Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11](O)C)=C[CH:2]=1.CN1C2C=CC=[C:19]([CH:24]=[O:25])C=2C=C1.C[Mg]I.C(OCC)C>O1CCCC1>[CH3:2][N:1]1[C:10]2[C:5](=[C:6]([CH:24]([OH:25])[CH3:19])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:11]1
Reactant: Cn1ccc2c(C=O)cccc21
Reactant: CC(O)c1ccnc2ccccc12
Agent: C[Mg]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cccc2c1ccn2C

Procedure:
The title compound was prepared by the same procedure for 1-quinolin-4-yl-ethanol from 1-methyl-1H-indole-4-carbaldehyde (2.8 g, 17.6 mmol), 3 M methyl magnesium iodide solution in diethyl ether (10 mL, 30 mmol, Aldrich) and anhydrous tetrahydrofuran (20 mL). The crude title compound obtained in form as yellow oil in 97% yield (3.0 g, 17.1 mmol).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:9]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]1[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]1.CI.[C:31](=O)([O-])O.[Na+]>O.CN(C)C=O>[CH3:31][N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][N:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=3)[C:4]2=[O:3])[CH2:23][C:24]1=[O:28]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc(-c2cccn(CCN3CCNC(=O)C3)c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cccn(CCN3CCN(C)C(=O)C3)c2=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
With cooling with ice, sodium hydride (60% oil suspension, 50 mg) was added to an N,N-dimethylformamide (10 ml) solution of methyl 4-{2-oxo-1-[2-(3-oxopiperazin-1-yl)ethyl]-1,2-dihydropyridin-3-yl}benzoate (380 mg), followed by stirring for 5 minutes, and then methyl iodide (70 μl) was added. With cooling with ice, the reaction mixture was stirred for 1.5 hours. Water with ice (20 ml) and aqueous saturated sodium hydrogencarbonate solution (10 ml) were added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain methyl 4-{1-[2-(4-methyl-3-oxopiperazin-1-yl)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}benzoate (350 mg) as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:6][CH:5]=1.Br[CH2:21][C:22]([O-:24])=[O:23].OS([O-])(=O)=O.[K+]>C1COCC1>[C:7]([O:24][C:22](=[O:23])[CH2:21][O:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=3)=[N:11][S:12][C:13]=2[CH:18]=1)([CH3:10])([CH3:8])[CH3:6]
Reactant: O=C([O-])CBr
Reactant: Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a suspension of 0.74 g (16.9 mmol) NaH (55% in mineral oil) in 40 ml THF was added a solution of 4 g (13.1 mmol) 3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-ol in 20 ml THF at RT. The solution was stirred at RT for 1 h, 2.1 ml (14.3 mmol) tbutyl bromoacetate was added. The solution was stirred at RT over night, 1M KHSO4 was added carefully and the layers separated. The inorganic one was extracted with EtOAc, the combined organic phases were washed with water and brine and dried over Na2SO4. Column chromatography on silica gel with EtOAc:hexane 1:4 yielded 4.95 g (90%) [3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-acetic acid tert-butyl ester as colorless oil, MS: 420 (MH+,1Br).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].[C:16](=O)([O-])[O-].[Cs+].[Cs+].IC>CC(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[N:15]([CH3:16])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1cccc([C@H](C)c2nccn2C)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of the compound of Example 58 (100 mg, 0.5 mmol) and caesium carbonate (407 mg, 1.25 mmol) in acetone (4 ml) was added iodomethane (78 μl, 1.25 mmol). The reaction mixture was stirred at room temperature, under nitrogen, for 4 h and then concentrated in vacuo. to the residue was added water (10 ml) and the solution was extracted with ethyl acetate (2×10 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:19]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][CH2:15][N:16]([C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]6[CH:33]=[CH:32][C:31]([C:34]([O:36]C)=O)=[CH:30][C:29]=6[CH3:38])=[CH:24][CH:23]=5)=[O:21])[C:17]=4[CH:18]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.O.[NH2:40][NH2:41]>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:19]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][CH2:15][N:16]([C:20]([C:22]5[CH:23]=[CH:24][C:25]([C:28]6[CH:33]=[CH:32][C:31]([C:34]([NH:40][NH2:41])=[O:36])=[CH:30][C:29]=6[CH3:38])=[CH:26][CH:27]=5)=[O:21])[C:17]=4[CH:18]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)N3CCCc4cc5c(cc43)C3(CCN(C)CC3)CO5)cc2)c(C)c1
Reactant: NN
Solvent: O
Product: Cc1cc(C(=O)NN)ccc1-c1ccc(C(=O)N2CCCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1

