Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7](=[S:14])[C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1.O1CCOC[CH2:18]1.[OH-].[K+].COS([O-])(=O)=O>CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([S:14][CH3:18])[C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: C1COCCO1
Reactant: S=C1Nc2ccc(Cl)cc2Nc2cscc21
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSC1=Nc2ccc(Cl)cc2Nc2cscc21
Reaction time: 3 h

Procedure:
To a stirred suspension of 0.7 g. of 6-chloro-4,9-dihydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-thione in 10 ml. of dioxane is added dropwise and simultaneously at 30°-40°C., a solution of 0.95 g. of potassium hydroxide in 10 ml. of methanol and 0.8 g. of methylsulfate. After addition is complete, the mixture is stirred for 3 hours, diluted with methanol and filtered. The filtrate is concentrated to 20 ml. and diluted with water. The precipitate is collected, washed with water and recrystallized from methanol-water to give yellow crystals, m.p. 152°-154°C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH3:21][CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24].Cl[CH:29]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[F:44])[C:30]1[C:31]([S:36][CH3:37])=[N:32][CH:33]=[N:34][CH:35]=1.Cl>CCCCCC.O1CCCC1.CCOCC>[CH3:21][C:22]([CH3:27])([CH:29]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[F:44])[C:30]1[C:31]([S:36][CH3:37])=[N:32][CH:33]=[N:34][CH:35]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: CSc1ncncc1C(Cl)c1ccccc1F
Reactant: COC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C)(C)C(c1ccccc1F)c1cncnc1SC
Temperature: 12 °C

Procedure:
To a solution of lithium diisopropylamide prepared from 5.3 g (57 mmol) of diisopropylamine and 21 mL (57 mmol) of 2.5M n-butyl lithium in hexane and 100 mL of dry tetrahydrofuran at -10° C. was slowly added with stirring 5.3 g (57 mmol) of methyl 2-methylpropanoate. The resulting solution was allowed to warm slowly to 12° C. and was then recooled to -10° C. To this was added in small portions with stirring 7.0 g (26 mmol) of 5-(chloro-(2-fluorophenyl)methyl)-4-methylthiopyrimidine. After 1 hr the resulting solution was warmed to ambient temperature. Ether and dilute aqueous hydrochloric acid were added and the ethereal phase was recovered, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 5.3 g (60 of theory) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:10][CH2:9][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:7])=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55.4 G. of p-chlorobenzoylaziridine and 26.5 g. of morpholine are boiled in 250 ml. of toluene for 2 hours under reflux. The solution is then cooled to room temperature, whereupon crystals separate out. The solution which crystallizes is allowed to stand overnight in a refrigerator. Thereafter, the product is removed by filtration, washed with toluene and recrystallized from isopropanol, and 75.9 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[N:13][C:14]=2[Cl:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2c1CCN(Cc1ccccc1)C2
Product: Clc1nccc2c1CCN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To 6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (2.56 g, 10.65 mmol) was added POCl3 (20 mL, 215 mmol). The mixture was heated to 100° C. for 17 h and cooled to rt. The excess POCl3 was removed under reduced pressure, and the residue quenched with sat. NaHCO3 (150 mL) and partitioned with dichloromethane (100 mL) and stirred for 30 minutes. The dichloromethane layer was collected, and the aqueous layer was extracted with dichloromethane (2×100). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration, and the organic solution was concentrated under reduced pressure. The residue was purified by BIOTAGE® flash chromatography using a 5-30% EtOAc in hexanes gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give 2-benzyl-5-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine (2.334 g, 9.02 mmol, 85% yield) as a yellow oil. LC/MS: m/z 259.01 (M+H)+, 0.775 min (method 2). 1H NMR (500 MHz, chloroform-d) δ ppm 8.10 (d, J=4.88 Hz, 1H) 7.26-7.41 (m, 5H) 6.86 (d, J=4.88 Hz, 1H) 3.69 (s, 2H) 3.58 (s, 2H) 2.84-2.89 (m, 2H) 2.78-2.83 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].O(C(C)(C)C)[K]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Brc1cncnc1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cncnc2)CC1
Yield: 47 %

