Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1.[H-].[Na+].Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Cl.CN1C(=O)N(C)CCC1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH2:14][O:15][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=1
Reactant: COCCOCOc1cccc(CO)c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Product: COCCOCOc1cccc(COCc2ccccn2)c1
Reaction time: 0.17 h

Procedure:
To a cooled solution (0° C.) of [3-(2-methoxy-ethoxymethoxy)-phenyl]-methanol (212 mg, 1 mmol, example 72) in THF (3 mL) is added 60% NaH (80 mg, 2 mmol) and the mixture stirred 10 min. Added 2-picolyl chloride hydrochloride (164 mg, 1 mmol) and DMPU (0.8 mL), removed cold bath and let reaction mixture stir for 2 hrs. Quenched reaction with sat NH4Cl soln. and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 70% ethyl acetate in hexanes) to give the title compound as a pale yellow oil. MS (ESI) 304 (M+H)+.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[Li].C([Li])CCC.[CH3:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.C(Br)C=C.[Cl-].[NH4+]>O1CCCC1.O>[N:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:15]=1[CH2:14][CH2:3][CH:1]=[CH2:2]
Reactant: CC(C)NC(C)C
Reactant: Cc1cnccn1
Agent: [Cl-]
Agent: [Li]
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Solvent: O
Product: C=CCCc1cnccn1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of lithium diisopropylamine [prepared from a solution of butyl lithium in hexanes (100 mL, 2.5M) and diispropylamine (25.3 g) at −35° C.] was treated with a solution of 2-methylpyrazine (23.5 g) in dry tetrahydrofuran (300 mL) at −20° C. The mixture was stirred at −20° C. for 1 hour then cooled to −78° C. and treated with a solution of allyl bromide (30.8 g) in dry tetrahydrofuran (300 mL). This mixture was warned to room temperature and stirred at this temperature for 2 hours then left overnight and then treated with saturated ammonium chloride solution (50 mL) followed by water (200 mL). The mixture was then extracted twice with ether (200 mL). The combined extracts were dried over magnesium sulfate then evaporated. The residue was distilled to give the title compound (22 g) as a colorless oil, b.p. 70° C./1 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH2:25]Br.[CH3:27][C:28]([O-:30])=[O:29].[Na+]>CC(O)=O>[C:28]([O:30][CH2:25][C:3]1[CH:4]=[C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:29])[CH3:27]
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c(CBr)c2)=NO1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 3-(4-bromo-3-(bromomethyl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (36 mg, 0.068 mmol) and NaOAc (6 mg, 0.074 mmol) in AcOH (1 mL) was refluxed for 16 h, cooled to rt and concentrated under reduced pressure. The residue was dissolved in EA, washed with H2O, dried over MgSO4, filtered and concentrated under reduced pressure to give 2-bromo-5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzyl acetate (29 mg; yield 85%) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.O.[NH2:12][NH2:13].O.[ClH:15]>C(O)C.C(OCC)C>[ClH:15].[NH:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1)[NH2:13]
Reactant: NN
Reactant: Cc1cc(F)ccc1C#N
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Cc1cc(NN)ccc1C#N
Temperature: 80 °C
Yield: 37 %

