Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.[CH2:12]([NH:14][C:15]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)=[O:16])[CH3:13].CN(CCN(C)C)C.[Cl:30]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[CH2:12]([NH:14][C:15]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[Cl:30])=[O:16])[CH3:13]
Reactant: CCNC(=O)c1ccsc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCNC(=O)c1ccsc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (44 mL, 57.2 mmol) was added dropwise to a -78° C. cooled solution of N-ethyl-3-thiophenecarboxamide (4.04 g, 26 mmol) and TMEDA (6.65 g, 57.2 mmol) in THF (100 mL). After stirring for 30 min at -78° C., a solution of hexachloroethane (13.54 g, 57.2 mmol) in THF (20 mL) was added dropwise. The resulting reaction mixture was warmed to RT over 1 h, quenched with dilute aq citric acid, and extracted with EtOAc (3×). The combined organic extracts were dried (MgSO4), concentrated, and purified by HPLC with 3:7 EtOAc/hexanes to give 2.8 g of N-ethyl-2-chloro-3-thiophenecarboxamide as a yellow oil, a 57% yield.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH:8]3[CH2:10][C:4]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:21][CH2:20][NH:19][C:18]5=[O:22])=[CH:13][CH:12]=4)([CH2:5][CH:6]1[CH2:7]3)[CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]#[N:39])=[O:32]>CS(C)=O.CCOC(C)=O>[O:22]=[C:18]1[NH:19][CH2:20][CH2:21][N:17]1[C:14]1[CH:13]=[CH:12][C:11]([C:4]23[CH2:10][CH:8]4[CH2:9][C:2]([NH:1][CH2:30][C:31]([N:33]5[CH2:37][CH2:36][CH2:35][C@H:34]5[C:38]#[N:39])=[O:32])([CH2:3]2)[CH:6]([CH2:7]4)[CH2:5]3)=[CH:16][CH:15]=1
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(c1ccc(N4CCNC4=O)cc1)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(N4CCNC4=O)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.9 %

Procedure:
To a stirred mixture of the compound obtained from step II (0.4 g, 1.35 mmol) and K2CO3 (0.56 g, 4.05 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.23 g, 1.35 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[4-(2-oxoimidazolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.21 g) in 36% yield. m/z (M+1) 434; 1H NMR (CDCl3) 300 MHz δ 7.45 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 4.86-4.76 (m, 1H), 4.67 (s (br), 1H), 3.93 (t, J=7.4 Hz, 2H), 3.75-3.40 (m, 4H), 3.48 (s, 2H), 3.46-2.38 (m, 1H), 2.36-2.23 (m, 2H), 2.23-1.70 (m, 12H), 1.65-1.57 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH:13]1([CH:16]([NH2:19])[CH2:17][CH3:18])[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>CC#N>[CH:13]1([CH:16]([NH:19][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH3:18])[CH2:15][CH2:14]1
Reactant: CCC(N)C1CC1
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCC(Nc1cc[nH]c(=O)c1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
Part A. A mixture of 4-chloro-3-nitro-2-pyridone (2.0 g, 11.4 mmol), 1-cyclopropylpropyl amine hydrochloride (1.5 g, 11.4 mmol) and N,N-diisopropylethylamine (4.8 ml, 27.4 mmol) in CH3CN (50 ml) were stirred at 25° C. for 16 h and at reflux for 4 h. After cooling it was stripped in vacuo, and the residue was partitioned between EtOAc (100 mL) and H2O (50 mL). The insolubles were separated, washed with H2O and EtOAc and vacuum dried 1.51 g. The filtrate layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The Combined extracts were washed with brine, dried over MgSO4, filtered and concd. in vacuo. The residue was washed with EtOAc (2×) and vacuum dried, to give 0.69 g, yellow solid. Combined wt. of 4-(1-cyclopropylpropyl)amino-3-nitro-2-pyridone 2.20 g, 81% yield. 1H NMR(300 MHz, dmso d6): 11.19 (1H, br), 8.94 (1H, d J=8.8 Hz), 7.33 (1H, t J=6.9 Hz), 6.03 (1H, d J=7.7 Hz), 3.18-3.24 (1H, m), 1.60-1.74 (2H, m), 1.03-1.11(1H, m), 0.91 (3H, t), 0.40-0.60 (1H, m), 0.20-0.39 (1H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=O.N1CCCCC1>CO>[NH:11]1[CH:15]=[CH:14][CH:13]=[C:12]1/[CH:16]=[C:3]1\[C:2](=[O:10])[NH:1][C:9]2[C:4]\1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc[nH]1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2ccccc2/C1=C/c1ccc[nH]1
Yield: 96.1 %

