Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]#[N:38]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:36][C:37]#[N:38])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(O)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(OCC#N)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.5 %

Procedure:
To a stirred solution of 4-[tert-butoxycarbonyl-(5-hydroxy-pyridin-2-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.79 g, 2.0 mmol, 1.0 equiv) in acetonitrile (20 mL) was added potassium carbonate (0.84 g, 6.0 mmol, 3.0 equiv), followed by bromoacetonitrile (0.21 mL, 0.37 g, 3.0 mmol, 1.5 equiv). After stirring at rt for 16 h, the reaction mixture was poured into ice water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.93 g (100%) of the title compound as light brown oil. MS (ISP): 433.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[OH:18])[C:5]([NH:7][CH:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[O:6].[CH3:19][O:20][C:21](OC)(OC)OC>>[CH2:9]([CH:8]([NH:7][C:5]([C:4]1[CH:15]=[CH:16][C:17]2[O:18][C:19]([O:20][CH3:21])=[N:1][C:2]=2[CH:3]=1)=[O:6])[CH2:12][CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: COC(OC)(OC)OC
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(N)c1
Product: CCCC(CCC)NC(=O)c1ccc2oc(OC)nc2c1
Yield: 60 %

Procedure:
Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N-(1-propylbutyl)benzamide (example 41a) and tetramethylorthocarbonate. Yield: 60%. mp 137-138° C.; MS (M+H, 291.10).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[C:4]2[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:3]=12.C(N(CC)C(C)C)(C)C.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.[Cl-].[Li+]>CN1CCCC1=O>[CH3:42][C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][CH:30]([NH:29][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[C:4]3[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:3]=23)[CH2:31][CH2:32]1)=[O:37])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C

Procedure:
A solution of ethyl 4-chloro-1,6-diethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (14.8 g, 52.6 mmol, e.g. which can be as prepared in Intermediate 3, first or alternative preparation thereof) in N-methyl-2-pyrrolidinone (140 ml) was treated with N,N-diisopropylethylamine (22.9 ml, 131 mmol) followed by 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (11.6 g, 57.9 mmol, commercially available e.g. from AstaTech) and the mixture was heated at 120° C. for 24 hours. The reaction mixture was cooled and poured into aqueous lithium chloride solution (5% LiCl, 1 L) and the aqueous phase was extracted with ethyl acetate (3×250 ml). The combined organic extracts were dried (Na2SO4) and the solvent was evaporated. The residue, an oil, was purified by column chromatography using a column of silica gel (ART9385, 500 ml) made up in 4:1 hexane:ethyl acetate, eluting with 4:1 hexane:ethyl acetate (500 ml) and then 2:1 hexane:ethyl acetate until the product eluted. The fractions containing the product were pooled and the solvent was evaporated to give the title compound (18.55 g) as an oil which solidified on standing. LCMS m/z 446 [MH+]; TRET=3.69 min.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(Cl)=[O:12]>C(OC(=O)C)C.C1(C)C=CC=CC=1>[C:2]1([C:1]2[O:8][C:11](=[O:12])[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=c1[nH]nc(-c2ccccc2)o1
Temperature: 25 °C

Procedure:
Into a stirred slurry of 25 g (0.18 mole) benzoylhydrazine in ethylacetate, 142.5 g (0.18 mole) 12.5% phosgene in toluene was dropped in. The reaction mixture was refluxed about 3 hours, and then allowed to stir over the weekend at ambient temperature. The flask was hooked to an aspirator and placed under vacuum to remove any possible peroxides. The mixture was filtered to give the above-identified product as a solid, melting point 133°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[C:19]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20]1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: O=C1CCCC(=O)O1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.7 %

Procedure:
N1-(4-Methoxybenzoyl)-1,2-benzenediamine (3.0 g, 12 mmol), glutaric anhydride (1.7 g, 15 mmol), and pyridine (7 mL) were dissolved in methylene chloride (2 mL) and allowed to stir at ambient temperature for 5 h. The reaction mixture was quenched with water (2 mL) and concentrated in vacuo. The resultant residue was acidified with aqueous sulfuric acid. The resulting white solid was collected and dried at 60° C. in vacuo to yield 3.88 g (88%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:28]=[CH:27][S:26][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:28]=[CH:27][S:26][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:29][C:30]4[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=4)=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nc(N3CCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.2 %