Procedure:
A mixture of 5-bromo-pyrimidine (1.59 g, 10.00 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 10.00 mmol, 1.0 equiv), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.25 g, 0.40 mmol, 0.04 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.21 g, 0.20 mmol, 0.02 equiv) and KOtert-Bu (1.35 g, 12.01 mmol, 1.2 equiv) in toluene (10 mL) was heated under Ar by microwave irradiation to 100° C. for 2 h. The crude reaction mixture was filtered through Hyflo Super Cel, a sat. solution of sodium chloride (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The combined organic phases were concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate to provide 1.30 g (47%) of the title compound. MS (ISP): 279.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C@@H:35]([CH3:46])[CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[CH:18]=[CH:17][S:16][C:5]=4[C:6](=[O:15])[NH:7][C:8]=3[C:9]([CH3:14])=[CH:10][C:11]=2[O:12][CH3:13])[CH:23]=[CH:22][C:21]=1[C@@H:35]([CH3:46])[CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:43])[CH3:42]
Reactant: C[C@@H](CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CN(C)C(=O)OC(C)(C)C)c(F)c1
Yield: 36 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (180 mg, 0.57 mmol) was reacted with (R)-tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl(methyl)carbamate (150 mg, 0.38 mmol) to afford the desired product (190 mg, 36%) as a yellow solid: ESI MS m/z 511 [C28H31FN2O4S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.[Na].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:15]([N+:22]([O-:24])=[O:23])=[C:16]([O:21][CH2:31][C:32]([F:35])([F:34])[F:33])[N:17]=[C:18]([CH3:20])[N:19]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1nc(N2CCN(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CC(C)=O
Product: Cc1nc(OCC(F)(F)F)c([N+](=O)[O-])c(N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
In analogy to the procedure described in example 9, the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1) was treated with 2,2,2-trifluoroethyl trifluoromethanesulfonate, sodium and potassium carbonate in acetone at room temperature to yield the 4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-6-(2,2,2-trifluoro-ethoxy)-pyrimidine as a light brown solid; m.p. 92-95° C.; MS: [M+H]+=416; and the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3-(2,2,2-trifluoro-ethyl)-3H-pyrimidin-4-one as yellow amorphous solid;
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8](=[O:16])[NH:7][C:6]1=[O:17])([OH:3])=[O:2].S(Cl)(Cl)=O.[CH2:22](O)[CH3:23]>S(=O)(=O)(O)O>[Cl:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]2[CH2:4][C:1]([O:3][CH2:22][CH3:23])=[O:2])=[CH:10][CH:11]=1
Reactant: CCO
Reactant: O=C(O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Yield: 75.8 %

Procedure:
To a suspension of 1-carboxymethyl-7-chloro-2,4(1H, 3H)-quinazolinedione (I) (0.5 g) in ethanol (10 ml) was added thionyl chloride (0.35 g) at 0° C. After one drop of concentrated sulfuric acid was added to the solution, the solution was refluxed for 7 hours, and cooled. The resulting crystal was collected by filtration, washed with ethanol and dried under vacuum to give 0.42 g of the desired compound (yield, 75.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][CH:64]1[O:69][CH2:68][CH2:67][NH:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][O:69][CH:64]([CH3:63])[CH2:65]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC1CNCCO1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC1CN(C(=O)c2cc3ncnc(NC(C)c4nc5cc(Cl)ccc5[nH]4)c3cc2Cl)CCO1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-methyl-morpholine in DMSO at ambient temperature.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>>[CH:43]1([C:40]2[CH:41]=[CH:42][C:37]([CH2:36][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]4[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=4[C:22]([NH:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]4)=[O:23])=[CH:4][CH:3]=3)=[CH:38][CH:39]=2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: ClCc1ccc(C2CCCCC2)cc1
Product: COC(=O)c1ccc(OCCCc2ccc(OCc3ccc(C4CCCCC4)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Methyl 4-(3-{4-[(4-cyclohexylbenzyl)oxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 1-(chloromethyl)-4-cyclohexylbenzene.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:40])[N:28]5[CH2:31][O:32][C:33]([CH:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[O:34])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:40])[N:28]5[CH2:31][O:32][C:33]([CH:35]5[CH2:36][CH2:37][CH2:38][CH2:39]5)=[O:34])=[CH:23][CH:22]=4)[CH2:14][CH2:15]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=C(OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)C1CCCC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)C1CCCC1
Temperature: 25 °C
Yield: 15.1 %

Procedure:
To a solution (10 ml) of cyclopentanecarboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester (252 mg) synthesized in the same manner as in Example 13 in THF was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (509 mg), and the mixture was stirred at room temperature stirred for 2 days. To the reaction mixture were added water and sodium carbonate, and the mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) and further by NH silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) to give the title compound (yield 38 mg, 15%) as a colorless amorphous solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#N.[N+:13]([C:16]1C=C(C=CC=1)CN)([O-])=O>C(O)C>[NH2:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:13][CH:16]=[CH:4]2
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: Nc1ccc2[nH]ccc2c1