Procedure:
In a dried reaction flask, 4-fluoro-2-methylbenzonitrile (4.055 g, 30.0 mmol) and hydrazine hydrate (85%) (3.54 mL, 60.0 mmol) were dissolved in ethanol (15.9 mL). In the protection from light and under the nitrogen atmosphere, the solution was heated under reflux at 80° C. for 48 hr. Water was added to the reaction solution. The mixture was filtered. The filtered cake was rinsed with water to produce a pale yellow solid, which was suspended in ethyl ether. A hydrogen chloride gas was passed into the suspension under an ice-salt bath. The suspension was filtered. The filtered cake was rinsed with ethyl ether to produce an off-white solid (2.04 g) in 37.0% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:30])([C:25]1[O:26][CH:27]=[CH:28][N:29]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:25]1[O:26][CH:27]=[CH:28][N:29]=1)[CH3:30]
Reactant: CC(C)(N)c1ncco1
Reactant: O=C(O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1
Product: CC(C)(NC(=O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1)c1ncco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid (Example 125 b) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=412.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[N:39]=[N:38][C:37]([NH2:40])=[CH:36][CH:35]=1>ClCCCl.CN(C=O)C.N1C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:18])[NH:40][C:37]3[N:38]=[N:39][C:34]([Cl:33])=[CH:35][CH:36]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Nc1ccc(Cl)nn1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(Cl)nn4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 0.500 g, 1.334 mmol) in 1,2-dichloroethane (1.3 ml) and DMF (1 drop) was added oxalyl chloride (0.1396 ml, 1.601 mmol), and the reaction was stirred for 1 hour at ambient temperature. The reaction was diluted with pyridine (5 ml) and 6-chloropyridazin-3-amine (0.2592 g, 2.001 mmol) was added. The reaction was heated to 80° C. for 16 hours, then diluted with EtOAc and washed with 1M hydrochloric acid, sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography eluting with a linear gradient of 5-70% EtOAc/hexanes to yield the desired compound (0.5 g, 1.028 mmol, 77.07% yield).
Reaction SMILES: CN(C=O)C.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[C:27]([O:26][C:24](=[O:25])[CH2:23][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)/C=C/c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc2ccccc2n1CC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To a 0.1 M DMF solution of ethyl (2E)-3-(1H-indol-2-yl) acrylate from Step 2 was added 1.4 equiv. of BrCH2CO2-t-Bu and 2.1 equiv. of Cs2CO3. The reaction mixture was stirred at 60° C. for 24 h, and was then diluted with an equal volume of acetone and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography eluted with EtOAc/Hex (1:2) to give the title compound (98%) as a syrup.
Reaction SMILES: [N:1](OCCC(C)C)=O.[NH2:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17](=[O:38])[CH:18]=[P:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>Cl>[F:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[N:9]=[N:1][C:18](=[P:19]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:17]2=[O:38]
Reactant: CC(C)CCON=O
Reactant: Nc1c(F)cccc1C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: O=C1C(=P(c2ccccc2)(c2ccccc2)c2ccccc2)N=Nc2c(F)cccc21
Temperature: 25 °C

Procedure:
Isoamyl nitrite (1.9 eq) was added to a stirred solution of D2 in HCl (0.5 M solution in MeOH) at 0° C. After the consumption of the starting material (15-30 min), the solution was allowed to warm to RT and was made alkaline (pH=9) by addition of 10% NaOH. The resulting precipitate was collected by filtration affording the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>CO>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: C=CCN1CCN(c2ccc(N)cn2)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
2.2 g (8.86 mmol) of 1-allyl-4-(5-nitropyridin-2-yl)piperazine from Example 1.1 were dissolved in 150 ml of methanol after which 18 g (79.75 mmol) of tin(II) chloride dihydrate were added and the mixture was stirred at 70° C. for 4 hours. After the solvent had been evaporated down to dryness, water was added to the residue. The aqueous reaction mixture was made alkaline with dilute sodium hydroxide solution and then extracted with ethyl acetate. The solid which had precipitated out was filtered off. After that, the phases were separated and the aqueous phase was extracted in each case twice with ethyl acetate and dichloromethane. The combined organic phases were dried over sodium sulfate. 1.74 g (90% of theory) of the title compound were obtained after the drying agent had been removed and the solvent had been evaporated down to dryness.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].[N:9]([CH2:12][Si:13]([O:17][CH3:18])([O:15][CH3:16])[CH3:14])=[C:10]=[O:11]>C(OCC)(=O)C>[CH:1]([C:4]1[N:5]([C:10](=[O:11])[NH:9][CH2:12][Si:13]([O:17][CH3:18])([O:15][CH3:16])[CH3:14])[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ncc[nH]1
Reactant: CO[Si](C)(CN=C=O)OC
Solvent: CCOC(C)=O
Product: CO[Si](C)(CNC(=O)n1ccnc1C(C)C)OC
Reaction time: 1 h

Procedure:
A stirred solution conditioned at a temperature of 50° C. of 3.00 g of 2-isopropylimidazole in 50 ml of ethyl acetate was admixed dropwise with 4.39 g of (isocyanatomethyl)dimethoxy(methyl)silane and the mixture was stirred for 60 min. This gave 2-isopropyl-1-{[dimethoxy(methyl)silyl]-methylcarbamoyl}imidazole after filtration as a colorless solid in quantitative yield with a purity of >95% (analysis by 29Si and 1H NMR).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]([CH3:19])([C:16](=[O:18])[CH3:17])[CH2:14][OH:15].N1C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[CH3:12][C:13]([CH3:19])([C:16](=[O:18])[CH3:17])[CH2:14][O:15][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CC(=O)C(C)(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.1 %

