Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](O)[C:5]([OH:9])=[CH:6][C:7]=1[F:8].[C:11]([O-])([O-])=[O:12].[Cs+].[Cs+].BrC[CH2:19][CH2:20]Br>CN(C=O)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[O:9][CH2:20][CH2:19][O:12][CH2:11][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(F)c(Br)cc1O
Reactant: BrCCCBr
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cc2c(cc1Br)COCCO2
Temperature: 120 °C

Procedure:
To 1.50 g (7.25 mmol) of 4-bromo-5-fluorobenzene-1,2-diol in 25 ml DMF are added 5.90 g (18.1 mmol) Cs2CO3 and 0.89 ml (8.70 mmol) 1,3-dibromopropane. The reaction mixture is stirred at 120° C. over night. The solvent is removed in vacuo and to the residue is added water. After extracting with EtOAc the org. phases are combined, washed with sat. aq. NaCl solution and dried over MgSO4. The solvent is removed in vacuo and the resulting residue is purified by column chromatography (silica gel, PE/EtOAc 9/1→7/3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][CH:20]([F:29])[N:21]1[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[N:22]1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:24]=[CH:25][N:21]([CH:20]([F:29])[F:19])[N:22]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccn(C(F)F)n1
Product: C[C@]1(c2cc(NC(=O)c3ccn(C(F)F)n3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 1-difluoromethyl-1H-pyrazole-3-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=404.3 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[CH:21]=[CH:20][C:19]4[CH2:18][CH2:17][CH2:16][C:15](=O)[C:14]=4[N:13]=3)[CH:9]=[N:8]2)[CH:2]=1.[C:23]([NH:26][NH2:27])(=[O:25])[CH3:24]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:18](=[N:27][NH:26][C:23](=[O:25])[CH3:24])[CH2:17][CH2:16][CH2:15][C:14]=4[N:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: O=C1CCCc2ccc(-c3cnn(-c4cccnc4)c3)nc21
Reactant: CC(=O)NN
Solvent: CCO
Product: CC(=O)NN=C1CCCc2nc(-c3cnn(-c4cccnc4)c3)ccc21

Procedure:
A solution of 2-(1-pyridin-3-yl-1H-pyrazol-4-yl)-6,7-dihydro-5H-quinolin-8-one (125 mg, 0.43 mmol) and acetic acid hydrazide (47 mg, 0.63 mmol) in ethanol (5 ml) was heated at 75° C. overnight. The reaction mixture was evaporated to dryness, the residue was taken up in ethyl acetate and washed twice with water. The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with ethyl acetate/methanol 19:1 gave the title product as white solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=2)[N:26]=1>>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([C:30]([F:31])([F:33])[F:32])=[N:28][N:29]=3)[N:26]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(C(c4ccccc4)c4ccccc4)CC3)nn12

Procedure:
A mixture of 1-benzhydrylpiperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Phenomenex Luna C18 100A column (10μ silica, 21 mm diameter, 150 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-(4-benzhydrylpiperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[BH4-].[Na+]>CO>[OH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([CH:14]2[C:5]3=[N:4][NH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=43)[NH:12][CH:13]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 12.9 %

Procedure:
A mixture of 4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (140 mg, 0.42 mmol) and 27% methylamine alcohol solution (194 mg, 1.69 mmol) in methanol (15 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium borohydride (48 mg, 1.26 mmol) was added. After the addition, the mixture was stirred at room temperature for 4 hr. TLC (petroleum ether/ethyl acetate=2:1) show the reaction was complete. Methanol was removed under reduced pressure. The residue was washed with ethyl acetate and filtered. The filtrate was concentrated to give 9-(4-(hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)— one (20 mg, yield: 13%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ: 4.33-4.35 (d, J=8.0 Hz, 1H), 4.53 (s, 2H), 4.74-4.76 (d, J=8.0 Hz, 1H), 7.08-7.10 (d, J=8.0 Hz, 2H), 7.18-7.24 (m, 6H), 7.27-7.29 (d, J=6.8 Hz, 2H), 7.54-7.56 (d, J=7.6 Hz, 1H), 7.62-7.66 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 370(M+1)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1.[Cl:24][CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[CH3:36]>>[ClH:24].[CH3:36][C:27]1[CH:28]=[CH:29][C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]=1[CH2:25][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCNC1)CC2
Reactant: Cc1ccc2ccccc2c1CCl
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(Cc3c(C)ccc4ccccc34)C1)CC2
Product: Cl