Procedure:
The title compound was prepared from 2,3,5,6,7,8-hexahydro-1'-methyl-5-(4'-methoxycarbonyl-2'-methylbiphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine] (E48) and hydrazine monohydrate, using a procedure similar to that of Example 25 (90%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7](C(C)C)[C:6]1=[O:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O.CC(C)CC(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:17])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: CC(C)n1c(=O)n(CCCCl)c2ccccc21
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(O)(c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 5 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethyl)-2H-benzimidazol-2-one, 3.9 parts of 4-(4-fluorophenyl)-4-piperidinol, 5.3 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxed for 48 hours with water-separator. The reaction mixture is cooled to room temperature, water is added and the whole is alkalized with 15 parts of a sodium hydroxide solution 60%. The layers are separated and the organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaported. The oily residue is dissolved in 2-propanone. The solution is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride, and the whole is stirred and refluxed for 15 minutes. The solvent is evaporated and the formed hydrochloride salt is dissolved in water. The free base is liberated in the conventional manner with a diluted sodium hydroxide solution. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is crystallized from methylbenzene. The product is filtered off and dried, yielding 2.5 parts of 1-{3-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 135.4° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([N:21]1[C:25]2[N:26]=[CH:27][N:28]=[CH:29][C:24]=2[C:23](I)=[CH:22]1)([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31]1([C:37](=[N:44][C:45]2[CH:46]=[N:47][CH:48]=[C:49]([CH:56]=2)[C:50](N(OC)C)=[O:51])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Si:1]([O:8][CH2:9][C:10]([N:21]1[C:25]2[N:26]=[CH:27][N:28]=[CH:29][C:24]=2[C:23]([C:50]([C:49]2[CH:48]=[N:47][CH:46]=[C:45]([N:44]=[C:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:56]=2)=[O:51])=[CH:22]1)([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cncnc21
Product: CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 28 using 7-[2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methylethyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 114) and 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (Preparation 23) to afford the title compound as a yellow foam in 69% yield, 1.76 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].Br.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:24]=2[Cl:23])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(Nc2ccc(OC)c(OC)c2)n1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(OC)c(OC)c2)n1

Procedure:
A mixture of 2.18 g (7.1 mmol) 2-(3,4-Dimethoxy-phenylamino)-thiazole-4-carboxylic acid ethyl ester; hydrobromide, 2.24 g (10.7 mmol) 2,4-Dichlorobenzoyl chloride and 2.96 ml (21.4 mmol) NEt3 in 30 ml DCM was stirred at room temperature for 24 h. After evaporation of the volatiles the residue was taken up in MeOH and purified with flash column chromatography on silica eluting with a gradient of heptane/ethyl acetate to yield after evaporation of the product fractions 0.75 g (22%) of the title compound. MS (m/e): 481.1 (MH+, 100%)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[C:13]2=[CH:17][N:18]=[C:19](I)[N:12]2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:35]2[CH2:36][CH2:37][O:38][CH2:39][CH:40]=2)O1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[C:13]2=[CH:17][N:18]=[C:19]([C:35]3[CH2:40][CH2:39][O:38][CH2:37][CH:36]=3)[N:12]2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(COCc2ccccc2)nn2c(I)ncc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(COCc2ccccc2)nn2c(C3=CCOCC3)ncc12
Temperature: 125 °C
Yield: 77 %