Procedure:
Compound 84 was prepared using methods shown in Example 1, wherein 2-fluoro-5-nitrobenzonitrile was reacted with 3-nitrobenzyl amine in Step A. Following steps B through E, the 3-nitrobenzyl intermediate was reduced using stannous chloride in ethanol to provide the corresponding 5-amino indole intermediate. Dimethylation of the 5-amino group was carried out using aqueous formaldehyde solution (37% w/w, 10 eq.) and MP-cyanoborohydride resion (2.42 mmol/g, 1.5 eq.) in methanol:acetic acid (9:1, v/v) at room temperature for about 15 hours.
Reaction SMILES: Br[C:2]1[C:6]([CH2:7][CH2:8][CH3:9])=[CH:5][S:4][C:3]=1[CH:10]1[C:19]2[C:14](=[CH:15][C:16]3[O:22][CH2:21][O:20][C:17]=3[CH:18]=2)[CH2:13][CH2:12][CH:11]1[NH2:23]>C(O)C.[Pd]>[CH2:7]([C:6]1[CH:2]=[C:3]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]4[O:22][CH2:21][O:20][C:17]=4[CH:18]=3)[CH2:13][CH2:12][CH:11]2[NH2:23])[S:4][CH:5]=1)[CH2:8][CH3:9]
Reactant: CCCc1csc(C2c3cc4c(cc3CCC2N)OCO4)c1Br
Agent: [Pd]
Solvent: CCO
Product: CCCc1csc(C2c3cc4c(cc3CCC2N)OCO4)c1
Yield: 105.1 %

Procedure:
A solution (0.78 g, 1.96 mmol) of 1-(3-bromo-4-propyl-2-thiophenyl)-1,2,3,4-tetrahydro-6,7-methylenedioxy-2-naphthylamine in ethanol was hydrogenated at 4 Atm H2 with 0.3 g of 10% Pd/C catalyst. The catalyst was removed by filtration, and the flitrate was concentrated to give 0.65 g of the title compound. NMR (CDCl3) δ:6.81 (s, 1H), 6,77 (s, 1H), 6.56 (s, 1H), 6.41 (s, 1H), 5.87 (s, 2H), 3.90 (d, J=8 Hz, 1H), 3.25-3.15 (m, 1H), 2.92-2.78 (m, 2H), 2.54 (t, J=7 Hz, 2H), 2.13-2.05 (m, 1H), 1.8-1.6 (m, 3H), 0.96 (t, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:17][C:16]3[C:15](=[O:18])[N:14]([CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[C:13](=[O:32])[N:12]([CH2:33][C:34]4[O:38][N:37]=[C:36]([CH2:39][CH3:40])[N:35]=4)[C:11]=3[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:41]>O1CCOCC1>[ClH:41].[F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:17][C:16]3[C:15](=[O:18])[N:14]([CH:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)[C:13](=[O:32])[N:12]([CH2:33][C:34]4[O:38][N:37]=[C:36]([CH2:39][CH3:40])[N:35]=4)[C:11]=3[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc(F)c(F)c4)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)c(F)c4)cc32)n1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 4-[6-(3,4-difluorophenyl)-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (400 mg, compound B67) in 1,4-dioxane (7 ml) is added a solution of hydrogen chloride in 1,4-dioxane (1.7 ml, 4.0 M). The reaction mixture is stirred for 3 h at 50° C. and subsequently for 12 h at RT. In order to complete the reaction an additional amount of a solution of hydrogen chloride in 1,4-dioxane (0.9 ml, 4.0 M) is added and the reaction mixture is stirred for 1 h at 65° C. Afterwards all volatiles are removed under reduced pressure to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][C@H:10]1[CH3:14])=[O:25]
Reactant: O=C(Cl)CCl
Reactant: C[C@@H]1CN(c2ccc(Cl)cc2)CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(Cl)cc2)CCN1C(=O)CCl

Procedure:
Protocol S was followed using 1-(4-Chloro-phenyl)-3-(R)-methyl-piperazine, Et3N, chloroacetyl chloride and methylene chloride. Column chromatography afforded the title compound
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[S:19][C:20]([C:23]#[N:24])=[CH:21][N:22]=1>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:18]3[S:19][C:20]([C:23]#[N:24])=[CH:21][N:22]=3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: CN1CCN(c2cc(N)ncn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2cc(Nc3ncc(C#N)s3)ncn2)CC1
Reaction time: 0.5 h

