Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]([CH:23]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[CH2:25][O:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:31](=[O:33])[CH3:32]>O1CCCC1>[CH2:13]([O:20][C:21]([C:23]1([CH:31]([OH:33])[CH3:32])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[CH2:25][O:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)COC(C(=O)OCc2ccccc2)CO1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)C1(C(=O)OCc2ccccc2)COC(C)(C)CO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of N,N-diisopropylamine (530 mg, 0.73 mL, 5.25 mmol) in anhydrous tetrahydrofuran (4 mL) was stirred at −78° C. under nitrogen. n-Butyl lithium (2.1 mL, 5.25 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min. A solution of 5,5-dimethyl-[1,4]dioxane-2-carboxylic acid benzyl ester (870 mg, 3.5 mmol) in tetrahydrofuran (8 mL) was added and the reaction mixture was stirred at −78° C. for 20 min. Acetaldehyde (462 mg, 0.6 mL, 10.5 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and ice-cold hydrochloric acid (2 M) was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the aqueous phase and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 6:1 to 0:1 followed by silica gel chromatography using iso-hexanes/ethyl acetate 3:1 to 0:1 to the title compound (400 mg, 40%) as an oil and as a 2:1 mixture of diastereoisomers. LCMS (m/z) 295.1 [M+H], Tr=2.11 min.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[N:13]([CH3:31])[CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].Cl.C(N1CCC(C2C3C(=CC(C(N4CCN(C(C)C)CC4)=O)=CC=3)NC=2)CC1)C(C)C.BrC[CH:65]([F:67])[F:66]>>[F:66][CH:65]([F:67])[CH2:31][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]3)=[O:21])[CH:15]=2)[C:11]([CH:8]2[CH2:7][CH2:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:10][CH2:9]2)=[CH:12]1
Reactant: CC(C)CN1CC=C(c2cn(C)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Reactant: FC(F)CBr
Agent: CC(C)CN1CCC(c2c[nH]c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Agent: Cl
Product: CC(C)CN1CCC(c2cn(CC(F)F)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1

Procedure:
According to the procedure described for the synthesis of [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone; hydrochloride (example 42) the title compound was prepared from [3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 2, free base) and 2-bromo-1,1-difluoroethane (commercially available). MS (m/e): 475.2 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:43][C@@H:44]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([CH:71]2[S:75](=[O:77])(=[O:76])[NH:74][C:73](=[O:78])[CH2:72]2)=[CH:67][CH:66]=1)[C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:62]=[CH:61][CH:60]=[C:59]([OH:63])[C:54]=1[C:55]([O:57][CH3:58])=[O:56])=[O:46]>CN(C=O)C>[O:76]=[S:75]1(=[O:77])[CH:71]([C:68]2[CH:67]=[CH:66][C:65]([CH2:64][C@H:44]([NH:43][C:7]([C@@H:5]3[CH2:4][CH2:3][C:2](=[O:1])[NH:6]3)=[O:9])[C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]3[CH:62]=[CH:61][CH:60]=[C:59]([OH:63])[C:54]=3[C:55]([O:57][CH3:58])=[O:56])=[O:46])=[CH:70][CH:69]=2)[CH2:72][C:73](=[O:78])[NH:74]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)NC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
To a solution of (2S)-5-oxopyrrolidine-2-carboxylic acid (2.0 mg, 0.015 mmol) in DMF (0.5 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (5.8 mg, 0.015 mmol) and N,N-diisopropylethylamine (0.008 mL, 0.045 mmol) and premixed for 5 minutes. To the solution was added methyl 2-[4-({(2S)-2-amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoyl}amino)-butoxy]-6-hydroxybenzoate (8.0 mg, 0.015 mmol) and stirred overnight at room temperature. The product was purified by preparative LCMS to afford the desired product (1.4 mg). LCMS found for C29H35N4O10S (M+H)+: m/z=631.0
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[S:10][C:11]([CH3:13])=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[C:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]>>[C:14]([C:17]1[CH:22]=[CH:21][C:20]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[C:11]([CH3:13])[S:10][C:6]2=3)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]
Reactant: CCN1Cc2cc(C)sc2C(O)C1
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Product: CCN1Cc2cc(C)sc2C(Oc2ccc(C(N)=O)cc2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 32) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I:13][C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)=[O:17].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[I:13][C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]=1[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]([O:2][CH3:1])=[O:12])[CH2:29][CH2:30]2)=[CH:23][CH:24]=1)=[O:17]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3I)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
α-Bromo-benzeneacetic acid methyl ester (0.0123 mol) was added at room temperature to a mixture of intermediate (28) (0.0123 mol) and Na2CO3 (0.0123 mol) in DMF (50 ml). The mixture was stirred at room temperature for 2 hours. Water was added. The mixture was stirred at room temperature for 15 minutes. The precipitate was filtered, washed with diethyl ether and dried, yielding 5.8 g of 4-[4-[(2-iodobenzoyl)amino]phenyl]-α-phenyl-1-piperazine-acetic acid, methyl ester (intermediate 29).
Reaction SMILES: [CH3:1][CH:2]1[S:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1.C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[CH3:16][N:17]([CH:19]=[C:3]1[CH:2]([CH3:1])[S:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:12])[CH3:18]
Reactant: CCOC(OCC)N(C)C
Reactant: CC1CC(=O)c2ccccc2S1
Product: CC1Sc2ccccc2C(=O)C1=CN(C)C