Procedure:
Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 1-chloromethyl-2-methylnaphthalene analogously to Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:29])[C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH3:41])=[C:35]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:36]=1>>[ClH:1].[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]2[N:13]([CH3:26])[C:12]3[CH:27]=[CH:28][C:9]([N:8]([CH3:29])[C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:30][C:31]5[CH:32]=[CH:33][C:34]([CH3:41])=[C:35]([S:37]([NH2:40])(=[O:38])=[O:39])[CH:36]=5)[N:7]=4)=[CH:10][C:11]=3[N:15]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Product: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Nc5ccc(C)c(S(N)(=O)=O)c5)n4)ccc3n2C)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-chloro-pyrimidin-4-yl)-N2-(4-methoxy-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (82 mg, 0.20 mmol) and 5-amino-2-methyl-benzenesulfonamide (37 mg, 0.20 mmol) as a white solid (89 mg, 75%). 1H NMR (300 MHz, d6-DMSO+NaHCO3). δ 10.25 (br s, 2H), 9.50 (br s, 1H), 8.46 (s, 1H), 7.88 (d, J=6.6 Hz, 1H), 7.60-7.67 (m, 2H), 7.41-7.46 (m, 3H), 7.23-7.32 (m, 4H), 6.93 (d. J=8.7 Hz, 2H), 5.78 (d, J=6.3 Hz, 1H), 6.68 (d, J=5.7 Hz, 2H), 3.74 (s, 3H), 3.71 (s, 3H), 3.51 (s, 3H), 2.53 (s, 3H). MS (ESI) m/z=559 [M+H]+.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].[Cl:7][C:8]1[C:17]([CH:18]=O)=[C:16]([Cl:20])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].[Cl-].O=C(C)C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>O1CCCC1>[Cl:7][C:8]1[C:17]([CH:18]=[CH:1][C:2](=[O:4])[CH3:3])=[C:16]([Cl:20])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(Cl)c(C=O)c1Cl
Reactant: CC(C)(C)[O-]
Agent: CC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(C=CC(C)=O)c1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 87.9 %

Procedure:
At room temperature, first 14.0 g (125 mmol) of potassium t-butoxide and then, after 30 minutes, 23.3 g (100 mmol) of methyl 2,4-dichloro-3-formylbenzoate in 200 ml of tetrahydrofuran were added to 53.2 g (150 mmol) of (2-oxopropyl)triphenylphosphonium chloride in 300 ml of tetrahydrofuran. The mixture was stirred at room temperature for 4.5 hours and 400 ml of water were then added, the organic phase was separated off and the aqueous phase was extracted with methyl t-butyl ether. The combined organic phases were dried and concentrated and the resulting residue was chromatographed over silica gel (eluent: cyclohexane:ethyl acetate=9:1). 24.0 g (88% of theory) of methyl 2,4-dichloro-3-(2-oxobut-3-en-4-yl)benzoate were obtained.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]([NH2:8])=[O:7])[CH3:2].[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13]N.N>>[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13][NH:8][C:6](=[O:7])[CH2:5][CH2:4][O:3][CH2:1][CH3:2]
Reactant: CN(C)CCCN
Reactant: CCOCCC(N)=O
Agent: N
Product: CCOCCC(=O)NCCCN(C)C