Procedure:
A mixture of oxindole (137 mg, 1.03 mmol), pyrrole-2-carboxaldehyde (115.1 mg, 1.21 mmol) and piperidine (40 μL, 0.404 mmol) in 2.0 mL MeOH was heated at reflux for 3 h. The mixture was cooled in an ice bath and the solid which formed was collected by filtration to give the title compounds (208 mg, 96%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[NH2:4].[C:11]([OH:15])(=[O:14])[CH:12]=O.[O:16]1[CH:20]=[CH:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:3]2[NH:4][CH:12]([C:11]([OH:15])=[O:14])[CH:18]3[CH2:19][CH2:20][O:16][CH:17]3[C:5]=2[C:6]([Cl:10])=[C:7]([Cl:9])[CH:8]=1
Reactant: C1=COCC1
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Reactant: O=CC(=O)O
Product: O=C(O)C1Nc2c(Cl)cc(Cl)c(Cl)c2C2OCCC12

Procedure:
Compound 67 was prepared from 2,4,5-trichloroaniline, glyoxylic acid and 2,3-dihydrofuran by the automated process.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:10]3[C:15](=[O:16])[NH:14][C:12](=[O:13])[C:11]=3[C:17]3[NH:21][CH:20]=[N:19][CH:18]=3)=[CH:8][NH:9][C:4]2=[CH:3][CH:2]=1.[OH-].[Na+]>CC(=O)CC.CCOC(C)=O>[CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][C:8]3[N:21]4[C:17](=[CH:18][N:19]=[CH:20]4)[C:11]4[C:12]([NH:14][C:15](=[O:16])[C:10]=4[C:7]=3[C:5]=2[CH:6]=1)=[O:13]
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1cnc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: O=C1NC(=O)c2c1c1c3ccccc3[nH]c1n1cncc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.1 %