Procedure:
3,4-Dihydro-2-dimethylaminomethylene-3-methyl-4-thia-1(2H)-naphthalenone was prepared from 3,4-dihydro-3-methyl-4-thia-1(2H)naphthalenone (1.55 mg, 0.87 mmol),[Clayton, S E et al. Tetrahedron (1993) 49, 939], and N,N-dimethyl formamide diethylacetal (2 ml) to give the compound as yellow crystals (161 mg). δH (CDCl3) 8.12 (1H, dd, J 1.5, 7.8 Hz), 7.50 (1H, s), 7.34-7.16 (3H, m), 4.36 (1H, q, J 7.1 Hz), 3.16 (6H, s) and 1.57 (1H, d, J 7.0 Hz). MS (ES+) 234 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.O.ClCCl.Br[CH2:14][C:15](OCC)=[O:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:14][C:15](=[O:16])[N:8]=2)[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(Br)cn1
Solvent: O
Solvent: ClCCl
Product: O=C1CN2C=C(Br)C=CC2=N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.0 g of 5-bromopyridin-2-ylamine in 5.8 ml of ethyl 2-bromoacetate are placed in a round-bottomed flask and stirred at ambient temperature for 48 h. A precipitate forms, and is recovered by filtration, washed with diethyl ether and oven-dried under reduced pressure. The solid is then taken up in 50 ml of ethanol, and 2.18 g of sodium hydrogencarbonate are added thereto. The reaction mixture is heated at the reflux of the solvent for 5 h, cooled to ambient temperature, and then concentrated under reduced pressure. The residue obtained is taken up between water and dichloromethane and the organic phase is separated, dried and concentrated under reduced pressure. 1.46 g of compound, used as it is in the subsequent stages, are obtained.
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[O:5][C:4]1=[O:23])[CH3:2].O.O.Cl[Sn]Cl>CO>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][CH:8]([C:6]3[O:5][C:4](=[O:23])[N:3]([CH2:1][CH3:2])[N:7]=3)[CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: CCn1nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)oc1=O
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: CCn1nc(C2CCN(c3ccc(N)cc3)CC2)oc1=O
Yield: 88.4 %

Procedure:
5-[1-(4-Nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.16 g, 4 mmol) on reacting with C2H5Br (0.53 g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-ethyl-5-[1-(4-nitro phenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6b, 1.17 g, 92%). Nitro compound (6b, 1.27 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-3-ethyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7c, 1.02 g, 89%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7c, 0.29g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperi dino]phenyl-5-nitro-2-furamide (8c, 367 mg, 86%).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.C([Sn](Cl)(CCCC)CCCC)CCC.[NH2:26][C:27]1[N:32]=[C:31](Br)[C:30]([C:34]#[N:35])=[C:29]([S:36][CH3:37])[N:28]=1>C1COCC1.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:26][C:27]1[N:32]=[C:31]([C:6]2[O:1][CH2:2][CH2:3][CH2:4][CH:5]=2)[C:30]([C:34]#[N:35])=[C:29]([S:36][CH3:37])[N:28]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: C1=COCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CSc1nc(N)nc(C2=CCCCO2)c1C#N