Procedure:
117.2 g of (1.0 mole) of 3-ethoxypropionamide are heated with 107.3 g (1.05 mole) of 3-dimethylaminopropylamine for 6 hours in a temperature range of 145°-170° C. until the evolution of ammonia is complete. In the subsequent distillation in a high vacuum 184 g (0.91 mole=91% of the theoretical yield) of colorless liquid are obtained having a Bp0.1 of 114°-118° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.NC1N=CC2C=CC=CC=2N(CCOC2CCCCO2)C1=O.[C:60]1([C:66]2[C:72]3[CH:73]=[CH:74][CH:75]=[CH:76][C:71]=3[N:70]([CH2:77][CH2:78][O:79][CH:80]3[CH2:85][CH2:84][CH2:83][CH2:82][O:81]3)[C:69](=[O:86])[CH:68]([NH2:87])[N:67]=2)[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:87][CH:68]1[N:67]=[C:66]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][C:71]=2[N:70]([CH2:77][CH2:78][O:79][CH:80]2[CH2:85][CH2:84][CH2:83][CH2:82][O:81]2)[C:69]1=[O:86])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CCOC2CCCCO2)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC1N=Cc2ccccc2N(CCOC2CCCCO2)C1=O
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOC2CCCCO2)C1=O)c1cc2ccccc2[nH]1

Procedure:
To a mixture of indole-2-carboxylic acid (0.19 g), N-hydroxybenzotriazole (0.16 g) and N,N'-dicyclohexylcarbodiimide (0.24 g) in chloroform (10 ml) was added amino-1-{2-((RS)-2-tetrahydropyranyloxy)ethyl}-2H-1,4- benzodiazepine-2-one and (3RS)-1,3-dihydro-5-phenyl-3-amino-1-{2-((SR) -2-tetrahydropyranyloxy)ethyl}-2H-1,4-benzodiazepine-2-one at ambient temperature under stirring. The mixture was stirred for 2 hours under the same conditions. The resultant precipitate was filtered off. The combined filtrate and washings were evaporated under reduced pressure and the residual oil (1.20 g) was subjected to column chromatography on silica gel with an eluent of a mixture of chloroform and ethyl acetate (10:1) to give a mixture (white powder, 0.45 g) of (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino) -5-phenyl-1-{2-((RS)-2-tetrahydropyranyloxy)ethyl}-2H-1,4-benzodiazepine-2-one and (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-1-{2-((SR) -2-tetrahydropyranyloxy)ethyl}-2H-1,4-benzodiazepine- 2-one.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1Br.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH:25]=[O:26])[CH3:20]>>[CH3:1][O:2][CH:3]([O:17][CH3:18])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1[C:25]([C:24]1[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH3:32])=[C:22]([O:21][CH2:19][CH3:20])[CH:23]=1)([OH:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc(C(OC)OC)c(Br)c(OC)c1OC
Reactant: CCOc1ccc(C=O)cc1OCC
Product: CCOc1ccc(C(O)(c2ccccc2)c2c(C(OC)OC)cc(OC)c(OC)c2OC)cc1OCC
Yield: 76 %

Procedure:
2-bromo-3,4,5-trimethoxybenzaldehyde dimethylacetal and 3,4-diethoxybenzaldehyde are reacted in the same manner as described in Example 1-(1), whereby 2-(3,4-diethoxyphenyl-α-hydroxybenzyl)-3,4,5-trimethoxybenzaldehyde dimethylacetal is obtained as pale yellow syrup.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[CH:11][C:12]([OH:14])=[O:13].[CH2:15]([N:17](CC)CC)[CH3:16].CC(C)=O.ClCC#N>O>[C:15]([CH2:16][O:13][C:12](=[O:14])[CH:11]=[CH:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)#[N:17]
Reactant: CCN(CC)CC
Reactant: O=C(O)C=Cc1cc2ccccc2o1
Agent: N#CCCl
Solvent: O
Solvent: CC(C)=O
Product: N#CCOC(=O)C=Cc1cc2ccccc2o1
Yield: 90.1 %