Procedure:
To a stirred solution of didemnimide A (32.6 mg, 0.117 mmol) in 2-butanone (7.0 mL) at rt is added sequentially 4Å molecular sieves (˜100 mg) and CUCl2 (79 mg, 0.59 mmol). The reaction mixture was stirred for 15 h at rt. The dark purple solution was treated with 10% solution of NaOH until the pH was neutral and diluted with EtOAc (30 mL). The phases were separated and the aqueous layer was extracted with EtOAc (5×10 mL). The combined organic extracts were washed with brine (10 mL), dried (MgSO4) and concentrated. Flash chromatography (15 g of silica gel, 15:1 CH2Cl2—MeOH) of the crude material afforded 19.5 mg (60%) of recovered didemnamide A as well as 12.3 mg (38%, 95% based on recovered starting material) of iso-granulatimide (5) as a purple solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[N:7]([C:10]2[S:11][C:12]([C:16]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:6]=[N:5]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>O1CCCC1.C(OCC)(=O)C>[CH3:33][S:34]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[N:7]([C:10]2[S:11][C:12]([C:16](=[O:17])[NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[C:13]([CH3:15])[N:14]=2)[CH:6]=[N:5]1)(=[O:36])=[O:35]
Reactant: Cc1nc(-n2cnn(CCO)c2=O)sc1C(=O)NCc1cccnc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nc(-n2cnn(CCOS(C)(=O)=O)c2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To the solution of 2-(1-(2-hydroxyethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.20 g, 0.56 mmol) and triethylamine (0.15 mL, 1.11 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise methanesulfonyl chloride (0.08 g, 0.67 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 3 hours, diluted with ethyl acetate (15 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to afford the title compound as a yellow solid in 70% yield (0.17 g): 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.55-8.51 (m, 1H), 8.31 (s, 1H), 7.72-7.66 (m, 1H), 7.31-7.25 (m, 1H), 6.26 (t, J=5.8 Hz, 1H), 4.60 (d, J=5.8 Hz, 2H), 4.54 (t, J=5.1 Hz, 2H), 4.19 (t, J=5.1 Hz, 2H), 3.02 (s, 3H), 2.65 (s, 3H); MS (ES+) m/z 439.2 (M+1).
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([N:8](CC)CC)C.[C:13](#N)[CH:14]=[CH2:15]>CN(C)C=O>[O:5]=[C:1]([CH2:13][CH2:14][CH3:15])[CH2:2][CH2:3][CH2:4][C:6]#[N:8]
Reactant: C=CC#N
Reactant: CCN(CC)CC
Reactant: CCCC=O
Solvent: CN(C)C=O
Product: CCCC(=O)CCCC#N
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 36 g (1.0 mol) of distilled n-butyraldehyde, 13.5 g (0.05 mol) of Catalyst 1, 400 ml of dimethylformamide and 20.2 g (0.2 mol) of triethylamine is initially introduced, under nitrogen, into the apparatus described in Example 1. The mixture is stirred for 2 hours at 80° C and a solution of 26.5 g (0.5 mol) of distilled acrylonitrile is then added dropwise over the course of 6 hours. The whole is then stirred for a further 16 hours at the same temperature. For working up, the solvent is distilled off in vacuo, the oil which remains is taken up in chloroform and the solution is washed with water, dilute sodium bisulphite solution and again with water. The organic layer is separated off and dried with magnesium sulphate. It is filtered, solvent is distilled off and the residue is distilled in a water-pump vacuum. 4-Oxo-heptane-1-carbonitrile is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10](=[O:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:19].[Na+].[CH2:21]=O>>[CH2:1]([N:8]1[CH2:12][C:11]([CH2:21][OH:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10](=[O:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: [OH-]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1=O
Agent: [Na+]
Product: CCOC(=O)C1(CO)CN(Cc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
50 g of 1-benzyl-4-ethoxycarbonyl-pyrrolidine-3-one was dissolved in 300 ml of isolpropanol and thereto 4 ml of 10% NaOH and 20.7 ml of formalin were added successively. The mixture was stirred for 30 minutes at room temperature and concentrated under the reduced pressure. 200 ml of water was added to the concentrated residue. The resulting solution was extracted twice with each 200 ml of ethylether, dried with magnesium sulfate, filtered and concentrated under the reduce pressure to give 46 g of 1-benzyl-4-hydroxymethyl-4-ethoxycarbonyl-pyrroline-3-one(yield 82.0%). The obtained compound was dissolved in 400 ml of pyridine and thereto methoxylamine hydrochloride was added and stirred for 1 hour at room temperature. The reaction mixture was concentrated under the reduced pressure, diluted with 400 ml of dichloromethane, washed with water and saline solution, dried with magnesium sulfate, filtered and concentrated under the reduced pressure to give 43 g of 1-benzyl-4-hydroxymethyl-4-ethoxycarbonyl-pyrroline-3-one-O-methyloxime(yield: 84.6%). Thus obtained compound was dissolved in a solution of 22 ml of triethylamine and 400 ml of dichloromethane and cooled to 0-5° C. and thereto 10 ml of methanesulfonylchloride was added dropwise and the reaction temperature was slowly increased up to room temperature. The reaction mixture was stirred for 1 hour, washed with water and saline solution, dried with magnesium sulfate, filtered and concentrated under the reduced pressure to give 50 g of 1-benzyl-4-methanesulfonyloxymethyl-4-ethoxycarbonyl-pyrroline-3-one-O-methyloxime(yield: 92.6%). It was dissolved in 200 ml of tetrahydrofuran and thereto 13 g of sodium borohydride and 400 ml of ethyl alcohol were added successively at room temperature and 11 g of lithium chloride was added slowly. The reaction mixture was stirred for 5 hours and poured into 300 ml of ice water. The resulting solution was adjusted to pH 5-6 with diluted hydrochloric acid, concentrated under the reduced pressure to remove most organic solvents therefrom, then extracted twice with each 200 ml of ethylether, dried with magnesium sulfate, filtered and concentrated under the reduced pressure. The residue was purified by silicagel column chromatography(ethylacetate:normal hexane=2:1) to give 42 g of the titled liquid compound(yield:94.3%).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.Cl[C:11]1[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:12]=1[CH2:13][NH2:14].F[C:22]1C=CC(F)=C[C:23]=1CN>>[Br:9][C:5]1[N:6]=[C:7]2[N:14]([CH2:13][C:12]3[CH:11]=[C:18]([F:19])[CH:17]=[CH:16][C:15]=3[F:20])[CH2:22][CH2:23][NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NCc1c(F)ccc(F)c1Cl
Reactant: NCc1cc(F)ccc1F
Reactant: Nc1ncc(Br)nc1Br
Product: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1

