NH:16][C@H:17]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[O:15])[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)(=[S:39])[NH2:2]
Reactant: S
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)NC(=O)C1CN(c2ccc(C#N)cc2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)NC(=O)C1CN(c2ccc(C(N)=S)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.6 g of tert-butyl (2R)-2-[3-(4-cyanophenyl)-2-oxo-5-oxazolidinylcarbonylamino]-3-phenylpropionate [obtainable according to Example 8] are dissolved in a solvent mixture consisting of 30 ml of pyridine and 5 ml of triethylamine and the mixture is stirred for 1.5 h with ice cooling, with H2S gas being passed in continuously during this phase. The reaction mixture is subsequently stirred at room temperature for 24 h. Concentration by evaporation and customary workup give tert-butyl (2R)-2-[3-(4-thiocarbamoylphenyl)-2-oxo-5-oxazolidinylcarbonylamino]-3-phenylpropionate, m.p. 185°-186°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.OC1C=C(C(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[C:11](=[O:12])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(/C=C/c1cc(F)cc(F)c1)c1cccc(O)c1
Agent: O=C(/C=C/c1ccccc1)c1cccc(O)c1
Product: O=C1CC(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reaction time: 120 h
Yield: 99 %

Procedure:
The procedure of Step 2 of Example 1 was repeated except for using (E)-3-(3,5-difluorophenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one obtained in Step 1 as a starting material instead of (E)-1-(3-hydroxyphenyl)-3-phenylprop-2-en-1-one and being stirred for 5 d to obtain the title compound (99%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.[CH3:9][NH2:10]>>[CH3:9][NH:10][CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1
Reactant: Nc1nc(CCl)cs1
Reactant: CN
Product: CNCc1csc(N)n1
Yield: 15 %

Procedure:
4-(Chloromethyl)-1,3-thiazol-2-amine (490 mg, 2.65 mmol) was stirred in 40% aqueous methylamine (25 ml) overnight. The reaction mixture was evaporated. The residue was then purified via reverse phase HPLC to provide 4-[(methylamino)methyl]-1,3-thiazol-2-amine (55 mg, 15%). LCMS: (M+H)+: 144.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: Cc1cccc(Br)c1
Product: Cc1cccc(-c2ccc(N)cc2)c1

Procedure:
The title compound was prepared by Suzuki coupling of 1-bromo-4-nitrobenzene and 1-bromo-3-methylbenzene.