Procedure:
A mixture of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxylic acid (95 mg, 0.236 mmol), tert-butyl 4-aminobenzoate (59 mg, 0.306 mmol), HATU (116 mg, 0.306 mmol) and DIEA (91 mg, 0.708 mmol) in 10 mL of DMF was stirred at room temperature for 72 hours. The solvent was evaporated at 80° C. at reduced pressure and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:1)) to give tert-butyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxamido)benzoate (105 mg, 77%) as a solid. LC-MS: 577.2 [M+H]+, tR=1.69 min
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16][C:17](=[CH2:19])[CH3:18].C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:17]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:19])([CH3:18])[CH3:16]
Reactant: C=C(C)C
Reactant: O=C(O)c1ccc(I)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Iodobenzoic Acid (25 g, 0.10M) was suspended in 200 ml of anhydrous dioxane containing 14 ml of concentrated sulfuric acid. Isobutylene (200 ml) was condensed and added to the suspension. The reaction vessel was sealed and stirred at room temperature for 3 days, during which time most of the material dissolved. The reaction mixture was cautiously poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium carbonate, filtered and evaporated to a colorless oil (18 g, (60%). 1H NMR (CDCl3) δ 1.59 (s, 9H), 7.68 (d, J=8 Hz, 2H), 7.75 (d, J=8 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[N:11]([C@H:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[C:12]=S>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[N:9]=[C:12]([NH:11][C@H:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16][CH2:15]3)[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: S=C=N[C@@H]1CCCc2ccccc21
Product: Cc1cc2nc(N[C@@H]3CCCc4ccccc43)[nH]c2cc1C

Procedure:
The title compound was prepared from 4,5-dimethylphenylenediamine and (R)-l-isothiocyanato-1,2,3,4-tetrahydronaphthalene by Procedure D. The title compound was isolated by column chromatography as the free base (solid, mp 121-124° C.). MS(ES+) m/z 292 ([M+1]+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1>>[CH3:13][C:10]1[C:9]([NH:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:35]=[CH:36][C:37]([C:40]4([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]4)=[CH:38][CH:39]=3)=[CH:3][CH:4]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Nc1nnc(-c2ccccc2)o1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1Nc1nnc(-c2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 166, Step 3, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[CH2:23]([CH2:25][NH2:26])[OH:24]>C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>[OH:24][CH2:23][CH2:25][NH:26][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Reactant: NCCO
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NCCO)s1
Yield: 81.1 %

Procedure:
To a stirred solution of 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (Example 93c, 1.0 g, 3.12 mmol) in toluene (7 mL) was added ethanolamine (229 mg, 3.75 mmol) and TBD (261 mg, 1.88 mmol). After 22 h the reaction mixture was diluted with Seignette's salt and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated in vacuo, then purified by chromatography (silica, 0 to 10% methanol in dichloromethane) then on a 5×50 cm Chiralpak AD column at room temperature using an isopropanol:heptane (2:8) mobile phase with UV detection at 220 nM to give the less polar component 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (884 mg, 81%) as a pale yellow solid then the most polar component 2-[(Z)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (80 mg, 7%) as a pale yellow solid. MS: m/e=350.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[N:18]=[C:17](Cl)[C:16]2[C:11](=[CH:12][C:13]([C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>C(O)C>[NH2:8][C:9]1[N:18]=[C:17]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:16]2[C:11](=[CH:12][C:13]([C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:15]=2)[N:10]=1
Reactant: COC(=O)c1ccc2c(Cl)nc(N)nc2c1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1
Temperature: 110 °C
Yield: 63.1 %

Procedure:
1-Methyl-piperazine (210 uL, 1.9 mmol) was added to a mixture of methyl 2-amino-4-chloroquinazoline-7-carboxylate (300 mg, 1 mmol) in ethanol (3 mL) and triethylamine (350 μL, 2.5 mmol). The mixture was heated in an oil bath at 110° C. for 1 h. The reaction mixture was concentrated to remove the ethanol and was partitioned between water and EtOAc. The organic phase was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered, and concentrated to give the crude product, (190 mg, 50%) as an off white amorphous solid. 1H NMR (300 MHz, DMSO) δ 2.23 (s, 3H), 3.56 (m, 4H), 3.86 (s, 3H), 3.90 (m, 4H), 6.53 (b, 2H), 7.50 (d, 1H), 7.80 (m, 2H); Analytic LCMS (M+H)+: m/z=302.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34]>O>[CH3:15][O:14][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:7][C:2]=1[O:1][CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34]
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Yield: 89.6 %

Procedure:
To a mixture of ethyl (4-hydroxy-3-methoxyphenyl)acetate (7.00 g), potassium carbonate (5.43 g) and N,N-dimethylformamide (100 mL) was added 4-chloromethyl-5-methyl-2-phenyl-1,3-oxazole (8.16 g) with stirring, and the mixture was stirred overnight at 80° C. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave ethyl {3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetate as white crystals (11.38 g, yield 76%). melting point: 86-87° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=2)=[CH:5][CH:4]=1.[C:27]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH:35][CH2:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=2)=[CH:5][CH:4]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: FC(F)(F)c1cc(SCc2ccc(CBr)cc2)ccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)CCN
Product: CC(C)(C)OC(=O)CCNCc1ccc(CSc2ccc(-c3ccccc3)c(C(F)(F)F)c2)cc1