Procedure:
To a solution of compound 5 (1.0 g, 2.61 mmol) in dioxane (12 mL) at room temperature was added dropwise a solution of Cs2CO3 (2.5 g, 7.66 mmol) in water (3 mL), followed by addition of Pd(PPh3)4 (300 mg, 0.26 mmol) and 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (636 mg, 3.0 mmol). The reaction mixture was degassed by purging with N2 for 15 min. Then the mixture was heated to 125° C. under microwave irradiation for 40 min. After removal the solvent, the residue was purified by chromatography on silica gel column eluted with PE/EtOAc=10:1 to 1:5) to afford compound 6 (680 mg, 76% yield) as a white solid. LC-MS: m/z 339.1 [M+H]+.
Reaction SMILES: P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:20]Br.[C:22]([CH:28]([O:39][SiH:40]([CH3:42])[CH3:41])[CH2:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35]O)=[CH:32][CH:31]=1)([CH:25]([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:22]([CH:28]([O:39][SiH:40]([CH3:42])[CH3:41])[CH2:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][Br:20])=[CH:32][CH:31]=1)([CH:25]([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: BrBr
Reactant: CC(C)C(C)(C)C(Cc1ccc(CCO)cc1)O[SiH](C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)C(C)(C)C(Cc1ccc(CCBr)cc1)O[SiH](C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
To a stirred solution of (C6H5)3P (9.03 g, 34.4 mmol) in 220 ml of toluene at 0° C. was added bromine (1.76 ml, 34.4 mmol) over 10 minutes. To this stirred slurry was then added a solution of p-(2-thexyldimethylsilyloxyethyl)phenethyl alcohol (10.6 g, 34.4 mmol) and pyridine (2.78 ml, 34.4 mmol) in 50 ml of toluene over 10 minutes. This mixture was stirred at room temperature for 4 hours and diluted with 300 ml of saturated NaHCO3 solution. The resulting mixture was extracted with ether (4×300 ml). The combined ether extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated in 200 ml of hexane-ether 4:1 and filtered. The filtrate was concentrated and distilled under vacuum to give 9.9 g of p-(2-thexyldimethylsilyloxyethyl)phenethyl bromide (78%) as an oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27]CO[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC([C:54]([O:56][CH3:57])=[O:55])C1>>[CH3:57][O:56][C:54]([CH:24]1[CH2:27][N:22]([C:7]2[C:8]3[N:13]=[N:12][N:11]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:9]=3[N:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[N:6]=2)[CH2:23]1)=[O:55]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: COC(=O)C1CNC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: COC(=O)C1CN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and methyl azetidine-3-carboxylate. MS(m/e): 415.3 (MH+).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:5](OCC)=[O:6].[NH:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[N:22]=[CH:21][N:20]=1)[NH2:18].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C[O-].[Na+].[ClH:50]>C(O)C>[ClH:50].[ClH:50].[CH3:31][N:28]1[CH2:29][CH2:30][N:25]([C:23]2[N:22]=[CH:21][N:20]=[C:19]([N:17]3[C:5](=[O:6])[C:4]([C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[CH:3][NH:18]3)[CH:24]=2)[CH2:26][CH2:27]1
Reactant: CN1CCN(c2cc(NN)ncn2)CC1
Reactant: CCOC(=O)C(=CN(C)C)c1cccnc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C[O-]
Agent: Cl
Solvent: CCO
Product: CN1CCN(c2cc(-n3[nH]cc(-c4cccnc4)c3=O)ncn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
146 mg (663 μmol) of the compound from Example 3A, 115 mg (552 μmol) of the compound from Example 6A and 13 mg (55 μmol) of camphor-10-sulfonic acid are dissolved in 5 ml of anhydrous ethanol, and the mixture is heated under reflux overnight. After cooling, the mixture is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid). The resulting mixture of target product and intermediate is dissolved in 5 ml of anhydrous ethanol, 109 mg (607 μmol) of a 30% strength methanolic sodium methoxide solution are added and the mixture is stirred at RT for 1 h. The mixture is then neutralized with 1 M hydrochloric acid and concentrated, and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid). The mixture of target product and intermediate obtained this time is again dissolved in 5 ml of anhydrous ethanol, 99 mg (552 μmol) of a 30% strength methanolic sodium methoxide solution are added and the mixture is stirred at RT for 2 h. The mixture is then again neutralized with 1 M hydrochloric acid and concentrated, and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid). This gives 9 mg (4% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[N:26]=[CH:27][C:28]([NH:31][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[O:9][C:10]=2[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:29][CH:30]=1
Reactant: O=C(O)c1nc(-c2ccccc2Br)oc1C(F)(F)F
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3Br)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H18BrF3N4O3 (m/e) 499, obsd 500 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C(OC(=O)N[C@H]1C[CH:43]=[CH:42][C@@H:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:40](C)[C:39]1=O)(C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][N:40]([CH:41]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH:42]=[CH2:43])[C:13]([C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH:17]=[CH2:18])=[O:15]
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC=C[C@H]1c1ccccc1
Reactant: C=CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CC[C@H](NC(=O)OCc1ccccc1)C(=O)N(C)C(C=C)c1ccccc1
Temperature: -20 °C
Reaction time: 8 h
Yield: 150.5 %