Procedure:
7-bromo-1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine was prepared as described in Example 1, from 2-amino-3,5-dibromopyrazine as described in Example 1 by replacing 2-chloro-3,6-difluorobenzylamine in step 1 with 2,5-difluorobenzylamine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]([NH:15][C@H:16]([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18])([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>C1CCCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:15]([CH:12]([CH3:13])[CH3:14])[C@H:16]([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC[C@@H](NC(C)C)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Product: CC[C@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 62.8 %

Procedure:
2,4-Dichloro-5-nitro-pyrimidine (19.90 g, 103 mmol) was dissolved in 300 mL of cyclohexane followed by the addition of methyl (2R)-2-(isopropylamino)butanoate 22a (16.40 g, 103 mmol) and sodium bicarbonate (36.61 g, 412 mmol). The reaction solution was heated to 80° C., stirred for 4 hours and filtered. The filtrate was concentrated under reduced pressure, added with 100 mL of water and extracted with dichloromethane (100 mL×3). The combined organic phase was washed with saturated sodium chloride solution (100 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl (2R)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]butanoate 22b (20.50 g, yield: 62.8%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])[NH2:11].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.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>[CH:8]([C:5]1[N:6]=[CH:7][C:2]([C:16]2[CH:17]=[CH:18][C:13]([C:10]([NH2:11])=[O:12])=[CH:14][CH:15]=2)=[CH:3][CH:4]=1)=[O:9]
Reactant: O=Cc1ccc(Br)cn1
Reactant: NC(=O)c1ccc(B(O)O)cc1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: NC(=O)c1ccc(-c2ccc(C=O)nc2)cc1
Temperature: 77.5 °C
Yield: 62.3 %

Procedure:
To a solution of 5-bromo picolinaldehyde (0.7 g, 3.76 mmol) in toluene (100 mL) and ethanol (75 mL) was added (4-carbamoylphenyl)boronic acid (1.24 g, 7.52 mmol), 2M sodium carbonate (2.8 g, 26.32 mmol, 6 mL water), Pd(PPh3)4 (0.217 g, 0.188 mmol) under argon. The resulting mixture was heated at 75-80° C., for 6 h. The contents were cooled to room temperature, diluted with ethyl acetate (150 mL) and washed with bicarbonate solution (2×100 mL) and brine solution (2×100 mL). The organic layer was dried over sodium sulphate and distilled off to obtain the crude product. The crude product was purified by flash chromatography (100-200μ; 35% ethyl acetate in hexane) to afford 4-(6-formylpyridin-3-yl)benzamide (0.53 g, 62% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.03 (s, 1H), 9.20 (s, 1H), 8.39 (d, 1H), 8.07 (s, 1H), 8.03 (d, 3H), 7.93 (d, 2H), 7.44 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[C:8]([Cl:23])=[C:7]([CH3:24])[C:6]=1[C:25](=[O:27])[CH3:26].[NH:28]1[CH2:33][CH2:32][S:31][CH2:30][CH2:29]1>>[Cl:23][C:8]1[C:7]([CH3:24])=[C:6]([C:25](=[O:27])[CH3:26])[C:5]([O:4][CH2:3][CH2:2][N:28]2[CH2:33][CH2:32][S:31][CH2:30][CH2:29]2)=[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[O:21][CH3:22]
Reactant: C1CSCCN1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccccc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCSCC2)c1OCCCc1ccccc1
Temperature: 65 °C
Yield: 79 %

Procedure:
Example 34b (201 mg, 0.44 mmol) and thiomorpholine were reacted as described under the General Procedure B (except heated to 65° C.) and the crude was purified by flash chromatography (silica-gel, EtOAc/hexane 1:4) yielding the title compound (166 mg, 79%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.33-7.02 (m, 5H), 4.13-4.06 (m, 4H); 3.88 (s, 3H); 2.82 (dd, J=9.3, 7.5 Hz, 2H); 2.76-2.73 (m, 4H); 2.68-2.64 (m, 6H); 2.52 (s, 3H); 2.20 (s, 3H), 2.13-2.03 (m, 2H). MS (ES+) m/z 478 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:16]3[N:15]=[C:14]([CH3:17])[C:13](=[O:18])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:21][CH3:22].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[N:34]=[C:35]=[O:36]>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[NH:34][C:35]([NH:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:16]3[N:15]=[C:14]([CH3:17])[C:13](=[O:18])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:21][CH3:22])=[O:36]
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)c(C)nc23)ccc1N
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: CSc1cc(Oc2ccnc3[nH]c(=O)c(C)nc23)ccc1NC(=O)Nc1cc(C(F)(F)F)ccc1F