Procedure:
From 3,4-dihydro-2H-pyran, tert-butyllithium and tributyltin chloride in THF. Then treatment with 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile and bis(triphenylphosphine)palladium(II) chloride in dioxane. ES-MS m/e (%): 271 (M+Na+, 39), 249 (M+H+, 100).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[N:17]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=[C:12]2[CH:11]=1.C(O)(=O)C.C(O[C:33]1(O[Si](C)(C)C)[CH2:35][CH2:34]1)C.[Na]>CO>[CH:33]1([N:23]2[CH2:24][CH2:25][CH:20]([C:18]3[N:19]=[C:12]4[N:13]([C:14](=[O:16])[NH:15][C:10]([C:4]5[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=5[Cl:2])=[CH:11]4)[N:17]=3)[CH2:21][CH2:22]2)[CH2:35][CH2:34]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCNCC3)nn12
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCN(C4CC4)CC3)nn12
Temperature: 25 °C

Procedure:
1.00 g (2.50 mmol) of 7-(2,4-dichlorophenyl)-2-(piperidin-4-yl)[1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one hydrochloride and 3 Å molecular sieve (1 g) were initially charged in 15 ml of dry methanol and acetic acid (1.43 ml, 25 mmol) of 3.01 ml (2.61 g, 15 mmol) of [(1-ethoxy-1-cyclopropyl)oxy]-trimethylsilane and 690 mg (11 mmol) of sodium cyanoborhydride were then added. The mixture was stirred at reflux overnight. The mixture was cooled to RT and the reaction mixture was filtered. 50 ml of dichloromethane and 50 ml of water were added to the filtrate, and the mixture was extracted. The organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. This gave 540 mg (53% of theory) of the product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:11](O)[CH2:12][CH3:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[SH:15][CH2:16][C:17]([OH:19])=[O:18].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1[C:3]([CH:11]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:12][CH3:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCC(O)c1cc2c(cc1C)OCO2
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCC(SCC(=O)O)c1cc2c(cc1C)OCO2
Yield: 90.2 %

Procedure:
2.27 g of 1-(6-methyl-1,3-benzodioxol-5-yl)-1-propanol, 0.1 g of p-toluenesulfonic acid and 1.52 g of mercaptoacetic acid were dissolved in 80 ml of benzene. The solution was heated under reflux for 12 h while water was removed. The reaction mixture was poured into water. The aqueous layer was made alkaline and washed with ether. The aqueous layer was then acidified and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain a faint yellow solid. It was purified according to silica gel column chromatography (ethyl acetate/hexane=2:8) to obtain 2.83 g of the intended compound in the form of white crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][C:2]=1[OH:12].N12CCCN=C1CCCCC2.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(C)C>[CH2:24]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[C:2]([OH:12])[CH:3]=[CH:4]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Oc1ccc2cccc(O)c2n1
Reactant: BrCc1ccccc1
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: Oc1ccc2cccc(OCc3ccccc3)c2n1
Yield: 77.4 %

Procedure:
This was prepared by a slight modification of the procedure of Guo et al, Tet Lett, 1999, 40, 6999. To a stirred solution of 2,8-quinolinediol (4.97 g, 30.84 mmol) and 1,8-diazabicylo[5.4.0]undec-7-ene (DBU) (40.2 mmol, 6 mL) in isopropyl alcohol (60 mL) was added benzyl bromide (3.7 mL, 30.84 mmol). The solution was heated at reflux overnight. The reaction mixture was allowed to cool and then concentrated in vacuo. The resulting residue was diluted with CH2Cl2 and washed with 0.5 N NaOH, 10% HCl and water and dried over Na2SO4. Concentration provided 6 g (77%) of a tan solid, which was used without further purification.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:22]
Reactant: COC(=O)c1ccccc1S
Reactant: CCOc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 14.1 %

Procedure:
A mixture of methyl thiosalicylate (0.17 g, 1.0 mmol), 2-cyano-6-ethoxypyridine (0.15 g, 1.0 mmol), triethylamine (0.21 ml, 1.5 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure. The residue was subjected to a column chromatography and eluted with hexane-ethyl acetate (3:1, v/v). The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.04 g, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[C:18]([Si:15]([CH3:17])([CH3:16])[O:14][CH2:13][CH2:12][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Cl:1])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1Cl
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of 3-chloro-4-hydroxy-benzaldehyde (227 mg, 1.45 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (347 mg, 1.45 mmol), cesium carbonate (709 mg, 2.18 mmol) and DMSO (2 mL) was stirred at 80° C. for 17 h. The reaction mixture was cooled to room temperature and water (50 mL) was added. The resulting precipitate was filtered off, washed with water, air-dried, dissolved in a small amount of ethyl acetate and purified by column chromatography. 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chlorobenzaldehyde was obtained as a white solid (yield: 267 mg, 58%). To a 100 mL round-bottomed flask was added 2-amino-4,6-dimethoxy-benzamide (166 mg, 0.85 mmol), 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chlorobenzaldehyde (267 mg, 0.85 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol), sodium hydrogensulfite (216 mg, 1.2 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen for 17 h. After cooling to room temperature, water (50 mL) was added. The precipitate was filtered off, washed with water and air-dried. The crude product was purified by column chromatography to give 2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (45 mg, 23%). Selected data: MS (ES) m/z: 377.03; MP 287-288° C. (decomposed).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Mg].Br[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1.Cl>C(OCC)C>[CH2:1]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCBr
Reactant: Brc1ccsc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCc1ccsc1
Temperature: 0 °C
Yield: 65 %