Procedure:
To a solution of (2S)-2-{[(benzyloxy)carbonyl]amino}pent-4-enoic acid (2a) (1.7 g) in DCM (8 mL) at −20° C. under N2 was added a mixture of EDAC.HCl (1.56 g) and DMAP (18 mg) in DCM (12 mL) portionwise. Methyl(1-phenylprop-2-en-1-yl)amine (1d) (1.0 g) in DCM (5 mL) was then added dropwise to the reaction mixture. The reaction mixture was stirred for 1 h at −20° C. and overnight at RT, then diluted with DCM (100 mL) and washed with 0.2 N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified via flash chromatography (20% EtOAc/hexanes) to give the desired product as a viscous oil (1.8 g, 70%). 1H NMR (300 MHz, CDCl3) δ 2.41-2.47 (m, 1H), 2.52-2.57 (m, 1H), 2.66-2.82 (m, 3H-diastereomer/rotamer mixture), 4.77 (m, 1H), 5.11-5.17 (m, 4H), 5.22-5.41 (m, 2H), 5.68-5.82 (m, 2H), 6.08 (m, 1H), 6.39-6.41 (m, 1H), 7.26-7.35 (m, 10H). MS APCI, m/z=379 (M+1). LC/MS 2.99 min., Method A.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: N#Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Yield: 55.8 %

Procedure:
A solution of 4-hydroxy benzonitrile (15 g, 0.126 moles), potassium carbonate (28.89 g, 0.208 moles) and 4-(Toluene-4-sulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (57.62 g, 0.162 moles) in dimethylformamide (150 mL) was stirred at 100° C. while monitoring the progress of the reaction by thin layer chromatography. After completion of reaction, the reaction mass was quenched on to water (400 mL) and extracted with ethyl acetate (3×300 mL). The resulting ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue, which was further purified by flash chromatography using (ethyl acetate:hexane, 1:9) to afford the title compound 21.25 g
Reaction SMILES: [CH2:1]([C@@H:6]1[CH2:8][C@H:7]1[OH:9])[CH2:2][CH2:3][CH:4]=[CH2:5].N1C=CC=CC=1.[CH2:16]1[C:21](=[O:22])[N:20]([O:23][C:24](ON2C(=O)CCC2=O)=[O:25])[C:18](=[O:19])[CH2:17]1>C(#N)C.CN(C1C=CN=CC=1)C.CCOCC>[CH2:1]([C@@H:6]1[CH2:8][C@H:7]1[O:9][C:24]([O:23][N:20]1[C:21](=[O:22])[CH2:16][CH2:17][C:18]1=[O:19])=[O:25])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: C=CCCC[C@@H]1C[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOCC
Product: C#CCCC[C@@H]1C[C@H]1OC(=O)ON1C(=O)CCC1=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,2R)-2-(pent-4-en-1-yl)cyclopropanol (See International Patent Application Publication No. WO08/057209) (2.13 g; 70% wt) in acetonitrile (20 ml) was added pyridine (1.5 ml), followed by N,N′-disuccinimidyl carbonate (3.74 g) and a crystal of DMAP. The mixture was stirred at 40° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ether and washed with HCl 1N, water and brine and dried over sodium sulfate. The organic layer was filtered and concentrated to provide the desired product (2.88 g) as an oil. 1H NMR (500 MHz, CDCl3): δ (ppm) 4.06-4.03 (m, 1H), 2.87 (s, 4H), 2.28-2.25 (m, 2H), 1.98-1.97 (m, 1H), 1.72-1.65 (m, 2H), 1.46-1.40 (m, 2H), 1.31-1.24 (m, 1H), 1.12-1.08 (m, 1H), 0.72-0.68 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[NH:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[OH:42][C:36]([C:38]([F:41])([F:40])[F:39])=[O:37].[N:6]1([C:4]([C:3]2[CH:20]=[C:21]([CH:22]=[CH:23][C:2]=2[F:1])[CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[NH:27][N:26]=2)=[O:5])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCCNCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To the solution of the crude tert-butyl 4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-1,4-diazepane-1-carboxylate (370 mg crude obtained from previous step) in DCM (20 ml) was added TFA (1 ml) and stirred for 14 h at room temperature. The reaction mixture was concentrated under vacuo to yield the crude product as yellow oil (300 mg), used in next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C-:13]#[N:14].[K+]>CS(C)=O>[C:13]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:14]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(CC#N)c1

Procedure:
A solution of methyl 3-(bromomethyl)benzoate (2.29 g, 0.01 mol) and potassium cyanide (3.26 g, 0.05 mol) in DMSO (20 mL) was heated to 100° C. for 1 h. The reaction mixture was cooled, partitioned between ether and water, washed with brine, dried (Na2SO4) and concentrated to give the title compound.