Procedure:
171.8 g of β-(2-benzofuryl)acrylic acid, synthesized in the manner as described in J. Chinese Chem. Soc. sev. II 8, pp. 374-379, and 101.5 g of triethylamine were added to 550 ml of acetone, to the mixture were added dropwise 75.9 g of chloroacetonitrile, and the mixture was refluxed by heating over a period of five hours. After the reaction, 400 ml of water were added to cool the reaction system, and the deposited crystals were filtered by a suction filter and then washed. The obtained crystals were recrystallized from acetone to thereby obtain 187 g of β-(2-benzofuryl)acrylic acid cyanomethyl ester having a melting point between 119° C. and 121° C.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH2:11]>C(Cl)Cl>[NH:4]1[C@H:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]2[NH:11][C:1]1=[S:3]
Reactant: S=C=S
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Product: S=C1N[C@H]2CCCC[C@H]2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of carbon disulfide (1.1 mL, 17.9 mmol) and CH2Cl2 (10 mL) was treated dropwise with cis-1,2-diaminocyclohexane 20-1 (Aldrich) (2.0 g, 17.5 mmol) while maintaining the reaction mixture temperature below 20° C. with an ice bath. The reaction mixture was stirred at ambient temperature for 2.0 h after the addition was complete. Concentration followed by refluxing the resulting solid in H2O (20 mL) for 20 h gave a yellow solution. The cooled solution was extracted with CH2Cl2 and the CH2Cl2 portion was dried (MgSO4) and concentrated. The pale yellow solid was recrystallized from CH2Cl2 /ether to give 20-2 as a pale yellow solid. mp=164-166° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:18][C@@H:19]([CH3:35])[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[CH:27]=2)=[N:22]1>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:18][C@@H:19]([CH3:35])[CH2:20][N:21]2[CH:25]=[CH:24][C:23]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[CH:27]=3)=[N:22]2)=[O:9])=[N:6][CH:7]=1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(Cl)c1cnc(Cl)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
5-Chloropyrazine-2-carbonyl chloride (3.28 mmol, 580 mg) was dissolved in dry THF (40 ml). Triethylamine (9.83 mmol, 995 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (3.28 mmol, 854 mg) were added and the resulting mixture was stirred for one day at RT. The crude product was purified by recrystallization from DCM. 900 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.25 (d, 3H), 4.29 (dd, 1H), 4.47 (dd, 1H), 4.59-4.71 (m, 1H), 6.66 (d, 1H), 7.51 (d, 1H), 7.68-7.73 (m, 1H), 7.75-7.80 (m, 1H), 8.12 (d, 1H), 8.64 (d, 1H), 8.77 (d, 1H), 9.17 (d, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[OH:23])(=[O:4])[CH2:2][CH3:3].[CH3:24][C:25](C)([O-:27])C.[K+].BrCCO>COCCOCCOC>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][OH:27])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: CC(C)(C)[O-]
Agent: OCCBr
Agent: [K+]
Solvent: COCCOCCOC
Product: CCC(=O)c1cnc2c(OCCO)cccc2c1Nc1ccccc1C
Reaction time: 2 h
Yield: 13.7 %

Procedure:
A solution of 3-propanoyl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.06 g, 10 mmol) and potassium t-butoxide (1.68 g, 15 mmol) in diglyme (50 ml) was heated to 150°, a solution of 2-bromoethanol (0.85 ml, 12 mmol) in diglyme (25 ml) added dropwise, then the mixture raised to reflux temperature with vigorous stirring. After 1 hour a further portion of 2-bromoethanol (0.85 ml) was added, and reflux continued for 2 hours. The diglyme was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, ethyl acetate/2% acetic acid/2%-5% methanol) and recrystallization from aqueous isobutyl alcohol gave 3-propanoyl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline (0.48 g), m.p. 174°-176°.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:10]1([S:20](Cl)(=[O:22])=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.Cl>O.[OH-].[Na+].O1CCCC1>[C:4]([CH2:3][C@H:2]([NH:1][S:20]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:22])=[O:21])[C:7]([OH:9])=[O:8])(=[O:6])[NH2:5]
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
132.12 g (1 mol) of (S)-asparagine were dissolved in a mixture of 800 ml of water and 500 ml of 2 N sodium hydroxide. Then 500 ml of tetrahydrofuran were added. The mixture was cooled to 0° C., and while keeping the pH at 12.0-12.5 with 2 N sodium hydroxide a solution of 226.7 g (1 mol) of naphthalene-1-sulfonyl chloride in 500 ml of tetrahydrofuran was added within 1 h. The mixture was stirred for 1 h at 0° C. while maintaining the pH at 12.5. Then the mixture was allowed to warm to room temperature, stirred for further 2 h and left at room temperature overnight. The pH was adjusted to about 7 with concentrated hydrochloric acid and the tetrahydrofuran was removed in vakuum in a rotary evaporator. The remaining aqueous solution was cooled to 0° C. and with stirring acidified to pH 0.8 by addition of concentrated hydrochloric acid. After stirring for 30 min at 0° C. the precipitated product was filtered off, washed with water and dried in vacuo at 40° C. Yield: 240 g (75%).
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH3:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][N:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:3]1
Reactant: CCOC(=O)C1(C)CCCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 65 °C
Reaction time: 6 h
Yield: 83.1 %