Procedure:
6-(4-Methyl-piperazin-1-yl)-pyrimidin-4-ylamine (97 mg, 0.50 mmol) was stirred in 2 mL anhydrous THF under N2. Sodium hydride (43 mg, 60% dispersion, 1.10 mmol) was added and after stirring for 30 minutes, 2-chloro-thiazole-5-carbonitrile (87 mg, 0.60 mmol). After LCMS indicated complete conversion, the reaction was quenched with MeOH, neutralized with 10% citric acid (aq). The resulting precipitate was filtered, washed with water and after air drying was washed with hexane. 1H-NMR (400 MHz, DMSO) 12.00 (1H, s), 8.42 (1H, s), 8.25 (1H, s), 6.21 (1H, s), 3.54 (m, 4H), 2.39 (m, 4H), 2.21 (s, 3H). M+1=302.3.
Reaction SMILES: O[CH:2]([CH2:7][CH:8]([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH3:9])[CH2:3][C:4](=[O:6])[CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:10][CH:8]([CH3:9])[CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5]
Reactant: CC(=O)CC(O)CC(C)Sc1ccccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CCC(C)Sc1ccccc1C
Yield: 86 %

Procedure:
1.00 Gram of 4-hydroxy-6-(2-methylphenylthio)-2-heptanone was dissolved in 100 ml of toluene, and 0.02 g of p-toluene sulfonic acid was added thereto. The resulting mixture was refluxed for 1.5 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 0.98 g of 6-(2-methylphenylthio)-3-hepten-2-one. (trans : cis =7.0 : 1) (purity: 81.5%). The yield was 86.0%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])([O-:16])=[O:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[N+:14]([C:17]1[CH:18]=[C:19]([NH:20][CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)[CH:21]=[CH:22][CH:23]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc([N+](=O)[O-])c2)C1
Reaction time: 10 h
Yield: 57.5 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3-pyrrolidinone (220 mg) and 3-nitroaniline (164 mg) in methylene chloride (3 mL), sodium triacetoxyborohydride (375 mg) and acetic acid (67 μL) were added at room temperature, and the mixture was stirred at the same temperature for 10 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 50% hexane in ethyl acetate) to obtain tert-butyl 3-((3-nitrophenyl)amino)pyrrolidine-1-carboxylate (C23, 210 mg).
Reaction SMILES: C[O-].[Na+].[N+:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[C-:5].[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13].C(O)(=O)C>CN(C)C=O>[CH:12]([C:11]1[O:15][CH:5]=[N:4][C:6]=1[C:7]([O:9][CH3:10])=[O:8])([CH3:14])[CH3:13]
Reactant: CC(C)C(=O)Cl
Reactant: [C-]#[N+]CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1ncoc1C(C)C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
13.7 g of sodium methoxide are dissolved in 200 ml of dimethylformamide, and 19.4 g of methyl α-isocyanoacetate are added dropwise thereto at -50° C. to -40° C. The mixture is stirred at the same temperature for 30 minutes. 25 g of isobutyryl chloride are gradually added to the mixture at -50° C. to -40° C., and said mixture is stirred at the same temperature for 2 hours. After the reaction, the mixture is adjusted to pH 3-4 with acetic acid and then condensed under reduced pressure to remove solvent. The residue is extracted with ethyl acetate and the extract is washed with aqueous sodium bicarbonate solution and water, successively. The extract is then dried and condensed under reduced pressure to remove solvent. 23.1 g of 5-isopropyl-4-methoxycarbonyloxazole are obtained. Yield: 70.0%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=O)=[C:5]([C:13]#[C:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:4]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].[Li]CCCC>>[CH3:20][N:21]([O:22][CH3:23])[C:7](=[O:9])[C:6]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:13]#[C:14][CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc(OC)cc1C#CCC(C)C
Reactant: CNOC
Agent: Cl
Agent: [Li]CCCC
Product: COc1ccc(C(=O)N(C)OC)c(C#CCC(C)C)c1
Yield: 85 %

Procedure:
Treatment of methyl 4-(methyloxy)-2-(4-methyl-1-pentyn-1-yl)benzoate (102) (0.76 g, 3.09 mmol) with a mixture of N,O-dimethylhydroxylamine hydrochloride and nBuLi gave 0.72 g (85%) of the title compound (103) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.02 (d, J=6.6 Hz, 6H), 1.80-1.95 (m, 1H), 2.28 (d, J=6.6 Hz, 2H), 3.28 (br s, 3H), 3.59 (br s, 3H), 3.80 (s, 3H), 6.84 (dd, J1=8.6 Hz, J2=2.5 Hz, 1H), 6.94 (d, J=2.6 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H). LCMS (ESI): m/z 276 (M+H)+.