Procedure:
Method F2 was used with 8-(4-amino-3-(methylthio)phenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene, to afford the title compound was obtained as a white solid (5 mg, 12%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[O:22][C:21]([SH:23])=[N:20][N:19]=3)=[CH:17][C:12]=2[O:11][CH2:10]1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[O:22][C:21]([S:23][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:20][N:19]=3)=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: Sc1nnc(-c2ccc3c(c2)OCO3)o1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: c1ccc(CSc2nnc(-c3ccc4c(c3)OCO4)o2)cc1
Reaction time: 2 h

Procedure:
Benzylbromide (20.2 g, 118.1 mmol) was added over 5 minutes time-period to a mixture of 5-benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazole-2-thiol (25 g, 112.5 mmol), trietylamine (22.8 g, 225 mmol) and ethanol (200 ml, 99%). The reaction mixture was stirred at room-temperature for 2 hours. Aqueous sodium hydroxide (150 ml, 1 M) and water (100 ml) was added followed by filtration. The product was isolated as a solid. Yield 31.0 g (94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[C:16](=[O:24])[C:15]3[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:30])([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[C:16](=[O:24])[C:15]3[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c1C(=O)C(C)(c1ncnn1C)C(c1ccc(F)cc1)N2
Temperature: 0 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of ethyl 2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (100 mg, 0.25 mmol) and potassium carbonate (70 mg, 0.51 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 1 hr. Then the solution was cooled to 0° C. and a solution of iodomethane (0.1 mL) in N,N-dimethylformamide (1 mL) was added dropwise at 0° C. over 1 hr, stirred at room temperature overnight. The mixture was quenched with water (30 mL), extracted with ethyl acetate, washed with brine, and then the extraction was evaporated to get the crude product, which was used in next step without further purification (80 mg, yield 77%). LC-MS (ESI) m/z: 409 (M+1)+.
Reaction SMILES: [CH2:1]([N:6]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:30])[N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([C:31](O)=[O:32])[CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:60][O:61][C:62]1[CH:73]=[CH:72][CH:71]=[CH:70][C:63]=1[CH2:64][N:65]([CH3:69])[CH2:66][CH2:67][NH2:68]>>[Cl:29][C:25]1[CH:24]=[C:23]([N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:7](=[O:8])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:10][C@H:11]2[C:31]([NH:68][CH2:67][CH2:66][N:65]([CH3:69])[CH2:64][C:63]2[CH:70]=[CH:71][CH:72]=[CH:73][C:62]=2[O:61][CH3:60])=[O:32])=[O:30])[CH:28]=[CH:27][CH:26]=1
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@H](C(=O)O)C1
Reactant: COc1ccccc1CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@H](C(=O)NCCN(C)Cc2ccccc2OC)C1
Yield: 84.5 %

Procedure:
According to the procedure of Example 1, Step E above, 43 mg (0.079 mmole) of (S)-4-(dipentylcarbamoyl)-1-(N-(3-chlorophenyl)-N-phenylcarbamoyl)piperazine-2-carboxylic acid, 12 mg (0.087 mmole) of HOBt, 21 mg (0.111 mmole) of EDAC, and 31 mg (0.158 mmole) of N-(2-methoxybenzyl)-N-methylethylenediamine after purification by flash chromatography on 16 g of silica gel eluting with 100:4 CH2Cl2 :methanol provided 48 mg (84%) of an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:28][CH2:29][CH:24]([N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH3:30])[CH2:25][CH2:26]3)=[CH:8][C:6]=2[N:7]=1
Reactant: COCCN(C)C1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: COCCN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (Example 3) and (2-methoxy-ethyl)-methyl-piperidin-4-yl-amine (Example 187) using General Procedure B-3 yielded 1-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-(2-methoxyethyl)-N-methylpiperidin-4-amine.