Procedure:
47.6 g (0.25 mol) of 4-toluenesulphonyl chloride were dissolved in 100 ml of chloroform, 35 g (0.3 mol) of 2,2-dimethyl-1-hydroxy-butan-3-one were added, and 40 ml (0.5 mol) of pyridine were added dropwise at 0° to 50° C. The reaction mixture was subsequently stirred at room temperature for 15 hours and poured on to 200 g of ice and 70 ml of concentrated hydrochloric acid and the organic phase was separated off, rinsed three times with 200 ml of water each time, dried over sodium sulphate and concentrated. The residue was taken up in 100 ml of petroleum ether, whereupon the end product crystallized out. 46 g (71% of theory) of 2,2-dimethyl-1-tosyloxy-butan-3-one were obtained as colorless crystals of melting point 49° to 52° C. ##STR763##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[N+:16]([O-])=O)[CH:9]=1)[CH3:6])[CH3:2].Cl>C(O)C.[Pd].C>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][NH2:16])[CH:9]=1)([CH3:19])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(/C=C/[N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Reaction time: 5 h
Yield: 62 %

Procedure:
7.82 g (28.0 mmol) of 2-methyl-2-[3-((E)-2-nitro-vinyl)-phenoxy]-propionic acid ethyl ester was dissolved in 150 ml ethanol; 6.2 ml (39.7 mmol) hydrochloric acid in ethanol and 1.6 g of Pd-charcoal (10%) were added and the reaction mixture was then hydrogenated under 1 atm of H2-pressure during 5 hours. It was subsequently filtered (Celite), the filter cake was washed twice with ethanol and filtrate was evaporated. The residue was then partitioned between crashed ice/Na2CO3-solution/MeCl2 and extracted twice with MeCl2; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (SiO2, MeCl2/MeOH) to give 4.36 g of the title compound as yellow oil.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[CH:11]=3)[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:25])C(=O)C1>C(Cl)Cl>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:15])([CH3:16])[C:12](=[O:17])[C:11]=3[Br:25])[CH:7]=[CH:6][C:5]=12
Reactant: CC1(C)OC(c2ccc3nonc3c2)=CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC1(C)OC(c2ccc3nonc3c2)=C(Br)C1=O
Reaction time: 3 h
Yield: 59.6 %

Procedure:
To a stirred solution of 5-(benzo[c][1,2,5]oxadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.25 g, 1.086 mmol) CHCl3 (15 mL), NBS (0.29 g, 1.630 mmol) was added portionwise at RT. The reaction mixture was then stirred for 3 h and diluted with DCM (10 mL). The organic layer was then washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(benzo[c][1,2,5]oxadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.2 g, 60%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:16])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:15])=[O:5])[CH3:2].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=1[O:28][CH2:29][CH2:30][C:31]1[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[C:20]([O:28][CH2:29][CH2:30][C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)[CH:21]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1=O
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(C)c1
Product: CCOC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1=O

Procedure:
2-Amino-1-oxo-indane-2-carboxylic acid ethyl ester (L. Benati et al., J. Org. Chem. 64 (1999), 7836-7841) (460 mg, 2.10 mmol) was reacted with 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 2 of example 13 to yield 0.331 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1cccc(C#N)c1N
Product: Cc1cccc(C#N)c1NC(=O)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 1a from 2-amino-3-methylbenzonitrile (Example 15b) and benzoyl isocyanate as a white powder (186 mg, 67%). MS 280 (MH+).
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(CN3C[C@@H](C)N(CC4C=CC=CN=4)[C@@H](C)C3)=CC=2N=1.[CH3:33][C@H:34]1[CH2:39][NH:38][CH2:37][C@@H:36]([CH3:40])[N:35]1[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1.[C:48]([O:52][C:53](N1C[C@H](C)N[C@H](C)C1)=[O:54])([CH3:51])([CH3:50])[CH3:49].Br.BrCC1C=CC=CN=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)Cl>[C:48]([O:52][C:53]([N:38]1[CH2:39][C@@H:34]([CH3:33])[N:35]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[C@@H:36]([CH3:40])[CH2:37]1)=[O:54])([CH3:51])([CH3:50])[CH3:49]
Reactant: C[C@@H]1CNC[C@H](C)N1Cc1ccccn1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Agent: Br
Agent: BrCc1ccccn1
Agent: C[C@@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C[C@H](C)N1Cc1ccccn1
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1Cc1ccccn1