Procedure:
3-[4-(2-Trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzylamino]-propionic acid tert-butyl ester is synthesized similarly as described above by reaction of 4-(4-bromomethyl-benzylsulfanyl)-2-trifluoromethyl-biphenyl with 3-amino-propionic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:32][CH3:33])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:21]>C(#N)C>[CH2:32]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:27]1)[CH3:33]
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Reactant: CCN(CC)CCCC1CCCNC1
Solvent: CC#N
Product: CCN(CC)CCCC1CCCN(C(=O)N2c3ccccc3NC(=O)c3cccnc32)C1
Yield: 38 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 3-[3-(diethylamino)propyl]piperidine in a yield of 38% of theory. Colourless crystals, m.p. 123°-125° C. (acetonitrile).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@H:16]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]([CH3:27])[CH3:26])=[O:18])C)(C)(C)C>ClCCl>[CH3:26][N:25]([CH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:17](=[O:18])[C@H:16]([NH:14][CH3:13])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:27]
Reactant: CN(C)C[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1CN(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.9 %

Procedure:
At 0° C., trifluoroacetic acid (8 ml) was added to a solution of N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methylcarbamic acid tert-butyl ester (2.26 g, 5.80 mmol) in dichloromethane (8 ml). The reaction mixture was stirred for 20 min at 0° C. The solvent was removed in vacuo. Dichloromethane (70 ml) was added, and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.24 g of (2R)-1-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-methylamino-3-phenylpropan-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([O:14]C)=O)[C:9](=[O:16])[S:8][C:5]2=[N:6][CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)=[O:14])[C:9](=[O:16])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)Cn1c(=O)sc2ncc(Cl)cc21
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)Cn2c(=O)sc3ncc(Cl)cc32)CC1
Temperature: 130 °C
Yield: 15.8 %

Procedure:
A mixture of 6-chloro-1-methoxycarbonylmethyl-2-oxo-1,2-dihydrothiazolo[5,4-b]pyridine (2.0 g) and N-methyl-piperazine (1.6 g) was heated at 130° C. for 15 min. After cooling, the mixture was purified on a silica gel column chromatography using a mixture of chloroform and methanol (10:1). The desired fractions containing the objective compound were collected and evaporated. The crude crystals obtained were recrystallized from a mixture of chloroform and diethyl ether to give 6-chloro-2-oxo-1-[(4-methyl-1-piperazinyl)carbonylmethyl]-1,2-dihydrothiazolo[5,4-b]pyridine (0.4 g).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[CH:42]=[CH:41][C:40]([C:43]2([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]2)=[CH:39][N:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:42]=[CH:41][C:40]([C:43]4([S:46]([CH3:49])(=[O:47])=[O:48])[CH2:45][CH2:44]4)=[CH:39][N:38]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)C1(c2ccc(Cl)nc2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(S(C)(=O)=O)CC3)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 20 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 2-chloro-5-(1-methanesulfonyl-cyclopropyl)-pyridine following a procedure analogous to that described in Example 1. Yield: 20% of theory; LC (method 1): tR=1.83 min; Mass spectrum (ESI+): m/z=549 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:21]([Cl:31])[N:20]=[C:19]2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:13][CH:12]=1)([O:3]C)=[O:2].C[S-].[K+]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:21]([Cl:31])[N:20]=[C:19]2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:13][CH:12]=1)([OH:3])=[O:2]
Reactant: CCCCc1nc(Cl)c(COCOCCOC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: C[S-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(COCOCCOC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 80 %

Procedure:
A solution of 3.15 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole and 2.77 g of potassium methanethiolate in 125 mL of dimethylformamide was stirred at 125° for 4 hours. After cooling the solvent was removed in vacuo, and the residue was dissolved in water. The resulting aqueous solution was washed with diethyl ether, adjusted to pH 3 employing 10% hydrochloric acid, and extracted with methylene chloride. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was recrystallized from chlorobutane to afford 2.45 g of 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole. NMR (200 MHz, CDCl3) δ 7.95 (d, 1H); 7.57 (t, 1H); 7.46 (t, 1H); 7.38 (m, 3H); 7.05 (d, 2H); 5.22 (s, 2H); 4.64 (s, 2H); 4.48 (s, 2H); 3.58 (m, 4H); 3.40 (s, 3H); 2.54 (t, 2H); 1.60 (quint., 2H); 1.32 (sext., 2H); 0.84 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH2:22][C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25](Br)[CH:24]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH2:22][C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:24]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)cc2ccoc12)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: CC(C)(C)OC(=O)N(Cc1cc(-c2ccccn2)cc2ccoc12)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
From cis-3-[(5-bromobenzofuran-7-ylmethyl)tert-butoxycarbonyl-amino]-2-phenyl-piperidine-1-carboxylic acid tert-butyl ester (409 mg) and 2-tributylstannanyl-pyridine (339 mg).