Procedure:
0.125 mole of n-hexylbromide was dissolved in 40 ml of ethyl ether. Then, 10 ml of ethyl ether was added in drops and also 0.13 mole of magnesium chip was added. The mixture was refluxed for 5 to 6 hours and the Grignard agent was obtained. The Grignard reagent was added to a solution consisting of 70 mg of NiDPPPCl2 and 0.106 mole of 3-bromo thiophene in drops at 0° C., then the mixture was refluxed for 12 to 15 hours. After that, the mixture was hydrolyzed with 40 ml of 1N hydrochloric acid and 150 ml of ice water. Then, ethyl ether was used to extract the mixture for a few times, and the mixture was washed with water until the solution was neutral. The extract was dried by sodium sulfate to remove the solvent. The product of 3-hexylthiophene was obtained with a yield of 65% after distillation under reduced pressure.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5].C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.O>[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:25])=[O:5]
Reactant: CN(C)C(=O)[C@@H]1CCCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)[C@@H]1CCCCN1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 74.3 %

Procedure:
(2S)—N,N-Dimethyl-2-piperidinecarboxamide hydrochloride (880 mg, 4.567 mmol) was dissolved in a mixture of CH2Cl2 (15 mL) and water (15 mL), and then solid sodium bicarbonate (1.534 g, 18.268 mmol) was added, followed by benzoyl chloride (0.556 mL, 4.795 mmol). After stirring overnight, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 0-10% methanol/dichloromethane) to provide (2S)—N,N-dimethyl-1-(phenylcarbonyl)-2-piperidinecarboxamide (883 mg, 74%). LCMS: (M+H)+: not detected.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.[S-:14][C:15]#[N:16].[K+].BrBr>CO>[S:14]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:3]=1[C:2]([F:1])([F:12])[F:13])[NH:9][CH2:8][CH2:7]2)[C:15]#[N:16]
Reactant: FC(F)(F)c1ccc2c(c1)NCC2
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CO
Product: N#CSc1cc2c(cc1C(F)(F)F)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of 6-trifluoromethylindoline (D1) (9.7 g, 52 mmol) and potassium thiocyanate (10.09 g, 104 mmol) in methanol (200 ml) was treated with a solution of bromine (2.82 ml, 55 mmol) in methanol (35 ml) dropwise over 0.5 h at −5-0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight then evaporated to dryness. The residue was partitioned between aqueous K2CO3 (100 ml) and dichloromethane (3×100 ml). The combined extracts were dried (Na2SO4) and evaporated and the residue chromatographed, on silica using 2-30% ethyl acetate/petroleum ether as eluant to afford the title compound (9.1 g, 72%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([OH:17])=O)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][N:25]([CH3:40])[CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]([NH2:39])[CH2:34][CH2:33][CH2:32]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([NH:39][CH:35]2[C:36]3[C:31](=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:25]([CH3:40])[CH3:24])=[CH:38][CH:37]=3)[CH2:32][CH2:33][CH2:34]2)=[O:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)CCOc1ccc2c(c1)CCCC2N
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)CCOc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1

Procedure:
To a 20 mL vial equipped with stirring was added 3-(3,4-dichloro-benzenesulfonylamino)-3-phenyl-propionic acid (128 mg, 0.34 mmol), 6-(2-dimethylamino-ethoxy)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (40 mg, 0.17 mmol), EDC (Aldrich, 49 mg, 0.26 mmol), HOBt (Aldrich, 23 mg, 0.17 mmol), and CH2Cl2 (1 mL). The reaction was stirred at RT overnight and diluted with CH2Cl2 (50 mL). The organic phase was washed with saturated NaHCO3, and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (4%-6% MeOH—CH2Cl2) to afford the title compound as a white solid. MS (ESI): 590 (M+H)+.