Procedure:
To a round bottom flask was added ethyl 3-methylpiperidine-3-carboxylate (2.040 g, 11.91 mmol), 1-fluoro-4-nitrobenzene (1.765 g, 12.51 mmol), DMF (20 ml) and K2CO3 (2.140 g, 15.49 mmol). The reaction was stirred at 65° C. for 6 hrs. After this time, the reaction was diluted with EtOAc. The resulting solution was washed with water (2×) and saturated aqueous NaCl. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex to give the product, ethyl 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxylate (2.922 g, 9.90 mmol, 83% yield) as a yellow oily residue. Anal. Calcd. for C15H20N2O4 m/z 292.3, found: 293.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (d, J=9.34 Hz, 2H), 6.87 (d, J=9.34 Hz, 2H), 4.18 (d, J=13.19 Hz, 1H), 4.11 (q, J=7.15 Hz, 2H), 3.80-3.58 (m, 1H), 3.00 (s, 1H), 2.90 (d, J=13.19 Hz, 1H), 2.40-2.23 (m, 1H), 1.75 (dd, J=8.52, 4.12 Hz, 2H), 1.42 (s, 1H), 1.26-1.14 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11](/[CH:12]=[C:13]2\[CH2:14][N:15]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH:18]\2O)=[CH:10][N:9]=[CH:8]1)=[O:5])[CH3:2].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[C:55]([OH:58])(=[S:57])[CH3:56]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:55]([S:57][CH:18]1[CH2:17][CH2:16][N:15]([C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:14]/[C:13]/1=[CH:12]\[C:11]1[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=[N:9][CH:10]=1)(=[O:58])[CH3:56]
Reactant: CC(O)=S
Reactant: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (3.15 g) in toluene (50 ml) were added N,N-dimethylformamide dineopentyl acetal (3.5 ml) and thioacetic acid (0.89 ml) at room temperature. After being stirred at room temperature for 1 hour, the mixture was diluted with ethyl acetate, washed successively with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure followed by purification of the residue by silica gel chromatography using ethyl acetate and hexane (1:4 to 1:0) as eluents gave crude (E)-4-(acetylsulfanyl)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (3.29 g) as a yellow amorphous solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30]([C:32]1([CH2:40][NH2:41])[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CCO>[C:25]([O:29][C:30]([C:32]1([CH2:40][NH:41][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=3)=[O:4])[CH2:33][CH2:34][S:35](=[O:38])(=[O:39])[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C1(CN)CCS(=O)(=O)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CCS(=O)(=O)CC1
Yield: 12.1 %

Procedure:
A mixture of 4-cyano-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carboxylic acid tert-butyl ester (208 mg) and Raney Ni (0.5 mL in water) in MeOH (20 mL) was stirred at rt under H2 atmosphere (balloon) overnight. Then the reaction mixture was filtered over Celite pad, filtrate was concentrated to give the desired product 4-aminomethyl-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carboxylic acid tert-butyl ester (212 mg), which was used in the next step. A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (24 mg) and 4-aminomethyl-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carboxylic acid tert-butyl ester (45 mg) in EtOH (1 mL) was microwaved at 140° C. for 2 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (5 mg). LC MS ESI+: 552 (M+1)+.