Procedure:
Via 2-Chloro-6-((3S,5R)-3,5-dimethyl-4-pyridin-2-ylmethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared from (2S,6R)-2,6-dimethyl-1-pyridin-2-ylmethyl-piperazine. Amine preparation: (3R,5S)-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (845 mg), 2-(bromomethyl)-pyridine hydrobromide (1 g) and potassium carbonate (1.15 g) was heated to reflux in MeCN (10 mL). After heating for 24 h the reaction mixture was diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield (3S,5R)-3,5-dimethyl-4-pyridin-2-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (867 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cccc(Cl)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-(3-chloro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.10 min; [M+H]+=425.02.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])[CH2:27][CH2:26]2)=[CH:4][C:5]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].[CH:38]1([C:41]2[O:42][CH:43]=[C:44]([C:46](O)=[O:47])[N:45]=2)[CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:46]([C:44]2[N:45]=[C:41]([CH:38]3[CH2:40][CH2:39]3)[O:42][CH:43]=2)=[O:47])=[C:3]([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])[CH2:29][CH2:30]2)[CH:4]=1
Reactant: COCCOc1cc(N2CCN(c3ccccc3C)CC2)c(N)cc1C(=O)NCCCN1CCCC1=O
Reactant: O=C(O)c1coc(C2CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2coc(C3CC3)n2)cc1C(=O)NCCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
5-Amino-2-(2-methoxy-ethoxy)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 8d (91.7 mg, 0.18 mmol, 100 mol %), 2-cyclopropyl-oxazole-4-carboxylic acid 1h (41.3 mg, 0.27 mmol, 150 mol %) and N,N-diisopropylethylamine (0.09 ml; 0.54 mmol; 300 mol %) were combined in N,N-dimethylformamide (4.0 ml) and HATU (102.6 mg, 0.27 mmol, 150 mol %) was added and the reaction was stirred at room temperature for 16 h. The reaction was then diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate and then concentrated to a residue that was purified by reverse phase HPLC (methanol+0.1% formic acid/water) to afford 2-cyclopropyl-oxazole-4-carboxylic acid [4-(2-methoxy-ethoxy)-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 8f (89.3 mg; 0.14 mmol, 77%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([C:20]1[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH:27]=1)[CH:25]=[O:26])([CH3:19])([CH3:18])[CH3:17].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([O:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:24]([CH:27]=1)[CH:25]=[O:26])([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C(C)(C)C)cc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-tert-butyl-2-hydroxybenzaldehyde (356 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 5-(tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][CH2:11][Si](C(C)(C)C)(C)C)=[CH:4][C:3]=1[NH:19][C:20]([N:22]1[CH:27]=[CH:26][C:25](=[O:28])[CH2:24][C@H:23]1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:21].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C[O:57]CC1>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][CH2:11][OH:57])=[CH:4][C:3]=1[NH:19][C:20]([N:22]1[CH:27]=[CH:26][C:25](=[O:28])[CH2:24][C@H:23]1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:21]
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)CCOc1cc(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)c(Br)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1C=CN(C(=O)Nc2cc(OCCO)c(Cl)cc2Br)[C@H](c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-(4-Fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid {2-bromo-5-[2-(tert-butyl-dimethyl-silanyl)-ethoxy]-4-chloro-phenyl}-amide (0.095 g, 0.158 mmol) in THF (5 ml) was added 1.0 M TBAF in THF (0.35 ml, 0.348 mmol). The mixture was stirred at room temperature for three hours. Buffer (pH 2) was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/1:1) gave (S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid [2-bromo-4-chloro-5-(2-hydroxy-ethoxy)-phenyl]-amide (0.198 g) as a white foam. MS (M+H) 484.